WO2016079549A1 - Process and intermediate for the preparation of apixaban - Google Patents
Process and intermediate for the preparation of apixaban Download PDFInfo
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- WO2016079549A1 WO2016079549A1 PCT/HU2015/050018 HU2015050018W WO2016079549A1 WO 2016079549 A1 WO2016079549 A1 WO 2016079549A1 HU 2015050018 W HU2015050018 W HU 2015050018W WO 2016079549 A1 WO2016079549 A1 WO 2016079549A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to a preparation process and an intermediate compound for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahy- dro- lH-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban) of formula 1.
- Apixaban of formula 1 is the active substance of the anticoagulant therapeutic drug marketed under the name ELIQUIS, which is an Xa blood coagulant factor inhibitor, developed in a joint venture by Bristol-Myers Squibb and Pfizer.
- apixaban of formula 1 which are described in patent applications WO2003026652, WO2003049681, WO2007001385, WO2010030983, CN101967145 and WO2012168364.
- These preparation processes have in common that the formation of the central bicyclic heterocycle of apixaban, that is 4,5-dihydropyrazolo[3,4-c]pyridine-2-on, is performed via a cycloaddition reaction shown on figure 1 between the methoxyphenyl hidrazone derivative compound of formula 2
- Z is a halogen atom or an R'-SC -O group, preferably chlorine;
- R' is a substituted or unsubstituted aryl group, a substituted or unsubstituted Ci-C 8 straight-chain or branched alkyl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted aralkyl group - and the l,3-disubstituted-5,6-dihydro-lH-pyridine-2-on of the general formula 3
- R 1 is a halogen atom, preferably chlorine, or a 1-morpholinyl group
- R 2 is H atomor a substituted phenyl group, preferably a p-nitrophenyl group.
- apixaban of formula 1
- This carboxamide formation step is typically performed either via a direct acylation of ammonium 4a carboxylic acid with ethyl ester (e.g. WO2003026652) or the two elemental step one-pot reaction of 4a carboxylic acid ethyl ester and formamide (e.g. WO2003049681).
- a production method of 1 apixaban is also described in the international patent application WO2003049681 using the 4c carboxylic acid precursor
- a further difficulty is that apixaban dissolves only in high dilution in the common solvents used in the industry (water, alcohols, carboxylic acid esters, ethers, etc.), and in order to confine the above mentioned contaminating compounds under the values given in the pharmacopoeia, in many cases even higher dilution conditions would be required than these highly diluted, but already saturated solutions. This obviously leads to further loss of product and in addition, the regeneration costs of these procedures are also high because of the large volume of solvents used, and further, they are unfavorable from environmental aspects.
- processing the 4a carboxylic acid ester usually involves some kind of treatment in an aqueous medium, which necessarily results in a - sometimes extensive - hydrolytic degradation of the 4a carboxylic acid ester due to its properties.
- the Hungarian patent application PI 400378 describes a much more favorable preparation process for synthetizing 1 apixaban compared to the previous ones, where the last key intermediate obtained is also the 4a carboxylic acid ester. This 4a carboxylic ester is then purified through one or several steps to remove contaminants occurring during the outlined preparation process in the patent application, typically via the hydrate form of the sodium salt of formula 4b
- the invention is a process for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban) of formula 1.
- the preparation process is characterized in that:
- the "raw" carboxylic acid of formula 4c is transformed into a salt of formula 4b - where M is an alkali metal ion, such as lithium, sodium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C 6 alkyl- or cycloalkyl-substituted primary, secondary or tertiary ammonium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) ion -, after which the 4b salt is separated from the contaminating compounds; then the salt of formula 4b is transformed into the "purified" carboxylic acid of formula 4c, and finally, 1 apixaban is produced directly from this purified carboxylic acid of formula 4c, or
- the ester of formula 4a is transformed into the "raw” carboxylic acid of formula 4c, then the "raw” carboxylic acid 4c is transformed into the salt form of formula 4b - where M is as described above -, followed by separating the 4b salt from the contaminants, then the salt of formula 4b is transformed into the "purified” carboxylic acid of formula 4c and finally, 1 apixaban is directly produced from the latter, purified carboxylic acid 4c.
- the process according to the invention is particularly suitable to purify, as described above, the ester of formula 4a produced according to the preparation process presented in the patent application WO2007001385.
- M is a sodium, cesium, calcium, zinc, ammonium, cyclohexyl-ammonium, diisopropyl-ammonium or DBU ion.
- M is a cesium or ammonium ion.
- the salts of formula 4b are produced in a dipolar aprotic or alcoholic solvent or in a mixture of both, or in the aqueous mixture of these, preferably in acetonitrile, ⁇ , ⁇ -dimetil-acetamide, N-methyl-pyrrolidone or Ci-C 6 alcohols, preferably in methanol, ethanol or isopropyl alcohol.
- the salts of formula 4b are separated from the contaminating compounds by filtration or by evaporation of the salt solution followed by solvent changing and filtration.
- aprotic solvent, ether or alcane preferably diisopropyl-ether or heptane is used when changing the solvent.
- the invention is the salt of formula 4b - where M is an alkali metal ion, such as lithium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C 6 alkyl- or cycloalkyl-substituted primary, secondary or tertiary ammonium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) -, with the provisio that M is other than sodium ion.
- DBU diisopropyl-ether or heptane
- the invention is the salt of formula 4b - where M is a cesium, calcium, zinc, ammonium, cyclohexyl-ammonium, diisopropyl-ammonium or DBU ion.
- the invention is the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b - where M is cesium ion.
- the invention is the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2 ⁇ ( ⁇ 0.2 °2 ⁇ ) are the followings: 5.88; 14.75; 16.67; 19.16.
- the invention is the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2 ⁇ ( ⁇ 0.2 °2 ⁇ ) are the followings: 5.88; 14.75; 15.53; 16.67; 17.62; 19.16; 20.63; 21.51; 30.75.
- the invention is the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b - where M is ammonium ion.
- the invention is the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2 ⁇ ( ⁇ 0.2 °2 ⁇ ) are the followings: 19.89; 23.68; 24.75.
- the invention is the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2 ⁇ ( ⁇ 0.2 °2 ⁇ ) are the followings: 9.64; 13.3; 17.1; 17.41; 18.47; 19.89; 22.22; 22.86; 23.68; 24.75.
- ester of formula 4a produced according to the steps shown on figure 3, can be simply and quantitatively in situ hydrolyzed into the carboxylic acid of formula 4c.
- This latter intermediate compound is easier to isolate in a robust way and with better production yield compared to the 4a ester, therefore it is a more favorable intermediate by itself than the 4a ethyl ester, which is equally sensitive both against acids and bases.
- the solid 4c carboxylic acid can be optimally transformed into 4b carboxylic acid salt - where M is as described above -, from which the 4c carboxylic acid can be recovered with a good chemical yield.
- the solubility properties of the 4c carboxylic acid significantly improve by changing the components of the solvent medium and by increasing its pH value, that is, by transforming the 4c free acid into 4b salt.
- the 4b carboxylic acids are intermediates that can be separated from the contaminants in solid form - by crystallization or stirring in solvent - and unequivocally characterized analytically, therefore they enable the realization of a significant purification from critical lipophilic contaminating compounds by means of a simple technology requiring only filtration and washing, as the lipophilic contaminating compounds remain in the solvent.
- the 4c acid and 4b salt forms can be mutually transformed, they enable us to perform the purification process of 4c carboxylic acid in a favorable way through a suitably realized process sequence of raw 4c 4b purified 4c so that the purification and concentration rates, the chemical yield and industrial feasibility are all more favorable compared to the simple and conventional crystallization of either the 4c carboxylic acid or 1 apixaban.
- the purification of the 4c acid is particularly favorable via ammonium and cesium salts. Analytical methods of measurement:
- Source site 0.6 mm divergence slit
- ICP-OES Inductively coupled plasma optical emission spectrometry
- the advantage of the method according to the invention is that the contaminating compounds - which are very similar in size and structure to the desired final product, have closely analogous physicochemical characteristics and are similarly or sometimes even more lipophilic - can be removed in a significantly more efficient way, with much less loss of product even under industrial conditions compared to the currently known methods, such as the "crystallization" of the final product apixaban by aqueous precipitation from dimethyl formamide (DMF) solution. This finally results in an increased purity of the final product apixaban.
- DMF dimethyl formamide
- Another advantage of the purification method according to the invention is that its concentration domain falls in the suitable range for industrial purposes, which is a further unexpected benefit, knowing the solubility characteristics of the final product apixaban in many solvent types; and that the aqueous medium treatment required for processing the 4a carboxylic acid ester - which necessarily results in the sometimes extensive hydrolytic degradation of the 4a carboxylic acid ester due to its properties - can be omitted.
- Another advantage of the purification method according to the invention is that the solubility characteristics of the 4c carboxylic acid can be improved significantly by altering the pH of the solvent medium, that is, by mutually transforming the salt and free acid forms into each other, thus, the 4c carboxylic acid intermediate can be purified easily and efficiently without the formation of additional contaminating compounds, and can be transformed to the final product 1 apixaban with high production yield, this way, the final product apixaban does not require any further purification, only the transformation into the form of the desired morphology.
- the advantage of the salts of formula 4b according to the invention is that their solubility properties are more favorable than that of the ester of formula 4a, therefore significantly less solvent is required, which in turn results in decreased loss of materials, lower regeneration cost of the procedure and a reduced degree of environmental pollution - with special regards to the extremely toxic nature of DMF.
- Figure 4 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the sodium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a sodium ion), produced according to the process described above, with characteristic X-ray powder dif- fraction peaks as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.15; 6.95; 8; 8.12; 8.72; 9.24; 10.04; 10.72; 12.55; 13.63; 14.37; 14.71; 14.91; 15.86; 16.3; 16.79; 17.26; 17.9; 18.14; 18.54; 18.83; 19.2; 19.44; 20.09; 20.55; 20.7; 21.07; 21.8; 22.34; 22.72; 23.98;
- Figure 5 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid formula 4b (where M is a cesium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks also listed in Table 1 as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.88; 6.93; 8.42; 9.53; 11.45; 11.8; 13.94; 14.75; 15.53; 15.95; 16.67; 17.27; 17.62; 18.44; 18.63; 19.16; 19.46; 20.27; 20.63; 20.97; 21.51; 22.26; 22.66; 22.95; 23.16; 23.8; 24.28; 24.
- Figure 6 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the calcium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a calcium ion), produced according to the process described above, with characteristic X-ray powder dif- fraction peaks as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.47; 5.41; 6.26; 6.8; 9.04; 9.55; 11.11; 12.87; 13.97; 14.85; 15.79; 16.57; 18.63; 20.59; 22.2; 23.77; 24.41; 26.35; 27.21; 29.41; and its most characteristic peaks are the following: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.41; 14.85; 16.57;
- Figure 7 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the zinc salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a zinc ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 6.86; 7.34; 7.73; 8.03; 8.49; 8.89; 9.42; 9.71; 10.49; 10.95; 11.73; 12.25; 12.7; 14.28; 14.71; 14.94; 15.5; 16.11; 16.44; 16.99; 17.71; 18.09; 18.4; 18.87; 19.14; 19.44; 19.89; 20.24; 20.67; 21.15; 21.53; 21.9
- Figure 8 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is an ammonium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks also listed in Table 2 as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 7.63; 8.69; 9.1; 9.64; 10.86; 11.48; 12.34; 13.3; 14.11; 14.48; 15.13; 16.35; 16.68; 17.1; 17.41; 18.18; 18.47; 19.24; 19.89; 20.25; 20.53; 21.19; 22.22; 22.86; 23.68; 24.26; 24.75; 25
- Figure 9 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the cyclohexyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a cyclohecxyl ammonium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.15; 5.03; 5.8; 6.85; 7.69; 8.9; 9.22; 10.09; 13.25; 13.74; 14.22; 14.78; 15.51; 16.73; 17.2; 17.82; 18.58; 19.28; 19.6;
- Figure 10 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the diisopropyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a diisopropyl ammonium ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.62; 6.78; 7.86; 9.34; 9.9; 10.28; 11.18; 11.56; 12.54; 13.36; 13.85; 14.36; 14.82; 15.6; 16.11; 16.98; 17.5; 18.06; 18.5; 18.76; 19.5; 20.26; 20.65; 20.98; 21.31; 22.43;
- HMBC (7 Hz): 7.40-158.55, 133.57, 7.34-141.25, 7.26-140.38, 6.96-158.55,133.57, 3.99- 157.53,125.37,22.04, 3.79-158.55, 3.52-165.46,48.00,28.46, 3.45-165.46,37.80,19.18, 3.26- 165.46,48.00,19.18, 3.16-148.36, 131.36,125.37,51.34, 2.74-165.46,28.46,23.67, 2.38- 168.98,23.15,21.04, 1.88-48.00,37.80, 1.59-28.46
- the FtPLC-measured purity of the initial "raw” carboxylic acid is 90.99%, while the HPLC-measured purity of the produced cesium salt - and the "purified” carboxylic acid released from this cesium salt - was 99.14%.
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Abstract
The invention relates to a preparation process and an intermediate compound for the preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban) of formula 1. Further, the invention is the cesium salt of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1- yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b - where M is cesium ion - and the ammonium salt of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b - where M is ammonium ion.
Description
Process and intermediate for the preparation of apixaban
Subject of invention
The present invention relates to a preparation process and an intermediate compound for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahy- dro- lH-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban) of formula 1.
1 State of the art
Apixaban of formula 1 is the active substance of the anticoagulant therapeutic drug marketed under the name ELIQUIS, which is an Xa blood coagulant factor inhibitor, developed in a joint venture by Bristol-Myers Squibb and Pfizer.
According to the current state of the art, several methods are available to produce apixaban of formula 1, which are described in patent applications WO2003026652, WO2003049681, WO2007001385, WO2010030983, CN101967145 and WO2012168364. These preparation processes have in common that the formation of the central bicyclic heterocycle of apixaban, that is 4,5-dihydropyrazolo[3,4-c]pyridine-2-on, is performed via a cycloaddition reaction shown on figure 1 between the methoxyphenyl hidrazone derivative compound of formula 2
2
- where Z is a halogen atom or an R'-SC -O group, preferably chlorine; R' is a substituted or unsubstituted aryl group, a substituted or unsubstituted Ci-C8 straight-chain or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group or a substituted or unsubstituted aralkyl group - and the l,3-disubstituted-5,6-dihydro-lH-pyridine-2-on of the general formula 3
3
- where R1 is a halogen atom, preferably chlorine, or a 1-morpholinyl group, and R2 is H atomor a substituted phenyl group, preferably a p-nitrophenyl group.
Each of the above listed patent applications share in common that the last intermediate during the described preparation process is l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester of formula 4a,
4a
which is finally transformed into the target product carboxamide, i.e., apixaban of formula 1. This carboxamide formation step is typically performed either via a direct acylation of ammonium 4a carboxylic acid with ethyl ester (e.g. WO2003026652) or the two elemental step one-pot reaction of 4a carboxylic acid ethyl ester and formamide (e.g. WO2003049681). A production method of 1 apixaban is also described in the international patent application WO2003049681 using the 4c carboxylic acid precursor
4c in aqueous ammonium in ethyl acetate, under the conditions of in situ carboxylic acid activation as mixed anhydride (figure 2). It is worth noting regarding this latter example that the 4c carboxylic acid is formed also via the 4a intermediate compound in this case, as a result of hydrolysis occurring during processing the reaction product.
An industrially feasible preparation method of 1 apixaban is described in the international patent application WO2007001385, according to which the final product is obtained via the steps shown on figure 3.
However, it can be concluded that none of the above mentioned patent applications include the removal of contaminants present in the highly lipophilic final product, with special regards to structurally analogous contaminating compounds. Meanwhile this is an extremely important issue as every sequential synthesis method results in by-products with a size and structure similar to those of the desired final product, which are likely to be present. The physicochemical characteristics of these by-products are closely related to those of the final product; moreover, in some cases they are even more lipophilic, thus their removal from the final product is remarkably difficult: even if it is successful, it usually entails a great loss of product. The reason for this is that
crystallization is not suitable to differentiate sufficiently between chemical compounds with similar physicochemical characteristics. A further difficulty is that apixaban dissolves only in high dilution in the common solvents used in the industry (water, alcohols, carboxylic acid esters, ethers, etc.), and in order to confine the above mentioned contaminating compounds under the values given in the pharmacopoeia, in many cases even higher dilution conditions would be required than these highly diluted, but already saturated solutions. This obviously leads to further loss of product and in addition, the regeneration costs of these procedures are also high because of the large volume of solvents used, and further, they are unfavorable from environmental aspects. Another important aspect when evaluating the different synthesis processes of apixaban is that processing the 4a carboxylic acid ester usually involves some kind of treatment in an aqueous medium, which necessarily results in a - sometimes extensive - hydrolytic degradation of the 4a carboxylic acid ester due to its properties.
The Hungarian patent application PI 400378 describes a much more favorable preparation process for synthetizing 1 apixaban compared to the previous ones, where the last key intermediate obtained is also the 4a carboxylic acid ester. This 4a carboxylic ester is then purified through one or several steps to remove contaminants occurring during the outlined preparation process in the patent application, typically via the hydrate form of the sodium salt of formula 4b
4b
- where M is a sodium ion -, formulated with 4 mol water, and via the carboxylic acid of formula 4c, afterwards, 1 apixaban is produced.
Short summary of the invention
By developing the preparation process according to this invention, we aimed to produce high purity apixaban active substance with a high production yield through an intermediate compound that is well separable from contaminating compounds in solid form and thus highly purifiable, and has more favorable solubility, usability and purification characteristics compared to the 4a carboxylic acid ester.
The invention is a process for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban) of formula 1. The preparation process is characterized in that:
a) the "raw" carboxylic acid of formula 4c is transformed into a salt of formula 4b - where M is an alkali metal ion, such as lithium, sodium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C6 alkyl- or cycloalkyl-substituted primary, secondary or tertiary ammonium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) ion -, after which the 4b salt is separated from the contaminating compounds; then the salt of formula 4b is transformed into the "purified" carboxylic acid of formula 4c, and finally, 1 apixaban is produced directly from this purified carboxylic acid of formula 4c, or
b) in the first step, the ester of formula 4a is transformed into the "raw" carboxylic acid of formula 4c, then the "raw" carboxylic acid 4c is transformed into the salt form of formula 4b - where M is as described above -, followed by separating the 4b salt from the contaminants, then the salt of formula 4b is transformed into the "purified" carboxylic acid of formula 4c and finally, 1 apixaban is directly produced from the latter, purified carboxylic acid 4c.
The process according to the invention is particularly suitable to purify, as described above, the ester of formula 4a produced according to the preparation process presented in the patent application WO2007001385.
In a preferred embodiment of the process according to the invention in the salt of formula 4b, M is a sodium, cesium, calcium, zinc, ammonium, cyclohexyl-ammonium, diisopropyl-ammonium or DBU ion.
In another preferred embodiment of the process according to the invention in the salt of formula 4b, M is a cesium or ammonium ion.
In a further preferred embodiment of the process according to the invention the salts of formula 4b are produced in a dipolar aprotic or alcoholic solvent or in a mixture of both, or in the aqueous mixture of these, preferably in acetonitrile, Ν,Ν-dimetil-acetamide, N-methyl-pyrrolidone or Ci-C6 alcohols, preferably in methanol, ethanol or isopropyl alcohol.
In a further preferred embodiment of the process according to the invention the salts of formula 4b are separated from the contaminating compounds by filtration or by evaporation of the salt solution followed by solvent changing and filtration.
In a further preferred embodiment of the process according to the invention some kind of aprotic solvent, ether or alcane, preferably diisopropyl-ether or heptane is used when changing the solvent. Further, the invention is the salt of formula 4b - where M is an alkali metal ion, such as lithium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C6 alkyl- or cycloalkyl-substituted primary, secondary or tertiary ammonium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) -, with the provisio that M is other than sodium ion.
Further, the invention is the salt of formula 4b - where M is a cesium, calcium, zinc, ammonium, cyclohexyl-ammonium, diisopropyl-ammonium or DBU ion. Further, the invention is the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b - where M is cesium ion.
Further, the invention is the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 5.88; 14.75; 16.67; 19.16.
Further, the invention is the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 5.88; 14.75; 15.53; 16.67; 17.62; 19.16; 20.63; 21.51; 30.75.
Further, the invention is the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b - where M is ammonium ion.
Further, the invention is the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 19.89; 23.68; 24.75.
Further, the invention is the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b, where the characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 9.64; 13.3; 17.1; 17.41; 18.47; 19.89; 22.22; 22.86; 23.68; 24.75.
During the development of the process according to the invention, we were surprised to notice that our goal/aim can be achieved if the active substance precursor ethyl ester of formula 4a, used in the preparation of apixaban - produced according to the elemental steps shown on figure 3 and described in the international patent application WO2007001385 -, is hydrolyzed into the "raw" carboxylic acid of formula 4c, which is then transformed into the salt of formula 4b - where M is an alkali metal ion, such as lithium, sodium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C6 alkyl- or cycloalkyl-substituted primary, secondary or tertiary ammo- nium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) ion-, and the 4b salt is separated from the contaminating compounds, then transformed into the "purified" carboxylic acid of formula 4c, from which the 1 apixaban is directly synthetized.
Detailed description of the invention
During our work we have found that the ester of formula 4a, produced according to the steps shown on figure 3, can be simply and quantitatively in situ hydrolyzed into the carboxylic acid of formula 4c. This latter intermediate compound is easier to isolate in a robust way and with better production yield compared to the 4a ester, therefore it is a more favorable intermediate by itself than the 4a ethyl ester, which is equally sensitive both against acids and bases. The solid 4c carboxylic acid can be optimally transformed into 4b carboxylic acid salt - where M is as described above -, from which the 4c carboxylic acid can be recovered with a good chemical yield. The solubility properties of the 4c carboxylic acid significantly improve by changing the components of the solvent medium and by increasing its pH value, that is, by transforming the 4c free acid into 4b salt. The 4b carboxylic acids are intermediates that can be separated from the contaminants in solid form - by crystallization or stirring in solvent - and unequivocally characterized analytically, therefore they enable the realization of a significant purification from critical lipophilic contaminating compounds by means of a simple technology requiring only filtration and washing, as the lipophilic contaminating compounds remain in the solvent. Consequently, the purification rate of the 4c carboxylic acid intermediate increases with this method, and thus also that of the final product apixaban, compared to the "crystallization" of the final product apixaban by aqueous precipitation from dimethyl formamide (DMF) solution.
As the 4c acid and 4b salt forms can be mutually transformed, they enable us to perform the purification process of 4c carboxylic acid in a favorable way through a suitably realized process sequence of raw 4c 4b purified 4c so that the purification and concentration rates, the chemical yield and industrial feasibility are all more favorable compared to the simple and conventional crystallization of either the 4c carboxylic acid or 1 apixaban. We used inorganic bases, salts and also organic amine bases for the salt formation. The purification of the 4c acid is particularly favorable via ammonium and cesium salts. Analytical methods of measurement:
To characterize the novel salt compounds according to our invention, we used several analytical methods from the options listed below, based on practical selection. It is well known that
measurement results and signal intensities depend on a number of parameters, for example the sample preparation procedures used or measurement conditions, therefore we also provide a description of the instruments and conditions that we applied:
• IR: Bruker Alpha FT IR spectrometer
· MR: Bruker Avance III 400 (400 Mhz) MR spectrometer
• X-ray powder diffraction (XPRD)
Instrument: Bruker D8 Advance X-ray powder diffractometer
- Radiation: CuKai (λ=1.54060 A), CuKa2 (λ=1.54439 A)
- Accelerating voltage: 40 kV
- Anode heating current: 40 raA
- Equipment: Goebel mirror (optics producing parallel beams),
Sample changer with 9-position, transmission configuration
- Detector: Bruker LynxEye 1-D detector
- Soller: 2.5 °
- Slits: Source site: 0.6 mm divergence slit
Diffraction site: 8 mm receiving slit
- Range: continuous Θ/Θ scan, 4 - 35° 2Θ
- Time per step: 1.2 s
- Step size: 0.02° 2Θ
- Sample preparation: the unpowdered sample was placed between Mylar foils
and measured at room temperature
- Sample rotation speed: 0.5 rev/s
- No. of scanning cycles: 1
- Scanning time: 35 minutes
• Inductively coupled plasma optical emission spectrometry (ICP-OES)
- Instrument: GBC Integra XL ICP-spectrometer
- Measurement conditions:
Name of Wavelength:
element:
Zn 213.856 nm
Ca 317.933 nm
Na 589.592 nm
Ion chromatography (IC)
- Chromatography system
■ Instrument: Dionex ICS 5000 ion chromatograph with eluent generator and conductivity detector
■ Column: Dionex IonPac CS 16 (with carboxylic acid) 3 x 250 mm analytical column with a CG-16 3 x 50 mm guard column.
■ System control, data processing: Chromeleon software, ver. 7.7.1.
- Chromatography settings:
■ Run time: 30 minutes
■ Eluent: 35 mM methanesulfonic acid
■ Flow rate: 0.40 mL/min
■ Sampler temperature: 25 °C
■ Column temperature: 40 °C
■ CD detector cell temperature: 25 °C
■ Temperature of other appliances: 35 °C
■ Suppression current: 36 raA
■ Injected volume: 25 μΐ^ The advantage of the method according to the invention is that the contaminating compounds - which are very similar in size and structure to the desired final product, have closely analogous physicochemical characteristics and are similarly or sometimes even more lipophilic - can be removed in a significantly more efficient way, with much less loss of product even under industrial conditions compared to the currently known methods, such as the "crystallization" of the final product apixaban by aqueous precipitation from dimethyl formamide (DMF) solution. This finally results in an increased purity of the final product apixaban.
Another advantage of the purification method according to the invention is that its concentration domain falls in the suitable range for industrial purposes, which is a further unexpected benefit, knowing the solubility characteristics of the final product apixaban in many solvent types; and that the aqueous medium treatment required for processing the 4a carboxylic acid ester - which necessarily results in the sometimes extensive hydrolytic degradation of the 4a carboxylic acid ester due to its properties - can be omitted.
Another advantage of the purification method according to the invention is that the solubility characteristics of the 4c carboxylic acid can be improved significantly by altering the pH of the solvent medium, that is, by mutually transforming the salt and free acid forms into each other, thus, the 4c carboxylic acid intermediate can be purified easily and efficiently without the formation of additional contaminating compounds, and can be transformed to the final product 1 apixaban with high production yield, this way, the final product apixaban does not require any further purification, only the transformation into the form of the desired morphology. The advantage of the salts of formula 4b according to the invention is that their solubility properties are more favorable than that of the ester of formula 4a, therefore significantly less solvent is required, which in turn results in decreased loss of materials, lower regeneration cost of the procedure and a reduced degree of environmental pollution - with special regards to the extremely toxic nature of DMF.
We demonstrate our invention through the following examples, without limiting the scope of the patent protection to these particular examples.
Example 1
Preparation of the l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo [3,4-c]pyridine-3-carboxylic acid of formula 4c Add 2.705 g lithium hydroxide monohydrate dissolved in 191 mL demineralized water dropwise under 5 minutes to 29.0 g ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxilate of formula 4a, produced according to figure 3 and dissolved in dimethylacetamide (238 mL DMA). Stir the mixture overnight and then pour it slowly onto 1790 g 5% solution of NaCl, then extract with isopropyl acetate. Sepa- rate the aqueous phase and acidify it with 1 M aqueous hydrochloric acid solution, that is, release the carboxylic acid under 10-15 °C temperature. Filtrate the precipitated white substance and wash with distillated water, then dry it.
Product: 26.30 g beige colored solid substance
melting point: 270.5-274 °C
IR (KBr): 3407, 2904, 2534, 1710, 1667, 1613, 1516, 1255, 1151 cm"1.
HNMR (DMSO-de): δ 13.19 (br s, 1H), 7.44 (d, 2H, J = 8.9 Hz), 7.35 (d, 2H, J = 8.7 Hz), 7.28 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 9.0 Hz), 4.06 (t, 2H, J = 6.5 Hz), 3.80 (s, 3H), 3.59 (t, 2H, J = 5.9 Hz), 3.19 (t, 2H, J = 6.5 Hz), 2.38 (t, 2H, J = 6.2 Hz), 1.85 (m, 2H), 1.84 (m, 2H) ppm. CNMR (DMSO-d6): δ 169.02, 163.06, 159.39, 156.66, 141.58, 139.91, 139.48, 133.06, 132.71, 126.98, 126.86, 126.50, 126.17, 113.61, 55.64, 50.99, 50.93, 32.77, 23.17, 21.39, 21.07 ppm. Example 2
General preparation method for purifying the l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl] -4,5,6,7-tetrahy dro- lH-pyrazolo [3,4-c] pyridine-3-carboxylic acid of formula 4c via the 4b salt forms
Prepare the 4b carboxylic acid salts listed in the examples below from the "raw" l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridine-3 -carboxylic acid of formula 4c, prepared in example 1. Dissolve or mix the produced 4b salts in water, and then acidify with 1 M hydrochloric acid solution, that is, release the carboxylic acid. Filtrate the precipitated 4c "purified" carboxylic acid, wash with water and dry in a vacuum drying oven.
Example 3
Preparation of the sodium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl] -4,5,6,7-tetrahydro- lH-pyrazolo [3,4-c] pyridine-3-carboxylic acid of formula 4b (where M is a sodium ion)
Heat 54.7 mg sodium hydrogen carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo- l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a mixture of 6.0 mL dimethylacetamide and 1.9 mL demineralized water to 100 °C, then cool the solution. Filtrate the solid phase, wash with a small amount of cold dimethylacetamide and dry under an IR lamp.
Product: 281 mg white crystal
melting point: 345-355 °C
IR (KBr): 3440, 2936, 1643, 1613, 1514, 1304, 1248, 1164, 1021 cm"1.
HNMR (DMSO-de): δ 7.44 (d, 2H, J = 8.7 Hz), 7.34 (d, 2H, J = 8.6 Hz), 7.26 (d, 2H, J = 8.5 Hz), 6.95 (d, 2H, J = 8.7 Hz), 4.00 (t, 2H, J = 6.3 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.8 Hz), 3.18 (t, 2H, J = 6.4 Hz), 2.38 (t, 2H, J = 5.6 Hz), 1.85 (m, 4H) ppm.
ICP-OES: 4.1 m/m% Na (theoretical: 4.8 m/m%)
Figure 4 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the sodium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a sodium ion), produced according to the process described above, with characteristic X-ray powder dif- fraction peaks as follows: °2Θ (±0.2 °2Θ): 4.15; 6.95; 8; 8.12; 8.72; 9.24; 10.04; 10.72; 12.55; 13.63; 14.37; 14.71; 14.91; 15.86; 16.3; 16.79; 17.26; 17.9; 18.14; 18.54; 18.83; 19.2; 19.44; 20.09; 20.55; 20.7; 21.07; 21.8; 22.34; 22.72; 23.98; 25.11; 25.51; 25.99; 26.5; 27.08; 27.37; 27.91; 28.29; 29.3; 29.53; 29.9; 30.51; 30.96; 31.33; 31.67; 32.27; 32.86; 33.13; 34.34; 34.64; and the most characteristic peaks are as follows: 2Θ (±0.02 °2Θ): 4.15; 6.95; 8; 8.12; 10.72; 14.37; 14.71; 14.91; 15.86; 16.3; 16.79; 18.14; 18.54; 18.83; 19.2; 20.09; 20.55; 20.7; 21.07; 21.8; 22.72; 25.11; 25.99; 26.5; 27.08; 27.91; 30.51.
Example 4
Preparation of the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo [3,4-c]pyridine-3-carboxylic acid of formula 4b (where M is a cesium ion)
Dissolve 110 mg cesium carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 1.6 mL demineralized water and 3.4 mL dimethyla- cetamide, then concentrate the solution to 50-60% volume in vacuum. Cool the solution and stir for 2 hours. Filtrate the precipitated solid substance, wash first with 2x 1 mL cold dimethyla- cetamide and then with 2x 1 mL cold diisopropyl ether, and finally dry it under an IR lamp.
Product: 362 mg white powder
melting point: 232-234.5 °C
IR (KBr): 3441, 2934, 1665, 1642, 1603, 1515, 1373, 1297, 1252 cm"1.
HNMR (DMSO-de): δ 7.40 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.7 Hz), 7.25 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.9 Hz), 3.98 (t, 2H, J = 6.6 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.9 Hz), 3.15 (t, 2H, J = 6.5 Hz), 2.38 (t, 2H, J = 6.0 Hz), 1.84 (m, 4H) ppm.
IC: 22.8 m/m% Cs (theoretical: 22.4 m/m%)
Figure 5 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid formula 4b (where M is a cesium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks also listed in Table 1 as follows: °2Θ (±0.2 °2Θ): 5.88; 6.93; 8.42; 9.53; 11.45; 11.8; 13.94; 14.75; 15.53; 15.95; 16.67; 17.27; 17.62; 18.44; 18.63; 19.16; 19.46; 20.27; 20.63; 20.97; 21.51; 22.26; 22.66; 22.95; 23.16; 23.8; 24.28; 24.67; 25.03; 25.48; 25.98; 26.27; 26.94; 27.29; 27.89; 28.11; 28.54; 28.95; 29.36; 29.81; 30.18; 30.75; 31.48; 32.1; 32.46; 33.22; 33.72; 34.1; 34.61; and the most characteristic peaks are as follows °2Θ (±0.2 °2Θ): 5.88; 14.75; 15.53; 16.67; 17.62; 19.16; 20.63; 21.51; 30.75; and the most characteristic peaks are as follows °2Θ (±0.2 °2Θ): 5.88; 14.75; 16.67; 19.16.
Table 1
Position and relative intensities of the characteristic X-ray powder diffraction peaks of the 4b cesium salt compound (relative intensity >2%):
14 18.44 4.81 22
15 18.63 4.76 20
16 19.16 4.63 68
17 19.46 4.56 7
18 20.27 4.38 16
19 20.63 4.30 44
20 20.97 4.23 25
21 21.51 4.13 49
22 22.26 3.99 18
23 22.66 3.92 6
24 22.95 3.87 6
25 23.16 3.84 9
26 23.80 3.74 2
27 24.28 3.66 32
28 24.67 3.61 38
29 25.03 3.55 21
30 25.48 3.49 3
31 25.98 3.43 6
32 26.27 3.39 21
33 26.94 3.31 18
34 27.29 3.27 5
35 27.89 3.20 10
36 28.11 3.17 6
37 28.54 3.12 11
38 28.95 3.08 28
39 29.36 3.04 37
40 29.81 2.99 23
41 30.18 2.96 17
42 30.75 2.91 41
43 31.48 2.84 16
44 32.10 2.79 5
45 32.46 2.76 20
46 33.22 2.69 11
47 33.72 2.66 3
48 34.10 2.63 13
49 34.61 2.59 4
Example 5
Preparation of the calcium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b (where M is a calcium ion)
Dissolve 24 mg calcium hydroxide and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula
4c as in example 1 in a warm mixture of 3.0 mL demineralized water and 3.0 mL acetonitrile, then evaporate the solution to dryness in vacuum. Dissolve the remaining substance in 3.0 mL acetonitrile and stir for 2 hours at room temperature. Filtrate the resulting solid phase, wash with
1.0 mL cold acetonitrile and dry under an IR lamp.
Product: 131 mg white powder
melting point: 318-332 °C
IR (KBr): 3418, 2940, 1664, 1600, 1513, 1385, 1301, 1251, 1167, 1142, 1022 cm"1.
HNMR (DMSO-de): δ 7.43 (d, 4H, J = 8.6 Hz), 7.32 (d, 4H, J = 7.5 Hz), 7.25 (d, 4H, J = 8.1
Hz), 6.93 (d, 4H, J = 8.2 Hz), 3.98 (m, 4H), 3.78 (s, 6H), 3.58 (t, 4H, J = 5.6 Hz), 3.17 (m, 4H),
2.39 (t, 4H, J = 5.9 Hz), 1.85 (m, 8H) ppm.
ICP-OES: 4.1 m/m% Ca (theoretical: 4.2 m/m%)
Figure 6 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the calcium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a calcium ion), produced according to the process described above, with characteristic X-ray powder dif- fraction peaks as follows: °2Θ (±0.2 °2Θ): 4.47; 5.41; 6.26; 6.8; 9.04; 9.55; 11.11; 12.87; 13.97; 14.85; 15.79; 16.57; 18.63; 20.59; 22.2; 23.77; 24.41; 26.35; 27.21; 29.41; and its most characteristic peaks are the following: °2Θ (±0.2 °2Θ): 5.41; 14.85; 16.57; 20.59; 22.2; 24.41
Example 6
Preparation of the zinc salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo [3,4-c]pyridine-3-carboxylic acid of formula 4b (where M is a zinc ion)
Dissolve 41 mg zinc carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 9.0 mL demineralized water, 7.0 mL acetonitrile and 0.5 mL dimethylacetamide, then concentrate the solution to a final volume of 10 mL in vacuum. Cool the solution while stirring, and then continue stirring for 1 hour. Filtrate the resulting solid phase, wash with 1 mL cold acetonitrile and dry under an IR lamp.
Product: 261 mg white powder
melting point: 291.5-300 °C
IR (KBr): 3425, 2948, 1672, 1632, 1513, 1300, 1251, 1170, 1147, 1022 cm"1.
HNMR (DMSO-de): δ 7.44 (d, 4H, J = 8.9 Hz), 7.34 (d, 4H, J = 8.7 Hz), 7.27 (d, 4H, J = 8.8 Hz), 6.91 (d, 4H, J = 9.0 Hz), 4.03 (t, 4H, J = 6.6 Hz), 3.76 (s, 6H), 3.59 (t, 4H, J = 5.9 Hz), 3.12 (t, 4H, J = 6.6 Hz), 2.38 (t, 4H, J = 6.0 Hz), 1.85 (m, 8H) ppm.
ICP-OES: 6.1 m/m% Zn (theoretical: 6.6 m/m%)
Figure 7 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the zinc salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a zinc ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: °2Θ (±0.2 °2Θ): 6.86; 7.34; 7.73; 8.03; 8.49; 8.89; 9.42; 9.71; 10.49; 10.95; 11.73; 12.25; 12.7; 14.28; 14.71; 14.94; 15.5; 16.11; 16.44; 16.99; 17.71; 18.09; 18.4; 18.87; 19.14; 19.44; 19.89; 20.24; 20.67; 21.15; 21.53; 21.9; 22.59; 23.1; 23.54; 23.82; 24.34; 24.79; 25.04; 25.5; 25.99; 26.42; 26.81; 27.18; 27.52; 28.2; 28.82; 29.51; 29.94; 30.55; 31.08; 31.66; 32.35; 32.63; 33.2; 33.5; 34.2; and its most characteristic peaks are the following: °2Θ (±0.2 °2Θ): 6.86; 7.34; 7.73; 9.71 ; 10.49; 10.95; 11.73; 12.25; 12.7; 14.94; 15.5; 16.11; 16.99; 17.71 ; 18.09; 18.4; 19.89; 20.24; 21.15; 21.53; 21.9; 23.1; 23.54; 23.82; 24.34; 24.79; 25.5; 27.18; 27.52; 28.2.
Example 7
Preparation of the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl] -4,5,6,7-tetrahy dro- lH-pyrazolo [3,4-c] pyridine-3-carboxylic acid of formula 4b (where M is an ammonium ion)
Dissolve 31 mg ammonium carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 3.0 mL ethanol and 0.6 mL demineralized water, then let the solution cool. After 3 hours of stirring, filtrate the precipitated solid substance, wash with 1 mL cold ethanol and dry under an IR lamp.
Product: 212 mg white powder
melting point: 280-281.5 °C
IR (KBr): 3483, 2946, 1661, 1631, 1515, 1303, 1254, 1165, 1141 cm"1.
HNMR (DMSO-de): δ 7.44 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.7 Hz), 7.26 (d, 2H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.9 Hz), 4.02 (t, 2H, J = 6.5 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.8 Hz), 3.17 (t, 2H, J = 6.6 Hz), 2.38 (t, 2H, J = 6.1 Hz), 1.85 (m, 4H) ppm.
IC: 3.1 m/m% H4 + (theoretical: 3.8 m/m%)
Figure 8 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is an ammonium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks also listed in Table 2 as follows: °2Θ (±0.2 °2Θ): 7.63; 8.69; 9.1; 9.64; 10.86; 11.48; 12.34; 13.3; 14.11; 14.48; 15.13; 16.35; 16.68; 17.1; 17.41; 18.18; 18.47; 19.24; 19.89; 20.25; 20.53; 21.19; 22.22; 22.86; 23.68; 24.26; 24.75; 25.56; 26.25; 27.5; 28.58; 28.82; 29.52; 29.98; 30.68; 31.73; 33.14; 33.7; and the most characteristic peaks are as follows °2Θ (±0.2 °2Θ): 9.64; 13.3; 17.1; 17.41 ; 18.47; 19.89; 22.22; 22.86; 23.68; 24.75; and the most characteristic peaks are as follows °2Θ (±0.2 °2Θ): 19.89; 23.68; 24.75.
Table 2
Position and relative intensities of the characteristic X-ray powder diffraction peaks of the 4b ammonium salt compound (relative intensity >2%):
26 24.26 3.67 19
27 24.75 3.59 94
28 25.56 3.48 15
29 26.25 3.39 5
30 27.50 3.24 17
31 28.58 3.12 15
32 28.82 3.10 18
33 29.52 3.02 7
34 29.98 2.98 9
35 30.68 2.91 17
36 31.73 2.82 13
37 33.14 2.70 6
38 33.70 2.66 7
Example 8
Preparation of the cyclohexyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl] -4,5,6,7-tetrahy dro- IH-pyrazolo [3,4-c] pyridine-3-carboxylic acid of formula 4b (where M is a cyclohexyl ammonium ion)
Warm up 75
cyclohexylamine and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a mixture of 30 mL ethanol and 20 mL acetonitrile. Leave the suspension to cool to room temperature while stirring, and continue stirring for 24 hours. Filtrate the solid substance, wash with 1 mL cold ethanol and dry under an IR lamp.
Product: 329 mg white powder
melting point: 249.5-259 °C
IR (KBr): 3441, 2941, 2860, 1674, 1646, 1570, 1540, 1516, 1375, 1298, 1257 cm"1.
HNMR (DMSO-de): δ 7.42 (d, 2H, J = 8.6 Hz), 7.34 (d, 2H, J = 8.2 Hz), 7.26 (d, 2H, J = 7.8
Hz), 6.96 (d, 2H, J = 8.1 Hz), 4.00 (t, 2H, J = 6.1 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.7 Hz), 3.16
(t, 2H, J = 5.9 Hz), 2.88 (m, 1H), 2.38 (t, 2H, J = 5.5 Hz), 1.85 (m, 6H), 1.69 (m, 2H),.1.56 (m,
1H), 1.21 (m, 4H), 1.07 (m, 1H) ppm.
Figure 9 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the cyclohexyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a cyclohecxyl ammonium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks as follows: °2Θ (±0.2 °2Θ): 4.15; 5.03; 5.8; 6.85; 7.69; 8.9; 9.22; 10.09; 13.25; 13.74; 14.22; 14.78; 15.51; 16.73; 17.2; 17.82; 18.58; 19.28; 19.6; 20.86; 21.3; 22.39; 23.31; 24.73; 25.53; 26.41; 27.17; 27.81; 29.08; 29.78; 30.24; 31.31; 32.22; 32.81; and the most characteristic peaks are as follows: 2Θ (±0.02 °2Θ): 5.03; 6.85; 7.69; 8.9; 15.51; 16.73; 17.2; 17.82; 18.58; 19.28; 19.6; 20.86; 21.3; 23.31
Example 9
Preparation of the diisopropyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl] -4,5,6,7-tetrahy dro- lH-pyrazolo [3,4-c] pyridine-3-carboxylic acid of formula 4b (where M is a diisopropyl ammonium ion)
Dissolve 92 [iL diisopropyl amine and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 20 mL ethanol and concentrate the solution to half volume in vacuum. Cool the solution to room temperature while stirring, and then continue stirring for 24 hour. Filtrate the solid substance, wash with 1 mL cold ethanol and dry under an IR lamp. Product: 348 mg white powder
melting point: 278-281 °C
IR (KBr): 3463, 2962, 2862, 2763, 1675, 1605, 1511, 1372, 1300, 1249 cm"1.
HNMR (DMSO-de): δ 7.43 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.6 Hz), 7.26 (d, 2H, J = 8.5 Hz), 6.97 (d, 2H, J = 8.8 Hz), 4.02 (t, 2H, J = 6.5 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.8 Hz), 3.27 (m, 2H), 3.19 (t, 2H, J = 6.6 Hz), 2.38 (t, 2H, J = 6.0 Hz), 1.85 (m, 4H), 1.20 (d, 12H, J = 6.4 Hz) ppm.
Figure 10 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the diisopropyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a diisopropyl ammonium ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: °2Θ (±0.2 °2Θ): 5.62; 6.78; 7.86;
9.34; 9.9; 10.28; 11.18; 11.56; 12.54; 13.36; 13.85; 14.36; 14.82; 15.6; 16.11; 16.98; 17.5; 18.06; 18.5; 18.76; 19.5; 20.26; 20.65; 20.98; 21.31; 22.43; 23.56; 24.13; 24.76; 25.49; 27.92; 28.74; 29.88; 31.53; 32.87; 33.69; 34.3; 34.72; and the most characteristic peaks are as follows: 2Θ (±0.02 °2Θ): 5.62; 6.78; 7.86; 9.34; 9.9; 1 1.18; 1 1.56; 12.54; 13.36; 13.85; 14.82; 16.11; 16.98; 17.5; 18.06; 18.5; 18.76; 19.5; 20.26; 20.65; 20.98; 21.31; 22.43; 23.56; 24.13; 27.92; 29.88.
Example 10
Preparation of the l,8-diazabycyclo[5.4.0]undec-7-ene (DBU) salt of l-(4-methoxyphenyl)- 7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3- carboxylic acid of formula 4b (where M is 1,8-diazabycyclo [5.4.0] undec-7-ene ion)
Dissolve 97 [iL l,8-diazabycyclo[5.4.0]undec-7-ene and 300 mg l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a mixture of 10 mL ethanol on reflux temperature and evaporate the solution to dryness in vacuum. Treat the remaining substance with diisopropyl ether at room temperature and after stirring it overnight, filtrate the solid phase, wash with 2x3 mL diisopropyl ether and dry under an IR lamp.
Product: 391 mg off-white powder
melting point: 86.5-92 °C
IR (KBr): 3406, 3239, 3129, 2938, 1665, 1647, 1588, 1541, 1516, 1689, 1457, 1373, 1338, 1324, 1295, 1251, 846 cm-1.
HNMR (DMSO-de): δ 11.04 (br s, 1H), 7.40 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.96 (t, Jl = J2 = 6.6 Hz, 2H), 3.79 (s, 3H), 3.59 (t, Jl = J2 = 5.1 Hz, 2H), 3.52 (m, 2H); 3.45 (t, Jl = J2 = 5.8 Hz, 2H), 3.26 (t, Jl = J2 = 5.8 Hz, 2H), 3.16 (t, Jl = J2 = 6.6 Hz, 2H), 2.74 (m, 2H), 2.38 (t, Jl = J2 = 6.2 Hz, 2H), 1.88 (m, 2H), 1.86 (m, 2H), 1.84 (m, 2H), 1.66 (m, 2H), 1.59 (m, 4H) ppm.
HNMR (DMSO-d6): δ 168.98, 165.46, 164.78, 158.55, 157.53, 148.36, 141.25, 140.38, 133.57, 131.36, 126.48, 126.37, 126.01, 125.37, 113.33, 55.53, 53.36, 51.34, 50.99, 48.00, 37.80, 32.74, 31.48, 28.46, 26.23, 23.67, 23.15, 22.04, 21.04, 19.18 ppm.
COSY: 7.40-6.96, 7.34-7.26, 7.26-7.34, 6.96-7.40, 3.99-3.16, 3.59-1.86, 3.52-1.59, 3.45-1.88, 3.26-1.88, 3.16-3.99, 2.74-1.59, 2.38-1.84, 1.88-3.45,3.26, 1.86-3.59, 1.84-2.38, 1.66-1.59, 1.59- 3.52,2.74,1.66
HSQC: 7.40-126.48, 7.34-126.10, 7.26-126.37, 6.96-1 13.33, 3.99-51.34, 3.79-55.53, 3.59-50.99, 3.52-53.36, 3.45-48.00, 3.26-37.80, 3.16-22.04, 2.74-31.48, 2.38-32.74, 1.88-19.18, 1.86-23.15, 1.84-21.04, 1.66-28.46, 1.59-26.23,23.67
HMBC (7 Hz): 7.40-158.55, 133.57, 7.34-141.25, 7.26-140.38, 6.96-158.55,133.57, 3.99- 157.53,125.37,22.04, 3.79-158.55, 3.52-165.46,48.00,28.46, 3.45-165.46,37.80,19.18, 3.26- 165.46,48.00,19.18, 3.16-148.36, 131.36,125.37,51.34, 2.74-165.46,28.46,23.67, 2.38- 168.98,23.15,21.04, 1.88-48.00,37.80, 1.59-28.46
Selective NOESY: 3.99-7.34,3.16. Selective TOCSY: 2.74-3.52,1.66,1.59, 2.38-3.59, 1.86, 1.84 Figure 11 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the DBU salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a 1,8- diazabycyclo[5.4.0]undec-7-ene ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: °2Θ (±0.2 °2Θ): 5.44; 6.74; 8; 8.54; 9.18; 10.98; 14.16; 16.35; 16.57; 17.1; 17.92; 18.64; 18.95; 19.45; 20.06; 20.73; 21.7; 22.27; 22.51; 23.33; 24.05; 25.21; 26.11 ; 26.64; 28.05; 30.3; 30.98; 31.58; 33.02; 33.29; and the most characteristic peaks are as follows: 2Θ (±0.02 °2Θ): 5.44; 6.74; 9.18; 10.98; 14.16; 16.35; 16.57; 17.1; 17.92; 18.64; 18.95; 19.45; 20.73; 21.7; 22.27; 22.51; 23.33; 25.21; 28.05 We achieved significant increase in purification in case of two salt forms out of the carboxylic acid salts of formula 4b as in examples 3 to 10, when produced according to the process sequence of raw 4c -> 4b purified 4c included in the invention: when producing the cesium salt as in example 4 and when producing the ammonium salt as in example 7. In case of the cesium salt produced in example 4, the FtPLC-measured purity of the initial "raw" carboxylic acid is 90.99%, while the HPLC-measured purity of the produced cesium salt - and the "purified" carboxylic acid released from this cesium salt - was 99.14%.
In case of the ammonium salt produced in example 7, the HPLC-measured purity of the initial "raw" carboxylic acid is 90.99%), while the HPLC-measured purity of the produced ammonium salt - and the "purified" carboxylic acid released from this ammonium salt - was 98.17%>.
Claims
1. Process for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban) of formula 1,
characterized by that,
a) the "raw" carboxylic acid of formula 4c
transformed into a salt of formula 4b
4b
- where M is an alkali metal ion, such as lithium, sodium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C6 alkyl- or cycloalkyl-substituted primary, secondary or tertiary ammonium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) ion-, after which the 4b salt is separated from the contaminating compounds; then the salt of formula 4b is transformed into the "purified" carboxylic acid of formula 4c, and finally, 1 apixaban is produced directly from this purified carboxylic acid of formula 4c, or
b) in the first step, the ester of formula 4a
4a is transformed into the "raw" carboxylic acid of formula 4c, then the "raw" carboxylic acid 4c is transformed into the salt form of formula 4b - where M is as described above -, followed by separating the 4b salt from the contaminants, then the salt of formula 4b is transformed into the "purified" carboxylic acid and finally, 1 apixaban is directly produced from this latter, purified carboxylic acid 4c.
2. Process according to claim 1, characterized by that, in the salt of formula 4b, M is a sodium, cesium, calcium, zinc, ammonium, cyclohexyl-ammonium, diisopropyl-ammonium or DBU ion.
3. Process according to claim 1, characterized by that, in the salt of formula 4b, M is a cesium or ammonium ion.
4. Process according to claim 1, characterized by that, the salts of formula 4b are produced in a dipolar aprotic or alcoholic solvent or in an mixture of both, or in the aqueous mixture of these, preferably in acetonitrile, Ν,Ν-dimetil-acetamide, N-methyl-pyrrolidone or Ci-C6 alcohols, pref- erably in methanol, ethanol or isopropyl alcohol.
5. Process according to claim 1, characterized by that, the salts of formula 4b are separated from the contaminating compounds by filtration or by evaporation of the salt solution followed by solvent changing and filtration.
6. Process according to claim 5, characterized by that, some kind of aprotic solvent, ether or al- cane, preferably diisopropyl-ether or heptane is used when changing the solvent.
7. The salt of formula 4b - where M is an alkali metal ion, such as lithium, potassium or cesium ion; or an alkali earth metal ion, such as magnesium or calcium ion; or a transitional metal ion, such as zinc or ammonium ion; or a Ci-C6 alkyl- or cycloalkyl- substituted primary, secondary or tertiary ammonium ion, such as cyclohexyl-ammonium, diisopropyl ammonium or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) -, with the provisio that M is other than sodium ion.
8. The salt of formula 4b - where M is a cesium, calcium, zinc, ammonium, cyclohexyl- ammonium, diisopropyl-ammonium or DBU ion.
9. The cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b - where M is cesium ion.
10. The cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4b, where the characteristic
X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 5.88; 14.75; 16.67; 19.16.
11. The cesium salt of formula 4b l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid, whose characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 5.88; 14.75; 15.53; 16.67; 17.62; 19.16; 20.63; 21.51; 30.75.
12. The ammonium salt of formula 4b l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid - where M is ammonium ion.
13. The ammonium salt of formula 4b l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid, whose characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 19.89; 23.68; 24.75.
14. The ammonium salt of formula 4b l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid, whose characteristic X-ray powder diffraction peaks measured with CuKa radiation at reflection angle °2Θ (±0.2 °2Θ) are the followings: 9.64; 13.3; 17.1; 17.41; 18.47; 19.89; 22.22; 22.86; 23.68; 24.75.
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| CN107434806A (en) * | 2016-12-09 | 2017-12-05 | 陕西科技大学 | γ crystal formation solid matters of a kind of Eliquis carboxylic acid derivates and preparation method thereof and purposes |
| WO2018127936A1 (en) * | 2017-01-05 | 2018-07-12 | Hikal Limited | Novel economic metal free process for apixaban |
| CN109400606A (en) * | 2018-12-26 | 2019-03-01 | 山东鲁抗医药股份有限公司 | A method of refining Eliquis from apixaban crude |
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| CN104045637A (en) * | 2014-04-18 | 2014-09-17 | 河北科技大学 | Apixaban preparation method |
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