WO2016079549A1 - Process and intermediate for the preparation of apixaban - Google Patents

Process and intermediate for the preparation of apixaban Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
carboxylic acid
salt
ammonium
ion
Prior art date
Application number
PCT/HU2015/050018
Other languages
English (en)
French (fr)
Inventor
Tamas Nagy
Andras Mravik
Balazs Volk
Gabor Nemeth
Gyozo CSONKA-KIS
Janos Farago
Peter Slegel
Zoltan Varga
Monika Mezovari
Original Assignee
Egis Gyógyszergyár Zrt.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Egis Gyógyszergyár Zrt. filed Critical Egis Gyógyszergyár Zrt.
Publication of WO2016079549A1 publication Critical patent/WO2016079549A1/en

Links

Classifications

    • 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
    • C07D471/04—Ortho-condensed systems
    • 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%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/HU2015/050018 2014-11-19 2015-11-18 Process and intermediate for the preparation of apixaban WO2016079549A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1400543A HU230991B1 (hu) 2014-11-19 2014-11-19 Eljárás és köztitermék apixaban előállítására
HUP1400543 2014-11-19

Publications (1)

Publication Number Publication Date
WO2016079549A1 true WO2016079549A1 (en) 2016-05-26

Family

ID=89991646

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2015/050018 WO2016079549A1 (en) 2014-11-19 2015-11-18 Process and intermediate for the preparation of apixaban

Country Status (2)

Country Link
HU (1) HU230991B1 (hu)
WO (1) WO2016079549A1 (hu)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107434806A (zh) * 2016-12-09 2017-12-05 陕西科技大学 一种阿哌沙班羧酸衍生物的γ晶型固体物质及其制备方法与用途
WO2018127936A1 (en) * 2017-01-05 2018-07-12 Hikal Limited Novel economic metal free process for apixaban
CN109400606A (zh) * 2018-12-26 2019-03-01 山东鲁抗医药股份有限公司 一种从阿哌沙班粗品中精制阿哌沙班的方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026652A1 (en) 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003049681A2 (en) 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2007001385A2 (en) 2004-09-28 2007-01-04 Bristol-Myers Squibb Company Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2010030983A2 (en) 2008-09-15 2010-03-18 Auspex Pharmaceuticals, Inc. Pyrazole carboxamide inhibitors of factor xa
CN101967145A (zh) 2010-09-09 2011-02-09 华东理工大学 一种抗血栓药物阿匹沙班的制备方法
WO2012168364A1 (en) 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Apixaban preparation process
CN104045637A (zh) * 2014-04-18 2014-09-17 河北科技大学 一种阿哌沙班的制备方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026652A1 (en) 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003049681A2 (en) 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
US20030181466A1 (en) * 2001-12-10 2003-09-25 Jiacheng Zhou Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2007001385A2 (en) 2004-09-28 2007-01-04 Bristol-Myers Squibb Company Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2010030983A2 (en) 2008-09-15 2010-03-18 Auspex Pharmaceuticals, Inc. Pyrazole carboxamide inhibitors of factor xa
CN101967145A (zh) 2010-09-09 2011-02-09 华东理工大学 一种抗血栓药物阿匹沙班的制备方法
WO2012168364A1 (en) 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Apixaban preparation process
CN104045637A (zh) * 2014-04-18 2014-09-17 河北科技大学 一种阿哌沙班的制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107434806A (zh) * 2016-12-09 2017-12-05 陕西科技大学 一种阿哌沙班羧酸衍生物的γ晶型固体物质及其制备方法与用途
WO2018127936A1 (en) * 2017-01-05 2018-07-12 Hikal Limited Novel economic metal free process for apixaban
CN109400606A (zh) * 2018-12-26 2019-03-01 山东鲁抗医药股份有限公司 一种从阿哌沙班粗品中精制阿哌沙班的方法
CN109400606B (zh) * 2018-12-26 2020-01-17 山东鲁抗医药股份有限公司 一种从阿哌沙班粗品中精制阿哌沙班的方法

Also Published As

Publication number Publication date
HUP1400543A2 (hu) 2016-05-30
HU230991B1 (hu) 2019-08-28

Similar Documents

Publication Publication Date Title
WO2016102438A1 (en) Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidine analogues
CN106976849B (zh) 一种双氟磺酰亚胺锂的提纯方法
KR20180127428A (ko) 슈가마덱스의 제조를 위한 개선된 방법
CA2855022C (en) 7-{(3s,4s)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
KR20010005907A (ko) 세프디니르의 결정성 아민 염
KR102665258B1 (ko) Ag-10, 이의 중간체, 및 이의 염을 제조하는 방법
WO2016079549A1 (en) Process and intermediate for the preparation of apixaban
PT2192117E (pt) Sal de 6-fluoro-3-hidroxi-2-pirazinacarbonitrilo com amina orgânica e método para o produzir
WO2016008461A1 (en) A new form of sofosbuvir and a method of its preparation
JP7365349B2 (ja) 一酸化窒素を供与するプロスタグランジン類似体の製造方法
JP2022552713A (ja) ジアステレオマー酒石酸エステルによるラセミ体分離により２－シアノエチル（４ｓ）－４－（４－シアノ－２－メトキシフェニル）－５－ヒドロキシ－２，８－ジメチル－１，４－ジヒドロ－１，６－ナフチリジン－３－カルボキシレートを調製する方法
AU2021277593A1 (en) Solid forms of [(1 S)-1 -[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-te trahydrofuran-2-yl]propyl] acetate
CN101076521B (zh) 毒蝇碱受体拮抗药的制备方法及其中间体
JP2023062038A (ja) ガドブトロールの製造方法
WO2016199824A1 (ja) ６－ブロモ－３－ヒドロキシ－２－ピラジンカルボキサミドの結晶およびその製造方法
CN104628679A (zh) Bitopertin的新合成方法及其中间体
ES2249591T3 (es) Procedimiento para la resolucion de racemato de 4-(2-cloro-4-fluorofenil)-2-(3,5-difluoro-2-piridinil)-6-metil-1,4-dihidro-5-pirimidincarboxilato de metilo.
KR20140099461A (ko) 아크릴아미도-２-메틸프로판술폰산의 염의 제조 및 정제 방법
RU2669785C2 (ru) Полиморфная форма гиодезоксихолата натрия (NAHDC) и способ ее получения
WO2014051077A1 (ja) 高純度の含窒素複素環化合物の製造方法
CA2520083A1 (en) Novel crystal of 7-[2-[(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) and method for preparation thereof
US7476760B2 (en) Purification and production methods of 1-aminocyclopropanecarboxylic acid
JP6275596B2 (ja) テルミサルタンのアンモニウム塩の製造方法
JP3723584B2 (ja) ４−ヒドロキシ−２，３，５−トリフルオル安息香酸の製法
RU2509074C2 (ru) Кристаллическая форма iv тилорона дигидрохлорида и промышленный способ ее получения (варианты)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15804931

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15804931

Country of ref document: EP

Kind code of ref document: A1