WO2016112880A1 - Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate - Google Patents

Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate Download PDF

Info

Publication number
WO2016112880A1
WO2016112880A1 PCT/CZ2016/000002 CZ2016000002W WO2016112880A1 WO 2016112880 A1 WO2016112880 A1 WO 2016112880A1 CZ 2016000002 W CZ2016000002 W CZ 2016000002W WO 2016112880 A1 WO2016112880 A1 WO 2016112880A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
butan
dihydro
acid
trifluorophenyl
Prior art date
Application number
PCT/CZ2016/000002
Other languages
French (fr)
Inventor
Jindrich Richter
Kamal JARRACH
Violetta Kiss
Eszter TIEGER
Jaroslav Havlicek
Ondrej Dammer
Original Assignee
Zentiva, K.S
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 Zentiva, K.S filed Critical Zentiva, K.S
Publication of WO2016112880A1 publication Critical patent/WO2016112880A1/en
Priority to DE102017200031.7A priority Critical patent/DE102017200031A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel crystalline Modification 3 of (3/?)-3-amino-l-[3- ⁇ trifluoromethy -e ⁇ -dihydro-SH-Cl ⁇ triazolo S- ipyrazin-y-yll- -taAS- trifluorophenyl)butan-l-one L-tartrate of Formula I,
  • Sitagliptin is a selective dipeptidyl-peptidase-4 (DPP-4) receptor inhibitor, used for the treatment of diabetes mellitus type 2 controlling the glucose (sugar) level of the blood.
  • DPP-4 is an enzyme that controls the incretin hormones. The level of the incretin hormones increases as an effect of saxagliptin and in parallel, pancreas produces more insulin and the amount of glucose produced by the liver decreases. These effects reduce the blood glucose level and help in the control of type-2 diabetes.
  • Sitagliptin is disclosed and a list of pharmaceutically acceptable salts thereof is generally included in patent WO03004498.
  • WO2004087650 discloses the sitagliptin free base in crystalline form.
  • WO2005003135 claims the dihydrogenphosphate salt of sitagliptin and its crystalline monohydrate. Three crystalline, anhydrous polymorphic forms of sitagliptin phosphate and various solvates are described and disclosed in patent WO2005020920. WO 2005030127 claims a fourth anhydrous polymorph of sitagliptin phosphate. The amorphous dihydrogenphosphate is described and disclosed in patent WO2006033848. Further crystalline solid phase of sitagliptin dihydrogenphosphate are described and claimed patents US2009/247532 and WO2010131035. WO2012166420 claims the phosphate salt of sitagliptin in a stoichiometric ratio of 2:1.
  • Crystalline salts of sitagliptin and hydrochloric acid, ben, D- and /.-tartaric acid, p- toluenesulfonic acid, benzenesulfonic acid and (lS)-(+)- and flRH- camphorsulfonic acid are disclosed in patent WO200507253O.
  • WO2009085990 claims crystalline salts of sitagliptin formed with sulfonic acid, hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, lactic acid and fumaric acid.
  • WO2010000469 claims various polymorphic forms of salts of sitagliptin and hydrochloric acid, fumaric acid, sulfuric acid, succinic acid, glycolic acid, maleic acid, methanesulfonic acid, malic acid, phosphoric acid, lactic acid and citric acid. Salts of sitagliptin formed with ethanesulfonic acid, lactic acid, thiocyanic acid and glutaric acid are disclosed in patent WO2010012781.
  • WO2010092090 discloses sitagliptin salts of (D)- and ⁇ -glucuronic acid, glutaric acid, sulfuric acid, (D)- and (L)-lactic acids, ethanesulfonic acid, oxalic acid, acetic acid, (D)- and (i)- mandelic acid, capric acid, benzoic acid, hippuric acid, trans-cinnamic acid, malonic acid, citric acid, l-hydroxy-2-naphtolic acid, crotonic acid and ascorbic acid.
  • WO2011018494 claims various crystalline forms of sitagliptin salt formed with fumaric acid.
  • WO2012007455 describes the orotate salt of sitagliptin in amorphous phase.
  • the objective of the present invention to provide a novel crystalline modif ication of a L-tartrate salt of sitagliptin with good chemical purity, chemical and physical stability and good processability during its preparation as an active pharmaceutical ingredient. It is very important from economical point of view that the preparation process is suitable for industrial scale application and easily reproducible.
  • the object of the present invention is to provide a novel crystalline modification of (3 )-3- amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3, in particular in a solid form suitable for oral administration which has advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound.
  • the invention further relates to pharmaceuticai formulations containing the novel crystalline modification of ⁇ 3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3- a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3.
  • Figure 1 is an XRPD pattern of the crystalline Modification 3 of (3R)-3-amino-l-[3- ⁇ trifluoromethy -e ⁇ -dihydro-SH-Cl ⁇ ltriazolot ⁇ S-olpyrazin-y-ylj ⁇ -f ⁇ S- trifluorophenyl)butan-l-one L-tartrate
  • Figure 2 is a FTIR spectra of the crystalline Modification 3 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l i 2 i 4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 3 is a Raman spectra of the crystalline Modification 3 of (3 ?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l i 2 J 4]triazolo[4,3-a]pyrazin-7-yl]-4-(2 i 4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 4 is a 13 C-ssNMR spectra of the crystalline Modification 3 of (3 ?)-3-amino-l-[3- ⁇ trifluoromethyl)-6,8-dihydro-5H-[l J 2,4]triazolo[4 i 3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 5 is a 19 F-ssNMR spectra of the crystalline Modification 3 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5f/-[l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 6 is a DCS curve of the crystalline Modification 3 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6 J1 8-dihydro-5H-[l / 2,4]triazolo[4 / 3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 7 is a TG curve of the crystalline Modification 3 of (3/?)-3-amino-l-[3-(trifluoromethyl)- 6,8-dihydro-5H-[l,2,4]tnazolo[4,3-o]pyrazin-7-yl]-4-(2 ; 4,5-trifluorophenyl)butan-l-one L- tartrate
  • the invention relates to a novel crystalline modification of (3/?)-3-amino-l-[3- (trifluoromethy - ⁇ S-dihydro-SH-tl ⁇ jtriazoloE ⁇ S-ol yrazin ⁇ -yn ⁇ -i ⁇ S- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3, which meets the pharmaceutical requirements regarding the physico-chemical properties and stability and have advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound, and which can be produced in reproducible manner even in industrial scale.
  • Figure 2 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 3474, 3060, 2941, 1701, 1654, 1511, 1138, 1082, 1019 and 676 cm “1 and
  • Figure 3 shows the Raman (FT-Raman Bruker RFS 100/S) spectrum comprising characteristic peaks at 3086, 3028, 2006, 2943, 2880, 1640, 1514, 758, 449 and 209 cm "1 .
  • Figure 4 shows the 13 C-ssNMR (Bruker AVANCE 250 MHz) spectrum
  • Figure 5 shows the 19 F-ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • step 1) any crystalline solid form of (3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyI)butan-l-one can be used as starting material.
  • step 2) the solution of 50°C - 55°C can be filtered optionally to get rid of the undissolved particles.
  • step 3 the crystallization of (3 ?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one
  • L-tartrate crystalline Modification 3 can be initiated by addition of L-tartaric acid in water solution to the clear solution of the starting material of 50°C - 55°C.
  • step 4) the suspension containing (Sffl-B-amino-l-ES-itrifluoromethy -e / S-dihydro-BH- [l,2,4]triazolo[4 i 3-o]pyrazin-7-yl]-4- ⁇ 2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be cooled to about 0°C by a controlled cooling profile.
  • Controlled cooling profile means a cooling rate of 10-30°C/h, preferably 20 e C/h. After cooling the suspension can be agitated for further 24 to 72 hours, preferably 48 hours.
  • step 5 the crystals obtained can be collected by any conventional method, e.g. filtration.
  • the obtained (SRJ-S-amino-l- ⁇ -ttrifiuoromethy -e ⁇ -dihydro-SH-tl ⁇ ltriazoloE ⁇ S- o]pyrazin-7-yl]-4-(2 i 4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be dried in vacuum oven at 30°C to 50°C applying 100 mbar to 300 mbar vacuum , preferably at 40°C applying 200 mbar vacuum.
  • the suspension was filtered and washed with 1,4-dioxane and dried in the vacuum oven at 40°C and 200 mbar vacuum for 16 hours.
  • the product was filtered and dried in vacuum oven at 40 e C and 200 mbar for 16 hours.
  • Incident beam optics programmable divergence slits (irradiated length 10 mm), 10 mm mask, 1/45 anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122 ⁇ 0.02 rad Soller slits, anti-scatter slit 5.0 mm, Ni filter. Analysis - FTIR (Fourier-Transformed Infra-Red) spectroscopy
  • FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
  • the samples were weighed in aluminium pans and covers (20 ⁇ ) and measured in a nitrogen flow (50 mL/min). Investigations were performed in a temperature range of 25 °C to 300 °C with a heating rate of 10°C/min.
  • the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks.
  • the specific heat is given in J/g.
  • the weight of the sample was about 3-4 mg.
  • the samples were weighed in aluminium pans (85 ⁇ ) and measured in nitrogen flow. TGA investigations were performed in a temperature range of 25°C to 300°C with a heating rate of 10°C/min.
  • the weight of the sample was about 5-6 mg.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Gasket Seals (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Crystalline Modification 3 of Sitagliptin L-tartrate salt, exhibiting following characteristic diffraction peaks: 4.22; 15.87; 16.58; 20.8; 22.72 ± 0.2° 2-theta. (Formula)

Description

Crystalline Modification 3 of (3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l^^ltriazolol^S-al yrazin-T-ylj- -tl^fS-trifluoro rienylJbutan-l-one L-tartrate
Technical Field The present invention relates to novel crystalline Modification 3 of (3/?)-3-amino-l-[3- {trifluoromethy -e^-dihydro-SH-Cl^^triazolo S- ipyrazin-y-yll- -taAS- trifluorophenyl)butan-l-one L-tartrate of Formula I,
Figure imgf000002_0001
process for its preparation, as well as said solid state form for use in pharmaceutical compositions.
Background Art
Sitagliptin is a selective dipeptidyl-peptidase-4 (DPP-4) receptor inhibitor, used for the treatment of diabetes mellitus type 2 controlling the glucose (sugar) level of the blood. DPP-4 is an enzyme that controls the incretin hormones. The level of the incretin hormones increases as an effect of saxagliptin and in parallel, pancreas produces more insulin and the amount of glucose produced by the liver decreases. These effects reduce the blood glucose level and help in the control of type-2 diabetes.
Sitagliptin is disclosed and a list of pharmaceutically acceptable salts thereof is generally included in patent WO03004498.
WO2004087650 discloses the sitagliptin free base in crystalline form.
WO2005003135 claims the dihydrogenphosphate salt of sitagliptin and its crystalline monohydrate. Three crystalline, anhydrous polymorphic forms of sitagliptin phosphate and various solvates are described and disclosed in patent WO2005020920. WO 2005030127 claims a fourth anhydrous polymorph of sitagliptin phosphate. The amorphous dihydrogenphosphate is described and disclosed in patent WO2006033848. Further crystalline solid phase of sitagliptin dihydrogenphosphate are described and claimed patents US2009/247532 and WO2010131035. WO2012166420 claims the phosphate salt of sitagliptin in a stoichiometric ratio of 2:1.
Crystalline salts of sitagliptin and hydrochloric acid, ben, D- and /.-tartaric acid, p- toluenesulfonic acid, benzenesulfonic acid and (lS)-(+)- and flRH- camphorsulfonic acid are disclosed in patent WO200507253O.
WO2009085990 claims crystalline salts of sitagliptin formed with sulfonic acid, hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, lactic acid and fumaric acid.
WO2010000469 claims various polymorphic forms of salts of sitagliptin and hydrochloric acid, fumaric acid, sulfuric acid, succinic acid, glycolic acid, maleic acid, methanesulfonic acid, malic acid, phosphoric acid, lactic acid and citric acid. Salts of sitagliptin formed with ethanesulfonic acid, lactic acid, thiocyanic acid and glutaric acid are disclosed in patent WO2010012781.
WO2010092090 discloses sitagliptin salts of (D)- and ^-glucuronic acid, glutaric acid, sulfuric acid, (D)- and (L)-lactic acids, ethanesulfonic acid, oxalic acid, acetic acid, (D)- and (i)- mandelic acid, capric acid, benzoic acid, hippuric acid, trans-cinnamic acid, malonic acid, citric acid, l-hydroxy-2-naphtolic acid, crotonic acid and ascorbic acid.
WO2011018494 claims various crystalline forms of sitagliptin salt formed with fumaric acid. WO2012007455 describes the orotate salt of sitagliptin in amorphous phase.
Journal of Medicinal Chemistry, 2005, 48, pages 141-151 describes that sitagliptin salt of fumaric acid with a stoichiometric ratio of 2:1 was used for in-vivo studies.
Therefore the objective of the present invention to provide a novel crystalline modif ication of a L-tartrate salt of sitagliptin with good chemical purity, chemical and physical stability and good processability during its preparation as an active pharmaceutical ingredient. It is very important from economical point of view that the preparation process is suitable for industrial scale application and easily reproducible.
Summary of the invention The object of the present invention is to provide a novel crystalline modification of (3 )-3- amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3, in particular in a solid form suitable for oral administration which has advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound. The invention further relates to pharmaceuticai formulations containing the novel crystalline modification of {3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3- a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3.
Brief description of the figures
Figure 1 is an XRPD pattern of the crystalline Modification 3 of (3R)-3-amino-l-[3- {trifluoromethy -e^-dihydro-SH-Cl^^ltriazolot^S-olpyrazin-y-ylj^-f^^S- trifluorophenyl)butan-l-one L-tartrate
Figure 2 is a FTIR spectra of the crystalline Modification 3 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[li2i4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
Figure 3 is a Raman spectra of the crystalline Modification 3 of (3 ?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[li2J4]triazolo[4,3-a]pyrazin-7-yl]-4-(2i4,5- trifluorophenyl)butan-l-one L-tartrate
Figure 4 is a 13C-ssNMR spectra of the crystalline Modification 3 of (3 ?)-3-amino-l-[3- {trifluoromethyl)-6,8-dihydro-5H-[lJ2,4]triazolo[4i3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
Figure 5 is a 19F-ssNMR spectra of the crystalline Modification 3 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5f/-[l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
Figure 6 is a DCS curve of the crystalline Modification 3 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6J18-dihydro-5H-[l/2,4]triazolo[4/3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
Figure 7 is a TG curve of the crystalline Modification 3 of (3/?)-3-amino-l-[3-(trifluoromethyl)- 6,8-dihydro-5H-[l,2,4]tnazolo[4,3-o]pyrazin-7-yl]-4-(2;4,5-trifluorophenyl)butan-l-one L- tartrate
Detailed description of the invention The invention relates to a novel crystalline modification of (3/?)-3-amino-l-[3- (trifluoromethy -^S-dihydro-SH-tl^^jtriazoloE^S-ol yrazin^-yn^-i^S- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3, which meets the pharmaceutical requirements regarding the physico-chemical properties and stability and have advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound, and which can be produced in reproducible manner even in industrial scale. The above aim has been achieved by the novel crystalline modification of (3 ?)-3-amino-l-[3- (trifluoromethylj-e^-dihydro-SH-tl^^ltriazoiot^S-alpyrazin-T-yn-^iZ^^- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3.
The novel crystalline modification of (SRJ-S-amino-l- -ttrifluoromethy -e^-dihydro-SH- [l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4i5-trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 3 can be obtained with good yield and high purity.
The novel crystalline Modification 3 of (3/?)-3-amino-l-[3-{trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2A5-trifluorophenyl)butan-l-one L-tartrate has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). (3/?)-3-Amino-l-[3-(trifluoromethyl)- 6,8-dihydro-5H-[l,2,4]triazolo[4f3-a]pyrazin-7-yl]-4-(2i4,5-trifluorophenyl)butan-l-one L- tartrate crystalline Modification 3 shows the following powder diffraction peaks as illustrated in Table 1, below:
Figure imgf000005_0001
Table 1
(3/?)-3-Amino-l-[3-(trifluoromethyl)-6,8-dihydro-5W-[l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4- (2,4,5~trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be further characterized by an FTIR, Raman and solid state NMR spectroscopy investigations. Figure 2 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 3474, 3060, 2941, 1701, 1654, 1511, 1138, 1082, 1019 and 676 cm"1 and Figure 3 shows the Raman (FT-Raman Bruker RFS 100/S) spectrum comprising characteristic peaks at 3086, 3028, 2006, 2943, 2880, 1640, 1514, 758, 449 and 209 cm"1. Figure 4 shows the 13C-ssNMR (Bruker AVANCE 250 MHz) spectrum and Figure 5 shows the 19F-ssNMR (Bruker AVANCE 250 MHz) spectrum.
(3 ?)-3-Amino-l-E3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4- (2,4,5-trifiuorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be further described by thermal analytical methods. Figure 6 shows the DSC (Mettler Toledo DSC 822e) curve measured in the range of 25°C to 300eC and gives a melting process with Tpeak,i=80.44°C and TPeak,2=194.89eC. Figure 7 shows the TGA (Netzsch TG 209} curve showing a 1.97% weight loss in the range of 25°C-to 300°C.
A process for the preparation of (3R)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazoio[4,3-o]pyrazin-7-yl3-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3.
(3/?)-3-Amino-l-E3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3-o3pyrazin-7-yl]-4- (2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be prepared by a salt formation and crystallization process comprising the steps of
1) dissolution of (3/?)-3-amino-l-[3-(trifluoromethyi)-6,8-dihydro-5H-[l,2,4]triazolo[4,3- o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l~one upon heating;
2) filtering the hot solution (optional);
3) addition of L-tartaric acid solution;
4) cooling the suspension;
5) collection of the crystals obtained by filtration and drying.
In step 1) any crystalline solid form of (3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyI)butan-l-one can be used as starting material. (3/?)-3-Amino-l"[3-(trifluoromethyl)-6,8-dihydro-5 /-[l,2,4]triazolo[4,3- o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one can be dissolved in a water-l,4-dioxane solvent mixture or ketones, preferably in a water-l,4-dioxane solvent mixture in a volumetric ratio of 50:50 or methyl-tetrahydrofurane. The temperature applied for dissolution depends on the initial amount and solid form of the starting material, preferably 50°C -55°C.
in step 2) the solution of 50°C - 55°C can be filtered optionally to get rid of the undissolved particles.
In step 3) the crystallization of (3 ?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be initiated by addition of L-tartaric acid in water solution to the clear solution of the starting material of 50°C - 55°C. In step 4) the suspension containing (Sffl-B-amino-l-ES-itrifluoromethy -e/S-dihydro-BH- [l,2,4]triazolo[4i3-o]pyrazin-7-yl]-4-{2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be cooled to about 0°C by a controlled cooling profile. Controlled cooling profile means a cooling rate of 10-30°C/h, preferably 20eC/h. After cooling the suspension can be agitated for further 24 to 72 hours, preferably 48 hours.
In step 5) the crystals obtained can be collected by any conventional method, e.g. filtration. The obtained (SRJ-S-amino-l-^-ttrifiuoromethy -e^-dihydro-SH-tl^^ltriazoloE^S- o]pyrazin-7-yl]-4-(2i4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3 can be dried in vacuum oven at 30°C to 50°C applying 100 mbar to 300 mbar vacuum , preferably at 40°C applying 200 mbar vacuum.
Examples Example 1
Preparation of {3ff)-3-amino-l-[3-(trifluoromethyl)-6,8-dihYdro-5H-[l,2,4]triazolo[4,3- o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3
500 mg {1.228 mmol) of (3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [li2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one was dissolved in 1.5 mL of solvent mixture of water and 1,4-dioxane with a volumetric ratio of 1:1 by heating to 50°C.
0.2 g (1.334 mmol) of L-tartaric acid was dissolved in 0.5 mL of water at room temperature and the solution of L-tartaric acid was added to the solution of (3 ?}-3-amino-l-[3- {trifluoromethyl)-6i8-dihydro-5H-[li2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2A5- trifluorophenyl)butan-l-one of 50°C. Thick slurry formed which was heated to 60 °C.
The suspension was filtered and washed with 1,4-dioxane and dried in the vacuum oven at 40°C and 200 mbar vacuum for 16 hours.
Yield: 98%
HPLC: 100%
1H- MR analysis confirmed the structure with a stoichiometry of 1:1.
Water content determination resulted in 1.7% of water content. Example 2
Preparation of (3 ?)-3-amino-l-i3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4ltriazolo[4,3- a3pyrazin-7-ylI-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 3
40 mL of (3/ )-3-amino-l-[3-(trifiuoromet^
yl]-4-(2,4,5-trifluorophenyl)butan-l-one dissolved in methyl-tetrahydrofurane (concentration: 0.73 g / 10 mL) was heated up to 50°C with a continuous stirring of 200 rpm.
1.51 g () of L-tartaric acid was dissolved in 20 mL of water and added to the solution of (3/?)- 3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5f -[l,2i4]triazolo[4i3-o]pyrazin-7-yl3-4-(2,4,5- trifluorophenyl)butan-l-one of 50°C with a feeding rate of 0.6667 mL/min.
Light precipitation started immediately. The suspension was stirred for additional 1 hour at 50°C and cooled back to 0°C with a cooling rate of 20°C/h and stirred for 16 hours at that temperature.
The product was filtered and dried in vacuum oven at 40eC and 200 mbar for 16 hours.
Yield: 85%
HPLC: 99.5%
1H-NM analysis confirmed the structure with a stoichiometry of 1:1.
Water content determination resulted in 1,7% of water content.
Analysis - XRPD (X-Ray Powder Diffractometry)
Diffractograms were obtained with laboratory X'PERT PRO MPD PANalytical diffractometer with CuKa (λ = 1.542A) radiation.
Generator settings:
excitation voltage 45 kV
- anodic current 40 mA.
Scan description:
- scan type - gonio
- measurement range 2 - 409 2Θ
- step size 0.012 2Θ
- time per step: 0.5s.
Sample was measured as received (not grinded) on Si substrate (zero-background holder). Incident beam optics: programmable divergence slits (irradiated length 10 mm), 10 mm mask, 1/45 anti-scatter fixed slit, 0.02 rad Soller slits.
Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122^ 0.02 rad Soller slits, anti-scatter slit 5.0 mm, Ni filter. Analysis - FTIR (Fourier-Transformed Infra-Red) spectroscopy
FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
General settings:
Number of sample scans: 45
Number of background scans: 45
Resolution: 4.000
Sample gain: 4.0
Optical velocity: 0.6329
Aperture: 100.00
Analysis - Raman spectroscopy
FTIR spectra were recorded by FT-Raman Bruker RFS 100/S Spectrometer
General settings:
Excitation source: Nd-YAG laser {1064 nm)
Applied spectral domain: 3600-200 cm"1
Applied laser power: 250 mW
Detector: liquid nitrogen cooled Ge-diode detector (D418-T)
Resolution: 4 cm'1
Number of accumulations: 256
Scattering geometry: 180° (back scattering)
Aperture: 3.5 mm
Analysis - NMR
For 1H NMR spectra the Bruker NMR spectrometer AVANCE 500 MHz and DMSO as solvent were used. The stoichiometry of salts were determined from integrals of corresponding signals of API and counterion.
13C and 19F ss NMR spectra were measured on Bruker 400 WB spectrometer in 4 mm rotors with 13 kHz spinning frequency. The spectra of salts were compared with the spectrum of initial API because the formation of a salt should be accompanied by changes of positions of signals of API and by the presence of signals of counterion. Analysis - DSC (Differential Scanning Caiorimetry)
DSC measurements were performed on a Mettler Toledo DSC822e instrument.
The samples were weighed in aluminium pans and covers (20 μί) and measured in a nitrogen flow (50 mL/min). Investigations were performed in a temperature range of 25 °C to 300 °C with a heating rate of 10°C/min. The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks. The specific heat is given in J/g.
The weight of the sample was about 3-4 mg.
Analysis - TGA (ThermoGravimetric Analysis)
TGA were performed on a Netzsch TG 209 instrument.
The samples were weighed in aluminium pans (85 μί) and measured in nitrogen flow. TGA investigations were performed in a temperature range of 25°C to 300°C with a heating rate of 10°C/min.
The weight of the sample was about 5-6 mg.

Claims

Claims:
1. Crystalline Modification 3 of Sitagtiptin L-tartrate salt, exhibiting following characteristic diffraction peaks: 4.22; 15.87; 16.58; 20.8; 22.72 ± 0.2" 2-theta.
2. Crystalline Modification 3 according to claim 1, further exhibiting following characteristic diffraction peaks: 13.97; 14.96; 17.04; 23.97; 26.02 ± 0.2° 2-theta.
PCT/CZ2016/000002 2015-01-13 2016-01-07 Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate WO2016112880A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE102017200031.7A DE102017200031A1 (en) 2015-01-13 2017-01-03 Upright seal for a heat exchanger

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-30579U CZ27930U1 (en) 2015-01-13 2015-01-13 Crystalline modification of 3 L-tartrate (3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
CZ2015-30579U 2015-01-13

Publications (1)

Publication Number Publication Date
WO2016112880A1 true WO2016112880A1 (en) 2016-07-21

Family

ID=52705855

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2016/000002 WO2016112880A1 (en) 2015-01-13 2016-01-07 Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate

Country Status (3)

Country Link
CZ (1) CZ27930U1 (en)
DE (1) DE102017200031A1 (en)
WO (1) WO2016112880A1 (en)

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004498A1 (en) 2001-07-06 2003-01-16 Merck & Co., Inc. Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004087650A2 (en) 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
WO2005003135A1 (en) 2003-06-24 2005-01-13 Merck & Co., Inc. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005020920A2 (en) 2003-09-02 2005-03-10 Merck & Co., Inc. Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005030127A2 (en) 2003-09-23 2005-04-07 Merck & Co., Inc. Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005072530A1 (en) 2004-01-16 2005-08-11 Merck & Co., Inc. Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor
WO2006033848A1 (en) 2004-09-15 2006-03-30 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2009085990A2 (en) 2007-12-20 2009-07-09 Dr. Reddy's Laboratories Limited Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof
US20090247532A1 (en) 2008-03-28 2009-10-01 Mae De Ltd. Crystalline polymorph of sitagliptin phosphate and its preparation
WO2010000469A2 (en) 2008-07-03 2010-01-07 Ratiopharm Gmbh Crystalline salts of sitagliptin
WO2010012781A2 (en) 2008-07-29 2010-02-04 Medichem, S.A. New crystalline salt forms of a 5,6,7,8-tetrahydro-1,2,4- triazolo[4,3-a]pyrazine derivative
WO2010032264A2 (en) * 2008-08-27 2010-03-25 Cadila Healthcare Limited Improved process for preparation of (2r)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro [1,2,4]-triazolo[4,3-a]pyrazin- 7(8h)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine & new impurities in preparation thereof
WO2010092090A2 (en) 2009-02-11 2010-08-19 Lek Pharmaceuticals D.D. Novel salts of sitagliptin
WO2010131035A1 (en) 2009-05-11 2010-11-18 Generics [Uk] Limited Novel crystalline polymorph of sitagliptin dihydrogen phosphate
WO2011018494A1 (en) 2009-08-13 2011-02-17 Sandoz Ag Crystalline compound of 7-[(3r)-3-amino-1-oxo-4-(2, 4, 5-trifluorphenyl)butyl]-5, 6, 7, 8-tetrahydro-3-(tri fluormethyl)-1, 2, 4 -triazolo[4,3-a]pyrazine
WO2012007455A1 (en) 2010-07-13 2012-01-19 Chemo Iberica, S.A. Process for the preparation of organic salts
WO2012166420A1 (en) 2011-05-27 2012-12-06 Merck Sharp & Dohme Corp. Phosphoric acid salts of sitagliptin
WO2015062562A1 (en) * 2013-11-01 2015-05-07 Zentiva, K.S. A stable polymorph of the salt of (2r)-4-oxo-4-[3-(trifiuoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-l-(2,4,54rifluorophenyl)butan-2-amine with l-tartaric acid

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004498A1 (en) 2001-07-06 2003-01-16 Merck & Co., Inc. Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004087650A2 (en) 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
WO2005003135A1 (en) 2003-06-24 2005-01-13 Merck & Co., Inc. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005020920A2 (en) 2003-09-02 2005-03-10 Merck & Co., Inc. Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005030127A2 (en) 2003-09-23 2005-04-07 Merck & Co., Inc. Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005072530A1 (en) 2004-01-16 2005-08-11 Merck & Co., Inc. Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor
WO2006033848A1 (en) 2004-09-15 2006-03-30 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2009085990A2 (en) 2007-12-20 2009-07-09 Dr. Reddy's Laboratories Limited Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof
US20090247532A1 (en) 2008-03-28 2009-10-01 Mae De Ltd. Crystalline polymorph of sitagliptin phosphate and its preparation
WO2010000469A2 (en) 2008-07-03 2010-01-07 Ratiopharm Gmbh Crystalline salts of sitagliptin
WO2010012781A2 (en) 2008-07-29 2010-02-04 Medichem, S.A. New crystalline salt forms of a 5,6,7,8-tetrahydro-1,2,4- triazolo[4,3-a]pyrazine derivative
WO2010032264A2 (en) * 2008-08-27 2010-03-25 Cadila Healthcare Limited Improved process for preparation of (2r)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro [1,2,4]-triazolo[4,3-a]pyrazin- 7(8h)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine & new impurities in preparation thereof
WO2010092090A2 (en) 2009-02-11 2010-08-19 Lek Pharmaceuticals D.D. Novel salts of sitagliptin
WO2010131035A1 (en) 2009-05-11 2010-11-18 Generics [Uk] Limited Novel crystalline polymorph of sitagliptin dihydrogen phosphate
WO2011018494A1 (en) 2009-08-13 2011-02-17 Sandoz Ag Crystalline compound of 7-[(3r)-3-amino-1-oxo-4-(2, 4, 5-trifluorphenyl)butyl]-5, 6, 7, 8-tetrahydro-3-(tri fluormethyl)-1, 2, 4 -triazolo[4,3-a]pyrazine
WO2012007455A1 (en) 2010-07-13 2012-01-19 Chemo Iberica, S.A. Process for the preparation of organic salts
WO2012166420A1 (en) 2011-05-27 2012-12-06 Merck Sharp & Dohme Corp. Phosphoric acid salts of sitagliptin
WO2015062562A1 (en) * 2013-11-01 2015-05-07 Zentiva, K.S. A stable polymorph of the salt of (2r)-4-oxo-4-[3-(trifiuoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-l-(2,4,54rifluorophenyl)butan-2-amine with l-tartaric acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, 2005, pages 141 - 151

Also Published As

Publication number Publication date
DE102017200031A1 (en) 2017-07-06
CZ27930U1 (en) 2015-03-10

Similar Documents

Publication Publication Date Title
USRE48825E1 (en) 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal forms
EP3248983B1 (en) Crystal form a of obeticholic acid and preparation method therefor
WO2019236889A1 (en) Novel salts and crystals
EP2451805A1 (en) A crystalline form of posaconazole
EP3256474B1 (en) Ibrutinib sulphate salt
US20080027223A1 (en) Polymorphs of eszopiclone malate
WO2017125097A1 (en) Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile salts and preparation thereof
WO2016127963A1 (en) Solid forms of palbociclib salts
JP2020535193A (en) Process for the preparation of crystalline linagliptin intermediates and linagliptin
EP3321267A1 (en) Crystalline forms of 2-[1-ethylsulfonyl-3-[7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile salts and preparation thereof
EP3322709B1 (en) Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile salts and preparation thereof
KR20120098745A (en) Crystalline forms of substituted pyrazolopyrimidines
WO2016172333A1 (en) A solid state form of perampanel
WO2016112880A1 (en) Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate
WO2016112879A1 (en) CRYSTALLINE MODIFICATION 2 OF (3/R)-3-AMINO-1-[3-(TRIFLUOROMETHYL)-6,8-DIHYDRO-5H-[1,2,4]TRIAZOLO[4,3-α]PYRAZIN-7-YL]-4-(2,4,5-TRIFLUOROPHENYL)BUTAN-1-ONE L-TARTRATE
WO2015085973A1 (en) Modifications of 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt
EP2771312B1 (en) Agomelatine-urea complex and crystalline forms thereof
CN108718526B (en) Crystal modification of nintedanib salt and process for producing the same
WO2023187762A1 (en) Co-crystals of vortioxetine hydrobromide
WO2011039670A1 (en) Novel forms of (2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1h-pyrido[4,3-b] indole)
WO2015067223A1 (en) L-tartrate salt of (1s,3s,5s)-2-[(2s)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and process for preparation thereof
EP2109613A2 (en) Polymorphs of eszopiclone malate

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: 16703419

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: 16703419

Country of ref document: EP

Kind code of ref document: A1