Synthesis of [1,2,3]triazolo[4,5-D]pyrimidines

Abstract

The present invention relates to a process for the preparation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives useful as pharma- ceutical active compounds, in particular 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol.

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives useful as pharma- ceutical active compounds, in particular 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. [Background technology]

[0002] A class of compounds disclosed in WO 2013 / 068306 exhibits activity as CB2 receptor agonists. Interest in CB2 receptor agonists has grown with some of the early compounds showing promise in treating chronic pain (Beltramo,M. Mini Rev Med Chem 2009,9(1),11-25), atherosclerosis (Mach,F. et al. J Neuroendocrinol 2008,20 Suppl 1,53-7), bone mass regulation (Bab,I. et al. Br J Pharmacol 2008,153(2),182-8), neuroinflammation (Cabral,GA et al. J Leukoc Biol 2005,78(6),1192-7), ischemia / reperfusion injury (Pacher,P. et al. Br J Pharmacol 2008,153(2),252-62), and systemic fibrosis (Akhmetshina,A. et al. Arthritis Rheum The number of patent applications filed has been steadily increasing over the past decade (currently at 30-40 patent applications / year) due to the fact that they have been shown to have beneficial effects in preclinical models of several human diseases, including inflammatory bowel disease (Rheumatology (Oxford) 2009, 60(4), 1129-36; Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6), and liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83). Summary of the Invention

[0003] The present invention relates to a compound represented by formula (I) [ka] (In the formula, R 1 is halogen, -OH, -NR a R b , (C1-C6)alkoxy, (C1-C6)alkyl, -O(O)CR c or -NR a C(O)R c In particular, R 1 is -OH; [R a and R b is independently selected from H, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, phenyl, halo-phenyl, or (C1-C6)alkyl-phenyl; R c is H, (C1-C6) alkyl, (C1-C6) alkoxy, -OH, C 1-6 halo-(C1-C6)alkyl, phenyl, halo-phenyl or (C1-C6)alkyl-phenyl). or a pharma- ceutically acceptable salt thereof, comprising the steps of: Formula (II) [ka] a compound of the formula (I), a salt thereof, a tautomer thereof or a mixture of tautomers thereof, Formula (III): [ka] where X is halogen, triflate or tosyl. in the presence of an organic acid. The present invention provides a method comprising: [Brief description of the drawings]

[0004] [Figure 1]FIG. 1 shows the IR spectrum of the crystalline form of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, also known as Form A. [Diagram 2] FIG. 2 shows the Raman spectrum of the crystalline form of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, also known as Form A. [Diagram 3] FIG. 3 shows the IR spectrum of the amorphous form of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. [Figure 4] FIG. 4 shows the Raman spectrum of the amorphous form of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. [Diagram 5] FIG. 5 shows the powder X-ray diffraction spectrum of the amorphous form of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. [Figure 6] FIG. 6 shows the powder X-ray diffraction spectrum of the crystalline form of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, also known as Form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0006] The term "(C1-C6) alkyl", alone or in combination, means a straight or branched chain alkyl group having 1 to 6 carbon atoms, in particular a straight or branched chain alkyl group having 1 to 6 carbon atoms, more in particular a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched chain C1-C6 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, in particular methyl, ethyl, propyl, butyl and pentyl, more in particular methyl, ethyl, propyl, isopropyl, isobutyl, tert.-butyl and isopentyl. Particular examples of alkyl are methyl, ethyl and pentyl, in particular methyl and ethyl.

[0007] "Compound of formula (I)" means [ka] Refers to...

[0008] The compound of formula (I') is also known as 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. In this specification, names or references to the compound of formula (I') may be used interchangeably.

[0009] As used herein, "Form A" refers to the crystalline polymorphic Form A of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol.

[0010] "XRPD" refers to the analytical method of X-ray powder diffraction. The reproducibility of the angle values ​​is within the range of 2 theta ± 0.2°. The term "about" given in combination with the angle values ​​indicates a reproducibility within the range of 2 theta ± 0.2°. The relative XRPD peak intensities depend on many factors, such as structure factors, temperature factors, crystallinity, polarization factors, multiplicity, and Lorentz factors. The relative intensities can vary considerably from measurement to measurement due to preferred orientation effects. According to USP941 (United States Pharmacopeia, 37th Edition, General Chapter 941), the relative intensities between two samples of the same material can vary considerably due to "preferred orientation" effects. Anisotropic materials that adopt preferred orientations result in anisotropy in the distribution of properties such as elastic modulus, strength, ductility, toughness, electrical conductivity, and thermal expansion, as described, for example, in Kocks UF et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In Raman spectroscopy as well as XRPD, preferred orientation induces changes in the intensity distribution. The preferred orientation effect is especially pronounced for crystalline APIs with relatively large particle sizes.

[0011] "Distinctive peaks" refers to the presence of powder X-ray diffraction peaks that unambiguously identify 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol as the reference crystalline form (Form A). Typically, powder X-ray diffraction analysis is performed at ambient conditions in transmission geometry using a STOE STADI P diffractometer (CuKα1 radiation, primary monochromator, silicon strip detector, angular range 3-42 degrees 2-theta, total measurement time of approximately 30 minutes). Samples (approximately 10-50 mg) are prepared between thin polymer films and analyzed without further processing (e.g., grinding or sieving) of the material.

[0012] "Polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystal. Generally, reference is made throughout this specification to the polymorph 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol.

[0013] The term "halo-(C1-C6)-alkyl" means a (C1-C6)alkyl substituted by one or more, preferably one to five, "halo" atoms, as such terms are defined in this application. Halo(C1-C6)alkyl includes monohalo(C1-C6)alkyl, dihalo(C1-C6)alkyl, trihalo(C1-C6)alkyl, perhalo(C1-C6)alkyl, and the like, such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.

[0014] The term "halo-phenyl" means a halogen-substituted phenyl, wherein the halogens are selected from chlorine, bromine, iodine, and fluorine.

[0015] The term "(C1-C6)alkyl-phenyl" means a straight or branched chain hydrocarbon having from 1 to 6 carbon atoms as defined above attached to a phenyl or substituted phenyl group.

[0016] The term "halogen" or "halo", alone or in combination, means fluorine, chlorine, bromine or iodine, particularly iodine, chlorine or bromine, more particularly iodine and chlorine. The term "halo", in combination with another group, means substitution of the group with at least one halogen, particularly 1 to 5 halogens, particularly 1 to 4 halogens, i.e. 1, 2, 3 or 4 halogens. Particular halogens are iodine, bromine and chlorine, more particularly iodine and chlorine.

[0017] The term "tautomers" refers to constitutional isomers that undergo rapid interconversion such that they cannot be isolated independently.

[0018] The term "phase transfer catalyst" refers to a compound capable of transferring water-soluble anions to an organic phase. Phase transfer catalysts include tetraalkylammonium salts, phosphonium salts, and crown ethers. Examples of phase transfer catalysts include tetrasubstituted ammonium salts and trisubstituted ammonium salts that can form tetrasubstituted ammonium salts in situ. Tetrasubstituted ammonium salts include tetrabutylammonium, benzyltrimethylammonium, tetraethylammonium, cetyltrimethylammonium salts, and the counterion can be fluorine, chlorine, bromine, or iodine. Trisubstituted amines include triethylamine, tributylamine, benzyldiethylamine, and diisopropylethylamine.

[0019] The term "inorganic base" means an alkaline base such as an alkaline carbonate, an alkaline bicarbonate, an alkaline borate, an alkaline phosphate, an alkaline hydroxide, etc. More preferred aqueous basic solutions are selected from sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, in particular sodium hydroxide, potassium hydroxide and lithium hydroxide, more in particular sodium hydroxide, sodium borate or mixtures thereof. Most preferred aqueous basic solutions are solutions of sodium bicarbonate, sodium hydroxide or mixtures thereof.

[0020] The term "heterogeneous transition metal hydrogenation catalyst" refers to a transition metal hydrogenation catalyst that operates in a different phase than the substrate. In particular, the transition metal hydrogenation catalyst is in the solid phase. In particular, the reactants are in the liquid phase while the transition metal hydrogenation catalyst is in the solid phase. Transition metal hydrogenation catalysts include transition metals that form one or more stable ions with incompletely filled d-orbitals (i.e., Pd, Pt, Rh, Au, Ni, Co, Ru, Ir), especially noble metals such as Pd, Pt, Rh or Au. In these catalysts, the transition metal is especially "supported", meaning that the catalyst is dispersed on a second material that enhances its effectiveness. The "support" may simply be a surface on which the metal is spread to increase the surface area. Supports are porous materials with high surface areas, most commonly alumina or various types of carbon. Further examples of supports include, but are not limited to, silicon dioxide, titanium dioxide, calcium carbonate, barium sulfate, diatomaceous earth and clay. The metal itself may also act as a support if no other support is present. More specifically, the term "heterogeneous transition metal hydrogenation catalyst" includes, but is not limited to, Raney catalysts (e.g., Ra-Ni, Ra-Co,) Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, or Pt / C.

[0021] The term "salts" refers to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, formic acid, acetic acid, phosphoric acid, and organic acids selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, and in particular salts referred to salts formed with hydrochloric acid and citric acid.

[0022] The terms "hydroxyl" and "hydroxy", alone or in combination, refer to an --OH group.

[0023] The term "(C1-C6)alkoxy", alone or in combination, means a radical of the formula (C1-C6)alkyl-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, especially methoxy, with the meaning previously given to the term "(C1-C6)".

[0024] The term "acidic organic solution" refers to a solution of a solvent containing an organic acid having a pH of 1 to 4, particularly 2 to 3, and more particularly about 2.5. The pH of a solution is determined by the hydrogen ion content (H + ) is measured.

[0025] The term "about" when referring to a pH range means ±5%, and preferably ±0.1.

[0026] The term "inorganic acid" refers to an inorganic compound that can provide a proton according to the Bronsted definition and dissociate into a proton and a counterion in water at 25°C to give a solution having a neutral pH or less. Specific examples of inorganic acids are phosphoric acid (orthophosphoric acid), sulfuric acid, nitric acid, phosphinic acid, phosphonic acid, diphosphonic acid, hydrochloric acid, pyrophosphoric acid, metaphosphoric acid, and nitrous acid. These acids may be used in the form of metal salts, ammonium salts, and the like; in particular inorganic acid refers to hydrochloric acid.

[0027] The term "work-up" refers to an isolation and / or purification operation carried out after the reaction has been completed, which process may include treatment of the reaction mixture with a base or acid solution, addition of a solvent to extract or precipitate a particular compound, filtration, distillation, extraction, recrystallization or precipitation. In particular, "work-up" refers to the treatment of the reaction mixture with an acidic organic solution.

[0028] The term "organic acid" refers to an acid, i.e., an acid that, in an aqueous medium, has a cation or a proton H + or H3O + means a compound capable of releasing at least one (optionally unsaturated) linear or branched C1-C 20The organic acid comprises a hydrocarbon-based chain, or a (hetero)cycloalkyl or (hetero)aryl group, and at least one acid chemical functional group selected in particular from carboxyl COOH, sulfonyl SO3H, sulfinyl SO2H, and phosphoric acid PO3H2, and in particular "organic acid" refers to lactic acid, formic acid, citric acid, oxalic acid, malic acid, and tartaric acid, in particular acetic acid and citric acid, more in particular citric acid.

[0029] In particular, the preparation of the compound of formula I is carried out in the presence of a biphasic solvent mixture, an inorganic base and a phase transfer catalyst, and in the presence of an acidic organic solution during workup; The acidic organic solution is in particular selected from organic acids in solution, more in particular lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid, in particular citric acid and acetic acid, more in particular citric acid, the acidic organic solution has a pH of 1 to 4, in particular 2 to 3, more in particular about 2.5, and the concentration of the organic acid in the solution is 1% to 30%, in particular 5% to 20% about 10%.

[0030] In some embodiments, the organic acid is in a suitable solvent to form an acidic organic solution. Particularly suitable solvents include, but are not limited to, water, methanol, or ethanol, especially water.

[0031] In a more particular embodiment, the present invention provides the above process for preparing a compound of formula (I) or (I'), wherein a biphasic solvent mixture is used between water and any of the solvents selected from ethyl acetate, diethyl carbonate, diethyl ether, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, tetrahydrofuran, MeTHF or combinations thereof, particularly between water and ethyl acetate, n-propyl acetate, isopropyl acetate, diethyl carbonate or combinations thereof, more particularly between water and n-propyl acetate.

[0032] In a more particular embodiment, the present invention provides the above process, wherein the inorganic base is sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, in particular sodium hydroxide, potassium hydroxide and lithium hydroxide, more in particular sodium hydroxide.

[0033] In a more particular embodiment, the present invention provides the above process, wherein the phase transfer catalyst is selected from a quaternary ammonium salt, an organic phosphonium salt or a crown ether, particularly the tetrasubstituted ammonium salt comprises tetrabutylammonium, benzyltrimethylammonium, benzyltriethylammonium, ethyltributylammonium, methyltrioctylammonium, methyltributylammonium, propyltributylammonium, methyltricaprylammonium, tetraethylammonium, cetyltrimethylammonium salt, and the counter ion may be fluorine, chlorine, bromine or iodine, more particularly tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, and most particularly tetrabutylammonium iodide.

[0034] In another embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is as defined herein) 1. A process for the preparation of a compound of the formula a) Formula (IV) [ka] (In the formula, R 1 is as defined herein) with H2, particularly in the presence of a suitable heterogeneous transition metal hydrogenation catalyst, to produce a compound of formula (II), a salt thereof, a tautomer thereof or a mixture of tautomers thereof; b) Formula (II) [ka] (In the formula, R 1 is as defined herein) The compound Formula (III): [ka] wherein X is as defined herein. in the presence of an organic acid; The present invention provides a method comprising:

[0035] In another embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is as defined herein) 1. A process for the preparation of a compound of the formula (a) Formula (IV) [ka] (In the formula, R 1 is as defined herein) with H2, particularly in the presence of a suitable heterogeneous transition metal hydrogenation catalyst, to produce a compound of formula (II); b) Formula (II) [ka] (In the formula, R 1 is as defined herein) The compound Formula (III): [ka] wherein X is as defined herein. in the presence of an organic acid during the work-up step. The present invention provides a method comprising:

[0036] In a more particular embodiment, the present invention provides a method as described herein for the preparation of a compound of formula (I) or (I'), wherein the heterogeneous transition metal hydrogenation catalyst is a Raney catalyst (e.g., Ra-Ni, Ra-Co,) Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, or Pt / C, in particular Pd / C.

[0037] In a more particular embodiment, the present invention provides a method as described herein for the preparation of a compound of formula (I) or (I') bearing H2 in the presence of an inorganic acid, particularly hydrochloric acid.

[0038] The present invention relates to a compound of formula (I): [ka] (In the formula, R 1 is halogen, -OH, -NR a R b , C 1-6 Alkoxy, (C1-C6) alkyl, -O(O)CR c or -NR a C(O)R c and; R a and R b is H, (C1-C6) alkyl, C 1-6 independently selected from alkoxy, haloalkyl, phenyl, halophenyl, or alkylphenyl, or combinations thereof; R c is H, (C1-C6) alkyl, (C1-C6) alkoxy, -OH, C 1-6 halo-(C1-C6)alkyl, phenyl, halo-phenyl or (C1-C6)alkyl-phenyl). or a pharma- ceutically acceptable salt thereof, comprising: Formula (II) [ka] a compound of the formula (I), a salt thereof, a tautomer thereof or a mixture of tautomers thereof, Formula (III) [ka] where X is halogen, triflate or tosyl. in the presence of an organic acid. The present invention provides a method comprising:

[0039] In certain embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is -OH.

[0040] In a particular embodiment, the present invention provides a method for preparing a compound of formula (I') by reacting a compound of formula (II'), a salt thereof, a tautomer thereof or a mixture of tautomers thereof with a compound of formula (III') in the presence of an organic acid, particularly as defined herein (Scheme 1). Scheme 1: [ka]

[0041] In another embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is as defined herein) 1. A process for the preparation of a compound of the formula Formula (IV) [ka] (In the formula, R 1 is as defined herein) with H2, particularly in the presence of a suitable heterogeneous transition metal hydrogenation catalyst, to produce a compound of formula (II'), a salt thereof, a tautomer thereof or a mixture of tautomers thereof; b) Formula (II) [ka] The compound Formula (III) [ka] wherein X is as defined herein in the presence of an organic acid. and reacting the compound with The present invention provides a method comprising:

[0042] In certain embodiments, the present invention provides a method for preparing a compound of formula (II'), a salt thereof, a tautomer thereof, or a mixture of tautomers thereof from a compound of formula (IV') comprising reduction. (Scheme 2) Scheme 2: [ka]

[0043] The present invention provides a process for preparing compounds of formula (I') and (Ia) by reacting a compound of formula (II'), a salt thereof, a tautomer thereof, or a mixture of tautomers thereof, with a compound of formula (III') (Scheme 3).

[0044] In a particular embodiment, the present invention provides for the purification of the compound of formula (I') by acidic work-up to remove the undesired regioisomeric compound of formula (Ia). Surprisingly, it has been found that the use of acidic extraction carried out using an organic acid, in particular an acidic organic solution, within a particular pH range allows for the separation of the undesired isomer. Scheme 3: [ka]

[0045] In another embodiment, the present invention provides a compound of formula (I'): [ka] 1. A process for the preparation of a compound of the formula a) Formula (IV') [ka] with H2, particularly in the presence of a suitable heterogeneous transition metal hydrogenation catalyst, to produce a compound of formula (II'), a salt thereof, a tautomer thereof or a mixture of tautomers thereof; b) Formula (II') [ka] a compound of the formula (I), a salt thereof, a tautomer thereof or a mixture of tautomers thereof, Formula (III) [ka] wherein X is as defined herein in the presence of an organic acid. and reacting the compound with c) recrystallizing the compound of formula (I') from a suitable solvent; d) A process of jet milling the compound of formula (I'). The present invention provides a method comprising:

[0046] In a particular embodiment, the present invention provides a multi-step synthetic route consisting of four steps as shown in Scheme 4. Scheme 4: [ka]

[0047] wherein C is the recrystallization step of the compound of formula (I') using a suitable solvent (eg, isoamyl alcohol, iPrOAc / pentane, etc.) and step D is the jet milling process of the compound of formula (I').

[0048] In certain embodiments, the present application further discloses a method for preparing a compound of formula (IV') from a compound of formula (V) according to Scheme 5. Scheme 5: [ka]

[0049] Starting materials, reagents and catalysts that do not have their synthetic routes explicitly disclosed herein are generally available from commercial sources or can be easily prepared using methods known to those skilled in the art.For example, compounds of formula (V) and (IV) can be prepared according to the procedures described in WO2013 / 068306.

[0050] The present invention provides solid form A of compound of formula (I') characterized by an IR spectrum comprising the following peaks: 1132 cm -1 ,1092cm -1 ,1071cm -1 ±2cm -1 .

[0051] In certain embodiments, the present invention provides solid form A of compound of formula (I'), having peaks at the positions set forth in Table 1.

[0052] In certain embodiments, the present invention provides solid form A of compound of formula (I') having peaks at positions according to FIG. [Table 1]

[0053] In certain embodiments, the present invention provides an IR spectrum of Form A of compound of formula (I'). The ATR FTIR spectrum was recorded without sample preparation using a ThermoNicolet iS5 FTIR spectrometer equipped with an ATR accessory. The spectral range is 4000 cm -1 ~650cm -1 and the resolution is 2cm -1and 50 simultaneous additive scans were collected. Happ-Genzel apodization was applied. Using ATR FTIR, the relative intensities of the infrared band regions differ from those seen in transmission FTIR spectra using KBr disks or Nujolmal sample preparations. Due to the nature of ATR FTIR, the lower wavenumber bands are more intense than the higher wavenumber bands.

[0054] Peak picking was performed using Thermo Scientific Omnic 8.3 software using the automated "Find Peak" function. "Threshold" and "Sensitivity" were manually adjusted to obtain representative peak counts.

[0055] The present invention is -1 ,1573cm -1 ,1313cm -1 ±2cm -1 The present invention provides a solid form A of compound of formula (I') characterized by a Raman spectrum comprising a peak:

[0056] In certain embodiments, the present invention provides a Raman spectrum of Form A of compound of formula (I') having Raman peaks at the positions shown in Table 2.

[0057] In certain embodiments, the present invention provides solid form A of compound of formula (I') having peaks at positions according to FIG. [Table 2]

[0058] In certain embodiments, the present invention provides a Raman spectrum of Form A of compound of formula (I'). The FT-Raman spectrum was recorded without sample preparation using a Bruker MultiRam FT-Raman spectrometer equipped with a liquid N2-cooled germanium detector and a 1064 nm NdYAG laser. The spectral range is 4000 cm -1 ~100cm -1 and the resolution is 2cm -1and 2048 simultaneous additional scans were collected. The laser power was set at 300 mW and Blackman-Harris 4-Term apodization was applied.

[0059] Peak picking was performed using Thermo Scientific Omnic 8.3 software using the automated "Find Peak" function. "Threshold" and "Sensitivity" were manually adjusted to obtain representative peak counts.

[0060] The present invention is -1 , 1098cm -1 , 918cm -1 ±2cm -1 The present invention provides a solid amorphous form of the compound of formula (I'), characterized by an IR spectrum comprising a peak of:

[0061] In certain embodiments, the present invention provides an IR spectrum of an amorphous form of the compound of formula (I') having the following peaks:

[0062] In certain embodiments, the present invention provides an amorphous form of the compound of formula (I') having a peak at a position according to FIG. [Table 3]

[0063] In certain embodiments, the present invention provides an IR spectrum of the amorphous form of the compound of formula (I'). The ATR FTIR spectrum was recorded without sample preparation using a ThermoNicolet iS5 FTIR spectrometer equipped with an ATR accessory. The spectral range is 4000 cm -1 ~650cm -1 and the resolution is 2cm -1and 50 simultaneous additive scans were collected. Happ-Genzel apodization was applied. Using ATR FTIR, the relative intensities of the infrared band regions differ from those seen in transmission FTIR spectra using KBr disks or Nujolmal sample preparations. Due to the nature of ATR FTIR, the lower wavenumber bands are more intense than the higher wavenumber bands.

[0064] Peak picking was performed using Thermo Scientific Omnic 8.3 software using the automated "Find Peak" function. "Threshold" and "Sensitivity" were manually adjusted to obtain representative peak counts.

[0065] The present invention is 2961, 1607 cm -1 , 1514cm -1 ±2cm -1 The present invention provides a solid amorphous form of the compound of formula (I'), characterized by a Raman spectrum comprising a peak:

[0066] In certain embodiments, the present invention provides a Raman spectrum of an amorphous form of compound of formula (I') having the following peaks:

[0067] In certain embodiments, the present invention provides an amorphous form of the compound of formula (I') having a peak at a position according to FIG. [Table 4]

[0068] In certain embodiments, the present invention provides a Raman spectrum of the amorphous form of the compound of formula (I'). The FT-Raman spectrum was recorded without sample preparation using a Bruker MultiRam FT-Raman spectrometer equipped with a liquid N2-cooled germanium detector and a 1064 nm NdYAG laser. The spectral range is 4000 cm -1 ~100cm -1 and the resolution is 2cm -1and 2048 simultaneous additional scans were collected. The laser power was set at 300 mW and Blackman-Harris 4-Term apodization was applied.

[0069] Peak picking was performed using Thermo Scientific Omnic 8.3 software using the automated "Find Peak" function. "Threshold" and "Sensitivity" were manually adjusted to obtain representative peak counts.

[0070] In certain embodiments, the present invention provides a powder X-ray diffraction spectrum of the amorphous form of the compound of formula (I'). The X-ray diffraction pattern is recorded at ambient conditions in transmission geometry using a STOE STADI P diffractometer (CuKα radiation, primary Ge monochromator, Mythen 1K silicon strip detector, angular range 3°-42° 2-theta, measurement time 20 seconds per step). Samples are prepared and analyzed without further processing of the material (e.g., grinding or sieving).

[0071] As used herein, unless otherwise stated, XRPD measurements are made using copper Kα radiation at a wavelength of 1.54187 A. XRPD peaks reported herein are measured using Cu Kα radiation, X=1.54187 A, typically at a temperature of 25±3° C.

[0072] Measurement and evaluation of X-ray diffraction data is carried out using WinXPOW software (STOE&Cie GmbH, Darmstadt, Germany).

[0073] In certain embodiments, the present invention provides solid form A of compound of formula (I') having peaks at positions according to FIG.

[0074] The present invention provides solid form A of compound of formula (I'), characterized by an X-ray powder diffraction pattern (XRPD) having characteristic peaks at diffraction angles 2-theta of about 9.88, 11.54, 16.01, 16.26, 18.17, and 20.31.

[0075] In certain embodiments, the present invention provides solid form A of compound of formula (I') having peaks at positions according to FIG.

[0076] In certain embodiments, Form A is characterized by an XRPD diffraction pattern comprising the XRPD peaks at diffraction angles 2 theta shown in Table 5. [Table 5] TIFF2024542997000034.tif210156

[0077] In certain embodiments, the present invention provides a powder X-ray diffraction spectrum of Form A of compound of formula (I'). The X-ray diffraction pattern is recorded at ambient conditions in transmission geometry using a STOE STADI P diffractometer (CuKα radiation, primary Ge monochromator, Mythen 1K silicon strip detector, angular range 3°-42° 2-theta, measurement time 20 seconds per step). Samples are prepared and analyzed without further processing of the material (e.g., grinding or sieving).

[0078] Measurement and evaluation of X-ray diffraction data is carried out using WinXPOW software (STOE&Cie GmbH, Darmstadt, Germany).

[0079] Table 6 lists the relevant crystal structure data for Form A. The lattice constants, unit cell volumes and calculated densities are based on ambient temperature data. [Table 6]

[0080] The invention described herein demonstrates improvements in the reaction, particularly with respect to yield, solvent consumption, selectivity and work-up. EXAMPLES

[0081] The following examples are given to illustrate the invention and should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0082] Example 1: Synthesis of (3S)-1-(3-benzyl-5-tert-butyl-triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol [ka]

[0083] 3-Benzyl-5-tert-butyl-6H-triazolo[4,5-d]pyrimidin-7-one (47.0 kg, 1.0 equiv.) was suspended in acetonitrile (321 kg) and N,N-dimethylformamide (30.3 kg, 2.5 equiv.) was added. Oxalyl chloride (42.1 kg, 2.0 equiv.) was added within 30 min at 35° C., and then the mixture was aged at 35° C. After complete conversion, the reaction mixture was added to a biphasic mixture of toluene (205 kg) and 8% aqueous KH2PO4 (281 kg). After phase separation, the organic layer was washed with 5% aqueous NaHCO3 (282 kg). The organic phase was concentrated under reduced pressure and stripped with toluene to remove acetonitrile and residual water. N,N-diisopropylethylamine (27.9 kg, 1.3 equiv.) was added to this solution at 20° C., followed by a solution of (S)-3-hydroxypyrrolidine (15.5 kg, 1.07 equiv.) in ethanol (74 kg). The resulting reaction mixture was stirred at ambient temperature. After complete conversion, the organic phase was washed with water (140 kg) and the phases were separated. The organic phase was concentrated and n-heptane (372 kg) was added at 55° C. The solution was seeded at 45° C., aged for 1 h, cooled to 0° C. and aged for 4 h. The solid was filtered off, washed and dried under reduced pressure at 55° C. 50.0 kg of product was obtained.

[0084] Example 2: Synthesis of (3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol [ka]

[0085] (3S)-1-(3-benzyl-5-tert-butyl-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol (89.0 kg, 1.0 equiv.) was dissolved in 1-propanol (356 kg). 10% Pd / CE 101 NE / W (9.6 kg as is, 4.43 kg dry), water (215 kg) and 37% HCl (29.9 kg, 1.2 equiv.) were added and the suspension was hydrogenated at 60° C. and 8 barg H2 for 4 h. 10% Pd / CE 101 NE / W (4.8 kg as is, 2.21 kg dry) was then added and the suspension was further hydrogenated for 14-25 h. Upon complete conversion, the mixture was cooled to 20° C. and the pressure was released. The mixture was filtered and the reactor and filter cake were washed with water (366 kg).

[0086] To the filtrate, 28% NaOH (87 kg, 2.4 equiv.) was added and 1-propanol was removed by distillation under reduced pressure. 5-(chloromethyl)-1-methyltetrazole (35.2 kg, 1.05 equiv.), n-Bu4NI (9.3 kg, 0.10 equiv.) and n-propyl acetate (185 kg) were added. The biphasic mixture was warmed to 45° C. and stirred for 4 h. Upon complete conversion, the phases were allowed to settle and the aqueous layer was drained. The organic layer was extracted three times with 10% aqueous citric acid (3×445 kg) followed by washing with water (445 kg). The organic layer was filtered through a ZetaCarbon and ZetaPlus module and concentrated under reduced pressure. N-heptane (138 kg) was added at 65-70° C. The solution was seeded, aged for 1 h, cooled to 0° C. and aged for 2 h. The solid was filtered, washed with n-propyl acetate / n-heptane 2:1 (354 kg) and dried to give (3S)-1-(3-benzyl-5-tert-butyl-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol (45.0 kg) as a white solid.

[0087] Example 3: Recrystallization of (3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol [ka]

[0088] The crude compound of (3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol (44.0 kg) was dissolved in isoamyl alcohol (263 kg) at 75° C. The solution was filtered through a polish filter and the reactor was rinsed with isoamyl alcohol (36 kg). The solution was cooled to 54° C., seeded, and aged for 4 hours. The suspension was cooled to 0° C., aged for 12 hours, and filtered. The wet cake was washed with isoamyl alcohol / n-heptane 3:2 (73 kg) and n-heptane (73 kg). After drying under reduced pressure at 50°C, recrystallized (3S)-1-(3-benzyl-5-tert-butyl-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol (36.5 kg) was obtained as a white solid. The recrystallized (3S)-1-(3-benzyl-5-tert-butyl-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol was further jet milled in a fluidized bed opposed jet mill to obtain 35.0 kg of jet milled (3S)-1-(3-benzyl-5-tert-butyl-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ is a halogen, —OH, —NR ａ R ｂ , (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl, —O(O)CR ｃ or -NR ａ C(O)R ｃ and R ａ and R ｂ is H, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, C １－６ Hello (C １ -C ６ ) alkyl, phenyl, halo-phenyl or (C １ -C ６ ) alkyl-phenyl; R ｃ is H, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, —OH, C １－６ Hello (C １ -C ６ ) alkyl, phenyl, halo-phenyl or (C １ -C ６ ) alkyl-phenyl) or a pharmaceutically acceptable salt thereof, comprising: Formula (II) 【Chemistry 2】 a compound of the formula (I), a salt thereof, a tautomer thereof or a mixture of tautomers thereof, Formula (III): 【Transformation 3】 wherein X is halogen, triflate or tosyl. in the presence of an organic acid. A method comprising:

2. a) Formula (IV) 【Chemistry 4】 (In the formula, R １ is as defined in claim 1) The compound of ２ in the presence of a suitable heterogeneous transition metal hydrogenation catalyst to produce a compound of formula (II), a salt thereof, a tautomer thereof or a mixture of tautomers thereof; b) Formula (II) 【Transformation 5】 a compound of the formula (I), a salt thereof, a tautomer thereof or a mixture of tautomers thereof, Formula (III): 【Transformation 6】 wherein X is as defined in claim 1. in the presence of an organic acid; The method of claim 1 , comprising:

3. Formula (I') 【Transformation 7】 10. The method of claim 1 for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: Formula (II') 【Transformation 8】 a compound of the formula (I), a salt thereof, a tautomer thereof, or a mixture of tautomers thereof Formula (III): 【Chemistry 9】 wherein X is as defined in claim 1. in the presence of an organic acid. A method comprising:

4. Formula (I') 【Chemistry 10】 4. The method of claim 3 for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: a) Formula (IV') 【Chemistry 11】 The compound of ２ in the presence of a suitable heterogeneous transition metal hydrogenation catalyst to produce a compound of formula (II'), a salt thereof, a tautomer thereof or a mixture of tautomers thereof; b) reacting a compound of formula (II'), a salt thereof, a tautomer thereof or a mixture of tautomers thereof with a compound of formula (III) (wherein X is as defined in claim 1) in the presence of an organic acid; A method comprising:

5. The method of any one of claims 1 to 4, wherein the compound of formula (II') or (II) is the hydrochloride salt thereof.

6. The heterogeneous transition metal hydrogenation catalyst is a Raney catalyst (e.g., Ra—Ni, Ra—Co), Pd / C, Pd(OH) ２ / C, Au / TiO ２ , Rh / C, Ru / Al ２ O ３ , Ir / CaCO ３ 5. The method according to claim 2 or 4, wherein the catalyst is Pt / C, in particular Pd / C.

7. The method according to claim 2 or 4, wherein the reaction a) is carried out in the presence of an inorganic acid, in particular HCl.

8. The method of claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst.

9. The method of claim 1 , wherein the organic acid is in a suitable solvent to form an acidic organic solution.

10. 10. The method according to claim 9, wherein the suitable solvent is selected from water, methanol or ethanol, in particular water.

11. 10. The method of claim 9, wherein the acidic organic solution has a pH of 1 to 4, particularly 2 to 3, more particularly about 2.

5.

12. 2. The method of claim 1, wherein the organic acid is selected from lactic acid, formic acid, citric acid, oxalic acid, malic acid, or tartaric acid, in particular acetic acid or citric acid, more in particular citric acid.

13. 2. The method of claim 1, wherein the concentration of the acidic organic solution is from 1% to 30%, particularly from 5% to 20%, more particularly about 10%.

14. The method of claim 1, wherein the reaction is carried out in the presence of a two-phase solvent mixture.

15. 15. The method of claim 14, wherein the biphasic solvent mixture is between water and any of the solvents selected from ethyl acetate, diethyl carbonate, diethyl ether, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, tetrahydrofuran, MeTHF or combinations thereof, particularly between water and ethyl acetate, n-propyl acetate, isopropyl acetate, diethyl carbonate or combinations thereof, more particularly between water and n-propyl acetate.

16. The method of claim 1, wherein the reaction is carried out in the presence of an inorganic base.

17. 17. The process according to claim 16, wherein the inorganic base is sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, in particular sodium hydroxide, potassium hydroxide and lithium hydroxide, more in particular sodium hydroxide.

18. 9. The method of claim 8, wherein the phase transfer catalyst is selected from a quaternary ammonium salt, an organic phosphonium salt, or a crown ether, and in particular the quaternary ammonium salt can be a tetrabutylammonium salt, a benzyltrimethylammonium salt, a benzyltriethylammonium salt, an ethyltributylammonium salt, a methyltrioctylammonium salt, a methyltributylammonium salt, a propyltributylammonium salt, a methyltricaprylammonium salt, a tetraethylammonium salt, or a cetyltrimethylammonium salt, and wherein the counterion can be fluorine, chlorine, bromine, or iodine, more particularly tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, and most particularly tetrabutylammonium iodide.

19. A crystalline solid form A of the compound of formula (I'), characterized by an X-ray powder diffraction pattern (XRPD) having characteristic peaks at diffraction angles 2-theta of about 9.88, 11.54, 16.01, 16.26, 18.17, and 20.31, wherein the XRPD measurement is performed using copper Kα radiation at a wavelength of 1.54187 Å.

20. Approximately 8.10, 9.88, 10.68, 11.54, 12.57, 12.79, 13.51, 14.38, 15.69, 16.01, 16.26, 18.17, 18.89, 19.53, 20.31, 20.93, 21.52, 21.69, 22.07, 22.45, 23.32, 24.40, 25.77, 26.79, 20. The crystal of claim 19, further characterized by an X-ray powder diffraction pattern (XRPD) having characteristic peaks at diffraction angles 2-theta of 27.03, 27.20, 27.34, 27.52, 27.94, 28.98, 29.44, 29.89, 30.20, 30.41, 31.88, 32.57, and 33.

86.

21. Peak: 1132 cm －１ , 1092 cm －１ , 1071 cm －１ ±2cm －１ 21. The crystal of claim 19 or 20, further characterized by an IR spectrum comprising:

22. Formulas (I') and (Ia) 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, comprising: Formula (II') 【Chemistry 13】 a compound of the formula (I), a salt thereof, a tautomer thereof or a mixture of tautomers thereof, Formula (III) 【Chemistry 14】 wherein X is as defined in claim 1. reacting with a compound of A method comprising:

23. Formula (V) 【Chemistry 15】 with hydroxypyrrolidine to give a compound of formula (IV') 【Chemistry 16】 4. The method of claim 3, further comprising preparing a compound of formula:

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