NZ746469B2 - Synthesis of indazoles - Google Patents
Synthesis of indazoles Download PDFInfo
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- NZ746469B2 NZ746469B2 NZ746469A NZ74646917A NZ746469B2 NZ 746469 B2 NZ746469 B2 NZ 746469B2 NZ 746469 A NZ746469 A NZ 746469A NZ 74646917 A NZ74646917 A NZ 74646917A NZ 746469 B2 NZ746469 B2 NZ 746469B2
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- New Zealand
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- 238000003786 synthesis reaction Methods 0.000 title description 16
- 150000002473 indoazoles Chemical class 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 96
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- -1 2-substituted indazole Chemical class 0.000 claims abstract description 38
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- 238000006243 chemical reaction Methods 0.000 claims description 60
- 239000002904 solvent Substances 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
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- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 9
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Abstract
The present invention relates to a novel method of preparing a 2-substituted indazole of structure:(I), to intermediate compounds, and to the use of intermediate compounds for the preparation of said 2-substituted indazole.
Description
SYNTHESIS of INDAZOLES The present invention relates to a novel method of preparing a 2-substituted le with the following structure (I) , to a novel rphic B form of said tituted indazole, to intermediate compounds, and to the use of intermediate compounds for the preparation of said 2-substituted indazole.
The present ion relates to the ation of substituted indazole of formula (I) which inhibits interleukin-1 or-associated kinase 4 (IRAK4).
Human IRAK4 (interleukin-1 or-associated kinase 4) plays a key role in the activation of the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inflammation-inhibiting substances. IRAK4 is expressed by a multitude of cells and mediates the signal transduction of Toll-like ors (TLR), except TLR3, and receptors of the interleukin (IL)-1ß family consisting of the IL-1R tor), IL-18R, IL-33R and IL-36R (Janeway and Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. l., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).
Neither IRAK4 knockout mice nor human cells from patients lacking IRAK4 react to stimulation by TLRs (except TLR3) and the IL-1ß family (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie, et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
The binding of the TLR ligands or the ligands of the IL-1ß family to the respective receptor leads to recruitment and binding of MyD88 [Myeloid differentiation primary response gene (88)] to the receptor. As a , MyD88 interacts with IRAK4, resulting in the formation of an active complex which interacts with and activates the kinases IRAK1 or IRAK2 (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009). As a result of this, the NF (nuclear factor)-kB signalling pathway and the MAPK (mitogen-activated protein kinase) signal pathway is activated (Wang, Deng, et a|., Nature, 2001). The activation both of the NF-kB signalling pathway and of the MAPK signalling pathway leads to processes associated with different immune processes. For example, there is increased sion of various inflammatory signal molecules and enzymes such as cytokines, chemokines and COX-2 (cyclooxygenase-2), and increased mRNA stability of inflammation-associated genes, for example COX-2, IL-6, IL-8 (Holtmann, Enninga, et a|., l of Biological Chemistry, 2001; Datta, Novotny, et a|., The Journal of Immunology, 2004). Furthermore, these ses may be associated with the proliferation and differentiation of particular cell types, for e monocytes, macrophages, dendritic cells, T cells and B cells (Wan, Chi, et a|., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007).
The central role of IRAK4 in the pathology of various inflammatory disorders had already been shown by direct comparison of wild-type (WT) mice with genetically modified animals having a kinase- inactivated form of IRAK4 (IRAK4 KDKI). IRAK4 KDKI animals have an improved clinical picture in the animal model of multiple sclerosis, sclerosis, myocardial infarction and Alzheimer's e (Rekhter, ke, et a|., Biochemical and Biophysical ch Communication, 2008; Maekawa, Mizue, et a|., Circulation, 2009; Staschke, Dong, et a|., The Journal of Immunology, 2009; Kim, io, et a|., The Journal of Immunology, 2011; Cameron, Tse, et a|., The Journal of Neuroscience, 2012). Furthermore, it was found that deletion of IRAK4 in the animal model protects t virus- induced myocarditis an improved anti-viral reaction with simultaneously d systemic inflammation (Valaperti, Nishii, et a|., Circulation, 2013). It has also been shown that the expression of IRAK4 correlates with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et a|., PLoS ONE, 2014) As well as the essential role of IRAK4 in congenital immunity, there are also hints that IRAK4 influences the differentiation of what are called the Th17 T cells, components of adaptive immunity.
In the absence of IRAK4 kinase activity, fewer |Lproducing T cells (Th17 T cells) are ted compared to WT mice. The inhibition of IRAK4 is therefore suitable for prophylaxis and/or treatment of atherosclerosis, type 1 diabetes, rheumatoid arthritis, spondyloarthritis, lupus erythematosus, sis, vitiligo, chronic inflammatory bowel disease and viral disorders, for example HIV (human immunodeficiency virus), hepatitis virus (Staschke, et a|., The Journal of Immunology, 2009; Zambrano-Zaragoza, et a|., ational Journal of Inflammation, 2014).
Owing to the central role of IRAK4 in the MyD88—mediated signal cascade of TLR5 (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4 can be utilized for the laxis and/or treatment of ers mediated by the receptors mentioned. TLR5 and also components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, metabolic syndrome, diabetes, osteoarthritis, Sjogren syndrome and sepsis (Scanzello, Plaas, et al. Curr Opin Rheumatol, 2008; Roger, Froidevaux, et al, PNAS, 2009; Gambuzza, Licata, et al., Journal of mmunology, 2011; Fresno, Archives Of Physiology And Biochemistry, 2011; Volin and Koch, J Interferon Cytokine Res, 2011; Akash, Shen, et al., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Clinical e, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013; Talabot-Aye, et al., Cytokine, 2014). Skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, allergic contact dermatitis, acne inversa and acne vulgaris are associated with the IRAK4-mediated TLR signalling pathway (Gilliet, Conrad, et al., Archives of Dermatology, 2004; Niebuhr, Langnickel, et al., Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali, et al., Am J Clin Dermatol, 2010; Viguier, Guigue, et al., Annals of Internal Medicine, 2010; Cevikbas, Steinhoff, J Invest ol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Dispenza, t, et al., J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of ology, 2012; Gresnigt and van de Veerdonk, Seminars in Immunology, 2013; Selway, Kurczab, et al., BMC ology, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013; Wollina, Koch, et al. Indian Dermatol Online, 2013; Foster, Baliwag, et al., The Journal of Immunology, 2014).
Pulmonary disorders such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary ension also show an association with various TLR-mediated signalling pathways. The pathogenesis of the pulmonary disorders may be either infectiously mediated or non-infectiously ed ses ez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004; Jeyaseelan, Chu, et al., Infection and Immunity, 2005; Seki, Tasaka, et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; ath, Carlo, et al., The FASEB Journal, 2011; l, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang, et al., PLoS One, 2013; Freeman, Martinez, et al., atory ch, 2013; Dubaniewicz, A., Human Immunology, 2013). TLR5 and also IL-1R family members are also ed in the pathogenesis of other matory disorders such as Behcet's disease, gout, lupus erythematosus, adult-onset Still's disease and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, and transplant rejection, and so inhibition of IRAK4 here is a suitable therapeutic approach (Liu-Bryan, Scott, et al., Arthritis & tism, 2005; Christensen, Shupe, et al., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen, et al., The Journal of Immunology, 2010; Rakoff-Nahoum, Hao, et al., ty, 2006; Heimesaat, Fischer, et al., PLoS ONE, 2007; , Yagi, et al., J Gastroenterol, 2010; Shi, Mucsi, et al., Immunological s, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther, 2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Walsh, Carthy, et al., Cytokine & Growth Factor Reviews, 2013; Zhu, Jiang, et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013). Because of the mechanism of action of the compound of formula (I), they are also suitable for prophylactic and/or eutic use of the TLR and IL-1R family-mediated disorders endometriosis and atherosclerosis (Akoum, Lawson, et al., Human Reproduction, 2007; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; , Bourcier, et al., Journal of Reproductive Immunology, 2008; Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Sikora, Mielczarek-Palacz, et al., American Journal of Reproductive Immunology, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Khan, Kitajima, et al., Journal of Obstetrics and Gynaecology Research, 2013; Santulli, Borghese, et al., Human Reproduction, 2013; i, f, et al., Cell Mol Life Sci, 2013) In on to the disorders already mentioned, IRAK4-mediated TLR processes have been described in the pathogenesis of eye disorders such as retinal ischaemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis (Kaarniranta and Salminen,J Mol Med (Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, mental Eye Research, 2010; Kezic, Taylor, et al., J Leukoc Biol, 2011; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012; Guo, Gao, et al., Immunol Cell Biol, 2012; Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao, et al., Investigative Ophthalmology & Visual Science, 2014).
Because of the central role of IRAK4 in diated ses, the tion of IRAK4 also enables the treatment and/or prevention of cardiovascular and neurological disorders, for example myocardial reperfusion damage, dial infarction, ension (Oyama, Blais, et al., Circulation, 2004; Timmers, Sluijter, et al., Circulation Research, 2008; Fang and Hu, Med Sci Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin Sci (Lond), 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013;), and also Alzheimer's disease, stroke, craniocerebral trauma and Parkinson's disease (Brough, Tyrrell, et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng, et al., The Journal of logy, 2011; Lim, Kou, et al., The American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms, 2013; Noelker, Morel, et al., Sci. Rep., 2013; Wang, Wang, et al., Stroke, 2013).
Because of the involvement of TLR signals and IL-1 receptor family-mediated signals via |RAK4 in the case of us and pain, for example cancer pain, post-operative pain, inflammation-induced and chronic pain, there may be assumed to be a therapeutic effect in the indications mentioned through the inhibition of |RAK4 (Wolf, Livshits, et al., Brain, Behavior, and ty, 2008; Kim, Lee, et al., ike Receptors: Roles in Infection and athology, 2009; del Rey, Apkarian, et al., Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha, et al., European Journal of Pharmacology, 2012; Kwok, Hutchinson, et al., PLoS ONE, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; Chopra and , J Neuroimmune Pharmacol, 2013; David, Ratnayake, et al., Neurobiology of Disease, 2013; Han, Zhao, et al., Neuroscience, 2013; Liu and Ji, rs Arch., 2013; Stokes, Cheung, et al., Journal of Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013; Liu, Y. Zhang, et al., Cell Research, 2014).
This also applies to some oncological disorders. ular lymphomas, for example ABC-DLBCL (activated B-cell diffuse large-cell B-cell lymphoma), mantle cell lymphoma and Waldenstrom's disease, and also chronic lymphatic leukaemia, melanoma and liver cell carcinoma, are characterized by mutations in MyD88 or changes in MyD88 activity which can be d by an |RAK4 inhibitor (Ngo, Young, et al., Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Srivastava, Geng, et al., Cancer Research, 2012; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013; (Liang, Chen, et al., Clinical Cancer Research, 2013). In addition, MyD88 plays an important role in pendent tumours, and so |RAK4 inhibitors are also suitable for treatment thereof (Kfoury, A., K. L. Corf, et al., Journal of the National Cancer Institute, 2013).
Inflammatory disorders such as CAPS (cryopyrin-associated periodic syndromes) including FCAS ial cold autoinflammatory syndrome), MWS (Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory e) and CONCA ic infantile, neurological, cutaneous, and lar) syndrome; FMF ial rranean fever), HIDS (hyper-IgD syndrome), TRAPS (tumour necrosis factor receptor 1-associated periodic m), juvenile idiopathic arthritis, adult-onset Still's disease, Adamantiades-Behcet's disease, rheumatoid tis, osteoarthritis, keratoconjunctivitis sicca and Sjogren syndrome are treated by blocking the IL-1 signal pathway; therefore here, too, an |RAK4 inhibitor is suitable for treatment of the diseases mentioned (Narayanan, Corrales, et al., Cornea, 2008; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, European Journal of logy, 2011; Gul, Tugal-Tutkun, et al., Ann Rheum Dis, 2012; Pettersson, Annals of MedicinePetterson, 2012; Ruperto, Brunner, et al., New England Journal of Medicine, 2012; Nordstrom, Knight, et al., The Journal of Rheumatology, 2012; Vijmasi, Chen, et al., Mol Vis, 2013; Yamada, Arakaki, et al., Opinion on Therapeutic Targets, 2013). The ligand of IL- 33R, IL-33, is involved particularly in the pathogenesis of acute kidney failure, and so the tion of IRAK4 for prophylaxis and/or treatment is a suitable eutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011). Components of the IL-1 receptor family are ated with myocardial infarction, different ary disorders such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS), and so prophylactic and/or therapeutic action is to be expected in the indications mentioned through the tion of IRAK4 (Kang, Homer, et al., The Journal of Immunology, 2007; |maoka, Hoshino, et al., European Respiratory Journal, 2008; Couillin, Vasseur, et al., The Journal of Immunology, 2009; Abbate, Kontos, et al., The American Journal of logy, 2010; Lloyd, Current Opinion in Immunology, 2010; s, Bracke, et al., European Respiratory Journal, 2011; Haenuki, Matsushita, et al., Journal of Allergy and Clinical logy, 2012; Yin, Li, et al., Clinical & Experimental Immunology, 2012; Abbate, Van l, et al., The American Journal of Cardiology, 2013; Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Bunting, Shadie, et al., BioMed Research International, 2013; Byers, Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J Interferon ne Res, 2013; Martinez-Gonzalez, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., l of y and Clinical Immunology, 2014; , Ketelaar, et al., Molecular Immunology, 2014).
The prior art discloses a multitude of IRAK4 inhibitors (see, for example, Annual Reports in nal Chemistry (2014), 49, 117 — 133).
US8293923 and U520130274241 disclose IRAK4 inhibitors having a tituted indazole structure.
There is no description of 2-substituted les.
W02013/106254 and /153588 disclose 2,3-disubstituted indazole derivatives.
W02007/091107 describes 2-substituted indazole derivatives for the treatment of Duchenne muscular dystrophy. The compounds disclosed do not have 6-hydroxyalkyl substitution.
W02015/091426 describes indazoles, the alkyl group thereof substituted at position 2 by a carboxamide structure.
W02015/104662 disloses indazole compounds of formula (I) (R2 " [\l Z] R3) . 0 which are therapeutically useful as kinase inhibitor, particularly |RAK4 inhibitors, and ceutically acceptable salts or stereoisomers thereof that are useful in the treatment and prevention of diseases or er, in particular their use in es or er mediated by kinase enzyme, particularly |RAK4 enzyme.
W02016/083433, published after the priority date of the present application, describes novel substituted indazoles of the following formula / O R" N 'N R HO \ R2 R3 methods for the production thereof, use thereof alone or in combinations to treat and/or prevent diseases, and use thereof to produce drugs for treating and/or preventing diseases, in particular for treating and/or preventing endometriosis and triosis-associated pain and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria, and dyschezia, lymphomas, rheumatoid arthritis, spondyloarthritides (in particular psoriatic spondyloarthritis and Bekhterev's e), lupus matosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver diseases, insulin resistance, tumor diseases, and psoriasis.
The novel |RAK4 inhibitor shall be especially le for treatment and for prevention of proliferative and inflammatory disorders characterized by an overreacting immune system. Particular mention should be made here of inflammatory skin disorders, cardiovascular disorders, lung ers, eye disorders, autoimmune disorders, gynaecological disorders, especially endometriosis, and cancer.
A s was to be disclosed that would allow the production of indazole (I) on technical scale with special focus on the following requirements: 0 Scale-up/scalability of the manufacturing process 0 High regioselectivity in the N2-alkylation reaction 0 Avoidance of chromatographic separation and purification steps 0 Final processing via crystallization 0 Final adjustment of the polymorphic form using Class 3 ts (in accordance with FDA guidelines) Remarkably, a process could be disclosed that meets all of the requirements mentioned above.
This invention describes the preparation of compound (I) via a surprisingly highly selective alkylation on N2: F | F ‘N O F HN N O Ho \N. —\_SI, (l) Preparations of N2-substituted indazoles have been previously described in the literature. These procedures, however, have considerable disadvantages rendering them unsuitable for technical scale. It is possible to selectively prepare stituted indazoles via complex sequences of synthetic steps, which involve no direct alkylation step. These sequences, however, are long and tedious and e considerable losses ultimately resulting in a low total yield. ore, synthetic routes which allow a direct preparation of N2-substituted les from 1H-indazole precursors via direct and selective alkylation at N2 are most interesting. At the attempt of directly alkylating the 1H- le precursor of the general formula (II), generally a mixture made up of the N1- (Illa) and N2- alkylated (III) somers is obtained. 5 R 5 R 4 \ O 4 \ O R N R4 \ O R N HN HN HN + \ / 1 N \N HO \/N_R "0 N/ HO / N H N\ 1 (Illa) (III) Indazole and its derivatives, a typical class of ic N-heterocycles, have sparked significant interest in synthetic and medicinal chemistry due to their diverse biological activities. Furthermore, diverse heterocyclic structures could be accessed from indazole-derived N-heterocyclic carbenes.
Among indazoles, N1/N2-substituted indazoles are widely used as anticancer, anti-inflammatory, anti-HIV, and antimicrobial drugs. Generally, the synthesis of N2-substituted indazoles involves cyclization procedures from miscellaneous starting materials. Unfortunately, general ologies remain scarce in the literature. Therein, only moderate yields were obtained.
With respect to the t state of technology, several publications are known and will be discussed in the following section. None of the published procedures feature reaction conditions that lead to a direct NZ-selective alkylation using methyl vinyl sulfone as alkylating agent. There is either no conversion observed or the ivity and yield are low. The problem of the prior art procedures consists in the use of relatively simple alkylating agents g no labile functional groups. These agents are mostly attached to the azole via nucleophilic substitution of their halides, tosylates, triflates or mesylates. When more functionalized moieties are used, yield and selectivity decrease dramatically. In the following section, the reasons are presented why these prior art procedures are not applicable to the challenge at hand: not work for the case at hand (methyl vinyl sulfone). The preparation of the corresponding triflate from e.g. the alcohol is not possible, as its decomposition occurs instantly. In addition, only a simple substrate with no onality in the side-chain was used. 2. S. R. Baddam, N. U. Kumar, A. P. Reddy, R. Bandichhor, edron Lett. 2013, 54, 1661: Only simple indazoles without functional groups were used in the reaction. Only methyl trichloroacetimidate was used as alkylating agent. Attempts to er acid-catalyzed ions to the ive introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed. This procedure cannot easily be scaled up. 3. Q. Tian, Z. Cheng, H. H. Yajima, S. J. Savage, K. L. Green, T. Humphries, M. E. Reynolds, 5.
Babu, F. Gosselin, D. Askin, Org. s Res. Dev. 2013, 17, 97: The preparation of a THP- ether with preference for N2 of the indazole is ted. This reaction proceeds via a different mechanism and does not represent a general method, since the THP-ether product cannot be easily ted further. Furthermore, selective methods for protection of indazoles using p-methoxybenzyl derivatives under acidic ions are presented.
Attempts to transfer these conditions to the selective uction of a methyl ethyl sulfone side at the N2 position of an indazole core ure via reaction with methyl vinyl sulfone failed.
D. J. Slade, N. F. Pelz, W. Bodnar, J. W. Lampe, P. S. Watson, J. Org. Chem. 2009, 74, 6331: THP-ether and PMB-protection using acidic conditions (PPTS: pyridinium para- esulfonate), see scheme 2; attempts to er these conditions to ive introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed.
M. Cheung, A. Boloor, J. A. Stafford, J. Org. Chem. 2003, 68, 4093: Highly reactive and highly carcinogenic Meerwein salts were used as alkylating agents (see scheme 2). This method only comprises simple non-functionalized ethyl and methyl Meerwein salts. The reaction proceeds in polar ethyl acetate at ambient temperature. These conditions could not be transferred to selective introduction of a methyl ethyl sulfone side chain at the N2 on of an indazole core structure via reaction with methyl vinyl sulfone.
Scheme 1: N-alkylation of 1H-indazoles Etgoerg {?mEiGAQ ItW©::M J00 2003 4093 0U O BrTY%N*m QUE:M"MN; :m.T50: WBYNCI/WmpSWW—PSE ,5 g~TsOHz pntoiuenasmfanic acid PPTS: Pyridiniam p—tofuanamifenate 8: PMBQH 8%" K m "m. x. CC¥3 (4; W. l N «W l N but-«PMS / hf 142535;};4 My» N" #PTS "a. "bf $939.13 mittens. H (Silvia; 9MB: pkmemaxyhenzyi J00 2083. 6331 4 5*: ‘N’N CWMG "K ":4 3—5: RzN H THF RgN PCT int. Apph 28116434TQ Scheme 2: N-alkylation methods of les known from prior art 6. M.-H. Lin, H.-J. Liu, W.-C. Lin, C.-K. Kuo, T.-H. Chuang, Org. Biomol. Chem. 2015, 13, 11376: The procedure is N2-selective; however, it cannot be scaled up with Ga and Al metal being used in stoichiometric amounts. Under the described on conditions, Broensted acids are formed which react with the corresponding metals to give hydrogen gas. Only relatively simple substrates are used as alkylating agents (no sulfone group). When more functionalized substrates were used, a significant decrease in yield was observed. Attempts to transfer these ions to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed. 7. G. Luo, L. Chen, G. hick, J. Org. Chem. 2006, 71, 5392: 2-(Trimethylsilyl)ethoxymethyl de (SEM-Cl) in THF was used for substitution on N2 of indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl e side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed. The corresponding products described in this publication are ethers and are not related to our target molecule. The use of highly carcinogenic 2-(trimethylsilyl)ethoxymethyl chloride (SEM- Cl) as well as benzyloxymethyl chloride (BOM-Cl) does not represent a scalable option for obtaining the target compound. 8. A. E. Shumeiko, A. A. Afon’kin, N. G. Pazumova, M. L. Kostrikin, Russ. J. Org. Chem. 2006, 42, 294: Only very simple substrates were used in this method. No significant ivity is reported. A slight preference for N1-alkylation at the indazole was observed. 9. G. A. Jaffari, A. J. Nunn, J. Chem. Soc. Perkin 1 1973, 2371: Very simple substrates and only methylation agents were used. A more complex substrate as e.g. a combination of formaldehyde with protonated methanol resulted in only N1-substituted product (ether).
. V. G. Tsypin et al., Russ. J. Org. Chem. 2002, 38, 90: The reaction proceeds in sulfuric acid and chloroform. Only conversions of simple indazoles with adamanthyl alcohol as sole alkylating agent are described. These conditions could not be transferred to the selective uction of a methyl ethyl e side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone. 11. S. K. Jains et al. RSC Advances 2012, 2, 8929: This publication features an example of N- benzylation of indazoles with low selectivity towards N1-substitution. This KF-/alumina- catalyzed method cannot be used efficiently for the synthesis of N2-substituted indazoles.
Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core ure via on with methyl vinyl sulfone failed. 12. L. Gavara et al. Tetrahedron 2011, 67, 1633: Only relatively simple substrates were used. The described acidic THP-ether ion and benzylation in refluxing THF are not applicable to our substrate. Attempts to er these ions to selective introduction of a methyl ethyl sulfone side chain at the ition of an indazole core structure via reaction with methyl vinyl sulfone failed. 13. M. Chakrabarty et al. Tetrahedron 2008, 64, 6711: N2-alkylation was observed but N1- alkylated product was obtained preferentially. The described conditions of using aqueous sodium hydroxide and phase transfer st in THF are not applicable to 2-substituted les. Attempts to transfer these conditions to our system (methyl vinyl e) failed. 14. M. T. Reddy et al. Der Pharma Chem/ca 2014, 6, 411: The on proceeds in the corresponding alkylating agent as solvent. Only the use of highly reactive ethyl bromoacetate as alkylating agent is reported. There are no data on the selectivity. These conditions are not applicable to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2 on of an indazole core structure via reaction with methyl vinyl sulfone failed. . 5. N. Haydar et al. J. Med. Chem. 2010, 53, 2521: Only simple non-functionalized alkyl groups are described (methyl, isopropyl, isobutyl). Cesium carbonate was used as base and the reaction ed in a e of N1- and N2-alkylated products. These conditions are not applicable to compounds as 2-indazoles. Attempts to transfer these ions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via on with methyl vinyl sulfone failed. 16. Zh. V. Chirkova et al. Russ. J. Org. Chem. 2012, 48, 1557: In this method, relatively simple substrates are ted with potassium carbonate as base in DMF. Mixtures of N1- and N2- alkylated products are obtained. The conditions are not applicable to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via on with methyl vinyl sulfone failed. 17. C. Marminon et al. Tetrahedron 2007, 63, 735: The ortho-substituent R in position 7 at the indazole directs the alkylation towards N2 via ing N1 from electrophilic attacks. The ions, sodium hydride as base in THF, are not applicable to a selective synthesis of N2- substituted indazoles as they preferentially result in alkylation at N1 in e of a substituent in position 7 of the indazole. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone . 18. D. A. Nicewicz et al. Angew. Chem. Int. Ed. 2014, 53, 6198: Only simple substrates were used.
This method describes a photochemical reaction that cannot easily be scaled up and is not applicable to a general, ive synthesis of N2-substituted indazoles Very specific styrene derivatives are used under radical reaction conditions. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the ition of an indazole core structure via reaction with methyl vinyl sulfone failed. 19. A. Togni et al. Angew. Chem. Int. Ed. 2011, 50, 1059: This publication solely describes a special type of substituent (hypervalent iodine as trifluoromethylation reagent in combination with acetonitrile). This special case is not applicable to a general, ive synthesis of N2-substituted indazoles.
. L. Salerno et al. European J. Med. Chem. 2012, 49, 118: This publication describes the conversion of indazoles in an oc—bromoketone melt. The reaction conditions cannot be transferred to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain at the N2- position of an indazole core structure via reaction with methyl vinyl sulfone failed. 21. K. W. Hunt, D. A. Moreno, N. , C. T. Clark, G. Kim, Org. Lett. 2009, 11, 5054: This publication essentially describes an ective alkylation method with addition of different bases. Simple substrates were used. Attempts to transfer these ions to the selective introduction of a methyl ethyl sulfone side chain at the ition of an indazole core structure via reaction with methyl vinyl sulfone failed. 22. J. Yang et al. sis 2016, 48, 48, 1139: This publication describes an N1-selective base- catalyzed aza-Michael reaction. No substitution at N2 was observed. Attempts to transfer these conditions to the ive introduction of a methyl ethyl sulfone side chain at the N2- position of an indazole core structure via reaction with methyl vinyl sulfone failed. 23. P. R. Kym et al. J. Med. Chem. 2006, 49, 2339: Essentially N1-alkylations are described. ts to transfer these conditions to selective introduction of a methyl ethyl e side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed. 24. A. J. Souers et al. J. Med. Chem. 2005, 48, 1318: This publication also describes the use of potassium carbonate as base. This method proceeds mainly with preference for substitution at N1 and is therefore not applicable to a selective sis of N2-substituted indazoles. ts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed. 25. P. Bethanamudi et al. E-Jouma/ of Chemistry 2012, 9, 1676: The use of ionic liquids along with potassium carbonate as base results in es of N1- and N2-alkylated indazoles with low yields. The selectivity shows a cy towards substitution at N1. The use of ionic liquid cannot be transferred to our system. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed. 26. 5. Palit et al. Synthesis 2015, 3371: The reaction bed herein is essentially non-selective with a slight ence of substitution at N1 of the indazole. Only simple, non-functionalized alkyl groups were used. Sodium hydride and similarly strong bases were used. Attempts to transfer these conditions to ive introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core ure via reaction with methyl vinyl sulfone failed.
It was shown that the compound of the formula (I) can be synthesized analogously to methods previously published in the literature via e.g. direct alkylation using 2-bromoethyl methyl sulfone.
However, a mixture of N1- and N2-alkylated products was obtained with a ence for the N1- somer (N1 : N2 = ca. 2 : 1). Desired N2-alkylated indazole of formula (I) could also be obtained in a very low yield as described in W02016/083433, hed after the priority date of the present application, with the following reaction procedure: 160 mg (0.44 mmol) of N-[6-(2-hydroxypropan-Z-yl)-1H-indazolyl]—6-(trifluoromethyl)pyridine carboxamide (Intermediate 5-1) were suspended together with 182 mg of potassium carbonate and 36 mg of ium iodide in 1.0 ml of DMF, and the mixture was stirred at room temperature for min. Then, 123 mg of oethyl methyl e were added and the mixture was stirred at room temperature overnight. Water was added, the mixture was extracted twice with ethyl acetate and the extracts were washed with saturated aqueous sodium chloride solution, filtered through a hydrophobic filter and concentrated. Purification of the residue by preparative HPLC gave 20 mg (9.7 % yield) of the title compound.
Consumptive preparative HPLC proved indispensable for an ent separation of the N1-/N2- regioismers. The aim of this new inventive process consists in avoiding HPLC separation via achieving a better selectivity in the reaction in favour of tution at N2 followed by a new inventive recrystallization procedure.
The present invention provides a process for preparing nds of the general formula (III) from compounds of the general formula (II) R5 R5 l l 4 \ O 4 \ O R N R N H N H N —’ / ’N—R1 HO \’N HO N \N (II) (III) in which R1 2-(methylsulfonyl)ethyl; R4 is romethyl, trifluoromethyl or methyl; and R5 is hydrogen or fluorine; with preferably R4 = trifluoromethyl and R5 = H: / / F l F \\_s"O F I \ O F ‘ O N N F H N F H N \ / N —’ N ,o H o H. H O \N —\—S\ (V) (I) Unexpectedly, we found that methyl vinyl sulfone (IX) can replace the corresponding alkyl halide in the reaction. The use of vinyl sulfones for alkylation of indazoles at N2 is surprisingly unprecedented and therefore highly inventive. Upon reaction of compounds of the general formula (II) with methyl vinyl sulfone in toluene, optionally with addition of an organic base, such as N,N-diisopropylethylamine or triethylamine, the desired NZ-isomer according to formulas (III) and (I) is obtained with very high ivity. The selectivity in the on mixture was found to be in n 8:1 to 10:1 in favor of the N2-alkylated product (III) as well as (I). The undesired N1- substituted by-product remained mainly in the mother liquor after work-up of the reaction mixture y < 2 % after crystallization).
The reaction works without the use of an additional base. The compound of the l formula (II) or (V) is placed in a reaction vessel. 1- 2 equivalents of methyl vinyl sulfone are added and the on mixture is heated at reflux in toluene (ca. 110°C internal temperature). The reaction can be performed using 5 to 30 volumes of toluene relative to the amount of starting material (II) or (V).
Preferably, the reaction is run with 8 to 15 volumes and best with 10 volumes of toluene. The time of the reaction spans 12 to 100 h. It is run preferably between 48 to 72 h. In some cases, it has proven advantageous to add the methyl vinyl sulfone in portions to the reaction mixture, e.g. start with 1 equivalent and then add 0.3 equivalents after 24 h and r 0.3 equivalents after 48 h.
Optionally, the reaction works with catalytic amounts of an organic auxiliary base, e.g. N,N- diisopropylethylamine. The nd of the general formula (II) or (V) is placed in a on vessel along with the solvent (toluene or xylene) and catalytic amounts of an orqanic base.
An auxiliary organic base, e.g. N,N-diisopropylethylamine, N,N-dicyclohexylamine or triethylamine can be added with s between 0.01 and 1 equivalent. The reaction proceeds with 0.01 to 0.1 equivalents of base.
It is noteworthy and certainly surprising that using chloro- or ethylbenzene as t at the same reaction ature or xylene as solvent at higher reaction temperature, alkene (IV) was obtained in higher amounts via ation of water. Strikingly, this elimination was observed in only very small amounts when e was used as solvent. Therefore, e must be considered as an inventive solvent with unique and completely unanticipated properties regarding this specific reaction. The formation of (IV) was also found to depend on the quality of (V). When (V) was used that had a higher than usual water content (1 wt% instead of <05 wt%), a more significant amount of (IV) was obtained in the reaction. It is noteworthy, that formation of the elimination product (VI) can be efficiently suppressed by removing excess water from (V) via azeotropic lation with toluene and by addition of catalytic amounts of an organic base, in particular N,N-diisopropylethylamine. ion ure: After completion of the reaction, toluene can be partly distilled off the reaction mixture. Subsequently, a second solvent, such as methyl tert—butyl ether (MTBE) or diisopropylether (preferably methyl tert-butyl ether) can be added to the reaction e. Upon addition of the respective solvent, the product precipitates almost quantitatively from the mixture. In some cases, it proved useful to seed the mixture with small amounts of crystals in order to obtain a reproducible crystallization. After cooling and ged stirring of the resulting suspension, the product is isolated via filtration, washed with solvent and dried at 50 to 60°C under vacuum resulting lly in 59 to 67% yield. The purity of the crude product typically amounts to 95 to 97 % (area) with less than 2 % (area) of N1-regioisomer.
It must be emphasized that the reaction of a substituted vinyl sulfone for a directed highly selective preparation of N2-functionalized indazoles is novel, without precedence in the literature and therefore a scientifically highly significant invention for the preparation of such substitution patterns.
The ation of GMP material, which will also be used in clinical trials, requires an additional purification step. Moreover, since the active pharmaceutical ient will be used for tion of a pharmaceutical composition, such as a tablet, a procedure is required that reproducibly furnishes the identical crystal habit. Surprisingly, this could be realized using ethanol or isopropanol as solvent for recrystallization. Ethanol is the preferred solvent. The compound is therefore first dissolved in acetone and subsequently passed h a particle filter (GMP filtration). Then, a solvent swap from acetone to ethanol is performed via distillation. Distillation is continued until a final volume of 6 to 7 volumes of ethanol ve to the input material is reached. The distillation is cancelled when the boiling point of l has been reached (ca. 77-78 °C) ensuring that all acetone was distilled off.
The mixture is then , stirred and the crystallized product is isolated via filtration and dried under vacuum at elevated temperature. The yield of the crystallization is lly > 90%. Product that is obtained from this llization procedure possesses the desired polymorphism properties required for preparation of a pharmaceutical composition, such as a tablet. The product displays a very high purity as well as a very high content. The most important analytical data for typical batches are given in Table 1: Table 1: Analytical data of batches examples as shown in Table 7 Purity (HPLC) 2 99% (area) Content (assay for use) 2 97.7% (weight) Ethanol < 0.25% (weight) Pd < 1 ppm The polymorph obtained via the above described crystallization procedure displays good stability during storage. It can also be easily micronized without losing its crystal properties.
The preparation of compounds according to the general formula (II) as well as (V) is described in F | F \N O F HN HO N'N In the hed patent application prepared via reaction of the methyl ester compound according to formula (VI): F | F \N O F HN ’0 N, using a solution of methylmagnesium e in diethylether. After work-up, the crude product is subjected to a column chromatographic cation furnishing compound according to formula (V) in 45 %yield.
W02016/083433, hed after the priority date of the present application, describes a synthesis route for the preparation of the compound according to formula (V) as well, starting from the compound according to formula (VI) by a Grignard reaction by using suitable alkylmagnesium halides, for example methylmagnesium chloride or methylmagnesium bromide in THF or in diethyl ether or else in mixtures of THF and diethyl ether.
This procedure is not suitable for production of the compound of formula (V) on technical scale due to the following drawbacks: 0 The use of diethylether must be avoided due to its low ignition point and its highly explosive potential. 0 The relatively costly methylmagnesium bromide was used instead of the more common methylmagnesium chloride, which is easier to procure. 0 Chromatographic separations should be avoided on technical scale as they usually require a massive uneconomical consumption of organic solvents. 0 No crystallization procedure has been described. According to the usual practice in research laboratories, the compound of formula (V) was evaporated until dryness. This operation is not feasible on technical scale. 0 The yield is sfactory: for technical purposes, a yield of at least 75 % should be achieved.
Surprisingly, it was found that the compound of formula (V) could be prepared with a significantly higher yield when magnesium de and lithium de (2:1) in THF were used instead.
The reactions proceeded with less byproducts which, using the method bed in WO 91426 and W02016/083433 as well, had to be removed via tedious column chromatography. The reaction was found to d best with THF as solvent. 6 to 10 equiv. methylmagnesium chloride (ca. 3 M in THF) and 3 to 5 equivalents lithium chloride are d and kept at -10 to 0°C. Within 1 to 3 h, preferably 2 h, the compound according to a (VI) is dropped to the mixture as solution in THF. The reaction mixture is stirred for 5 to 30 min at the indicated temperature range (-10 °C to 0 °C) and subsequently quenched by being poured into water. The resulting mixture is stirred vigorously. The pH of the mixture is then adjusted to app. 4 via addition of a mineral or organic acid (preferably citric acid) and ethyl acetate is added. Phases were separated and the organic phase was washed several times with brine (aqueous sodium chloride solution). The resulting organic solution was subjected to a solvent swap with toluene via distillation. During this process, the nd according to formula (V) started to crystallize and could be isolated via filtration. The precipitate was dried at elevated temperature (50 - 60°C) under . Typically, yields at this stage were in the range of 80 to 96% and purities between 95 to 99 area% (HPLC).
For the preparation of material with current good manufacturing gractice (cGMP) quality, it proved beneficial to y stir this product in a mixture of isopropanol/water (1 : 1; 2 to 10 volumes relative to input material). The material is stirred for 1 to 5 h, preferably 3 h. It is then ted and washed twice with small amounts of a 1 : 1 panol/water mixture. The product is dried at elevated temperature (50 - 60 °C) under . Typically, yields > 90% and purities > 97 area% (HPLC) are In the following examples in the experimental section, a variant (see example #2, variant #3) is also described in which, after treatment with ted charcoal, a solvent swap directly to isopropanol is performed. The product is crystallized by addition of water. In this way, the product is directly obtained with very high purity.
The preparation of the compound ing to formula (VI) has also been described in the patent application 211904) was coupled with the aniline-like compound of formula (VIII) (methylamino-1H- indazolcarboxylate; CAS no.: 10003734) using 1-[bis(dimethylamino)methylene]—1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (CAS no.: 1488931) as ng agent.
Amide (VI) was obtained with 84% yield.
/ HZN F | ‘N F ‘N O + | x0 N' F OH 0 (VII) (VIII) F | F \N O F HN ’0 N' Due to process safety reasons, an ling of uronium-based ng reagents is not possible because of their explosive potential. Therefore, an alternative coupling method had to be found.
The safe and scalable method for the preparation of like compound of formula (VI) is based on the use of T3P -tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; CAS no.: 68957 8) as coupling agent.
The reaction proceeds smoothly and furnishes amide-like compound of formula (VI) with high yields.
In a one-pot process, carboxylic acid-like compound of formula (VII) (best used with a slight shortage relative to aniline (VIII), ca. 0.90 - 0.95 equivalents) is placed along with 1.5 equivalents N,N- diisopropylethylamine in 16 volumes THF. Subsequently, 2 equivalents T3P (50 wt% solution in ethyl acetate) are slowly added at 0 to 5 °C. The reaction mixture is additionally stirred for 2 to 4 h, preferably 2 h at 0 to 5 °C.
The mixture was then quenched with water, its pH adjusted with sodium carbonate aq. solution to app. 7.4 and the THF/ethyl acetate mixture was y led off (200 mbar, 45 - 50°C internal ature). Subsequently, water and ethanol were added and the pH was adjusted to app. 7.0 by adding sodium carbonate aq. solution. The mixture was stirred 1 to 5 h, preferably 1 to 2 h, at 50°C, then cooled to 20 to 25°C and stirred for 10 to 30 min. The product was isolated via filtration and subsequently washed with a mixture of ethanol and water and finally dried under vacuum at 45°C.
With this process, typically very high yields between 95 to 96% were obtained. The purity was in all cases > 98 area% (HPLC).
In some cases, especially when aniline-like compound of formula (VIII) of poor optical quality (e.g. dark brown color) was used as starting material, it proved useful to m a treatment with activated charcoal. This ure is bed in the following section: Crude amide (VI) was dissolved in a mixture of methanol and THF (2 : 1) and activated al was added. The mixture was heated to 60 to 65°C for 1 to 1.5 h. The activated charcoal was filtered off and the filtrate was trated (down to 2 volumes relative to input material). Water was added and the product precipitated, was ed, washed and dried at 55 to 60 °C (under vacuum).
Synthesis of compounds of formulas (VII) and (VIII) have been described in the literature and both are commercially available in large quantities.
For compound according to formula (VII): Cottet, Fabrice; Marull, Marc; Lefebvre, r; Schlosser, Manfred, European Journal of Organic Chemistry, 2003 , 8 p. 1559 – 1568; Carter, Percy H.; Cherney, Robert J.; Batt, Douglas G.; Duncia, John V.; Gardner, Daniel S.; Ko, Soo S.; Srivastava, Anurag S.; Yang, Michael G. Patent: US2005/54627 A1, 2005 ; Ashimori; Ono; Uchida; Ohtaki; Fukaya; Watanabe; Yokoyama Chemical and Pharmaceutical Bulletin, 1990 , vol. 38, 9 p. 2446 – 2458.
For compound according to a (VIII): Nissan Chemical Industries, Ltd.; CHUGAI SEIYAKU KABUSHIKI KAISHA, EP2045253 A1, 2009.
Evaluation of the total process: Scheme 2 depicts the total synthesis of pure t of formula (I) from aniline-like compound of formula (VIII). Product of formula (I) is ed with a purity of > 99 area % (HPLC). When calculating with the best yields achieved for each step, a total yield of 50% is ed. This also includes the installation of the final crystal form.
Scheme 2: Total synthesis of pure product of formula (I) from the aniline-like compound according to formula (VIII) When comparing this total yield with the published prior art data: 1. amide coupling (preparation of compound according to formula (VI)): 84% yield; 2. Grignard reaction followed by tographic cation: 45% yield; 3. alkylation with 2-bromoethyl methyl sulfone analogously to methods known in the literature followed by chromatographic purification: 9.68% yield; the ages of the new process become very clear: With the method known from the prior art and as described above, a total yield of only 3.7% could be achieved with the installation of the final crystal form not included.
To de, the new inventive s furnishes compound ing to formula (I) with a > 13 times higher total yield as compared to the prior art. It, moreover, includes the directed and ucible preparation of the targeted polymorph for production of a pharmaceutical composition, such as a tablet.
It must be emphasized that the reaction of a substituted vinyl e for a directed highly selective preparation of N2-functionalized indazoles is novel, without precedence in the literature and therefore a highly significant invention for the preparation of such substitution patterns.
Hence, in a first aspect, the present invention relates to a method of preparing a compound of formula (I) via the following steps shown in reaction scheme IA, vide infra: Scheme IA: Preparation of compound of formula (I) from compound of formula (VIII) as starting material in which R ents an alkyl group, such as a methyl, ethyl or n-propyl group for example, or an aryl group, such as a phenyl group for example, and aromatic arbon solvent is a solvent such as toluene or xylene for example.
In an embodiment of the first aspect, the present invention relates to a method of preparing a compound of formula (I) via the following steps shown in reaction scheme I, vide infra: Scheme I: Preparation of compound of formula (I) from nd of formula (VIII) as ng material In an embodiment of the first aspect, the present invention relates to a method of preparing a compound of formula (I): comprising the following step (A): wherein a compound of formula (V): is allowed to react with a vinyl e compound of formula (IX’): (IX') in which R represents an alkyl group, such as a methyl, ethyl or n-propyl group for example, or an aryl group, such as a phenyl group for example, ally in an aromatic hydrocarbon solvent, such as toluene or xylene for example, preferably at the reflux temperature of said solvent, thereby providing said compound of formula (I).
In an embodiment of the first aspect, the present invention relates to a method of preparing a compound of formula (I) as described supra, wherein said aromatic hydrocarbon t is toluene.
In an ment of the first aspect, the present invention relates to a method of preparing a compound of formula (I) as described supra, wherein said compound of formula (V): is prepared by the following step (B): wherein a nd of formula (VI): is allowed to react with a reductive methylating agent, such as a methylmetallic agent, such as a methylmagnesium halide, such as methylmagnesium chloride for example, optionally in the presence of an alkali metal halide, such as m chloride for e, thereby providing said compound of formula (V).
In an embodiment of the first aspect, the present invention relates to a method of preparing a compound of formula (I) as described supra, wherein said compound of formula (VI): (VI) is prepared by the following step (C): wherein a compound of a (VIII): (VII) (VIII) is allowed to react with a compound of formula (VII): (VII) optionally in the presence of an c base, particularly a weak organic base, such as a ry amine, such as isopropylethylamine for example, optionally in the presence of a coupling agent, such as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) for e, thereby providing said compound of formula (VI).
In a further embodiment of the first aspect, the present invention relates to a method of preparing a nd of formula (I) as described supra, n said compound of formula (I) is purified by crystallization, particularly from a solvent such as ethanol or isopropanol, for example.
In a variant of said further embodiment of the first aspect, said solvent is ethanol.
In a variant of said further embodiment of the first aspect, said solvent is isopropanol.
In an embodiment of the first aspect, the present invention relates to a method of preparing a compound of formula (I) as described supra, wherein said compound of formula (I) is in the form of polymorph (B).
In ance with a second aspect, the present invention relates to polymorph (B) of the compound of formula (I): (I) , as prepared by the method as described supra.
In accordance with a third aspect, the present invention relates to polymorph (B) of the compound of formula (I): (I) .
In accordance with an embodiment of the third aspect, the present ion relates to said polymorph (B) as described supra, having an XRPD peak maxima ta] (Copper (Cu)) as follows: Table 2: XRPD of polymorph B of compound (I) tions [Peak maximum °2Theta] Polymorph B 24. 9 Figure 1 shows the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) of the nd of formula (I) in the polymorphic form B.
In accordance with a fourth aspect, the present invention relates to the use of a nd selected from: (V) , (VI) , (VII) (VIII) , (VII) , for preparing a compound of formula (I): (VI) (I) , or polymorph B of the nd of formula (I) as described supra, by the method as described supra.
In accordance with a fifth aspect, the present invention relates to the use of a vinyl sulfone compound of a (IX’): (IX') in which R represents an alkyl group, such as a , ethyl or n-propyl group for example, or an aryl group, such as a phenyl group for example, for preparing a compound of formula (I): (I) , or polymorph B of the compound of formula (I) as described supra.
In an embodiment of the fifth aspect, the present invention relates to use wherein said vinyl compound of formula (IX’) is methyl vinyl sulfone.
Methods Method A Device: Agilent Technologie 1260 Infinity with 1290 Infinity Sampler & t 1100 Series Zorbax SB-AQ, 50*4,6 mm, 1,5 um Buffer: Ammonium dihydrogen phosphate pH: 2.4 Acetonitrile 0 min. 5% buffer 8.3 min 80% buffer 11 min. 80% buffer 210 nm / 4 nm 1.2 ml / min.
Method B tus 1. Agilent Technologies, HPLC 1290 Infinity (with DAD): Ultra-High performance liquid chromatograph thermostatically controlled column oven, UV- detector and data evaluation system 2. Stainless steel column Length: 5 cm Internal diameter: 2.1 mm Filling: SB-Aq Rapid Resolution HD, 1.8 um Reagents 1. Acetonitrile, for the HPLC 2. ydrofuran, for the HPLC 3. Water, analytical grade 3. Phosphoric acid 85%, analytical grade Test solution Dissolve the sample nd of formula (I) in a tetrahydrofuran in a concentration of 0.5 mg/ml. (e. g. ve approx. 25 mg sample compound of a (I), accurately weighed in acetonitrile 50 ml) Calibration solution Dissolve the reference standard nd* in acetonitrile in a concentration of 0.5 mg/ml (e.g. dissolve approx. 25 mg reference standard, accurately weighed, in acetonitrile 50 ml). * reference standard compound means the compound, which has to be analyzed, as highly pure compound, i.e. >97 area% HPLC Control solution Prepare a control solution that is cal with the calibration solution. onally, the control solution contains small amounts of the organic impurities.
Detection sensitivity solution Prepare a solution containing the component Solbrol P (CAS-no.: 943; propyl 4-hydroxybenzoate) (RT approx. 2.80 min) diluted to a concentration of 0.76 ug/ml.
HPLC conditions The above described conditions are for example. To achieve l separations, they should, if necessary, be d to the technical possibilities ofthe chromatograph and the properties of the respective column.
Eluent A. water: tetrahydrofuran (v : v) 9 : 1, then add 0.1% phosphoric acid 85% B. Acetonitrile: tetrahydrofuran 9 : 1 Flow rate 0.8 mL/min Temperature ofthe column oven 40°C Temperature ofthe sample chamber room ature Detection Measuring wavelength: 220 nm Bandwidth: 6 nm Injection volume 2.0 uL Draw Speed 200 uL/min Needle Wash Solvent for flush port: ydrofuran Datenrate 10 Hz Cell Dimension 10 mm Equilibration time 10 min (at starting conditions) TIme [min]' ' 0AA 0A: B Gradient 0 95 5 1 85 15 4 80 20 6 4O 60 8 20 80 12 20 80 Runtime ofthe togram 12 min Calculation ofassay(content) The assay is calculated using linear regression and taking into account the sample weight, assay and weight of the reference standard, with a validated chromatographic data system (e.g. r).
GC-HS Residual solvent analysis via headspace gas chromatography (GC-HS) Agilent 6890 gas chromatograph with split-injection and FID (column: Restek in Sil MS; length: m; internal diameter: 0.18 mm; df= 1 um). Injector temp 160°C, flow 1.2 ml/min (H2) Split Ratio 18, oven Temp 40°C n) — 14°C/min — 70°C — 90°C/min — 220°C (1.69 min). or: temp 300°C, 400 ml/min (synth air), 40 ml/min (H2), 30 ml/min (N2), rate 20 Hz.
Perkin Elmer Turbomatrix 40 headspace sampler: oven 80°C, needle 150°C, transfer line 160°C, system pressure 140 kPa, equilibration time 32 min, pressurization 4.0 min, injection time 0.04 min (Sampler) 0.05 min (GC).
Sample tration: 20 mg substance in 2 ml DMF X-ray crystallography: measurement conditions : Anode material Cu K-Alpha1 [A] 1,54060 Generator settings 40 mA, 40 kV y beam monochromator focussing X-ray mirror Rotated sample Yes Scan axis Gonio Start Position [°2Th.] 2.0066 End Position [°2Th.] 37.9906 Working Examples The following examples illustrate the present invention.
Preparation of N-{6-(2-Hydroxypropan-Z-yl)[2-(methylsulphonyl)ethyl]-2H-indazolyl} (trifluoromethyl)pyridine-Z-carboxamide (I) Example #1 Methyl 5-({[6-(trifluoromethyl)pyridinyl]carbonyl}amino)-1H-indazolecarboxylate (VI) 2000 g (10.46 mol) methyl 5-amino-1H-indazolecarboxylate, 1899 g (9.94 mol) 6-(trifluoromethyl)pyridinecarboxylic acid und 2028 g (15.69 mol) N,N-diisopropylethy|amine are mixed in 14.2 kg THF. At 0 to 5°C, 13.3 kg of a on of T3P in ethyl acetate (50 wt%) is added dropwise within 30 min. Stirring is continued for 2 h at the same temperature.
Work-Up: The reaction mixture is warmed to ambient temperature (20°C). 3000 g of water are added while the temperature is kept at 20 to 25 °C. Stirring is continued for 10 min. The pH is adjusted to ca. 7.4 (7 - 8) using 4 N aq. sodium carbonate solution. Stirring is continued for 10 min. If necessary the pH is again adjusted to 7.4 using 4 N aq. sodium carbonate solution.
The solvents (THF/ethyl acetate) are ated under reduced pressure (appr. 200 mbar, 45 - 50°C internal temperature) until the limit of stirring is reached. A mixture of 4.7 kg ethanol and 14.0 kg water is added and the pH is again adjusted to pH 7.4 (7 - 8) using 4N aq. sodium carbonate on.
The mixture is stirred for 1 h at 50 °C, uently cooled to 20 to 25 °C. Stirring is continued for min at the same temperature. The precipitated crystals are filtered, washed with a mixture of l and water (1.3 kg ethanol with 4 kg water) and dried under vacuum in a drying oven (45°C, N2 flux, at least 12 h).
According to the above described procedure four s using 2 kg of starting material (methyl -amino-1H-indazolecarboxylate) were produced in the cal laboratory: Yields: Batch #1: 3476 g (95%) Batch #2: 3449 g (95%) Batch #3: 3476 g (95%) Batch #4: 3494 g (96%) The purities of all batches were determined to be > 98 area% (HPLC).
HPLC (Method A): Rt = 6.5 min.
MS (ESI pos): m/z = 365 (M+H)+ 1H NMR (500 MHz, DMSO-d6): 8 [ppm]: 3.98 (s, 3 H), 8.21 (d, 1H), 8.25 (s, 1H), 8.31 (s, 1H), 8.39 (t, 1H), 8.48 (d, 1H), 9.16 (s, 1H), 12.57 (s, 1H), 13.45 (br s, 1H). 1H NMR (300 MHz, DMSO-d6): 8 [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (br s, 1 H).
Example #2 N-[6-(2-hydroxypropany|)-1H-indazo|y|](trif|uoromethyl)pyridine-Z-carboxamide (V) In the following section, ent variants of the reaction procedure and work-up are described.
These procedures are oriented at the given conditions in the respective technical plants.
The following experiments were performed at the exclusion of water and air using inert gas (N2 or Variant #1 50 g (137.255 mmol) of methyl 5-({[6-(trifluoromethyl)pyridiny|]carbonyl}amino)-1H-indazole- oxylate (VI) were dissolved in 800 ml THF. Under normal pressure (1 atm) ca. 300 ml THF were distilled off at 70 °C. The solution was then cooled to 0 to 3°C.
The solution was kept at this temperature and added dropwise within 120 min to a cooled mixture of 457.5 ml (1372.6 mmol) methylmagnesium chloride 3 M in THF and 29.1g lithium chloride (686.3 mmol) at 0 to 3°C. After the addition was completed, a sample was taken out of the mixture and ted to HPLC analysis showing that conversion was completely done. The mixture was poured carefully over 25 min at Oto 3°C into 500 ml 1/2-sat. aq. sodium chloride solution (attention: exothermic! During the first 50 ml a strong rise in temperature to 29 °C was observed!). A suspension was ed which dissolved when 358 ml 20 wt% aq. citric acid were added (pH dropped from 8.08 to 4.28). ng was continued for 10 min at 20 to 25°C. 500 ml of ethyl acetate were added and stirring was ued for 10 min. The phases were separated. The mulm was added to the organic phase. 5 g of activated charcoal were added to the organic phase.
The e was heated to 78°C (internal temperature), stirred for 30 min at that temperature and subsequently cooled to 50°C (internal temperature). The warm solution was filtered over celite and washed twice with 125 ml ethyl acetate. The mixture was concentrated to ca. 150 ml at ambient pressure (1 atm) and 110°C. 350 ml of toluene were added and 200 ml were distilled off at ambient pressure (1 atm) and 110°C. The product precipitated. At 60°C internal temperature, 200 ml n-heptane were added over 45 min. The mixture was cooled to 0 to 3°C and stirred for 2 h at this ature. The product was ed and washed twice with a mixture of 50 ml toluene/n-heptane (1 : 1). The precipitated product was dried in a drying oven at 40°C and mbar for > 48 h.
Yield: 39.42 g (78.83%, purity 97.84 area% HPLC) HPLC (Method A): Rt = 5.8 min.
MS (ESIpos): m/z = 365 (M+H)+ 1H-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H). 13 batches were produced following the procedure of variant #1. The table 3 below summarizes the respective yields. The reactions were performed at 1 kg scale with regard to the use of methyl -({[6-(trifluoromethyl)pyridinyl]carbonyl}amino)-1H-indazolecarboxylate (VI) as starting material. In most cases, two of batches were united after treatment with activated al: Table 3: Yields obtained for batches 1 to 13 of synthesis of (V) from (VI) Yield [kg] *) single batch Variant #2 g (82.4 mmol) methyl 5-({[6-(trifluoromethyl)pyridinyl]carbonyl}amino)-1H-indazole carboxylate (VI) were dissolved in 480 ml THF. Under normal pressure (1 atm) ca. 180 ml THF were distilled off at 70°C. The mixture (slight suspension) was then cooled to 0 to 3°C.
The solution was kept at this temperature and added dropwise within 120 min to a cooled mixture of 274.5 ml (823.5 mmol) methylmagnesium chloride 3M in THF and 17.5g lithium chloride (411.8 mmol) at 0 to 3°C. 15 min after the addition was completed, a sample was taken out of the mixture and subjected to HPLC analysis showing that (VI) was completely converted.
The mixture was poured lly over 15 min at 0 to 3°C into 300 ml of water (attention: rmic! During the first 50 ml a strong rise in ature was observed!). 310 ml 20 wt% aq. citric acid were added (pH dropped to 4.05). Stirring was continued for 60 min at 20 to 25°C. 300 ml of ethyl acetate were added and stirring was continued for 30 min. The phases were separated. The mulm was added to the c phase. The c phase was washed twice with 450 ml of water. The organic phase was concentrated to 350 ml at 65 °C (internal temperature) and ambient pressure (1 atm). 250 ml ethyl acetate were added. 6g of activated charcoal were added to the organic phase. The mixture was heated to 65 °C (internal temperature), stirred for 120 min at that temperature and subsequently cooled to 50 °C (internal temperature). The warm solution was filtered over celite and washed twice with 125 ml ethyl acetate. The mixture was concentrated to ca. 150 ml at ambient pressure (1 atm) and 110 °C. 300 ml of e were added and 200 ml were distilled off at ambient pressure (1 atm) and 110 °C. The product itated. At 60 °C internal temperature, 200 ml n-heptane were added over 45 min. The e was cooled to 0 - 3 °C and stirred for 2 h at this temperature. The product was filtered and washed twice with a mixture of 50 ml toluene/n-heptane (1:1). The precipitated product was dried in a drying oven WO 86689 2017/059744 at 40 "C and 20 mbar for >48 h.
Yield: 24.0 g (80%, purity: 95.8 area% HPLC) HPLC (Method A): Rt = 5.8 min.
MS (ESI pos): m/z = 365 (M+H)+ lH-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H).
Variant #3 g (82.4 mmol) methyl 5-({[6-(trifluoromethyl)pyridinyl]carbonyl}amino)-1H-indazole carboxylate (VI) were dissolved in 600 ml THF. Under normal pressure (1 atm) ca. 150 ml THF were distilled off at 70 "C. The mixture (slight suspension) was then cooled to 0 - 3 "C.
The solution was kept at this temperature and added dropwise within 120 min to a cooled mixture of 274.5 ml (823.5 mmol) methylmagnesium chloride 3 M in THF and 17.5 g (411.8 mmol) lithium chloride at 0 - 3 "C. The dropping funnel was rinsed twice with 10 ml THF. 15 min after the addition was complete, a sample was taken out of the mixture and subjected to HPLC analysis showing that (VI) was completely converted. The mixture was poured carefully over 10 min at 0 - 3 "C into 300 ml of water tion: exothermic! During the first 50 ml a strong rise in ature to 25 "C was observed!). 250 ml 20 wt% aq. citric acid were added (pH dropped from 8 to 4). Stirring was continued for 30 min at 20 - 25 "C. 300 ml of ethyl acetate were added and stirring was continued for 10 min. The phases were separated. The mulm was added to the c phase. The organic phase was washed twice with 200 ml of 1 wt% sodium chloride aq. solution. The phases were separated. The organic phase was concentrated to 250 ml at 65 "C (internal temperature) and ambient pressure (1 atm). 150 ml ethyl acetate and 6 g of activated charcoal were added to the organic phase. The mixture was heated to 65 "C (internal temperature), stirred for 120 min at that temperature and subsequently cooled to 50 "C nal temperature). The warm solution was filtered over celite and washed twice with 50 ml ethyl acetate. The mixture was trated to ca. 100 ml at ambient pressure (1 atm) and 110 "C. 300 ml of isopropanol were added. 300 ml were distilled off at ambient pressure (1 atm) and 110 "C. 300 ml isopropanol were added again and led off (ca. 355 ml) at 110 "C. The resulting suspension was cooled to 20-25 "C. 45 ml water were added over 45 min. The mixture was stirred for 1 h. The precipitated product was ed and washed with 50 ml of a water/isopropanol (1:1) mixture. The precipitated product was dried in a drying oven at 50 "C and 20 mbar for >48 h.
Yield: 24.9 g (83 %, purity: 97.84 area% HPLC) HPLC (Method A): Rt = 5.8 min.
MS (ESI pos): m/z = 365 (M+H)+ lH-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H).
Variant #4 This variant was used for the production of technical batches at kg scale (>10 kg) (see table 4). 60 g (164.7 mmol) methyl 5-({[6-(trifluoromethyl)pyridinyl]carbonyl}amino)-1H-indazole carboxylate (VI) were dissolved in 1500 ml THF. Under normal pressure (1 atm) ca. 600 ml THF were distilled off at 70 "C. The mixture (yellow solution) was then cooled to 0 - 3 "C.
The solution was kept at this temperature and added dropwise within 120 min to a cooled mixture of 550 ml (1647.1 mmol) methylmagnesium chloride 3 M in THF and 35 g (823.5 mmol) lithium de at 0 - 3 "C. 15 min after the addition was complete, a sample was taken out of the mixture and subjected to HPLC analysis g that (VI) was completely converted. The mixture was poured carefully over 15 min at 0 - 3 "C into 600 ml of water (attention: exothermic! During the first 50 ml a strong rise in temperature was observed!). 600 ml 20 wt% aq. citric acid were added (pH dropped to 4). Stirring was continued for 30 min at 20-25 "C. The phases were separated. The organic phase was washed twice with 400 ml of 1 wt% sodium de aq. solution. The mulm was added to the organic phase. The phases were separated. The organic phase was concentrated to 700 ml at 65 "C (internal temperature) and ambient pressure (1 atm). 500 ml ethyl acetate and 12 g of activated charcoal were added to the c phase. The mixture was heated to 65 "C (internal temperature), stirred for 120 min at that temperature and uently cooled to 50 "C (internal temperature). The warm solution was filtered over celite and washed twice with 200 ml ethyl acetate. Concentration was ued under reduced pressure (200 mbar). A solvent swap to e was performed (remaining volume ca. 850 mL).
The resulting suspension was cooled to 0 - 3 "C. The precipitated product was filtered and washed with 50 ml of toluene. The precipitated product was dried in a drying oven at 50 "C and 20 mbar for >48 h.
Yield: 51.2 g (85.3 %, purity 96.51 area% HPLC) HPLC (Method A): Rt = 5.8 min.
MS (ESI pos): m/z = 365 (M+H)+ 1H-NMR (400MHz, DMSO-d6): 5 [ppm]: 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H).
Variant #5 Purification via stirring in isopropanol/water Depending on the purity of the crude product, an additional purification step via stirring in mixtures of isopropanol and water, preferably 1:1, can be performed. Depending on the purity of the crude product, stirring is performed in a range of 2 - 10 volumes with regard to the crude starting material. The following example describes stirring in 3 s isopropanol/water: 7,5 g N-[6-(2-hydroxypropanyl)-1H-indazolyl]—6-(trifluoromethyl)pyridinecarboxamide (V) with a purity of 95 area% (HPLC) are stirred in 22.5 ml of a 1:1 (vol) mixture of water and isopropanol for 2 h at 20 0C. The suspension was then filtered and the product washed with 4 ml of the same solvent mixture. The product was dried in drying oven at 50°C under vacuum (<100 mbar).
Yield: 6.8 g (90.7 %, purity > 98 area% HPLC) HPLC d A): Rt = 5.8 min.
MS (ESlpos): m/z = 365 (M+H)+ 1H-NMR z, DMSO-4): 5 [ppm]: 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H).
A combination of variant #4 and #5 was performed at 44 kg scale (see table 4 below).
Table 4: Manufacturing of compound ing to formula (V) following the ols of variant #4 and #5 38.4 kg 95.9 % 33.6 kg Example #3 N-{6-(2-Hyd roxypropan-Z-yl)[2-(methylsulphonyl)ethy|]-2H-indazo|—5-y|} (trifluoromethyl)pyridine-Z-carboxamide (I) Variant #1 This variant was used for the production of technical batches at kg scale and follows the protocol described in W02016/083433. 2.5 kg (6.86 mol) N-[6-(2-hydroxypropanyl)-1H-indazolyl]—6-(trifluoromethyl)pyridine carboxamide (V) were suspended in 33 | (28.6 kg) toluene. The mixture was heated to reflux and app. 8| toluene were distilled off the mixture. The mixture was cooled to 90 °C and 44 g (0.34 mol) of N,N-diisopropylethylamine were dosed to the mixture. The e was d for further 15 min at 90 "C before 1.17 kg (10.98 mmol) methyl vinyl sulfone were added. The reaction mixture was kept at 112 °C (reflux toluene) and stirred for at least 72 h. The mixture was cooled to 20 0C. The mixture was then heated to reflux and 8 | of toluene were distilled off the mixture. The mixture was then cooled to 70 °C and 12.6 kg methyl tert-butyl ether (MTBE) were added within 30 min. The mixture was cooled to 20 °C within 2 h and stirred at 20 °C overnight. It was then cooled to 0 °C and stirred for 1 h. The precipitate was filtered off and washed twice with 3 | of cold MTBE. The lline product was dried in an oven at 50 °C under .
Yield: 2.39 kg (73.9 %, purity: 97.8 area% HPLC) HPLC (Method B): Rt = 3.07 min.
MS (ESI pos): m/z = 471 (M+H)+ 1H NMR (400 MHz, DMSO-de): 5 [ppm]: 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4.86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.13 - 8.19 (m, 1 H), 8.37 (s, 1 H), 8.41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 Table 5: Yields and purity (in % after HPLC) obtained for three batches of (I) from (V) Starting Material Product (I) Product (I) Yield [kg], [%] Purity [area%] Amount [kg] (HPLCl* 2.50 2.47, 76.5 97.4 2.50 2.32, 71.4 97.2 2.50 2.39, 73.9 97.8 (described) (described) * Method B For obtaining material with very high purity and with a defined crystalline form (polymorph B), an additional purification step was introduced. 1.85 kg of crude N-{6-(2-hydroxypropanyl)[2-(methylsu|phonyl)ethyl]-2H-indazoly|} (trifluoromethyl)pyridinecarboxamide (I) were dissolved in 36.6 kg (46.3 |) of acetone at ambient temperature. The resulting solution was dosed into refluxing ethanol during 2.5 h. During the dosing process 54 | of solvent were distilled off and an al temperature of 63°C was reached. onal 20.8 | ethanol were added and 27 | of solvents were distilled off the mixture. Additionally, .2l additional ethanol were added and 9.3l were distilled off the e. Finally, another 10.2 | additional l were added and 10.2 | of solvents were distilled off the mixture. The mixture was cooled to 20 °C within 3 h and d overnight. The mixture was cooled to 0-2 °C within 1.5 h and stirred at this temperature for additional 3 h. The suspension was ed and the precipitate was washed with 2x 0.93 | cold ethanol. The product was dried in a drying oven at 50 °C under vacuum.
Yield: 1.59 kg (85.7 %, purity: 99.0 area% HPLC) HPLC (Method B): Rt = 3.07 min.
MS (ESI pos): m/z = 471 (M+H)+ lHNMRvaMHzomaywysmmmk163u6Hrzeou3HL3s5m2Hr436m2Hr5e7u1 I?,759(s,1tn,816(d,1FU,837(n1IH,841-8A8(nu2I?,874(s1.HL1237(s,1H) Table 6: Yield and purity obtained from synthesis as well as purity (%) after HPLC for (I) synthesized from (V) ng Material: Product (I) Product (I) Crude (I) Yield [kg], [%] Purity [area%] Amount [kg], (HPLCl* Purity [area%] (HPLC) 1.85, 97.4 1.56, 84.2 98.9 1.85, 97.2 1.59, 86.1 99.1 1.85, 97.8 1.59, 85.7 99.0 ibed) (described) Variant #2 This variant was used for the production of technical batches at kg scale. g (27.448 mmol) N-[6-(2-hydroxypropanyl)-1H-indazolyl](trifluoromethyl)pyridine carboxamide (V) were suspended in 100 ml e. 3.496 g (32.937 mmol) methyl vinyl sulfone were added. The reaction mixture was heated to 110 °C (reflux toluene) and stirred for at least h. An additional portion of 583 mg (5.49 mmol) methyl vinyl sulfone was added and the reaction mixture stirred for 7 h at reflux. Further 583 mg (5.49 mmol) methyl vinyl e were added and the reaction mixture stirred for >15 h. According to HPLC analysis, 2.5% of ng material (V) were still in the reaction mixture. The selectivity N1/N2 had amounted to 1:8. 30 ml of toluene were distilled off. The mixture was cooled to 70 0C. At this temperature, 70 ml MTBE were dropped within 5 min to the mixture resulting in a suspension. The mixture was cooled to °C overnight. It was then cooled to 0 °C and stirred for 2 h. The precipitate was ed off and washed twice with 10 ml of cold MTBE. The crystalline product was dried in drying oven for at least 48 h at 50 °C and <100 mbar.
Yield: 8.6 g (66.6 %, purity: 94.7 area% HPLC) HPLC (Method B): Rt = 3.07 min.
MS (ESI pos): m/z = 471 (M+H)+ 1H NMR (400 MHz, DMSO-de): 6 [ppm]: 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4.86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.16 (d, 1 H), 8.37 (t, 1 H), 8.41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 H).
Batches at technical scale: ing the procedure described as variant #2 batches at scales of 3.396 kg and 1.699 kg with regard to starting material (V) were produced: Table 7: Yield for compound (I) synthesized from compound (V) Starting Material (V) t (I) Amount Yield 3.40 kg 2.81 kg, 64.1 % 1.70 kg 1.28 kg, 58.2 % For the production of GMP-grade material and for obtaining a defined crystalline form (polymorph B) for production ofa pharmaceutical composition, such as a tablet, an additional cation step was introduced. 1.5 kg of crude N-{6-(2-hydroxypropanyl)[2-(methylsulphonyl)ethyl]-2H-indazolyl} uoromethyl)pyridinecarboxamide (I) as obtained from synthesis as described under variant #2 were dissolved in 45 kg of acetone and subjected to clarification filtration (filter cartridge: 3.0 um 9 GMP-filtration). The te was concentrated and a solvent swap to ethanol was performed. Thereby, ethanol was added during simultaneous distillation until an internal temperature of 77 °C was reached. The solution was trated to 6-7 volumes of ethanol with regard to the starting volume. The mixture was cooled to 20°C and stirred for 12 h at this temperature. It was then cooled to 0 °C and stirred for additional 3 h. The product was filtered off, and washed twice with 1 kg cold ethanol. The product was dried in a drying oven at 60°C under vacuum (<100 mbar).
Yield: 1370 g (91.33 %). Analogous to the described procedure, three s were carried out at technical scale, see table 7.
Table 8: Yield of pure compound (I) ed by purification described supra from crude (I) ng Material (crude I) t (pure I) [kg] Yield [kg], [%1 1.50 1.37 (91.3 %) 2.04 1.78 (87.5 %) 2.03 1.86 (91.4 %) Table 9: Analytical data of combined three batches as shown in table 8 Purity (HPLC)* 2 99% (area) Content (assay for use) 2 97.7% (weight) Ethanol < 0.25 % (weight)** Pd <1ppm * Method B; ** GC-HS The X-ray diffractogram is given in Figure 1.
Claims (25)
1. A method of preparing a compound of formula (I): comprising the following step (A): wherein a compound of formula (V): is allowed to react with a vinyl e compound of formula (IX'): (IX') in which R represents a methyl group, thereby providing said compound of formula (I).
2. The method according to claim 1, wherein step (A) is performed in the presence of an aromatic arbon solvent.
3. The method according to claim 2, wherein said aromatic hydrocarbon solvent is toluene.
4. The method according to claim 2 or claim 3, wherein the reaction is at the reflux temperature of said aromatic arbon t.
5. The method according to any one of claims 1 to 4, wherein said compound of formula is prepared by the following step (B): wherein a compound of a (VI): is allowed to react with a reductive methylating agent, thereby providing said compound of formula (V).
6. The method according to claim 5, wherein the methylating agent is a methylmetallic agent.
7. The method according to claim 6, wherein the methylmetallic agent is a methylmagnesium halide.
8. The method according to claim 7, wherein the magnesium halide is methylmagnesium chloride.
9. The method according to any one of claims 5 to 8, wherein step (B) is performed in the presence of an alkali metal .
10. The method according to claim 9, wherein the alkali metal halide is lithium chloride.
11. The method according to any one of claims 5 to 10, wherein said compound of formula (VI): is prepared by the following step (C): wherein a compound of formula : (VII) (VIII) is allowed to react with a compound of formula (VII): (VII) thereby providing said compound of formula (VI).
12. The method according to claim 11, wherein step (C) is performed in the presence of an organic base.
13. The method according to claim 12, wherein the c base is a weak organic base.
14. The method according to claim 13, wherein the weak organic base is a tertiary amine.
15. The method according to claim 14, wherein the tertiary amine is N,N- diisopropylethylamine.
16. The method ing to any one of claims 12 to 15, wherein step (C) is performed in the ce of a coupling agent.
17. The method according to claim 16, wherein the coupling agent is 2,4,6-triisopropyl- 1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (T3P).
18. The method according to any one of claims 1 to 17, wherein said compound of formula (I) is prepared via the following steps shown in reaction scheme IA, infra: Scheme IA, in which R and the aromatic hydrocarbon solvent are defined in any one of claims 1 to 4.
19. The method according to any one of claims 1 to 18, wherein said compound of formula (I) is prepared via the ing steps shown in reaction scheme I, infra: Scheme I.
20. The method according to any one of claims 1 to 19, wherein said compound of formula (I) is purified by crystallization.
21. The method according to claim 20, wherein said compound of formula (I) is purified by crystallisation from a solvent.
22. The method according to claim 21, n said solvent is ethanol.
23. The method according to claim 21, wherein said solvent is isopropanol.
24. Use of a compound selected from the group consisting of: (V) , (VI) , (VII) (VIII) , and (VII) , for preparing a compound of formula (I): according to the method of any one of claims 1 to 23.
25. Use of a vinyl sulfone compound of formula (IX'): (IX') in which R represents a methyl group, for preparing a compound of formula (I): by ng with a compound of formula (V): ing to the method of any one of claims 1 to 23.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP16167652 | 2016-04-29 | ||
PCT/EP2017/059744 WO2017186689A1 (en) | 2016-04-29 | 2017-04-25 | Synthesis of indazoles |
Publications (2)
Publication Number | Publication Date |
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NZ746469A NZ746469A (en) | 2023-08-25 |
NZ746469B2 true NZ746469B2 (en) | 2023-11-28 |
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