WO2021119236A1 - Préparation d'un composé inhibiteur de chk1 - Google Patents

Préparation d'un composé inhibiteur de chk1 Download PDF

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WO2021119236A1
WO2021119236A1 PCT/US2020/064182 US2020064182W WO2021119236A1 WO 2021119236 A1 WO2021119236 A1 WO 2021119236A1 US 2020064182 W US2020064182 W US 2020064182W WO 2021119236 A1 WO2021119236 A1 WO 2021119236A1
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compound
formula
reaction
preparation
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Omid SOLTANI
Bradley GORSLINE
Yunyu Mao
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Seagen Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • This invention relates to processes for preparing the Chk-1 inhibiitor compound 5-[[5- [4-(4-Fluoro-1-methyl-4-piperidyl)-2-methoxy-phenyl]-1H-pyrazol-3-yl]amino]pyrazine- 2-carbonitrile, processes for preparing synthetic intermediates, and to novel chemical intermediates for use in the processes.
  • Chk-1 is a serine/threonine kinase involved in the induction of cell cycle checkpoints in response to DNA damage and replicative stress [Clin. Can. Res. 2007; 13(7)].
  • Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions.
  • Most cancer cells have impaired G1 checkpoint activation due to a defective p53 tumor suppressor protein. Hahn et al., “Rules for making human tumor cells” N. Engl. J. Med.
  • tumours are associated with mutations in the p53 gene, a tumour suppressor gene found in about 50% of all human cancers.
  • Chk-1 inhibition abrogates the intra S and G2/M checkpoints and has been shown to selectively sensitise tumour cells to well known DNA damaging agents.
  • DNA damaging agents where this sensitising effect has been demonstrated include Gemcitabine, Pemetrexed, Cytarabine, Irinotecan, Camptothecin, Cisplatin, Carboplatin [Clin. Cancer Res. 2010, 16, 376], Temozolomide [Journal of Neurosurgery 2004, 100, 1060], Doxorubicin [Bioorg. Med. Chem. Lett. 2006;16:421- 6], Paclitaxel [WO2010149394], Hydroxy urea [Nat. Cell. Biol.
  • Chk-1 inhibitors may act synergistically with PARP inhibitors [Cancer Res:, 66: (16)], Mek inhibitors [Blood. 2008 September 15; 112(6): 2439-2449], Farnesyltransferase inhibitors [Blood. 2005 Feb 15; 105(4): 1706- 16], Rapamycin [Mol. Cancer Ther. 2005 Mar;4(3):457-70], Src inhibitors [Blood. 2011 Feb 10; 117(6): 1947-57] and WEE1 inhibitors (Chaudhuri et al., Haematologica, 2013.093187).
  • Chk-1 activation is associated with radioresistence in glioblastoma [Nature ; 2006; 444(7):756-760] and the inhibition of Chk-1 sensitises lung cancer brain metastases to radiotherapy [Biochem. Biophys. Res. Commun. 2011 March 4;406(1):53-8]).
  • Chk-1 inhibitors may be useful in treating tumour cells in which constitutive activation of DNA damage and checkpoint pathways drive genomic instability.
  • This phenotype is associated with complex karyotypes in samples from patients with acute myeloid leukemia (AML) [Cancer Research 2009, 89, 8652], In vitro antagonisation of the Chk-1 kinase with a small molecule inhibitor or by RNA interference strongly reduces the clonogenic properties of high-DNA damage level AML samples. In contrast Chk-1 inhibition has no effect on normal hematopoietic progenitors. Furthermore, recent studies have shown that the tumour microenvironment drives genetic instability [Nature ;
  • PF-00477736 inhibits the growth of thirty ovarian cancer cell lines [Bukczynska et al, 23 rd Lome Cancer Conference] and triple negative negative breast cancer cells [Cancer Science 2011, 102, 882]. Also, PF-00477736 has displayed selective single agent activity in a MYC oncogene driven murine spontaneous cancer model [Ferrao et al, Oncogene (15 August 2011)].
  • Chk-1 inhibition by either RNA interference or selective small molecule inhibitors, results in apoptosis of MYC- overexpressing cells both in vitro and in an in vivo mouse model of B-cell lymphoma [Hoglund et al., Clinical Cancer Research, Online First September 20, 2011], The latter data suggest that Chk-1 inhibitors would have utility for the treatment of MYC- driven malignancies such as B-cell lymphoma/leukemia, neuroblastoma and some breast and lung cancers.
  • Ewing sarcoma cell lines have also been reported to be sensitive to Chk kinase inhibitors (McCalla et al., Kinase Targets in Ewing's Sarcoma Cell Lines using RNAi-based & Investigational Agents Screening Approaches, Molecular Targets 2013, Boston, USA).
  • WO 03/10444 and WO 2005/072733 disclose aryl/heteroaryl urea compounds as Chk-1 kinase inhibitors.
  • US2005/215556 discloses macrocyclic ureas as kinase inhibitors.
  • WO 02/070494, WO2006014359 and WO2006021002 disclose aryl and heteroaryl ureas as Chk-1 inhibitors.
  • WO/2011/141716 and WO/2013/072502 both disclose substituted pyrazinyl- phenyl ureas as Chk-1 kinase inhibitors.
  • WO2005/009435 (Pfizer) and WO2010/077758 (Eli Lilly) disclose aminopyrazoles as Chk-1 kinase inhibitors.
  • WO2015/120390 discloses a class of substituted phenyl-pyrazolyl-amines as Chk-1 kinase inhibitors.
  • One of the compounds disclosed is the compound 5-[[5-[4-(4-fluoro- 1-methyl-4-piperidyl)-2-methoxy-phenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carbonitrile, the synthesis of which is described in Example 64 and Synthetic Method L in WO2015/120390, as illustrated in Figure 46 of the present application.
  • Chk-1 kinase inhibitor compound 5-[[5-[4-(4-fluoro-1-methyl-4-piperidyl)-2- methoxy-phenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carbonitrile is useful in the treatment of cancers as disclosed in WO2015/120390.
  • the present invention provides improved processes for making the Chk-1 kinase inhibitor compound 5-[[5-[4-(4-fluoro-1-methyl-4-piperidyl)-2-methoxy-phenyl]-1H- pyrazol-3-yl]amino]pyrazine-2-carbonitrile (referred to herein also as the compound of formula (I), compound (13) or the Chk-1 inhibitor.
  • the improved process of the present invention is represented by the sequence of reactions set out in Scheme 1 below (and in Figure 44).
  • the synthetic route shown in Scheme 1 and Figure 44 has a number of advantages over the synthetic route described in WO2015/120390.
  • the route depicted in Scheme 1 is significantly shorter in terms of both longest linear sequence (6 vs 10 steps) and total steps (7 vs 10).
  • the new route will also provide enhanced yields of product due to the shorter sequence as well as the avoidance of the low yielding cryogenic chemistry with n-butyl lithium described in the WO2015/120390 process.
  • the improved process of the present invention uses readily available and stable building blocks and the subsequent intermediates derived from the process are readily isolable crystalline solids.
  • the improved synthetic route makes use of the same two final steps (removal of the Boc protecting group followed by reductive methylation) as the synthetic route described in WO 2015/120390 but the synthesis of the Boc-protected intermediate 11 in the present route differs from the synthesis of intermediate (11) in WO2015/120390.
  • the invention provides a process for the preparation of a compound of the formula (11): which process comprises the reaction of a compound of the formula (A) with a compound of the formula (B): where LG 1 is a leaving group (for example chlorine, bromine, iodine or trifluoromethansulfonate), and BG is a B(OH) 2 or a boronate ester group such as in the presence of a palladium catalyst and a base.
  • LG 1 is a leaving group (for example chlorine, bromine, iodine or trifluoromethansulfonate)
  • BG is a B(OH) 2 or a boronate ester group such as in the presence of a palladium catalyst and a base.
  • the palladium catalyst typically comprises one or more phosphine ligands such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), triphenylphosphine, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos), one preferred ligand being XPhos.
  • phosphine ligands such as 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), triphenylphosphine, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos
  • the base can be a carbonate base such as potassium carbonate or caesium carbonate and the reaction may be carried out in a polar solvent such as dimethyl formamide (DMF) or dioxane (e.g. aqueous dioxane).
  • a polar solvent such as dimethyl formamide (DMF) or dioxane (e.g. aqueous dioxane).
  • the reaction mixture is typically subjected to heating, for example to a temperature of about 100°C.
  • the invention provides:
  • BG is or B(OH) 2 .
  • the palladium catalyst comprises a phosphine ligand selected from 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), triphenylphosphine, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos).
  • a phosphine ligand selected from 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), triphenylphosphine, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos).
  • Embodiment 1.7 wherein the phosphine ligand is XPhos. 1.10 A process according to any one of Embodiments 1.1 to 1.7 wherein the palladium catalyst is selected from Pd 2 dba 3 /XPhos, Pd 2 dba 3 /SPhos and Pd G2 Pt-Bu 3 .
  • the invention provides a process for the preparation of a compound of the formula (A): which process comprises the reaction of a compound of the formula (C) with a compound of the formula (D): where LG 2 is a leaving group (e.g. bromine or chlorine) in the presence of a base.
  • LG 2 is a leaving group (e.g. bromine or chlorine) in the presence of a base.
  • the polar solvent can be a non-aqueous aprotic solvent such as dimethylformamide.
  • the base is typically a carbonate base such as potassium carbonate.
  • the reaction is typically carried out with heating to a non-extreme temperature, for example a temperature in the range from 60 °C to °80 C, e.g. about °70 C.
  • the invention provides: 2.2 A process according to Embodiment 2.1 wherein the leaving group LG 2 is chlorine.
  • Embodiment 2.1 or Embodiment 2.2 wherein the base is potassium carbonate.
  • 2.4 A process according to any one of Embodiments 2.1 to 2.3 wherein the reaction is carried out in a non-aqueous aprotic solvent such as dimethylformamide.
  • the invention provides a process for the preparation of a compound of the formula (B): which process comprises the reaction of a compound of the formula (E): where LG 3 is a group capable of being displaced by a boronate or boronic acid group by reaction in the presence of a palladium catalyst and a base with a compound of the formula R x R y B-BR x' R y' where Rx, Ry, Rx' and Ry' are all hydrogen, or R x R y B and BR x' R y' each form boronate ester groups such
  • the group LG 3 can be a halogen such as chlorine or bromine, or a trifluoromethanesulfonate group, a particular example being chlorine.
  • the palladium catalyst can be, for example Pd 2 dba 3 / XPhos, or Pd 2 dba 3 /SPhos where (Pd 2 (dba) 3 ) is tris(dibenzylideneacetone)dipalladium(0), XPhos is 2-dicyclohexyl- phosphino-2',4',6'-triisopropylbiphenyl and SPhos is 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl, with one preferred ligand being XPhos.
  • the base can be a carbonate base such as an alkali metal carbonate (e.g. sodium or potassium carbonate), or an alkoxide or alkanoate base such as an alkaline metal alkoxide or alkanoate, examples being potassium acetate and sodium tert- butoxide and mixtures thereof.
  • the reaction is typically carried out in a polar solvent, for example ethanol or dioxane, at a moderately elevated temperature, for example to a temperature in the range from about 65 °C to about 105 °C, e.g. about 100 °C.
  • the invention provides:
  • LG 3 is selected from chlorine, bromine and a trifluoromethanesulfonate group.
  • the invention provides a process for the preparation of a compound of the formula (E) by the reaction of a compound of the formula (F): with a fluorinating agent capable of replacing the hydroxyl group with fluorine.
  • the invention provides:
  • Embodiment 4.1 A process according to Embodiment 4.1 wherein the fluorinating agent is selected from diethylaminosulfur trifluoride (DAST), diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M).
  • DAST diethylaminosulfur trifluoride
  • XtalFluor-E diethylaminodifluorosulfinium tetrafluoroborate
  • XtalFluor-M morpholinodifluorosulfinium tetrafluoroborate
  • the compound of formula (F) can be prepared by reacting a compound of the formula (5) with a compound of the formula (G) in the presence of magnesium under Grignard reaction conditions:
  • the reaction is usually carried out in an ether solvent, for example 2-methyl- tetrahydrofuran, typically in the presence of a catalytic amount of iodine.
  • an ether solvent for example 2-methyl- tetrahydrofuran
  • the invention provides a process comprising a sequence of process steps correspondingly generally to the process steps disclosed in synthetic route L in WO2015/120390 but with modifications to improve yields, product quality and suitability for scale-up.
  • the modified process is represented by the sequence of reaction steps shown in Scheme 2 (and Figure 45).
  • the reductive methylation of the final intermediate 24 to give the Chk-1 inhibitor compound (compound 13) is carried out using sodium cyanoborohydride (NaCNBH 3 ) as the reducing agent whereas the corresponding step in the process in Scheme L in WO2015/120390 uses sodium triacetoxy borohydride (Na(OAc) 3 BH) as the reducing agent.
  • NaCNBH 3 sodium cyanoborohydride
  • Na(OAc) 3 BH sodium triacetoxy borohydride
  • the invention provides:
  • a process for the preparation of a compound of the formula 17, which process comprises the reaction of a compound of the formula 15 with a compound of the formula 16 in the presence of hexyl lithium:
  • a process for the preparation of a compound of the formula 18, which process comprises the reaction of a compound of the formula 17: with a fluorinating agent selected from diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M), preferably diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E).
  • a fluorinating agent selected from diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M), preferably diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E).
  • a process for the preparation of a compound of the formula 19, which process comprises the reaction of a compound of the formula 18 with acetonitrile in the presence of a strong base (e.g. potassium tert- butoxide):
  • a strong base e.g. potassium tert- butoxide
  • a process for the preparation of a compound of formula 24 which process comprises the process of any one of Embodiments 1.1 to 1.11 followed by removal of the protecting group PG, for example using an acid such as hydrochloric acid.
  • the invention provides novel intermediates for use in the processes of the invention.
  • the invention provides: 6.1 A compound of the formula (A):
  • LG 1 is as defined in any one of the preceding embodiments.
  • 6.2 A compound of the formula (B): wherein BG is as defined in any one of the preceding embodiments.
  • Figure 1 is a 1 H NMR spectrum of Compound 3 formed by the reaction of Compound 1 with Compound 2 as shown in Scheme 1 and described in Example 1A.
  • Figure 2 is a 1 H NMR spectrum of Compound 6 formed by the reaction of Compound 4 with Compound 5 as shown in Scheme 1 and described in Example 1B.
  • Figure 3 is a 1 H NMR spectrum of Compound 7 formed by the reaction of Compound 6 with the fluorinating agent XtalFluor-E as shown in Scheme 1 and described in Example 1C.
  • Figure 4 is is a mass spectrum of Compound 7 showing an [M+Na] peak at 366.1 (Expected [M+Na]: 366.12)
  • Figure 5 is is a mass spectrum of Compound 8a formed by the reaction of Compound 7 with B 2 (OH) 4 in the presence of a palladium catalyst as described in Example 1D.
  • Figure 6 is a 1 H NMR spectrum of Compound 8a.
  • Figure 7 is the mass spectrum of Compound 11 formed by the reaction of Compound 3 and Compound 8 as shown in Scheme 1 and described in Example 1F.
  • Figure 8 is the in-process control (IPC) profile obtained by HPLC of the reaction of compound 1 with sodium methoxide to give 4-bromo-2-methoxy-benzaldehyde as described in Example 2A.
  • Figure 9 is the HPLC profile of the product of Example 2A after purification.
  • Figure 10 is the 1 H NMR spectrum of the product of Example 2A.
  • Figure 11 is the 13 C NMR spectrum of the product of Example 2A.
  • Figure 12 is the IPC of the reaction described in Example 2B (preparation of compound 15)
  • Figure 13 is the HPLC profile of the product of the reaction described in Example 2B after workup and solvent removal.
  • Figure 14 is the HPLC profile obtained using the process for preparing compound 15 described in WO2015/120390.
  • Figure 15 is the 1 H NMR spectrum for the compound 15.
  • Figure 16 is the 13 C NMR spectrum for the compound 15.
  • Figure 17 is an HPLC trace of the reaction mixture obtained after 1.5 hours and before ketone addition in the process step described in Example 2C.
  • Figure 18 is the HPLC trace of the reaction mixture obtained after warming to room temperature for 1 hour after ketone addition in the process step described in Example 2C.
  • Figure 19 is the HPLC trace after work up and solvent removal in the process step described in Example 2C.
  • Figure 20 is the 1 H NMR spectrum for compound 17.
  • Figure 21 is the 13 C NMR spectrum for compound 17.
  • Figure 22 is the IPC for the fluorination of compound 17 to give compound 18 as described in Exampe 2D.
  • Figure 23 is the IPC obtained 1 hour after p-TSA addition in the process of Example 2D.
  • Figure 24 is the IPC obtained for the final purified solid in the process of Example 2D
  • Figure 25 is the 1 H NMR spectrum for the product of the process of Example 2D (compound 18).
  • Figure 26 is the 13 C NMR spectrum for the product of the process of Example 2D (compound 18).
  • Figure 27 is the HPLC profile for the product of Example 2E (Compound 19)
  • Figure 28 is the 1H NMR spectrum for compound 19.
  • Figure 29 is the HPLC profile for the product of Example 2F (compound 20)
  • Figure 30 is the 1 H NMR spectrum for compound 20.
  • Figure 31 is the HPLC profile for the product of Example 2G (compound 21)
  • Figure 32 is the HPLC profile compound 21 when produced by the process described in WO2015/120390.
  • Figure 33 is the 1 H NMR spectrum of compound 21.
  • Figure 34 is the 1 H NMR spectrum of compound 21 with the addition of D 2 0.
  • Figure 35 is an HPLC profile of the reaction product of Example 2H.
  • Figure 36 is is the 1 H NMR spectrum of compound 23 formed by the process of Example 2H.
  • Figure 37 is the 1 H NMR spectrum of compound 23 with the addition of D 2 0.
  • Figure 38 is the HPLC profile of the product of the reaction described in Example 3.
  • Figure 39 is 1 H NMR spectrum of compound 24 formed by the process of Example 3.
  • Figure 40 is the HPLC profile obtained in Run 2 in the process of Example 3.
  • Figure 41 is the HPLC profile of the product of the reaction described in Example 4 (preparation of compound 13 - the Chk-1 inhibitor).
  • Figure 42 is the 1 H NMR spectrum for the Chk-1 inhibitor compound.
  • Figure 43 is the HPLC profile of the product obtained from Run 2 of the process described in Example 4.
  • Figure 44 is reaction Scheme 1 showing the novel reaction of the first aspect of the invention.
  • Figure 45 is a reaction scheme showing an improved version of the synthetic route described in WO2015/120390.
  • Figure 46 is shows Synthetic Method L from WO2015/120390.
  • Figure 47 is the mass spectrum of compound 8.
  • Figure 48 is the 1 H NMR specrum of compound 8.
  • Retention Time Marker Preparation Weigh out approximately 10mg of retention time marker into a flask. Dissolve with 10mL of sample diluent.
  • Purity Sample Preparation Weigh out approximately 10mg of material into a flask. Dissolve with 10mL of sample diluent.
  • reaction Sample Preparation Dilute 10uL of reaction solution into 0.5mL of diluent, and filter if necessary.
  • Retention Time Marker Preparation Weigh out approximately 10mg of retention time marker into a flask. Dissolve with 10mL of sample diluent.
  • Aryl bromide (1.0 g, 1 equiv), aryl chloride (1.29 g, 1.5 equiv), K 2 CO 3 (1.719 g, 2.0 equiv) and a magnetic stir bar were added to a 20 mL vial with 5 mL (5.0 V) DMF and heated to 70 °C. The reaction was stirred for 20 hours. Upon completion monitored by HPLC, the reaction was cooled to rt, precipitated with 20 mL (20 V) water and stirred for 30 minutes. The slurry was filtered and washed with 5 mL (5 V) water then 10 mL (10 V) /- PrOAc. HPLC analysis of the product showed a major peak at 5.326.
  • Alcohol 6 (8.54 g) was added to a 200 mL round bottom flask with a magnetic stir bar and dissolved in 40 ml (5.0 V) anhydrous DCM.
  • NEt 3 -3HF (4.88 ml, 1.2 equiv) was added to the solution.
  • the vessel was cooled to 0 °C.
  • Xtal-Fluor-E (6.87 g, 1.2 equiv) was slowly added.
  • the reaction was stirred for 1 hour then allowed to warm to room temperature and stirred for 1 hour.
  • the reaction was quenched with saturated sodium bicarbonate.
  • the organic layer was removed, and the DCM was removed by rotovap to give an orange oil.
  • the product was purified by column chromatography (4:1 heptane: EtOAc) to give a white solid after the solvent is removed (5.66 g, 66% yield).
  • Pd 2 dba 3 (7 mg, 0.01 equiv), KOAc (0.2 g, 2.5 equiv), XPhos (16 mg, 0.04 equiv), B 2 Pin 2 (0.517 g, 2.5 equiv), and a magnetic stir bar were added to a 20 ml vial and put under N 2 .
  • a 10.0 V dioxane stock solution (2.8 ml) of arylchloride 7 (0.28 g, 1 equiv) was made under N 2 and added to the vial. The reaction mixture was heated to 100 °C and stirred for 4 hours.
  • the reaction was cooled to rt and 15V of water was added to precipitate brown and black solids.
  • the reaction was purified by column chromatography to give a white solid.
  • references to the “original process” or “original procedure” or “previous process” and like terms refer to the process described in Synthetic Method L as disclosed in WO2015/120390.
  • 2A 4-Bromo-2-methoxy-benzaldehyde
  • Aldehyde 13 (500 g) was charged to a 12 L reactor. 6.6 V MeOH (3.3 L) was added to the reactor and cooled to 0 - 5 °C. NaOMe solution (25 wt% in MeOH, 1597 g, 1690 ml) was added (exotherm 0 -> 20 °C). The reaction was agitated under reflux (65 - 70 °C) for 1 hour (light yellow slurry). The reaction was cooled to 0 - 5 °C and 15.0V (7.5 L) of water was added over 2 minutes (exotherm 0 -> 20 °C). A white slurry resulted. The reactor was cooled to 10 °C.
  • the solid was filtered and washed with 5.0 V water (2.5 L) to give a white solid (450 g, 83% yield).
  • the solid was dissolved in 7.0 V of toluene (3.5 L) and washed with 5.0 V water (2.5 L) (to remove trace basic salts which interfere with the next reaction).
  • the toluene solution of 14 was used as is in the next step.
  • the IPC at 2 hours is shown in Figure 8 and the data obtained are shown in the table below.
  • the HPLC trace after purification is shown in Figure 9 and the data for the HPLC trace are as set out in the table below.
  • the 1 H NMR spectrum of the product is shown in Figure 10 and the 13 C NMR spectrum in Figure 11.
  • the 1 H and 13 C NMR data are as follows:
  • HPLC trace after workup and solvent removal (new HPLC method) is shown in Figure 13 and the data are set out in the table below.
  • Aryl bromide 15 (460 g) was dissolved in 4.0 V 2-MeTHF (1850 ml) and added to a 12L 4-neck RBF with a mechanical stirrer. The vessel was put under N 2 and cooled to -78 °C. n-HexLi in hexane (2.3 M) (925 ml) was added dropwise to the reaction via an addition funnel over 30 minutes keeping the reaction below -60 °C (some precipitate forms on the side then a brown suspension is formed by the end of the addition) and stirred for 1 additional hour at -78 °C.
  • N-Boc piperidone 16 (441 g) was dissolved in 2.0 V 2-MeTHF (920 ml) and filtered to remove insoluble solids that clog addition funnel. The solution was added dropwise to the reaction over 1 hour via an addition funnel keeping the temperature below -60 °C (turns to a brown solution). The reaction was warmed to rt over 1 hour and stirred for 1 hour at rt. 5.0 V of saturated NH4CI (2300 ml) was slowly added to the reaction over 1 minute (marginal exotherm). The aqueous layer was removed, and the organic layer was washed with 5.0 V water (2300 ml). The solvent was removed by rotovap and chased with 2 L of 2-MeTHF. 2L of DCM was added and removed by rotovap to give 17 as an orange oil (991 g crude, 302.7 g, NMR, 45% yield).
  • HPLC trace obtained after 1.5 hours and before ketone addition is shown in Figure 17 and the HPLC data are set out below.
  • the HPLC trace obtained after warming to room temperature for 1 hour after ketone addition (old column) is shown in Figure 18 and the data from the HPLC are shown below.
  • the HPLC trace after work up and solvent removal (fresh column) is shown in Figure
  • the alcohol 17 (231 g crude from previous step, 66 g) was added to a 1 L 3-neck RBF equipped with a magnetic stir bar. 5.0 V anhydrous DCM (330 ml) was added to the flask and put under N 2 . The solution was cooled to 0 °C. NEt 3 -3HF (34 ml) was added in one portion to the reaction mixture. XtalFluor-E (47.8 g) was added slowly over 15 minutes (exotherm 0 °C -> 10 °C). The reaction was stirred at 0 °C for 1 hour. The reaction was warmed to rt and stirred for 1 additional hour at rt (turns from red orange to dark).
  • the reaction was then slowly added to a 15.0 V solution saturated NaHCO 3 solution (1000 ml) over 10 minutes at rt with significant gas evolution.
  • the organic layer was separated, and the solvent was removed by rotovap to give an orange oil.
  • the crude oil was dissolved in 5.0 V 2-MeTHF (330 ml) and added to a 1000 ml RBF with a magnetic stir bar.
  • 2 V H 2 O (125 ml) was added to the vessel along with p-TSA- H 2 O (3 g). The reaction was stirred for 1 hour at rt, then filtered.
  • this updated process with a more stable fluorinating agent provides higher yield (50 vs 40%) and also similar overall quality ( ⁇ 96.8% Purity) while the filtration is significantly faster with the updated solvent system isopropanol.
  • the IPC data for the final purified solid are shown in Figure 24 and the table of data below.
  • the 1 H and 13 C NMR spectra are shown in Figures 25 and 26 and the NMR data are set out below.
  • Alcohol 19 (14.00 g) was charged to 500 mL reactor with overhead stirrer.
  • DCM 280 mL anhydrous, contains 40-150 ppm amylene as stabilizer, Sigma Aldrich 270997 lot #SHBK5890
  • the flask was purged with nitrogen and cooled to -12.5 °C (jacket temperature, reaction T was -9.0 °C) while stirring at 200r/m.
  • Dess Martin 24.08 g, 1.5 eq., Sigma Aldrich 274623 Lot MKCG4097 was then added in one portion.
  • the reaction mixture temperature slightly increased to -8.7 °C. And then slowly down to -9.9 °C.
  • HPLC trace for the product is shown in Figure 29 and the data are set out below.
  • HPLC trade for the reaction product is shown in Figure 31 and the data are set out below.
  • HPLC profile for the previous process is shown in Figure 32.
  • the reaction was slow based on LC analysis with 85.0% 24; 12.0% CHK1 Inhibitor and a 2.9% impurity.
  • Paraformaldehyde (0.4 g) and NaBH(OAc) 3 (5.4 g) were added and stirred at rt overnight.
  • the reaction was still slow with 60.7% SM; 29.6% product and three impurities at 2.6%, 6.1% and 1.0%.
  • Water (0.25 mL ) was added to the reaction and stirred at rt overnight.
  • the reaction was almost complete with 0.72% Compound , 95.0% CHK1 inhibitor, and two impurities at 3.3% and 1.0% level.
  • the HPLC profile of the Chk-1 inhibitor compound is shown in Figure 41 and the HPLC data are set out below.

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  • Organic Chemistry (AREA)
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Abstract

L'invention concerne une nouvelle voie de synthèse pour la préparation du composé inhibiteur de Chk-1 ; l'invention concerne également un nouveau procédé de préparation de l'intermédiaire synthétique de formule (11) ; ainsi que de nouveaux intermédiaires de procédé per se.
PCT/US2020/064182 2019-12-10 2020-12-10 Préparation d'un composé inhibiteur de chk1 WO2021119236A1 (fr)

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WO2024062250A1 (fr) 2022-09-21 2024-03-28 Benevolentai Bio Limited Imidazolyl-amino-pyrazine-carbonitrils en tant qu'inhibiteurs de chk-1

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2024062250A1 (fr) 2022-09-21 2024-03-28 Benevolentai Bio Limited Imidazolyl-amino-pyrazine-carbonitrils en tant qu'inhibiteurs de chk-1

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