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Chemical Structure| 109-85-3 Chemical Structure| 109-85-3

Structure of 109-85-3

Chemical Structure| 109-85-3

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Product Citations      Show More

Klaudia T. Angula ; Lesetja J. Legoabe ; Audrey Jordaan ; Digby F. Warner ; Richard M. Beteck ;

Abstract: A recent study identified quinolone-based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating >50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.

Keywords: tuberculosis ; ESKAPE pathogens ; aminoguanidine ; quinolones ; thiosemicarzone

Purchased from AmBeed: ; ; ; ; ;

Hern, Morgan ; Foley, Rebecca ; Bacsa, John ; Wallen, Christian M. ;

Abstract: Second-sphere hydrogen bonds are known for playing significant roles in homogeneous catalysis and in biol. processes with metal-containing mols. In this work, the authors highlight a tetradentate asym. ether-sulfonamidate ligand that facilitates second-sphere hydrogen bonding in transition metal complexes. We explored its ability to bind mono-, di-, tri-, and tetra-protic ligands when supporting a cobalt(II) ion. The structures of three such cobalt complexes containing bound water, ammonia, and hydrazine are presented. Addnl., spectroscopic anal. of a strongly bound hydroxide ion complex is presented. A hydrogen-bonding configuration, not yet observed in crystal structures of this type, resulted in a bridging hydrazine complex with the two cobalt ions separated by a distance of 5 Å.

Keywords: Cobalt ; hydrogen-bonding ; second-sphere ; small molecule ; protic ligand

Purchased from AmBeed: ; ;

Alternative Products

Product Details of [ 109-85-3 ]

CAS No. :109-85-3
Formula : C3H9NO
M.W : 75.11
SMILES Code : NCCOC
MDL No. :MFCD00008180
InChI Key :ASUDFOJKTJLAIK-UHFFFAOYSA-N
Pubchem ID :8018

Safety of [ 109-85-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H314
Precautionary Statements:P210-P280-P305+P351+P338-P310
Class:3(8)
UN#:2733
Packing Group:

Application In Synthesis of [ 109-85-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 109-85-3 ]
  • Downstream synthetic route of [ 109-85-3 ]

[ 109-85-3 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 79099-07-3 ]
  • [ 109-85-3 ]
  • [ 710972-40-0 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With sodium cyanoborohydride; acetic acid In methanol at 25℃; for 12 h;
Stage #2: With sodium carbonate In methanol; water
To a solution of 1 ,1-dimethylethyl 4-oxo-1 -piperidinecarboxylate (1 g, 5.0 mmol), acetic acid (0.3 ml_, 5.0 mmol) and [2-(methyloxy)ethyl]amine (0.44 ml_, 5.0 mmol) in MeOH (20 mL) were added NaCNBH4 (346 mg, 5.5 mmol). After 12 h at 25 0C, the solution was diluted with the aqueous solution of Na2CO3. The aqueous solution was extracted several times with ethyl acetate. The organic fractions were combined, concentrated and purified with chromatography separation (silica, 0-10percent MeOH in DCM) yielding the title compound (1.2 g, 93percent) as a yellow oil: LC/MS (ES) m/e 259 (M+H)+
37%
Stage #1: With triethylamine; zinc(II) chloride In methanol at 65℃; for 7 h;
Stage #2: With sodium cyanoborohydride In methanol at 25℃; for 17 h;
Intermediate 1, tert-butyl 4-oxopiperidine-1-carboxylate (1.0 g, 5.02 mmol), was dissolved in methanol (15 mL) and treated with Intermediate 118, 2-methoxyethylamine (490 mg, 6.53 mmol), triethylamine (2.1 mL, 15.1 mmol) and ZnCI2 (68 mg, 0.50 mmol). The reaction mixturewas stirred at 65 C for 7 h, then NaBH3CN (949 mg, 15.1 mmol) was added portionwise. The resulting reaction mixture was stirred at 25 C for 17 h. The solvents were removed in vacuo, and the residue was partitioned between H20 (150 mL) and EtOAc (120 mL). The aqueous layer was extracted with EtOAc (2 x 120 mL), and the organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by columnchromatography (Normal basic activated alumina, 40 percent to 50 percent EtOAc in hexane) to give tertbutyl 4-[(2-methoxyethyl)amino]piperidine-1-carboxylate (480 mg, 37 percent) as a liquid.LCMS (Method I): mlz 203 (M+H-56) (ES), at 3.60 mi UV active.
References: [1] Patent: WO2007/16610, 2007, A2, . Location in patent: Page/Page column 49; 50.
[2] Patent: WO2017/21730, 2017, A1, . Location in patent: Page/Page column 59.
[3] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 56; 58.
[4] Patent: CN107814792, 2018, A, . Location in patent: Paragraph 0223; 0224.
[5] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 94-95; 101-102.
  • 2
  • [ 124-63-0 ]
  • [ 109-85-3 ]
  • [ 1234356-69-4 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With sodium hydroxide In 2-methyltetrahydrofuran at 20 - 25℃; for 1 h; Large scale
Stage #2: With triethylamine In 2-methyltetrahydrofuran at 0 - 25℃; for 6 h; Large scale
Stage #3: at 50 - 55℃; for 13 h; Large scale
Starting material: Compound 4 Methanesulfonyl chloride (MsCl) [CAS 124-63-0] 2-Methoxyethylamine [CAS 109-85-3] Reagents: Sodium Chloride (NaCl) 50percent Sodium Hydroxide (NaOH) Triethylamine (Et3N) (0258) Solvents: n-Heptane Isopropyl Acetate (zPrOAc) 2-Methyl Tetrahydrofuran (2-MeTHF) A 100-gallon reactor was charged with Compound 4 (10.4 kg, 23.2 mol, 1.0 eq) and 2- methyltetrahydrofuran (2-MeTHF, 132.6 kg, 155.2 L, 15 vol). A solution of 1.0 M NaOH (48.5 L, 48.5 mol, 2.1 eq) was added in one portion to the slurry and the resulting biphasic mixture was allowed to stir at 20-25 °C for 1.0 h. The phases were allowed to settle, the lower aqueous layer was removed and the organic layer was washed with 2.5percent NaCl (52 L, 5 vol). The organic layer was concentrated down to 104 L (10 vol) and chased with 2-MeTHF (44.0 kg, 51.5 L, 5 vol) a total of five times to achieve the desired water content of <0.1percent (0.08percent). After pohsh-filtering the 2-MeTHF solution into a clean 100-gallon reactor, triethylamine (Et3N, 3.5 kg, 4.9 L, 34.8 mol, 1.5 eq) was added and the mixture was cooled to 0-5 °C. Methanesulfonyl chloride (MsCL 4.0 kg, 2.7 L, 34.8 mol, 1.5 eq) was added over a period of 1 h while keeping the internal temperature < 20 °C. Once the addition of MsCl was complete, the reaction temperature was adjusted to 20-25 ''C and the mixture was stirred for 2 h. Analysis by HPLC indicated the presence of 3.7percent Compound 4. Additional Et3N (0.4 kg, mL, 0.55 L, 4.0 mol, 0.2 eq) and MsCl (0.4 kg, 0.27 L, 3.5 mol, 0.15 eq) were charged and the mixture was stirred at 20-25 °C for 1.5 h. At this point, 0.57percent Compound 4 was detected by HPLC. Additional Et3N (0.1 kg, mL, 0.14 L, 1.0 mol, 0.05 eq) and MsCl (0.1 kg, 0.07 L, 1.0 mol, 0.05 eq) were charged and the mixture was stirred at 20-25 °C for 1.5 h. Water (93.5 kg, 9 vol) was added and the biphasic mixture was stirred for 2.5 h. The phases were allowed to settle for 1 h and the aqueous layer was then transferred to a clean 200-gallon reactor. The aqueous layer was back-extracted with 2-MeTHF (44.6 kg, 52.2 L, 5 vol) and the upper layer was transferred to the 100-gallon reactor to combine organic layers before being washed with 5percent NaCl (51.6 kg, 5 vol). The resulting 2-MeTHF solution was concentrated down to -104 L (10 vol) and then chased with 2-MeTHF (44.0 kg, 51.5 L, 5 vol) a total of five times to achieve the desired water content of <0.1percent (0.02percent). After polish-filtering the 2-MeTHF solution into a clean 100-gallon reactor, the solution containing Compound 5 was concentrated down to 52 L (5 vol). 2-methoxyethylamine (35.8 kg, 41.4 L, 4 vol) was added, and the resulting reaction mixture was heated to 50-55 °C. The reaction mixture was allowed to stir at temperature for 13 h and HPLC analysis indicated complete conversion. Once the transformation was deemed complete, isopropylacetate (iPrOAc, 117.8 kg, 135L, 13 vol) and water (104 kg, 10 vol) were charged to the reactor while maintaining a temperature of 50-55 °C. After stirring for 1.5 h, the water layer was transferred to a clean 200-gallon reactor and extracted with iPrOAc (61.8 kg, 70.9 L, 7 vol). The upper layer was transferred to the 100- gallon reactor to combine organic layers and then re-equilibrated at 50-55 °C. The combined organic layer was washed with water (4x20.8 kg, 4x2 vol) before being vacuum distilled down to 63L (6 vol). The resulting slurry was chased with w-heptane (3x85.0 kg, 3x124 L, 3x12 vol) down to ~6 vol to achieve < 8.5 wtpercent of residual iPrOAc (1.1 wtpercent). The slurry was diluted with n-heptane (42.7 kg, 62.4 L, 6 vol) and stirred at 20-25 °C for 16.0 h before being filtered. The filter cake was washed with heptane (2x28.4 kg, 2x41.5 L, 2x4 vol) and then dried at 40-45 °C for 30 h. Compound A was obtained (9.4 kg, 86percent yield, 96.6percent AUC by HPLC) as a cream colored solid. Example 4. Preparation of ARQ 087-2 HC1 Crystalline Form D
References: [1] Patent: WO2017/106639, 2017, A1, . Location in patent: Page/Page column 38; 39.
 

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