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Structure of 109-85-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Investigation of quinolone‐tethered aminoguanidine as novel antibacterial agents
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.
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Keywords: tuberculosis ; ESKAPE pathogens ; aminoguanidine ; quinolones ; thiosemicarzone
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Binding polyprotic small molecules with second-sphere hydrogen bonds
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.
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Keywords: Cobalt ; hydrogen-bonding ; second-sphere ; small molecule ; protic ligand
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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 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225-H314 |
Precautionary Statements: | P210-P280-P305+P351+P338-P310 |
Class: | 3(8) |
UN#: | 2733 |
Packing Group: | Ⅱ |
* 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.
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 180℃; for 0.416667h; | c) (2-Methoxy-ethyl)- (2-methoxy-6-nitro-phenyl)-amine; A mixture of 7.5g (40mol) <strong>[3970-39-6]2-chloro-1-methoxy-3-nitro-benzene</strong>, 14ml diisopropylethylamine and 35ml 2-methoxyethyl amine is heated (180C oil bath temperature) in a closed steel reactor for 25 min. Then the reaction mixture is cooled to room temperature and is concentrated in vacuo (3 x coevaporation with toluene) to obtain ca. 20g (which contains 85% of the title compound) of a red oil which is used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; for 2h; | 5-Formyl-thiophene-2-carboxylic acid (740 mg, 4.7 mmol), methoxyethylamine (412 muL, 4.7 nnnnol), HATU (4.5 g 11.8 nnnnol), ethyldiisopropylamine (4 ml) and DMF (2 m) in DCM (20 ml) was stirred for 2 hrs. The mixture was extracted with DCM and aq. bicarbonate. The organic layer was dried and concentrated. This residue was oxidized in t-BuOH (4ml) by the addition of sodium phosphate buffer (0.5M, 2 ml) and aq. KMnO4 (1M, 2ml). After 10 min. addition of sat. aq. Na2SO4 (2ml) was done and pH was adjusted to 3 with aq. HCI. Extracted with EtOAc. Organic layer was dried and concentrated. | |
Example 1 Synthesis of the present aldehyde derivative is described in Examples 1-1 to 1-15.Example 1-1 Synthesis of the present aldehyde derivative [Compound No. (a)] To a solution of 1.56 g of 5-formylthiophene-2-carboxylic acid in 40 ml of tetrahydrofuran was added 2.11 g of carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours and 30 minutes. To the mixture was added 1 ml of 2-methoxyethylamine. The mixture was stirred at room temperature for 1 hour and 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in 70 ml of ethyl acetate, washed with 2N hydrochloric acid and then an aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.88 g of 5-formylthiophene-2-carboxylic acid 2-methoxyethylamide [Compound No. (a)] as a white solid. 1H-NMR(270MHz,DMSO-d6) delta (ppm): 3.27 (s, 3H), 3.38~3.50 (m, 4H), 7.89 (d, 1H, J=4.1Hz), 8.01 (d, 1H, J=4.1Hz), 8.91 (broad, 1H), 9.95 (s, 1H). | ||
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; for 2h; | 4.50 5-(2-Methoxy-ethylcarbamoyl)-thiophene-2-carboxylic acid; delta-Formyl-thiophene^-carboxylic acid (740 mg, 4.7 mmol), methoxyethylamine (412 mul_, 4.7 mmol), HATU (4.5 g 1 1.8 mmol), ethyldiisopropylamine (4 ml) and DMF (2 m) in DCM (20 ml) was stirred for 2 hrs. The mixture was extracted with DCM and aq. bicarbonate. The organic layer was dried and concentrated. This residue was oxidized in t-BuOH (4ml) by the addition of sodium phosphate buffer (0.5M, 2 ml) and aq. KMnO4 (1 M, 2ml). After 10 min sat. aq. Na2SO4 (2 ml) was added and the pH was adjusted to 3 with aq. HCI. Extracted with EtOAc. The organic layer was dried and concentrated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 20℃; | Intermediate 102.5; A mixture of 3-Bromomethyl-5-methoxy-benzoic acid methyl ester (300 mg, 1.16 mmol) (see e.g. Tetrahedron Lett, 1993, 31, 6313) , 2-Methoxy-ethylamine (260 mg, 3.47 mmol) and K2CO3 (0.32 g, 2.32 mmol) in CH3CN (5 mL) are stirred at RT. for over night. After adding H2O (20 mL), the reaction mixure is extracted with CH2CI2 (20 mL, 2x). The combined organic phases are washed with H2O, brine and dried (Na2SO4), concentrated under reduced EPO <DP n="155"/>to give 3-Methoxy-5-[(2-methoxy-ethylamino)-methyl]-benzoic acid methyl ester as an oil (217 mg, 0.85 mmol; 85%; ES-MS: M+H = 254 ; HPLC: tRtheta, = 2.29 minutes). This crude material is used without purification. To a mixture of this crude material and Et3N (0.48 ml, 3.47 mmol), (BOC)2O (380 mg, 1.74 mmol) in DCM (5 mL) is added at RT. After stirring for 1 h, the reaction mixture is quenched by adding H2O, and mixture is extracted with DCM. The combined organic phases are washed with H2O, brine and dried (MgSO4), concentrated under reduced pressure and silica gel flash chromatography to give Intermediate 102.5 as white amorphous; Rf = 0.47 (AcOEt:n-Hex=1:2) 1H NMR (400 MHz, CDCI3); J1.40-1.55 (brs, 9H), 3.30 (s, 3H), 3.35-3.55 (m, 4H), 3.80 (s, 3H), 3.90 (s, 3H), 4.45 (brs, 2H), 6.95-7.0 (brs, 1H), 7.40 (m, 1H), 7.50 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; water; N,N-dimethyl-formamide; mineral oil; | b 4-Chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrile oxalate (R)-alpha-(2-Chloroethyl)-3-furanmethanol (100 mg, 0.62 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature. To this solution was added sodium hydride as a 60% suspension in mineral oil (3 7 mg, 0.93 mmol) and the mixture was stirred for 10 minutes before solid <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (107.6 mg, 0.62 mmol) was added in one portion. The resultant mixture was stirred for 1 h before water (2 ml) was added and the mixture concentrated in vacuo. The residues were partitioned between dichloromethane and water. The organics were collected, dried over magnesium sulphate, filtered and concentrated to dryness in vacuo. The resultant residue was dissolved in N,N-dimethylformamide (2 ml) and treated with sodium iodide (93 mg, 0.62 mmol), triethylamine (172 mul, 1.24 mmol) and 2-methoxyethanamine (107 mul, 1.24 mmol) before being heated to 60 C. for 72 h. After being allowed to cool the mixture was filtered and purified via reverse phase HPLC to give the title compound as a free base which was treated with a 50% saturated solution of oxalic acid in ether. The resultant white solid was collected via filtration to yield the title compound (61 mg, 28%). MS APCI+ve m/z 353/355 [(M+H)+]. 1H NMR 300 MHz (d6-DMSO) 8.02 (1H, d), 7.82 (1H, s), 7.70 (1H, s), 7.59 (1H, s), 5.72 (2H, t), 3.57 (2H, m), 3.31 (3H, s), 3.16 (2H, m), 3.09-2.98 (2H, b), 2.37 (1H, bm), 2.27 (1H br m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; methanol; water; N,N-dimethyl-formamide; mineral oil; | EXAMPLE 25 4-Chloro-2-[1-ethyl-3-[(2-methoxyethyl)amino]propoxy]-5-fluorobenzonitrile Oxalate 1-Chloro-3-pentanol (1 g, 8.15 mmol) was dissolved in tetrahydrofuran (20 ml) and treated with sodium hydride as a 60% suspension in mineral oil (480 mg, 12.2 mmol) followed after 10 minutes by <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (1.41 g, 8.15 mmol). The mixture was stirred at room temperature for 18 h before being treated with methanol (1 ml) and then water (10 ml). The tetrahydrofuran was then removed via heating the vessel to 80 C. and applying a nitrogen stream. Once the tetrahydrofuran was evaporated off, the residue was extracted into dichloromethane, dried over magnesium sulphate and concentrated in vacuo. The resultant material was re-dissolved into N,N-dimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03 mmol), triethylamine (565 mul, 4.06 mmol) and 2-methoxyethanamine (352 mul, 4.06 mmol) before being heated to 60 C. for 5 days. The mixture was filtered and purified via RP-HPLC on the crude reaction material. The purified compound was then treated with 50% saturated oxalic acid in ether to produce a white powder which was collected via filtration. (378 mg, 15%). MS APCI+ve m/z 315 ([M+H]+). 1H NMR 300 MHz (d6-DMSO) 8.03 (1H, d), 7.65 (1H, d), 4.66 (1H, m), 3.56 (2H, m), 3.30 (3H, s), 3.14-3.06 (2H, m), 3.06-2.97 (2H, m), 2.03 (2H, m), 1.65 (2H, m), 0.92 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; In N-methyl-acetamide; dichloromethane; toluene; | Example 1 Pyrimidine 4,6-dicarboxylic acid di-(2-methoxyethyl)-amide (formula I: R1 =CH2 -CH2 -OCH3; R2 =H) 1.7 g of <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> are suspended in 20 ml of toluene, and 2.4 g of thionyl chloride and 0.2 ml of dimethylformamide are added. The mixture is heated to the reflux temperature until no further evolution of gas is to be observed (about 3 hours). About 5 ml of solvent are distilled off, the mixture is cooled to 0-10 C. and 1.9 g of 2-methoxyethylamine and 2.8 ml of triethylamine, dissolved in 10 ml of toluene, are added. The solution is heated slowly to room temperature, stirred at room temperature for 12 hours and evaporated to dryness. The residue is taken up in 50 ml of methylene chloride, the mixture is extracted 3 times by shaking with saturated sodium bicarbonate solution and the organic phase is washed with water, dried with magnesium sulfate and evaporated. The solid is recrystallized from diisopropyl ether. Yield: 2.1 g; melting point: 85-86 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | In tetrahydrofuran; at 20℃; for 9.33333h; | EXAMPLE 715-(4-{4-f|UOro-1 -[2-(methyloxy)ethyl]-1 H-benzimidazol-2-yl}-1 H-imidazol-2-yl)-1 ,3- benzothiazole trifluoroacetateStep 1 . (3-fluoro-2-nitrophenyl)[2-(methyloxy)ethyl]amine: To a solution of 2,6- difluorodinitrobenzene (4 g, 24.64 mmol) in Tetrahydrofuran (THF) (80 ml) at rt was added 2-methoxyethlyamine (2.164 ml, 24.64 mmol). This was stirred at rt for 80 min, at which time, LCMS showed nearly half complete. Allowed to stir for 8 hr. LCMS showed 12%sm, 85% product, and 3% double addition product. Diluted with Et20 and water, separated layers and back-extracted with Et20 twice. Washed with Brine and dried on MgS04. Filtered and concentrated. Purified via Biotage FCC (40 g SNAP column, 0-10%EtOAC/hex); baseline separation was acheived. Combined an concentrated product fractions to provide (3-fluoro-2-nitrophenyl)[2-(methyloxy)ethyl]amine (3.76 g, 17.55 mmol, 71 .2 % yield) as a bright orange oil. MS (m/z) 215.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 150℃; for 0.25h;Microwave irradiation; | PREPARATION 2N-methyl-4-[2-(methyloxy)ethyl]amino}-3-nitrobenzamideThe <strong>[475216-25-2]4-fluoro-N-methyl-3-nitrobenzamide</strong> (2.63 g, 13.3 mmol) was partially dissolved in ethanol (7 ml.) in a microwave vial and /V,/V-diisopropylethylamine (DIEA) (2.3 ml_, 13.3 mmol) and [2-(methyloxy)ethyl]amine (1.16 ml_, 13.3 mmol) were added. The vial was capped and heated in the microwave at 150C for 15 minutes. Reaction was repeated two times on same scale and all crude reactions were combined. Mixture was cooled to room temperature and left to sit for 2 hours. A solid formed and it was filtered, rinsed with diethyl ether and dried to give the title compound as an orange solid (9.19 g, 86%, >95% purity). Product was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) delta 8.63 (d, J = 2.27 Hz, 1 H), 8.48 (d, J = 4.55 Hz, 1 H), 8.36 - 8.44 (m, 1 H), 7.99 (dd, J = 2.02, 9.09 Hz, 1 H), 7.16 (d, J = 9.09 Hz, 1 H), 3.51 - 3.69 (m, 4H), 3.32 (s, 3H), 2.77 (d, J = 4.55 Hz, 3H); MS (m/z) 254.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h; | Example 32A tert-Butyl {1-(2-chlorophenyl)-2-[(2-methoxyethyl)-amino]-2-oxoethyl}carbamate A mixture of 250 mg (0.88 mmol) of <strong>[313490-25-4][(tert-butoxycarbonyl)amino](2-chlorophenyl)acetic acid</strong>, 177 mg (1.31 mmol) of HOBt, 252 mg (1.31 mmol) of EDC and 72 mg (0.96 mmol) of 2-methoxyethanamine in 6.3 ml of DMF was stirred at RT for 2 h. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 269 mg (90% of theory) of the title compound. LC-MS [Method 5]: Rt=0.88 min; MS [ESIpos]: m/z=343 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.38 (s, 9H), 3.18-3.29 (m, 2H), 3.22 (s, 3H), 3.29-3.37 (m, 2H), 5.45 (d, 1H), 7.28-7.34 (m, 2H), 7.35-7.46 (m, 2H), 7.49 (d, 1H), 8.06 (br. t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 80℃; | Step 1: To a solution of compound 4a-l (5 g, 26 mmol) in DMSO (20 mL) was 2- methoxyethylamine (7ml, 80mmol). The mixture was stirred overnight at 80C, Subsequently the reaction solution was concentrated to the residue. The residue was purified by silica-gel column chromatography, eluting with PE/EA=10/1, to give the desired product 2. LC-MS: m/z = 244 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.96 g | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 0 - 20℃;Reflux; | Intermediate D3: 3-Amino-5-bromo-N-(2-methoxyethyl)benzamide. To a stirred solution of <strong>[42237-85-4]3-amino-5-bromobenzoic acid</strong> (1.90 g, 8.53 mmol), 2-methoxy- ethanamine (1.50 ml, 17.08 mmol) and triethylamine (3.60 mL, 25.8 mmol) in DCM (30 mL) at 0C was added 50 wt% T3P in EtOAc (7.65 ml, 12.85 mmol). The reaction was stirred at rt overnight then refluxed for 90 min. The reaction was cooled to rt, whereupon a further quantity of triethylamine (3.60 ml, 25.8 mmol) was added. The reaction vessel was then cooled in an ice bath and 50 wt% T3P in EtOAc (7.65 ml, 12.85 mmol) from a fresh bottle was added. The ice bath was removed, the reaction allowed to warm to rt, and stirred at this temperature for 1 h. The reaction was partitioned between sat. NaHC03 (50 mL) and DCM (50 mL). The aqueous phase was back extracted with fresh DCM (50 mL). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo to afford an orange oil (3.12 g). The crude product was purified by chromatography on silica gel (80 g column, 0- 10% MeOH in DCM) to afford Intermediate D3 (1.96 g) as an orange oil. 1H NMR (DMSO-d6) 400 MHz, delta: 8.37 (t, 1 H), 7.08 (t, 1 H), 7.00-6.99 (m, 1 H), 6.84 (t, 1 H), 5.57 (s, 2H), 3.44-3.41 (m, 2H), 3.39-3.33 (m, 2H), 3.25 (s, 3H). LCMS m/z 273/275 (M+H)+ (ES+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (5.7 g, 22 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of methoxyethylamine 3-1 (2 g, 27 mmol), and potassium carbonate (3.73 g, 27 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70° C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 3-2 (2.1 g, 58percent) as a pale yellow oil, LC-MS: m/z=164[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Starting material: Compound 4 Methanesulfonyl chloride (MsCl) [CAS 124-63-0] 2-Methoxyethylamine [CAS 109-85-3] Reagents: Sodium Chloride (NaCl) 50% 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 2.5% 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 <0.1% (0.08%). 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 3.7% 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, 0.57% 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 5% 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 <0.1% (0.02%). 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 wt% of residual iPrOAc (1.1 wt%). 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, 86% yield, 96.6% AUC by HPLC) as a cream colored solid. Example 4. Preparation of ARQ 087-2 HC1 Crystalline Form D |
Tags: 109-85-3 synthesis path| 109-85-3 SDS| 109-85-3 COA| 109-85-3 purity| 109-85-3 application| 109-85-3 NMR| 109-85-3 COA| 109-85-3 structure
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