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[ CAS No. 154350-29-5 ] {[proInfo.proName]}

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Chemical Structure| 154350-29-5
Chemical Structure| 154350-29-5
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Product Details of [ 154350-29-5 ]

CAS No. :154350-29-5 MDL No. :MFCD08705286
Formula : C3H7NO2S Boiling Point : -
Linear Structure Formula :- InChI Key :WMSPXQIQBQAWLL-UHFFFAOYSA-N
M.W : 121.16 Pubchem ID :15765418
Synonyms :

Calculated chemistry of [ 154350-29-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 26.09
TPSA : 68.54 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.41 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.04
Log Po/w (XLOGP3) : -0.52
Log Po/w (WLOGP) : 0.46
Log Po/w (MLOGP) : -1.35
Log Po/w (SILICOS-IT) : -0.55
Consensus Log Po/w : -0.38

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.2
Solubility : 76.9 mg/ml ; 0.634 mol/l
Class : Very soluble
Log S (Ali) : -0.45
Solubility : 42.9 mg/ml ; 0.354 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 0.0
Solubility : 122.0 mg/ml ; 1.0 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.42

Safety of [ 154350-29-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 154350-29-5 ]

* 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.

  • Downstream synthetic route of [ 154350-29-5 ]

[ 154350-29-5 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 154350-29-5 ]
  • tert-butyl ((2R,6S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxo-2-((3-(thiophen-2-yl)quinoxalin-2-yl)oxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% The title compound from Example 2 (21.0 mg, 0.031 mmol) and carbonyldiimidazole (6.0 mg, 0.037 mmol) were dissolved in 0.7 ml anhydrous DMF and the resulting solution was heated to 40 C. for 1 hour. Cyclopropylsulfonamide (8.0 mg, 0.06 mmol) was added to the reaction followed by DBU (7.0 mg, 0.046 mmol). The reaction mixture was stirred at 40 C. for 10 hour. LCMS showed the formation of the desired product. The reaction was cooled down and 10 ml ethyl acetate was added to the solution. The mixture was washed with saturated aqueous NaHCO3 solution, water and brine. The organic layer was dried over anhydrous sodium sulfate. The organic phase was then filtered, concentrated in vacuo and subsequently purified by flash chromatography (ethyl acetate/hexanes 1:1) to give 17.0 mg (71%) of the title compound. MS (ESI) m/z 779.2 (M+H)+. 1H-NMR (500 MHz, CD3Cl): δ 10.24 (1H, s), 8.10 (1H, s), 8.00 (1H, d, J=8.0 Hz), 7.82 (1H, d, J=8.0 Hz), 7.60 (2H, m), 7.49 (1H, d, J=5.0 Hz), 7.16 (1H, s), 6.91 (1H, s), 6.09 (1H, s), 5.67 (1H, m), 5.12 (1H, m), 4.98 (1H, t, J=8.0 Hz), 4.70 (1H, t, J=8.0 Hz), 4.62 (2H, s), 4.33 (1H, m), 4.10 (1H, m), 2.92 (1H, m), 2.75 (2H, m), 2.58 (2H, m), 2.28 (1H, m), 1.91 (2H, m), 1.60-0.80 (20H, m). 13C-NMR (125 MHz, CD3Cl, 200-40 ppm region): δ 177.1, 173.5, 168.1, 155.2, 152.5, 140.7, 139.8, 139.1, 136.5, 130.5, 130.4, 129.7, 128.7, 128.3, 127.6, 127.1, 124.8, 80.1, 75.8, 59.7, 53.5, 52.3, 44.8.
  • 2
  • [ 154350-29-5 ]
  • Cyclopropanesulfonic acid 4-[(R)-4-(7-methoxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2,5-dioxo-imidazolidin-4-ylethynyl]-benzoylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% Example 1570 Compound 1570 A was prepared from Compound 400 and 4-iodobenzoic acid by sequential application of the procedures given in Parts H and I in Example 400. Solid carbonyl diimidazole (19 mg, 0.12 mmol) was added in one portion to a stirred solution of Compound 1570A in THF (200 mL). The solution was stirred at 70 0C for 1.5 h, and was subsequently allowed to cool to rt. Solid <strong>[154350-29-5]cyclopropanesulfonamide</strong> (17 mg, 0.14 mmol) and DBU (43 mL, 43 mg, 0.29 mmol) were added sequentially and the reaction mixture was stirred at rt for 18 h. The solvent was evaporated and the residue was dissolved in DCM (50 mL). The solution was washed sequentially with 0.1 N aq hydrochloric acid (~25 mL), water (~25 mL) and brine (~25 mL). The organic phase was dried over anhydrous MgSCM, filtered and concentrated under reduced pressure to afford an off-white solid. The crude product was purified by PTLC (3:1 EtOAc-hexanes + 1% HCO2H) to afford the desired Compound 1570 (24 mg, 48% yield) as a beige solid.
  • 3
  • [ 154350-29-5 ]
  • C41H50N6O8S [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% The title compound from Example 2 (2c) (6.0 mg, 0.01 mmol) and carbonyldiimidazole (2.0 mg, 0.01 mmol) were dissolved in 0.75 ml anhydrous DMF and the resulting solution was heated to 40 0C for 1 h. Cyclopropylsulfonamide (3.6 mg, 0.03 mmol) was added to the reaction followed by DBU (4.5 mg, 0.03 mmol). The reaction mixture was stirred at 40 0C, until completion was confirmed by MS analysis. The reaction was diluted with 10 ml ethyl acetate and extracted with saturated aqueous with NaHCO3 (2 x 2 mL) and brine (1 x 2 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash chromatography using gradient elution with MeOH in DCM (1%→2%→5%) affording affording pyridazinone 4a. (4.0 mg, 51 %) MS (ESI) m/z = 787.3 (M+H)+.
  • 4
  • [ 154350-29-5 ]
  • C38H46N6O8S3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% The title compound from Example 2 (6.0 mg) and carbonyldiimidazole (2.0 mg) were dissolved in 0.75 ml anhydrous DMF and the resulting solution was heated to 40 0C for 1 h. Cyclopropylsulfonamide (3.6 mg) was added to the reaction followed by DBU (4.5 mg). The reaction mixture was stirred at 40 0C, until completion was confirmed by MS analysis. The reaction was diluted with 10 ml ethyl acetate and extracted with saturated aqueous with NaHCCh (2 x 2 mL) and brine (1 x 2 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash chromatography using gradient elution with MeOH in DCM (1%- >2%- >5%) affording the title compound. (4.0 mg, 51 %) MS (ESI) m/z = 811.42 (M+H)+.
  • 5
  • [ 139631-62-2 ]
  • [ 154350-29-5 ]
YieldReaction ConditionsOperation in experiment
100% With ammonia; In tetrahydrofuran; at 0 - 20℃; for 24h;Product distribution / selectivity; II. Preparation of P1' Intermediates 1. Preparation of Cyclopropylsulfonamide Method 1 (of 2): To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to room temperature overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% ethyl acetate/hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 20℃;Product distribution / selectivity; To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to room temperature overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% ethyl acetate/hexanes) to provide 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01. Anal. Calcd. For C3H7NO2S: C, 29.74; H, 5.82; N, 11.56. Found: C, 29.99; H, 5.89, N, 11.50.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃; To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF. The solution was warmed to room temperature overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained and poured onto a 30 g plug of SiO2 (eluted with 30% to 60% ethyl acetate/hexanes) to provide 3.45 g (100%) of cyclopropylsulfonamide as a white solid. 1H NMR (methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity; To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃; To a solution of 100 mL of THF cooled to 0 C was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g(28. 45 mmol) of cyclopropylsulfonyl chloride (purchased from ArrayBiopharma) in 50mL of THF, the solution warmed to rtovernite and stirred one additional day. The mixture was concentrated until 1-2mL of solvent remained, applied onto 30 g plug ofSi02 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45g (100%) of cyclopropyl sulfonamide as a whitesolid.'H NMR (Methanol-d4) 0.94-1. 07 (m, 4H), 2.52-2. 60 (m,1H); 13C NMR(methanol-d4)8 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃; Method A: To a solution of 100 mL of TUF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied onto 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropylsulfonamide as a white solid.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity; To a solution of 100 mL of THF cooled to 0 C was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied onto 30 g plug of Si02 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3. 45g (100%) of cyclopropyl sulfonamide as a white solid NMR (Methanol-d4) 8 0.94-1. 07 (m, 4H), 2.52-2. 60 (m, 1H) ; 13C NMR (methanol-d4) 8 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 20℃;Product distribution / selectivity; Method A:; O NH3 ( sat ) THF O^ ^ -S I l -Cl ? n _ h I ^ S -NHO 0 0C to rt OTo a solution of 100 mL of THF cooled to 0 0C was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol^) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, IH); 13C NMR (methanol^) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity; To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃; for 24h;Product distribution / selectivity; Method A To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to it overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity; To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃; To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity; Method 2 To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF. The solution was warmed to room temperature overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained and poured onto a 30 g plug of SiO2 (eluted with 30% to 60% ethyl acetate/hexanes) to provide 3.45 g (100%) of cyclopropylsulfonamide as a white solid. 1H NMR (methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
100% With ammonia; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity; To a solution of 100 mL of THF cooled to 0 0C was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol^) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, IH); 13C NMR (methanol^) δ 5.92, 33.01.
95% With ammonia; In dichloromethane; at -78 - 20℃; for 3.25h; Example 27Synthesis of new sulfonamides[0529] Preparation of compound 3: compound 1 (1Og, 71mmol) was dissolved in dry DCM (150ml) under nitrogen. The resulting solution was bubbled through NH3 for 15 minutes at -78 -C, then it was allowed to rise to room temperature and stirred for 3 h. Before filtration, the Filtrate was concentrated to provide compound 2 as white solid 8.2 g (yield
> 90% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Cyclopropylsulfonyl chloride (5 g, 35.56 mmol) was dissolved in 0.5 M ammonia in dioxane (200 ml, 100 mmol) at RT. The reaction was stirred at RT for 3 days. The large amount of precipitation was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 hours to give the cyclopropylsulfonamide (>90%). 1H-NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (1H, m), 1.20 (2H, m), 1.02 (2H, m).
89% With ammonia; In tetrahydrofuran; at 0 - 20℃; for 17h; Ammonia gas was bubbled through THF (355 mL) at 0 C. for 20 min. Neat cyclopropylsulfonyl chloride (1a, 15 g, 0.11 mol) was dropwise added to the solution. The resulting solution was allowed to warm to room temperature and stirred for 17 h. The resulting suspension was filtered through a plug of silica gel, eluting with ethyl acetate. The filtrate was concentrated in vacuo to afford 11.5 g (89%) of cyclopropylsulfonamide 1b. 1H NMR (300 MHz, CD3OD): δ 2.63-2.53 (m, 1H), 1.09-0.95 (m, 4H).
87% With ammonia; In tetrahydrofuran; at 0 - 20℃; [00279] Ammonia gas was bubbled through a gas dispersion tube into THF (40 mL) cooled to 0 0C for 5 minutes. To this solution at 0 0C was added cyclopropylsulfonylchloride (1 gram, 7.1 mmol). The reaction was stirred at room temperature overnight, then filtered through a plug of silica gel, followed by elution with EtOAc to yield 750 mg (6.19 mmol, EPO <DP n="294"/>87%) of cyclopropylsulfonamide. 1H-NMR (500 MHz, Methanol-d4): 4.79 (s, 2H), 2.59-2.54 (m, IH), 1.06-0.96 (m, 4H).
74% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Example 46 Compound of Formula IV, wherein Step 46a: Cyclopropylsulfonyl chloride (1.4 g, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at RT. The reaction was kept at RT for 3 days. The large amount of precipitation was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 hours to give the cyclopropylsulfonamide (0.88 g, 74%). 1H-NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (1H, m), 1.20 (2H, m), 1.02 (2H, m).
74% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Cyclopropylsulfonyl chloride (1.4g, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at rt. The reaction was stirred at rt for 72 h. The precipitate was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 h to give cyclopropylsulfonamide (0.88 g, 74%).1H NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (IH, m), 1.20 (2H, m), 1.02 (2H, m).
74% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Cyclopropylsulfonyl chloride (1.4g, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at rt. The reaction was stirred at rt for 72 h. The precipitate was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 h to give cyclopropylsulfonamide (0.88 g, 74%).1H NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (IH, m), 1.20 (2H, m), 1.02 (2H, m).
74% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Cyclopropylsulfonyl chloride (1.4 g, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at RT. The reaction was kept at RT for 3 days. The large amount of precipitation was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 hours to give the cyclopropylsulfonamide (0.88 g, 74%). 1H-NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (1H, m), 1.20 (2H, m), 1.02 (2H, m).
74% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Cyclopropylsulfonyl chloride (IAg, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at RT. The reaction was kept at RT for 3 days. The large amount of precipitation was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 hours to give the cyclopropylsulfonamide (0.88 g, 74%). 1H- NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (IH, m), 1.20 (2H, m), 1.02 (2H, m).
74% With ammonia; In 1,4-dioxane; at 20℃; for 72h; Step 3A: Cyclopropylsulfonyl chloride (1.4g, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at RT. The reaction was kept at RT for 3 days. The large amount of precipitation was filtered and discarded. The clear filtrate was <n="44"/>evaporated in vacuo and the white residue was dried on vacuum for 24 hours to give the cyclopropylsulfonamide (0.88 g, 74%). 1H-NMR (500 MHz, CD3Cl): δ 4.62 (2H, s), 2.59 (IH, m), 1.20 (2H, m), 1.02 (2H, m).
52% With ammonium hydroxide; In methanol; at 20℃; for 16h; General procedure: Standard Procedure D for the Preparation of Sulfonamides (0054) A solution of sulfonyl chloride in methanol and ammonium hydroxide solution was stirred at 0 C. or room temperature. After the reaction was complete, methanol was removed under reduced pressure. The solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO4(s), filtered, and concentrated to give the desired products without further purification. Step 1. Cyclopropanesulfonamide Following standard procedure D, cyclopropanesulfonyl chloride (0.400 mL, 3.95 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work up, cyclopropanesulfonamide (0.249 g, 52%) was obtained as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 6.78 (br s, 2H), 2.50-2.46 (m, 1H), 0.89-0.86 (m, 4H).
3.45 g (100%) In tetrahydrofuran; ammonia; Preparation of cyclopropyl sulfonamide To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied onto 30 g plug of SiO2 (eluted with 30% to 60% EtOAc/Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
1.70 g (99%) In tetrahydrofuran; ammonia; Preparation of Cyclopropyl Sulfonamide Moiety for Use in Step 2e: To a solution of 20 mL THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added 2 g (5.69 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma). The solution was warmed to room temperature over two hours and the crude solution was filtered through a plug of silica gel eluding the product with ethyl acetate. The fractions were concentrated in vacuo to yield 1.70 g (99%) of cyclopropyl sulfonamide as a white solid: 1H NMR (d4-MeOH, 500 MHz) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H).
3.45 g (100%) In tetrahydrofuran; ammonia; Method 2 To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF. The solution was warmed to room temperature overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained and poured onto a 30 g plug of SiO2 (eluted with 30% to 60% ethyl acetate/hexanes) to provide 3.45 g (100%) of cyclopropylsulfonamide as a white solid. 1H NMR (methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
3.45 g (100%) In tetrahydrofuran; ammonia; Method 2 To a solution of 100 mL of THF cooled to 0 C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF. The solution was warmed to room temperature overnight and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained and poured onto a 30 g plug of SiO2 (eluted with 30% to 60% ethyl acetate/hexanes) to provide 3.45 g (100%) of cyclopropylsulfonamide as a white solid. 1H NMR (methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.
With ammonia; In dichloromethane; at 0 - 20℃; To a solution of cyclopropylmagnesium bromide (0 5 M 20 mL, 10 0 mmol) in anhydrous THF (10 mL) at about -100C is added a solution of SO; in THF (~ 16 wt%, 4 8 mL, 12 mmo.) slowiy over 10 mm at -10 to -5C Tne reaction mixture is warmed to ambient temperature over 0 5h, and then NCS (2 O g 15 mmo.) is added at about -5 to 0C The reaction mixture is warmed up to ambient temperature and diluted with 50 mL oi methyl terl-buty. ether To tne reaction mixture ι≤ added 50 mL water and the mixture is stirred for 5 mm The organic layer is washed with 50 mL of bnne The organic layer is concentrated and the resultant cyclopropylsuifony. chloride is dissolved in CH2Ci2 (total volume was about 50 mL) and ammonia gas is bubbled in at about O'C for about 5 mm and the mixture is slowly warmed up to ambient temperature and stored at that temperature for 2 h The mixture is filtered through Cehte to remove the solid (NH4C.), and the filtrate is concentrated to obtain a crude cyclopropyisulfonamide solid (~ 1 2g) Re-cryslailization of the crude product from EtOAc/hexane produces cyclopropyisuifonarnide 42 in 80% overall yield.
7.03 g With ammonia; In tetrahydrofuran; for 16h; Cyclopropanesulfonamide A mixture of 50 ml of 25% aqueous ammonia solution and 50 ml of THF was initially charged, and then 10.00 g of cyclopropanesulfonyl chloride in 10 ml of THY were slowly added dropwise and the mixture was stirred for 16 hours. After concentration by rotary evaporation and coevaporation with toluene, the residue was extracted by stirring with 100 ml of ethyl acetate and the solids were filtered off. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (7.03 g) with a molecular weight of 121.2 g/mol (C3H7NO2S); MS (ESI): m/e=122 (M+H+).
7.03 g With ammonium hydroxide; In tetrahydrofuran; water; for 16h; Cyclopropanesulfonamide A mixture of 50 ml of 25% aqueous ammonia solution and 50 ml of THF was initially charged, and then 10.00 g of cyclopropanesulfonyl chloride in 10 ml of THF were slowly added dropwise and the mixture was stirred for 16 hours. After concentration by rotary evaporation and coevaporation with toluene, the residue was extracted by stirring with 100 ml of ethyl acetate and the solids were filtered off. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (7.03 g) with a molecular weight of 121.2 g/mol (C3H7NO2S); MS (ESI): m/e=122 (M+H+).
7.03 g In tetrahydrofuran; water; for 16h; A mixture of 50 ml of 25% aqueous ammonia solution and 50 ml of THF was initially charged, and then 10.00 g of cyclopropanesulfonyl chloride in 10 ml of THF were slowly added dropwise and the mixture was stirred for 16 hours. After concentration by rotary evaporation and coevaporation with toluene, the residue was extracted by stirring with 100 ml of ethyl acetate and the solids were filtered off. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (7.03 g) with a molecular weight of 121.2 g/mol (C3H7NO2S); MS (ESI): m/e=122 (M+H+).
With ammonia; In tetrahydrofuran; at 0 - 20℃; [0314] Ammonia gas was bubbled through a gas dispersion tube into THF (40 mL) cooled to 0 0C for 5 minutes. To this solution at 00C was added cyclopropylsulfonylchloride (1 gram, 7.1 mmol). The reaction was stirred at room temperature overnight, then filtered through a plug of silica gel, followed by elution with EtOAc to yield 750 mg (6.19 mmol) of cyclopropylsulfonamide. 1H-NMR (500 MHz, Methanol-d4): 4.79 (s, 2H), 2.59-2.54 (m, IH), 1.06-0.96 (m, 4H).

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  • 6
  • [ 154350-29-5 ]
  • [ 630421-48-6 ]
YieldReaction ConditionsOperation in experiment
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated to reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of <strong>[154350-29-5]cyclopropylsulfonamide</strong> (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2*50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) provided the desired product (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9% acetone in dichloromethane) to give a second batch of the desired product (1.1 g). Both batches were combined (total yield 92%). 1H NMR (DMSO-d6) δ 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 minutes, method B), MS m/z 331 (M++H).
  • 7
  • [ 154350-29-5 ]
  • [ 24424-99-5 ]
  • [ 681808-26-4 ]
YieldReaction ConditionsOperation in experiment
99% Stage lc:oI IBocHN-SI Io[0182] Cyclopropanesulfonamide (5.0 g, 41.26 mmol, 1.0 eq.), triethylamine (8.62 g, 61.90 mmol, 1.5 eq.) and dichloromethane (50 mL) were charged in a 100 mL round bottom flask. Di-te/t-butyldicarbonate (10.8 g, 49.52 mmol, 1.2 eq.) and N,N- dimethylaminopyridine (252 mg, 2.06 mmol, 0.05 eq.) were added portion wise and the reaction mixture stirred at ambient temperature for 48 hours. The solvent was removed in vacuo and the residue diluted with water (20 mL). The aqueous phase was acidified to pH = 1 with 1M hydrochloric acid, and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 9.1 g (99% yield) of the title compound as a white solid. 1H NMR (500 MHz, CDC13) δ ppm 7.14 (br. s., 1 H) 2.90 (tt, 7=8.09, 4.73 Hz, 1 H) 1.50 - 1.54 (m, 9 H) 1.35 - 1.40 (m, 2 H) 1.09 - 1.15 (m, 2 H). LC-MS: purity 100% (UV), tR 1.62 min m/z [M+Na]+ 243.95 (MET/CR/1278).
96% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; To an iced slurry of <strong>[154350-29-5]cyclopropanesulfonamide</strong> (1.21 g, 9.99 mmol), Triethylamine (2.95 mL, 20.97 mmol), and 4-Dimethylaminopyridine (0.061 g, 0.499 mmol) in CH2Cl2 (50 mL) was added solution of Di-tert-butyl dicarbonate (2.423 mL, 10.99 mmol) in DCM (10 mL) dropwise. The formed solution was stirred at room temperature overnight, Removed the solvent in vacuo. The residual oil was taken up in EtOAc and washed with 1M HCl and brine. Dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%50% acetone-hexane to yield the desired produce tert-butyl cyclopropylsulfonylcarbamate (2.17 g, 9.61 mmol, 96% yield) as a viscous oil, which solidified upon standing on bench. 1H NMR (400 MHz, CDCl3) ppm 1.11-1.13 (m, 2H) 1.37-1.39 9m, 2H) 1.53 (s, 9H), 2.89-2.92 (m, 1H) 7.00-7.05 (b, NH).
94% With dmap; triethylamine; In dichloromethane; at 20℃; Step 4:; To the solid <strong>[154350-29-5]cyclopropanesulfonamide</strong> 2d4 (1.51 g ; 12.46 mmol) was added insequence: di-t-butyl-dicarbonate (3.26 g ; 14.95 mmol) dissolved in anhydrousdichloromethane (15 ml_), triethylamine (2.6 ml; 18.65 mmol) anddimethylaminopyridine (76 mg; 0.622 mmol). The resulting solution was stirred atroom temperature overnight and subsequently evaporated to near dryness. Theresidue was diluted with EtOAc, washed with 1N aq. HCI (3x) and brine (1x), dried(MgSO4), filtered and evaporated to dryness to provide the Boc-<strong>[154350-29-5]cyclopropylsulfonamide</strong> product 2d5 as a white solid (2.6 g ; 94%).
94% With dmap; triethylamine; In dichloromethane; at 20℃; To the solid <strong>[154350-29-5]cyclopropanesulfonamide</strong> 2d4 (1.51 g; 12.46 mmol) was added in sequence: di-t-butyl-dicarbonate (3.26 g; 14.95 mmol) dissolved in anhydrous dichloromethane (15 mL), triethylamine (2.6 mL; 18.65 mmol) and dimethylaminopyridine (76 mg; 0.622 mmol). The resulting solution was stirred at room temperature overnight and subsequently evaporated to near dryness. The residue was diluted with EtOAc, washed with 1 N aq. HCl (3×) and brine (1×), dried (MgSO4), filtered and evaporated to dryness to provide the Boc-<strong>[154350-29-5]cyclopropylsulfonamide</strong> product 2d5 as a white solid (2.6 g; 94%).
94% With dmap; triethylamine; In dichloromethane; at 18 - 22℃; Step D; To the solid <strong>[154350-29-5]cyclopropanesulfonamide</strong> 4A4 (1.51 g ; 12.46 mmol) was added in sequence: di-t-butyl-dicarbonate (3.26 g ; 14.95 mmol) dissolved in anhydrous dichloromethane (15 mL), triethylamine (2.6 mL; 18.65 mmol) and dimethylaminopyridine (76 mg; 0.622 mmol). The resulting solution was stirred at room temperature overnight and subsequently evaporated to near dryness. The residue was diluted with EtOAc, washed with 1 N aq. HCI (3x) and brine (1x), dried EPO <DP n="44"/>(MgSO4), filtered and evaporated to dryness to provide the Boc- <strong>[154350-29-5]cyclopropylsulfonamide</strong> product 4A5 as a white solid (2.6 g ; 94%).
93% With dmap; triethylamine; In dichloromethane; for 5.08333h; Compound 2 (4g, 33 mmol) was suspended in dry DCM (100 mL) containing Et3N (5 mL, 36.3 mmol) and DMAP (0.4g , 3.3 mmol). A solution of (Boc)20 (8.3g, 38 mmol) in dry DCM (50 mL) was added dropwise with stirring over 5 min. after 5h, the solution was concentrated in vacuo and the residue treated with EtOAc (30OmL) and IN HCl. The EtOAc layer was washed successively with water (40 mLl) and brine (40 mL), dried (Na2SO4), and concentrated to leave a solid. Heating with hexane (30 mL), cooling to room temperature, and filtration provide compound 3 as a white solid 6.8 g (yield 93%).
88% With dmap; triethylamine; In dichloromethane; To a solution of <strong>[154350-29-5]cyclopropanesulfonamide</strong> (6 g, 50 mmol) in DCM (50 ml) were added triethylamine (7.5 ml, 74 mmol) followed by DMAP (0.3 g, 7.5 mmol) and di-tert-butyl dicarbonate (13 g, 59 ml) and the reaction was left stirring overnight. The solvent was removed; water, 2N HCl (40 ml) and ethyl acetate were added. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give Boc-<strong>[154350-29-5]cyclopropanesulfonamide</strong> as a white solid, used on the next step without further purification. Yield 9.73 g (88%).
87% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 3.5h; Step 1: Preparation of Boc-cyclopropane sulfonyl amide 50. To a solution of <strong>[154350-29-5]cyclopropanesulfonamide</strong>, TEA (13.9 mL), and DMAP (1.11 g, 0.1 eq.) (10.72 g, leq.) in DCM (160 mL) was added a solution of BoC2O (21.88 g, 0.8 eq.) in DCM (10OmL) was added dropwise at 0 0C over 30 min. The mixture was then allowed to warm up to room temperature and stirred for 3 hrs. The solution was washed with IN HCl, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield after trituration in hexane compound 50 as a white solid in 87% yield.1H NMR (CDCl3, 400 MHz): δ 0.92-0.96 (td, J = 6.5 and 1.50 Hz, 2H), 1.51 (s, 9H), 1.60- 1.64 (td, 7 = 6.46 and 1.50 Hz, 2H), 1.25 (m, IH), 6.99 (brs, IH).
85% With dmap; triethylamine; In dichloromethane; at 20℃;Product distribution / selectivity; C.5) Alternative Preparation of Cyclopropylsulfonylamine tert-butyl carbamate To a solution of <strong>[154350-29-5]cyclopropylsulfonamide</strong> (6.0 g, 50.0 mmol) in CH2Cl2 (50 mL) was added BOC2O (13.0 g, 59.0 mmol), triethylamine (7.5 mL, 74 mmol), and 4-DMAP (0.30 g, 2.5 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (300 mL), partitioned with 1 N HCl (3*100 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide 9.3 g (85%) of cyclopropylsulfonylamine tert-butylcarbamate.
85% With dmap; triethylamine; In dichloromethane; at 20℃;Product distribution / selectivity; Step ii) To a solution of <strong>[154350-29-5]cyclopropylsulfonamide</strong> (6.0 g, 50.0 mmol) in CH2Cl2 (50 mL) was added BOC2O(13.0 g, 59.0 mmol), Et3N (7.5 mL, 74 mmol), and 4-DMAP (0.30 g, 2.5 mmol). The reaction mixture was stirred overnite at rt, diluted with EtOAc (300 mL), partitioned with 1 N HCl (3*100 mL), dried over MgSO4 and concentrated in vacuo to afford 9.3 g (85%) of cyclopropylsulfonylamine tert-butylcarbamate as a white solid having identical data to its preparation in Step IIc.
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Step a: tert-butyl (cyciopropyisuifonyi)carbamate To a mixture of 15 g (124 mmof) cyclopropanβsulfo nic acid amide, 25.9 mL (186 mmol) triethylamine and 0.8 g (6.2 mmol) DMAP in 150 ml DCM was added 32.4 g (149 mmol) Boc- anhydride at OC. The mixture was slowly warmed to RT and stirred for 48 h. After dilution with DCM the mixture was washed with 1 N aq. HCi solution. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield the title compound which was used in the next step without further purification. LC-MS (method E): Rt = 1.254 min; MIz = 220.2 [M-H].
2.66 g With dmap; triethylamine; In dichloromethane; for 16h; N-tert-Butyloxycarbonyl<strong>[154350-29-5]cyclopropanesulfonamide</strong> 1.46 g of <strong>[154350-29-5]cyclopropanesulfonamide</strong> were initially charged in a mixture of 30 ml of dichloromethane and 1.67 ml of triethylamine, and then 2.63 g of di-tert-butyl dicarbonate and 0.15 g of 4-dimethylaminopyridine were added and the mixture was stirred for 16 hours. The reaction solution was washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium chloride solution and water, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (2.66 g) with a molecular weight of 221.3 g/mol (C8H15NO4S); MS (ESI): m/e=166 (M-tert-Butyl+H+).
2.66 g With dmap; triethylamine; In dichloromethane; for 16h; N-tert-Butyloxycarbonyl<strong>[154350-29-5]cyclopropanesulfonamide</strong> 1.46 g of <strong>[154350-29-5]cyclopropanesulfonamide</strong> were initially charged in a mixture of 30 ml of dichloromethane and 1.67 ml of triethylamine, and then 2.63 g of di-tert-butyl dicarbonate and 0.15 g of 4-dimethylaminopyridine were added and the mixture was stirred for 16 hours. The reaction solution was washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium chloride solution and water, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (2.66 g) with a molecular weight of 221.3 g/mol (C8H15NO4S); MS (EST): m/e=166 (M-tert-Butyl+H+).
2.66 g With dmap; triethylamine; In dichloromethane; for 16h; 1.46 g of <strong>[154350-29-5]cyclopropanesulfonamide</strong> were initially charged in a mixture of 30 ml of dichloromethane and 1.67 ml of triethylamine, and then 2.63 g of di-tert-butyl dicarbonate and 0.15 g of 4-dimethylaminopyridine were added and the mixture was stirred for 16 hours. The reaction solution was washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium chloride solution and water, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (2.66 g) with a molecular weight of 221.3 g/mol (C8H15NO4S); MS (ESI): m/e=166 (M-tert-butyl+H+).
With dmap; triethylamine; In dichloromethane; at 0 - 25℃; Step 2: Preparation of tert-butyl cyclopropylsulfonylcarbamate: To a solution of A3 (2.0 g, 16.5 mmol) in DCM (30 mL) at 0 C was added DMAP (0.1 g, 0.825 mmol), Et3N (3.52 mL, 24.7 mmol) and Boc20 (4.32 g, 19.8 mmol). The reaction mixture was allowed to warm to RT and stir overnight. After that time, the volatiles were removed under reduced pressure. To the crude residue was added water. The aqueous phase was acidified to pH= 1 with the addition of aqueous 1.0 N HC1 and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, then dried over Na2S04, filtered and concentrated to yield compound A4. NMR (CDC13, 300 MHz): δ 7.20 (bs, 1H), 2.92 - 2.86 (m, 1H), 1.55 (s, 9H), 1.39 - 1.35 (m, 2H), 1.28 - 1.24 (m, 2H).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h; To a solution of <strong>[154350-29-5]cyclopropanesulfonamide</strong> (100 g, 82.6 mmol) in DCM (800 ml) was added triethylamine (234 ml, 165 mmol) followed by DMAP (10.28 g, 82.6 mmol) at 0 C. under nitrogen. To this reaction mixture Boc anhydride (247 ml, 107 mmol) in DCM (400 ml) was added slowly. The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combine organic layer was washed with 1.5 N HCl solution and 10% NaHCO3and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound (143 g, 65.0%) as solid. The crude compound was directly taken for the next step.1H NMR (400 MHz, DMSO-d6): δ ppm 11.08 (s, 1H), 2.90 (m, 1H), 1.48 (s, 9H), 1.06 (m, 4H).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;Inert atmosphere; To a solution of <strong>[154350-29-5]cyclopropanesulfonamide</strong> (100 g, 82.6 mmol) in DCM (800 ml) was added triethylamine (234 ml, 165 mmol) followed by DMAP (10.28 g, 82.6 mmol) at 0 C. under nitrogen. To this reaction mixture Boc anhydride (247 ml, 107 mmol) in DCM (400 ml) was added slowly. The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combine organic layer was washed with 1.5 N HCl solution and 10% NaHCO3 and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound (143 g, 65%) as a solid. The crude compound was directly taken for the next step. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.08 (s, 1H), 2.90 (m, 1H), 1.48 (s, 9H), 1.06 (m, 4H).
65% (143 g) With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h; Step 1: Preparation of tert-butyl cyclopropylsulfonylcarbamate To a solution of <strong>[154350-29-5]cyclopropanesulfonamide</strong> (100 g, 82.6 mmol) in DCM (800 ml) was added triethylamine (234 ml, 165 mmol) followed by DMAP (10.28 g, 82.6 mmol) at 0 C. under nitrogen. To this reaction mixture Boc anhydride (247 ml, 107 mmol) in DCM (400 ml) was added slowly. The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combine organic layer was washed with 1.5 N HCl solution and 10% NaHCO3 and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound (143 g, 65.0%) as solid. The crude compound was directly taken for the next step. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.08 (s, 1H), 2.90 (m, 1H), 1.48 (s, 9H), 1.06 (m, 4H).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 12h; To a solution of <strong>[154350-29-5]cyclopropanesulfonamide</strong> (100 g, 825 mmol) in DCM (1 L) at 0 C was sequentially added DMAP (5.0 g, 41.3 mmol), TEA (173 mL, 1238 mmol), and Boc-anhydride (216 g, 813 mmol). The reaction mixture was allowed to warm to RT and stirred for 12 h. After the completion of reaction (monitored by TLC), it was concentrated under reduced pressure. The crude residue was taken in EtOAc (2000 mL) and washed with aqueous 1.5 _ HC1 (2 x 1000 mL). The organic layer was washed with water (1000 mL), brine (1000 mL) and dried over Na2SO4. The organic layer was concentrated under reduced pressure to afford 22a (180 g, 99%) as a transparent liquid, which was used in next step without purification. MS (ESI -ve ion) m/z: [M-1] = 220.2.1H NMR (400 MHz, chloroform-d) ^ 7.36 (s, 1H), 2.93- 2.88 (m, 1H), 1.53 (d, J = 0.6 Hz, 9H), 1.39-1.36 (m, 2H), 1.15-1.10 (m, 2H).

  • 8
  • [ 154350-29-5 ]
  • [ 914823-96-4 ]
YieldReaction ConditionsOperation in experiment
54% To a solution of EXAMPLE 11 (35 mg, 0.052 mmol) in DMF (0.3 mL) at 400C was added carbonyldiimidazole (8 mg, 0.052 mmol) and the reaction mixture was stirred for Ih. Cyclopropylsulfonamide (10 mg, 0.078 mmol) and DBU (16 mg, 0.01 mmol) were added and the reaction mixture was stirred for 1 h. Following cooling, the reaction mixture was purified on reverse phase HPLC to afford EXAMPLE 17 (22 mg, 54% yield). 1H NMR (500 MHz, CD3OD, ppm) 5 8.19 (d, J= 1.5 Hz, 1 H), 8.14 (d, J= 8.8 Hz, 1 H), 8.09 (m, 2 H), 7.98 (dd, J= 8.8, 1.5 Hz, 1 H), 7.82 (s, 1 H), 7.75 (m, 3 H), 6.01 (m, 1 H), 5.75 (ddd, J= 17.1, 10.3, 8.8 Hz, 1 H), 5.29 (dd, J= 17.1, 1.5 Hz, 1 H), 5.13 (dd, J= 10.5, 1.5 Hz, 1 H), 4.57 (dd, J= 10.7, 6.8 Hz, 1 H), 4.41 (t, J= 7.6 Hz, 1 H), 4.27 (m, 1 H), 4.12 (dd, J= 12.0, 2.9 Hz, 1 H), 3.78 (m, 1 H), 3.02-2.95 (m, 2 H), 2.83 (m, 1 H), 2.68 (dd, J= 13.9, 6.6 EPO <DP n="58"/>Hz, 1 H), 2.44 (m, 1 H), 2.20 (q, J= 8.8 Hz, 1 H), 1.90 (dd, J= 8.1, 5.4 Hz, 1 H), 1.88-1.69 (m, 5 H), 1.57 (m, 1 H), 1.42-1.32 (m, 7 H), 1.29 (m, 2 H), 1.21 (m, 1 H), 1.10 (m, 2 H), and 0.96 (m, 3 H). LRMS (M+H)+ calcd = 772.3; found = 772.4.
  • 9
  • [ 154350-29-5 ]
  • [ 1338580-58-7 ]
YieldReaction ConditionsOperation in experiment
82% Step 2:; To a solution of acid 2e2 (567 mg, 2.49 mmol), in THF (20 mL), was added GDI (515mg, 3.17 mmol). The resulting solution was stirred for 30 min, refluxed for 30 min andallowed to cool down to RT. Cyclopropylsulfonamide 2d4 (455 mg, 3.76 mmol) wasadded followed by the addition of DBU (0.75 mL, 5.02 mmol) and the reaction wasstirred 12 h. The THF was removed in vacuo and the residue was diluted with EtOAc,washed with 1 M HCI (2 X 100 ml) and brine, dried (MgSO4) and purified by flashchromatography (elution conditions: 70:30 hexane/EtOAc) to afford 682 mg (82%) ofcompound 2e3 as a white solid.
  • 10
  • [ 154350-29-5 ]
  • [ 923275-55-2 ]
YieldReaction ConditionsOperation in experiment
77% Example 5: Preparation of 4-Hydroxy-cyclopentane-l,2-dicarboxylic acid 1-[(1- cyclopropanesulfonylamino carbonyl-2-vinyl-cyclopropyl)-amide] 2-(hex-5-enyl- methyl-amide) (8).; EPO <DP n="67"/>The crude acid 7 (410 mg, 1.09 mmol) was dissolved in DMF (1.5 ml) and DCM (4.5 ml) followed by addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 min incubation at room temperature. Subsequently, a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 ml) and DCM (2 ml) was added followed by heating in the microwave to 100C for 30 min. The resulting red solution was concentrated in vacuo and re-dissolved in ethyl acetate (20 ml). The organic phase was washed with 1 M HCl (aqueous) (3x 10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo to yield the crude sulfonamide which was further purified by chromatography (Silica, ethyl acetate/methanol, 97.5:2.5) to afford the target compound 8 (403 mg, 77%); LC/MS (Method A): tR= 3.31 min, >95%, m/z (ESI+)= 482(MH+).
  • 11
  • [ 154350-29-5 ]
  • [ 923946-74-1 ]
YieldReaction ConditionsOperation in experiment
68% Example 38; Cyclopropanesulfonic acid [18-(tert-butyl-dimethyl-silanyloxy)-14-(4-methoxy- benzyl)-2,15-dioxo-3,14,16-triaza-tricvclori4.3.0.0*4,6*lnonadec-7-ene-4-carbonyll- amide (128); A mixture of the acid 127 (275 mg, 0.472 mmol) and CDI (153 mg, 0.944 mmol) in dry THF (40 mL) was refluxed under argon for 2 h. Cyclopropylsulfonamide (172 mg, 1.416 mmol) and DBU (162 μl, 1.086 mmol) were added and the reaction mixture was stirred at 55C over night. The reaction mixture was concentrated by rotary evaporation, mixed with water, acidified with 5% citric acid and extracted into EtOAc. The organic phase was washed with brine, dried over magnesium sulfate and purified by column chromatography to give the title compound (220 mg, 68%). M+H=689.
  • 12
  • [ 154350-29-5 ]
  • [ 923274-51-5 ]
  • [ 923275-55-2 ]
YieldReaction ConditionsOperation in experiment
77% With dmap; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation; Example 5: Synthesis of 4-Hydroxy-cyclopentane-l,2-dicarboxylic acid 1-[(1- cyclopropanesulfonylamino carbonyl-2-vinyl-cyclopropyl)-amide] 2-(hex-5-enyl- methyl-amide) (8).;The crude acid 7 (410 mg, 1.09 mmol) was dissolved in DMF (1.5 mL) and DCM (4.5 mL) followed by addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 min incubation at room temperature. Subsequently, a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 mL) and DCM (2 mL) was added followed by heating in the microwave oven to 100C for 30 min. The resulting red solution was concentrated in vacuo and re-dissolved in EtOAc (20 mL). The organic phase was washed with 1 M HCl (aq) (3x 10 mL) and brine (10 mL), dried (MgSO4) and filtered. The solvent was evaporated in vacuo to yield the EPO <DP n="67"/>crude sulfonamide which was further purified by chromatography (Silica, EtOAc:MeOH, 97.5:2.5) to afford the target compound 8 (403 mg, 77%); LC/MS (Method A): tR= 3.31 min, >95%, m/z (ESI+)= 482(MH+).
77% The crude acid 20a (410 mg, 1.09 mmol) was dissolved in DMF (1.5 ml) and DCM (4.5 ml) followed by addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 min incubation at room temperature. Subsequently, a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 ml) and DCM (2 ml) was added followed by heating in the microwave to 1000C for 30 min. The resulting red solution was concentrated in vacuo and re-dissolved in EtOAc (20 ml). The organic phase was washed with 1 M HCl (aq) (3x 10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo to yield the crude sulfonamide which was further purified by chromatography (Silica, EtOAc/MeOH, <n="77"/>97.5:2.5) to afford the title compound (403 mg, 77%); LC/MS, >95%, m/z (ESI+)=482(MH+).
77% Step e: N-(l-Cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl)-2-(hex-5-enyl- methyl-amino-carbonyl)-4-hydroxy-cyclopentane-carboxamide (IQe); The crude acid 1Od (410 mg, 1.09 mmol) was dissolved in DMF (1.5 ml) and DCM (4.5 ml) followed by addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 min incubation at room temperature. Subsequently, a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 ml) and DCM (2 ml) was added followed by heating in the microwave to 1000C for 30 min. The resulting red solution was concentrated in vacuo and re-dissolved in EtOAc (20 ml). The organic phase was washed with 1 M HCl (aq) (3x 10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo to yield the crude sulfonamide which was further purified by chromatography (Silica, EtOAc:MeOH, 97.5:2.5) which gave the title compound (403 mg, 77%); LC/MS >95%, m/z (ESI+)= 482(MH+).
  • 13
  • [ 154350-29-5 ]
  • C21H30N2O5 [ No CAS ]
  • cyclopropansulfonic acid (Z)-(1R,4R,6S,15R,17R)-(17-ethoxymethoxy-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]-octadec-7-ene-4-carbonyl)amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 20℃; Example 28; Cyclopropanesulfonic acid (17-ethoxymethoxy- 13 -methyl-2, 14-dioxo-3 , 13 -diaza- tricvclor 13.3 0.0*4.6*loctadec-7-ene-4-carbonyl>amidef 118); To a stirred solution of the oxazolinone prepared in example 27 (0.85 g, 2.18 mmol) in dichloromethane (10 ml) was added <strong>[154350-29-5]cyclopropylsulfonamide</strong> (0.29 g, 2.39 mmol) and l,8-diazabicyclo[5.4.0]-undec-7-ene (0.49 ml, 3.3 mmol), then stirred at room temperature overnight. The reaction mixture was monitored by TLC (9:1 ethyl acetate- methanol), then diluted with dichloromethane (25 ml), washed successively with aq. 10 % citric acid (3 x 25 ml) and brine (1 x 25 ml), then dried (Na2SO4), filtered and concentrated into a foam. Flash chromatography of the residue using stepwise gradient elution (ethyl acetate in toluene 60-100 %) followed by concentration and drying of the appropriate fractions gave the title compound as a colorless foam (0.90 g, 81 %). LR- MS: Calcd for C24H38N3O7S: 512. Found: 512 [M+H].
  • 14
  • [ 154350-29-5 ]
  • [ 923604-55-1 ]
  • simeprevir [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 50℃; for 15h; Example 5: Preparation of JV-ri7-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinolin-4- yloxyl - 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclol" 13.3.0.04'6loctadec- 7-ene-4-carbonyll (cvclopropyPsulfonamide (47); A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[l 3.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and <strong>[154350-29-5]cyclopropylsulfonamide</strong> (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2CI2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2CI2) afforded 314 mg of an off-white solid which was further washed with water, EPO <DP n="79"/>then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 as a white powder: m/z = 750 (M+H)+. 1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).
  • 15
  • [ 154350-29-5 ]
  • [ 159622-10-3 ]
  • [ 630421-48-6 ]
YieldReaction ConditionsOperation in experiment
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92% A solution of the product of Step 6 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40mL) was heated at reflux for 50 min under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 h. The mixture was quenched with IN HCI to pH1 and THF was evaporated in vacuo. The suspension was extracted with EtOAc (2 x 50 mL) and the combined organic extracts dried(Na2S04). Purification by recystallization from hexanes-EtOAc (1: 1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in DCM) to give a second batch of the title compound(1.1 g). Both batches were combined (total yield 92percent). 'H NMR : (DMSO-d6)8 0.96-1. 10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2. 24(m, 1H), 2.90(m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d,J=17 Hz,1H), 5.45(m,1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 min, method B), MS m/z 331 (M++H).
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1.0M HCl to pH=1, and THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the organic extracts were combined and dried (Na2SO4). Filtration, concentration, and purification by recrystallization from hexanes-ethyl acetate (1:1) provided the desired product (2.4 g) as a white solid. The mother liquor was purified by flash column chromatography (SiO2, eluted 9percent acetone in dichloromethane) to give a second batch of the desired product (1.1 g). Both batches were combined (total yield 92percent). 1H NMR: (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5,5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers)); LC-MS, MS m/z 331 (M++H).
92% Step 2: Preparation of cyclopropanesulfonic acid (l-(R)-tert-butoxycarbonylamino- 2-(S)-vinylcyclopropanecarbonyl)-amide; A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with IN HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2 x 50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1: 1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 4OS column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR <n="67"/>(DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=S.5, 9.5 Hz, IH), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, IH), 2.19-2.24 (m, IH), 2.90 (m, IH), 5.08 (d, J=IO Hz, IH), 5.23 (d, J=Yl Hz, IH), 5.45 (m, IH), 6.85, 7.22 (s, NH (rotamers); MS mk 331 (M++H).
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2*50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92% A solution of <strong>[159622-10-3](1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid</strong> (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 min under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 h. The mixture was quenched with 1N HCl to pH 1 and THF was evaporated in vacuo. The suspension was extracted with EtOAc (2×50 mL) and the combined organic extracts dried (Na2SO4). Purification by recrystallization from hexanes-EtOAc (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in DCM) to give a second batch of the compound tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate (1.1 g). Both batches were combined (total yield 92percent). (0146) 1H NMR: (DMSO-d6) delta ppm 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS MS m/z 331 (M++H).
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recrystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92% Step 2:; A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1.0M HCl to pH=1, and THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the organic extracts were combined and dried (Na2SO4). Filtration, concentration, and purification by recrystallization from hexanes-ethyl acetate (1:1) provideed the desired product (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the desired product (1.1 g). Both batches were combined (total yield 92percent). 1H NMR: (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers)); LC-MS, MS m/z 331 (M++H).
85% A solution of the acid 1d (8.70 g, 38.3 mmol) and carbonyldiimidazole (8.0 g, 50 mmol) in THF (125 mL) was refluxed for 1 h. To a slurry of cyclopropylsulfonamide 1b (6.03 g, 49.8 mmol) in THF (20 mL) was added at room temperature the above solution via cannular, followed by DBU (8.3 mL, 55.5 mmol). The mixture was stirred for 17 h whereupon it was acidified to pH 7 with 1N HCl. The organic solvent was removed in vacuo and ethyl acetate (200 mL) was added. The aqueous layer was further acidified to pH 1, and the organic layer drawn off. The aqueous layer was extracted with ethyl acetate (2.x.150 mL) and the combined organic layers were washed with brine (110 mL), dried over sodium sulfate, and concentrated in vacuo. The crude solid was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 11.0 g of the product 1e in 85percent yield. 1H NMR (300 MHz, CD3OD): delta 5.64-5.52 (m, 1H), 5.29 (d, J=17.1 Hz, 1H), 5.12 (d, J=10.5 Hz, 1H), 2.95 (bs, 1H), 2.29-2.15 (m, 1H), 1.88-1.82 (m, 1H), 1.47 (s, 9H), 1.33-1.00 (m, 5H).
82% Step B; To a solution of acid 4B2 (567 mg, 2.49 mmol), in THF (20 mL), was added CDI (515 mg, 3.17 mmol). The resulting solution was stirred for 30 min, refluxed for 30 min and allowed to cool down to RT. Cyclopropylsulfonamide 4A4 (455 mg, 3.76 mmol) was added followed by the addition of DBU (0.75 mL, 5.02 mmol) and the reaction was stirred 12 h. The THF was removed in vacuo and the residue was diluted with EtOAc, washed with 1 M HCI (2 X 100 mL) and brine, dried (MgSO4) and purified by flash chromatography (elution conditions: 70:30 hexane/EtOAc) to afford 682 mg (82percent) of compound 4B3 as a white solid.
66% A solution of compound I-1 (0.52 g, 2.3 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluoro-phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 11.6 mmol) in CH2Cl2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition of cyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over 15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound I-2 (0.51 g, 66percent). MS m/z 353.1 (M|+23); 1H NMR (CDCl3) delta 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J=17.4 H), 5.16 (d, J=10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).
66% Example 1Synthesis of {4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-[2-(4-trifluoromethyl-phenyl)-benzo[4,5]furo[3,2-d]pyrimidin-4-yloxy]-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-14-yl}-carbamic acid cyclopentyl ester (Compound 1)Compound I-3 was first prepared from commercially available 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester via the route shown below:To a solution of 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added a suspension of LiOH (0.13 g, 5.3 mmol) in water (1.4 mL). After being stirred overnight at room temperature, the reaction was quenched with 10percent HCl (2 mL) and the solvent was removed under vacuum. The resultant solid powder was washed with water (10 mL) to give compound I-1 (0.27 g, 90percent). MS m/z 249.9 (M++23); 1H NMR (CDCl3) delta 10.35 (brs, 1H), 5.84-5.71 (m, 1H), 5.29 (d, J=17.4 Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 2.23-2.14 (m, 1H), 1.87-1.65 (m, 1H), 1.58-1.41 (m, 1H), 1.43 (s, 9H).A solution of compound I-1 (0.52 g, 2.3 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluoro-phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 11.6 mmol) in CH2Cl2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition of cyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over 15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound I-2 (0.51 g, 66percent). MS m/z 353.1 (M++423); 1H NMR (CDCl3) delta 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J=17.4H), 5.16 (d, J=10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).To a solution of compound I-2 (0.50 g, 1.5 mmol) in MeOH (8 mL) was added SOCl2 (0.26 g, 2.2 mmol) at room temperature. After the reaction mixture was refluxed for 1 hour, MeOH and SOCl2 was removed under vacuum. The residue was triturated from pentane and filtered to give intermediate I-3 as an off-white solid (0.32 g, 91percent). MS m/z (M++1); 1H NMR (CD3COD) delta 5.77-5.65 (m, 1H), 5.43 (d, J=17.4 Hz, 1H), 5.32 (d, J=10.2 Hz, 1H), 3.06-2.97 (m, 1H), 2.45 (dd, J=17.4 Hz, J=7.8, 1H), 2.16 (dd, J=8.0 Hz, J=7.8 Hz, 1H), 1.75 (dd, J=10.1 Hz, J=7.8 Hz, 1H), 1.32-0.86 (m, 4H).Compound 1 was prepared via the route shown below:A solution of 3-amino-benzofuran-2-carboxylic acid amide (1.00 g, 5.7 mmol) and pyridine (1 mL, 12.26 mmol) in THF (25 mL) was stirred at 0° C. for 10 min. To the resulting solution was slowly added 4-trifluoromethyl-benzoyl chloride (1.48 g, 7.1 mmol). Then the temperature was raised to room temperature and the mixture was stirred for 12 h. After the solvent was removed under reduced pressure, the resulting solid was collected, washed with water, and air-dried to yield I-4 (1.92 g, 96.0percent). MS: m/z 349.0 (M++1).To a suspension of I-4 (1.92 g, 5.5 mmol) and 2N NaOH (13 mL) in EtOH (25 mL) was heated at 85° C. for 12 h. After cooled, the mixture was acidified and then EtOH was removed. The resulting solid was collected, filtrated, washed with water, and dried to afford I-5 (1.71 g, 95.0percent). MS m/z 331 (M++1).A solution of I-5 (1.71 g, 5.2 mmol) and excess phosphorus oxychloride (POCl3) was refluxed for 2 hours. After cooled and thoroughly concentrated, the mixture was subjected to extraction with methylene chloride and 10percent sodium hydroxide. The organic layer was dried over MgSO4, concentrated, and crystallized from CH2Cl2 and n-hexane to give compound I-6 (1.49 g, 82percent). MS m/z 348.8, 350.9 (M++1); 1H NMR (CDCl3) delta 8.70 (d, 2H), 8.34 (d, 1H), 7.82-7.75 (m, 4H), 7.57 (ddd, 1H).To a suspension of boc-trans-4-hydroxy-L-proline (0.53 g, 2.3 mmol) in DMSO (25 mL) was added t-BuOK (0.82 g, 5.1 mmol) at 0° C. After the mixture was allowed to warm to room temperature and stirred for 1 hour, compound I-6 (0.81 g, 2.3 mmol) was added slowly at 10° C. Stirring was continued overnight. Iodomethane (1.02 g, 6.9 mmol) was added and the reaction mixture was stirred at room temperature for additional 30 minutes. The reaction mixture was neutralized to pH 6-7 by 10percent HCl aqueous solution and subjected to extraction with methylene chloride. The organic layer was dried over MgSO4, evaporated under vacuum, and purified by silica gel column chromatography to give compound I-7 (1.12 g, 86percent). MS m/z 557.8 (M++1); 1H NMR (CDCl3) delta 8.63 (d, 2H), 8.28 (d, 1H), 7.80-7.74 (m, 2H), 7.70 (d, 2H), 7.51 (ddd, 1H).To a solution of compound I-7 (1.13 g, 2.0 mmol) in MeOH (20 mL) was added SOCl2 (1.21 g, 9.8 mmol) at room temperature. The reaction mixture was refluxed for 1 hour, and MeOH and SOCl2 were removed. The residue was triturated in penta...
66% A solution of compound 1-1 (0.52 g, 2.3 mmol), 2-(lH-7-azabenzotriazol-l-yl)- 1,1 ,3,3-tetramethyl uronium hexafluoro -phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 1 1.6 mmol) in CH2CI2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition ofcyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and l ,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound 1-2 (0.51 g, 66percent). MS m/z 353.1 (M++23); !H NMR (CDCI3) d 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J = 17.4 H), 5.16 (d, J = 10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).
To a solution of Boc-D-beta-vinyl cyclopropane amino acid (4.5g) in DMF was added CDI (3.97g). The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide (4.66g) and DBU (5.78ml). The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was desolved in 4NHCL/Dioxane. The reaction was stirred at RT for lhour and then concentrated in vacuo. The resulted solid was carrired out to next step without further purification. MS (ESI): m/z = 231.10 [M+H].
With hydrogenchloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; In tetrahydrofuran; [(2)H6]acetone; Step 1: tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate A solution of <strong>[159622-10-3](1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid</strong> (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 min under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 h. The mixture was quenched with 1N HCl to pH 1 and THF was evaporated in vacuo. The suspension was extracted with EtOAc (2*50 mL) and the combined organic extracts dried (Na2SO4). Purification by recystallization from hexanes-EtOAc (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in DCM) to give a second batch of the compound tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate (1.1 g).
2.8 g Intermediate C6: tert-butyl (1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate (0154) (0155) Following the procedure in Scheme III, Intermediate C5 (6.0 g, 23.5 mmol) was added in a solution of LiOH (3.0 g, 73.5 mmol) in THF/MeOH/H2O (20 mL/20 mL/10 mL). After 1 h at r.t., the pH was adjusted to 4 with 1N HCl, aqueous layer was separated, EA was added, and the mixture was extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the yellow oil, which was used directly in the next reaction without further purification. (0156) Then the intermediate (5.6 g, 24.2 mmol) and CDI (5.2 g, 31.5 mmol) were dissolved in THF (20 mL). After refluxed for 1 h, the mixture was cooled to r.t. and then a solution of cyclopropanesulfonamide (3.8 g, 31.5 mmol) in DCM (30 mL) was added followed by adding DBU (5.2 mg, 34.0 mmol). The mixture was stirred overnight at the room temperature, concentrated and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title compound C6 (2.8 g, 36.4percent) as white solid. (0157) 1H NMR (400 MHz, CDC3) delta 9.52 (s, 1H), 5.66-5.57 (m, 1H), 5.32 (d, J=13.2 Hz, 1H), 5.17 (dd, J=10.4, 0.8 Hz, 1H), 2.94-2.87 (m, 1H), 2.17 (q, J=8.4 Hz, 1H), 1.92-1.89 (m, 1H), 1.48 (s, 9H), 1.45-1.39 (m, 1H), 1.32-1.25 (m, 2H), 1.13-1.00 (m, 2H).

  • 16
  • [ 154350-29-5 ]
  • (1S,4R,6S,14S,18R)-14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0(4,6)]nonadec-7-ene-4-carboxylic acid [ No CAS ]
  • [18-(tert-butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0<SP>4,6</SP>]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% 14-tert-Butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmoL) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for 2 h, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (135 mg, 1.12 mmoL) and DBU (170 mg, 1.12 mmoL). The reaction mixture was stirred for 4 h at rt, and the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by flash chromatography (eluting with 33% ethyl acetate in hexane) to give 300 mg (51%) of [18-(tert-butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CD3OD) δ 1H 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (s, 9H), 0.87-1.49 (m, 21H), 1.73-1.95 (m, 3H), 2.08-2.16 (m, 1H), 2.25-2.36 (m, 2H), 2.42-2.56 (m, 1H), 2.85-2.93 (m, 1H), 3.65-3.74 (dd, J=10.61, 3.66 Hz, 1H), 3.89 (d, J=10.25 Hz, 1H), 4.34 (m, J=9.70, 9.70 Hz, 1H), 4.43 (t, J=7.87 Hz, 1H), 4.57 (s, 1H), 4.94-5.01 (m, 1H), 5.10 (d, J=8.78 Hz, 1H), 5.66-5.75 (m, 1H), 6.55 (s, 1H), 10.13 (s, 1H); MS m/z 683 (M++1).
51% Step 6: preparation of [18-(tert-Butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester 14-tert-Butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmoL) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for two hours, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (135 mg, 1.12 mmoL) and DBU (170 mg, 1.12 mmoL). After stirring for 4 h at rt, the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give the crude product. It was then purified by flash column, eluting with 33% ethyl acetate in hexane to isolate a white solid (300 mg, 51%). 1H NMR (300 MHz, CD3OD) δ ppm 1H 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (s, 9H), 0.87-1.49 (m, 21H), 1.73-1.95 (m, 3H), 2.08-2.16 (m, 1H), 2.25-2.36 (m, 2H), 2.42-2.56 (m, 1H), 2.85-2.93 (m, 1H), 3.65-3.74(dd, J=10.61, 3.66 Hz, 1H), 3.89 (d, J=10.25 Hz, 1H), 4.34 (m, J=9.70, 9.70 Hz, 1H), 4.43 (t, J=7.87 Hz, 1H), 4.57 (s, 1H), 4.94-5.01 (m, 1H), 5.10 (d, J=8.78 Hz, 1H), 5.66-5.75 (m, 1H), 6.55 (s, 1H), 10.13 (s, 1H). MS m/z 683 (M++1).
51% 14-tert-Butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmoL) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for 2 h, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (135 mg, 1.12 mmoL) and DBU (170 mg, 1.12 mmoL). The reaction mixture was stirred for 4 h at rt, and the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by flash chromatography (eluding with 33% ethyl acetate in hexane) to give 300 mg (51%) of [18-(tert-butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CD3OD) δ 1H 0.07 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H), 0.87-1.49 (m, 21 H), 1.73-1.95 (m, 3 H), 2.08-2.16 (m, 1 H), 2.25-2.36 (m, 2 H), 2.42-2.56 (m, 1 H), 2.85-2.93 (m, 1 H), 3.65-3.74(dd, J=10.61, 3.66 Hz, 1 H), 3.89 (d, J=10.25 Hz, 1 H), 4.34 (m, J=9.70, 9.70 Hz, 1 H), 4.43 (t, J=7.87 Hz, 1 H), 4.57 (s, 1 H), 4.94-5.01 (m, 1 H), 5.10 (d, J=8.78 Hz, 1 H), 5.66-5.75 (m, 1 H), 6.55 (s, 1 H), 10.13 (s, 1 H); MS m/z 683 (M++1).
51% 14-tert-Butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmol.) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmol.). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for 2 h, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (135 mg, 1.12 mmol.) and DBU (170 mg, 1.12 mmol.). The reaction mixture was stirred for 4 h at rt, and the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by flash chromatography (eluting with 33% ethyl acetate in hexane) to give 300 mg (51%) of [18-(tert-butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CD3OD) δ 1H 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (s, 9H), 0.87-1.49 (m, 21H), 1.73-1.95 (m, 3H), 2.08-2.16 (m, 1H), 2.25-2.36 (m, 2H), 2.42-2.56 (m, 1H), 2.85-2.93 (m, 1H), 3.65-3.74 (dd, J=10.61, 3.66 Hz, 1H), 3.89 (d, J=10.25 Hz, 1H), 4.34 (m, J=9.70, 9.70 Hz, 1H), 4.43 (t, J=7.87 Hz, 1H), 4.57 (s, 1H), 4.94-5.01 (m, 1H), 5.10 (d, J=8.78 Hz, 1H), 5.66-5.75 (m, 1H), 6.55 (s, 1H), 10.13 (s, 1H); MS m/z 683 (M++1).
51% 14-tert-Butoxycarbonylamino- 18-(tert-butyl-dimethyl-silanyloxy)-2, 15-dioxo-3, 16- diaza-tricyclo[14.3.0.04'6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmoL) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for 2 h, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (135 mg, 1.12 mmoL) and DBU (170 mg, 1.12 mmoL). The reaction mixture was stirred for 4 h at rt, and the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by flash chromatography (eluting with 33% ethyl acetate in hexane) to give 300 mg (51%) of [ 18-(tert-butyl- dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.04'6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CD3OD) δ IH 0.07 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H), 0.87-1.49 (m, 21 H), 1.73-1.95 (m, 3 H), 2.08-2.16 (m, 1 H), 2.25-2.36 (m, 2 H), 2.42-2.56 (m, 1 H), 2.85-2.93 (m, 1 H), 3.65-3.74(dd, ./=10.61, 3.66 Hz, 1 H), 3.89 (d, J=10.25 Hz, 1 H), 4.34 (m, J=9.70, 9.70 Hz, 1 H), 4.43 (t, J=7.87 Hz, 1 H), 4.57 (s, 1 H), 4.94-5.01 (m, 1 H), 5.10 (d, J=8.78 Hz, 1 H), 5.66-5.75 (m, 1 H), 6.55 (s, 1 H), 10.13 (s, 1 H); MS m/z 683 (M++l).

  • 17
  • [ 154350-29-5 ]
  • [ 934475-58-8 ]
  • [ 934475-59-9 ]
YieldReaction ConditionsOperation in experiment
53% Step 7: Synthesis of (IS, 4R, 6S, 14S, 18R)- [7-cis-4-Cyclopropanesulfonylaminocarbonyl-12-cyclopropyl-18-(tert-butyldimethylsilyloxy)- 2, 15-dioxo-3, 12,16-triaza-tricyclo[14.3.0. (f'6]nonadec-7 -en-14-yl] carbamic acid, tert-butyl ester.; (15, AR, 65, 145, 18R)-7-c-14-tert-Butoxycarbonylamino-18-(tert- butyldimethylsilyloxy)-2,15-dioxo-3, 12,16-triazatricyclo[ 14.3.0.04'6]nonadec-7-ene- 4-carboxylic acid (490 mg, 0.79 mmol) was dissolved in 15 mL of THF and treated with CDI (179 mg, 1.10 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for two hours, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (134 mg, 1.10 mmoL) and DBU (168 mg, 1.10 mmoL). <n="95"/>After stirring overnight at rt, the THF was removed by rotary evaporation. The residue was dissolved in water and IN HCl was added until the pH = 5. This aqueous solution was extracted with EtOAc (3x). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by flash column, eluting with 3% methanol in methylene chloride, gave 300 mg (53%) Of (IS", 4R, 65, 145, 18R)- [7-c-4-Cyclopropanesulfonylaminocarbonyl-12- cyclopropyl- 18-(tert-butyldimethylsilyloxy)-2, 15 -dioxo-3 ,12,16-triaza- tricyclo[14.3.0.04'6]nonadec-7-en-14-yl]carbamic acid, tert-butyl ester as a white solid: LC-MS (Phenomenex 10 μm Cl 8 HPLC column: 3.0x50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH / 90% H2O / 0.1% TFA. Solvent B: 10% H2O / 90% MeOH / 0.1% TFA.) (Retention time: 2.40 min), MS m/z 724 (M++l).
53% (1S, 4R, 6S, 14S, 18R)-7-cis-14-tert-Butoxycarbonylamino-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (490 mg, 0.79 mmol) was dissolved in 15 mL of THF and treated with CDI (179 mg, 1.10 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for two hours, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (134 mg, 1.10 mmoL) and DBU (168 mg, 1.10 mmoL). After stirring overnight at rt, the THF was removed by rotary evaporation. The residue was dissolved in water and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by flash column, eluting with 3% methanol in methylene chloride, gave 300 mg (53%) of (1S, 4R, 6S, 14S, 18R)-[7-cis-4-Cyclopropanesulfonylaminocarbonyl-12-cyclopropyl-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]carbamic acid, tert-butyl ester as a white solid: LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.40 min), MS m/z 724 (M++1).
53% Compound 1f (490 mg, 0.79 mmol) was dissolved in 15 mL of THF and treated with CDI (179 mg, 1.10 mmoL). (Care was taken to exclude moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for two hours, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (134 mg, 1.10 mmoL) and DBU (168 mg, 1.10 mmoL). After stirring overnight at rt, the THF was removed by rotary evaporation. The residue was dissolved in water and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by flash column, eluting with 3% methanol in methylene chloride, gave 300 mg (53%) of 1 g as a white solid: LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.40 min), MS m/z 724 (M++1).
53% (15, 4R, 65, 145, 18R)-7-c-14-tert-Butoxycarbonylamino-18-(tert- butyldimethylsilyloxy)-2,15-dioxo-3, 12,16-triazatricyclo[ 14.3.0.04'6]nonadec-7-ene- 4-carboxylic acid (490 mg, 0.79 mmol) was dissolved in 15 mL of THF and treated with CDI (179 mg, 1.10 mmoL). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for two hours, it was cooled to rt and treated sequentially with <strong>[154350-29-5]cyclopropylsulfonamide</strong> (134 mg, 1.10 mmoL) and DBU (168 mg, 1.10 mmoL). After stirring overnight at rt, the THF was removed by rotary evaporation. The residue was dissolved in water and IN HCl was added until the pH = 5. This aqueous solution was extracted with EtOAc (3x). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by flash column, eluting with 3% methanol in methylene chloride, gave 300 mg (53%) of (15, AR, 65, 145, 18R)- [1-cis-A-Cyclopropanesulfonylaminocarbonyl- 12-cyclopropyl- 18-(tert- butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04'6]nonadec-7-en- 14-yl]carbamic acid, tert-butyl ester as a white solid: LC-MS (Phenomenex 10 μm Cl 8 HPLC column: 3.0x50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH / 90% H2O / 0.1% TFA. Solvent B: 10% H2O / 90% MeOH / 0.1% TFA.) (Retention time: 2.40 min), MS m/z 724 (M++l).

  • 18
  • [ 259217-95-3 ]
  • [ 154350-29-5 ]
  • [ 630421-48-6 ]
YieldReaction ConditionsOperation in experiment
92% A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of <strong>[154350-29-5]cyclopropylsulfonamide</strong> (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with IN HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2 x 50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1: 1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 4OS column (eluted 9% acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92%). 1H NMR (DMSO-d6) δ 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, IH), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, IH), 2.19-2.24 (m, IH), 2.90 (m, IH), 5.08 (d, J=IO Hz, IH), 5.23 (d, J=Il Hz, IH), 5.45 (m, IH), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
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