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[ CAS No. 41720-98-3 ] {[proInfo.proName]}

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Product Details of [ 41720-98-3 ]

CAS No. :41720-98-3 MDL No. :MFCD07783026
Formula : C5H11N Boiling Point : -
Linear Structure Formula :- InChI Key :RGHPCLZJAFCTIK-RXMQYKEDSA-N
M.W : 85.15 Pubchem ID :641544
Synonyms :

Calculated chemistry of [ 41720-98-3 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 30.75
TPSA : 12.03 Ų

Pharmacokinetics

GI absorption : Low
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) : -6.31 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.78
Log Po/w (XLOGP3) : 0.72
Log Po/w (WLOGP) : 0.38
Log Po/w (MLOGP) : 0.76
Log Po/w (SILICOS-IT) : 1.39
Consensus Log Po/w : 1.01

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.82
Solubility : 12.8 mg/ml ; 0.151 mol/l
Class : Very soluble
Log S (Ali) : -0.55
Solubility : 23.9 mg/ml ; 0.281 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.09
Solubility : 6.94 mg/ml ; 0.0815 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 41720-98-3 ]

Signal Word:Danger Class:3,8
Precautionary Statements:P242-P264-P271-P280-P301+P330+P331-P304+P340-P305+P351+P338-P310-P363-P370+P378-P403+P233-P501 UN#:2733
Hazard Statements:H225-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 41720-98-3 ]

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

  • Downstream synthetic route of [ 41720-98-3 ]

[ 41720-98-3 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 41720-98-3 ]
  • [ 59335-85-2 ]
  • 2
  • [ 23418-85-1 ]
  • [ 41720-98-3 ]
  • [ 460747-73-3 ]
  • 3
  • [ 157007-54-0 ]
  • [ 41720-98-3 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride; In 1,4-dioxane; for 0.5h; Step B: (i)-2-Methylpyrrolidine Hydrochloride; (i?)-ter/-Butyl 2-methylpyrrolidine-l-carboxylate (22.7 g, 123 mmol) was dissolved in a 4 M hydrogen chloride solution in dioxane (100 mL) and the reaction was stirred for 30 min. TLC (2:1, ethyl acetate/hexanes) confirmed that there was no starting material left. The solvent was removed under reduced pressure. The crude residue was dissolved in acetonitrile and toluene. The solvent was removed under reduced pressure and the resulting white powder was dried overnight under reduced pressure to give the title compound (14.6 g) in 98percent yield. 1H NMR (400 MHz, CDCl3) delta 1.55 (d, J= 6.57 Hz, 3 H), 1.66 - 1.77 (m, 1 H), 1.95 - 2.04 (m, 1 H), 2.05 - 2.23 (m, 2 H), 3.25 - 3.36 (m, 1 H), 3.37 - 3.48 (m, 1 H), 3.62 - 3.74 (m, 1 H), 9.38 (s, 1 H), 9.86 (s, 1 H).
95.6% With hydrogenchloride; In ethyl acetate; at 20℃; for 2.08333h;pH 1.0; Example 4 Preparation of 2-(R)-methyl-pyrrolidine.HCl (6) 2-(R)-Methyl-pyrrolidine-1-carboxylic tert-butyl ester (compound (5), 12 g, 64 mmol), obtained from Example 1, Step 4, was dissolved in ethyl acetate and HCl gas was passed through it for 5 minutes until the pH of the reaction mixture was below 1. The reaction mixture was mixed at room temperature for 2 hours. HPLC showed the absence of the starting material. The reaction mixture was concentrated to leave a residue, which was triturated with methyl tert-butyl ether (3*30 mL) while decanting the liquors.
With hydrogenchloride; acetic acid; at 20℃; for 1h; To a 500 mL flask is placed 2R-Methyl-pyrrolidine-l-carboxylic acid tert-butyl ester (see Intermediate 6) (5.4 g, 29.1 mmol) and HC1 / acetic acid (1M, 45 mL) at ambient temperature. The mixture is stirred for 1 hour and then concentrated to an oily solid. The solid is triturated with 2:1 diethyl ether / hexane and dried to give 3.02 g of pure titled compound. 400 MHz NMR (Methanol- d4) 8 3.67 (m, 1H), 3.35 (m, 2H), 2.25 (m, 1H) 2.1 (m, 2H), 1.66 (m, 1H), and 1.43 (d, 7= 8Hz, 3H)
  • 4
  • [ 41720-98-3 ]
  • [ 590-17-0 ]
  • [ 904679-05-6 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine; In methanol; at 0 - 20℃; for 1h; (Step 1) <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> (1.66 g, 13.7 mmol) prepared in a similar manner to the method described in was dissolved in methanol (20 mL) and the solution was added with triethylamine (9.55 mL, 68.5 mmol) and bromoacetonitrile (2.86 mL, 41.1 mmol) under ice bath, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was added with saturated brine and extracted with chloroform. After washing with saturated brine, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate (7:3)) to obtain (R)-1-cyanomethyl-2-methylpyrrolidine (1.70 g, 100 percent) as a clear oily substance. 1H NMR (CDCl3, deltappm): 1.10 (d, J = 6.0 Hz, 3H), 1.39-1.53 (m, 1H), 1.71-1.91 (m, 2H), 1.94-2.08 (m, 1H), 2.53-2.66 (m, 2H), 3.03 (td, J =3.2 Hz, 8.4 Hz, 1H), 3.68 (s, 2H).
  • 5
  • [ 1005402-21-0 ]
  • [ 41720-98-3 ]
  • CEP-19938 [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% 6-[4-(3-Chloropropoxy)phenyl]-2-methyl-2H-pyridazin-3-one (1.5 g, 5.4 mmol), K2CO3 (2.2 g 16.2 mmol), NaI (805 mg, 5.4 mmol) R-methylpyrrolidine HCl (1.3 g, 10.8 mmol) in CH3CN (30 mL) was heated under N2 at 90° C. for 2 days. The reaction was filtered and concentrated. The residue was dissolved in EtOAc and washed with 2N Na2CO3 (1.x.), NaCl solution (1.x.) dried (MgSO4) and concentrated. The product was purified by ISCO chromatography (80 g silica gel column, 95:5 DCM:MeOH). The fractions were combined and concentrated to yield 850 mg (48percent) of free base. The HCl was prepared by adding a 1N HCl-ether solution to the based in ether. The product was collected, and recrystallized from CH3CN-ether. mp 183-185° C. 1H NMR (DMSO-d6) delta 1.38 (d, 3H), 1.62 (m, 1H), 1.92-1.3.1 (m, 3H), 3.4 (m, 3H), 3.7 (m, 1H), 3.7 (s, 3H), 4.15 (m, 2H), 7.0-7.17 (m, 3H), 7.8 (d, 2H), 8.0 (d, 1H), 10.1 (s, 1H). MS m/z=328 (M+H).
  • 6
  • [ 1005402-22-1 ]
  • [ 41720-98-3 ]
  • Irdabisant [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of the product from step 2 (5.5 g, 21 mmol), K2CO3 (3.5 eq, 10.1 g), 100 mg of NaI, and R-2-methylpyrrolidine hydrochloride (2 eq., 5.1 g) in 250 mL of acetonitrile was heated to 80° C. for 2 days. The reaction mixture was then filtered, washed with CH2Cl2 (2.x.50 mL), and concentrated. The residue was dissolved in 200 mL of CH2Cl2, and washed with saturated NaHCO3, saturated NaCl, dried with Na2SO4 and concentrated. The residue was purified by ISCO graduate chromatography with 100percent CH2Cl2 to 5percent MeOH: 95percent CH2Cl2:0.5 mL of 2-aminopropane and then to 10percent MeOH: 90percent CH2Cl2:0.5 mL of 2-aminopropane to give the product. The product was dissolved in 15 mL of MeOH and then added 30 mL of 0.5 N HCl in EtOH. Evaporation of the solvent, and crystallization from MeOH:Et2O afforded the example 11 as the HCl salt (2.65 g, 41percent): Mp 240-2° C.; MS m/z 314 (M+H).
  • 7
  • [ 1005402-25-4 ]
  • [ 41720-98-3 ]
  • 5-Isopropyl-7-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-5H-thieno[2,3-d]pyridazin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of the product of step 4 (109 mg, 0.3 mmol), K2CO3 (3.5 eq, 145 mg), 50 mg of NaI, and R-2-methylpyrrolidine hydrochloride (1.2 eq., 44 mg) in 10 mL of acetonitrile was heated to 80° C. for 2 days. The reaction mixture was then filtered, washed with CH2Cl2 (2.x.20 mL) and concentrated. The residue was dissolved in 20 mL of CH2Cl2, and washed with saturated NaHCO3 solution, saturated NaCl solution, dried with Na2SO4, and concentrated. The residue was purified by preparative TLC or ISCO graduate silica gel chromatography (MeOH:CH2Cl2:2-aminopropane; 5:95:0.5) to give the product. The product was dissolved in 5 mL of MeOH, and added 0.5 mL of 1N HCl in EtOH. Evaporation of the solvent, and crystallization from MeOH:Et2O afforded the HCl salt of example 22 (5-isopropyl-7-(4-(3-((R)-2-methyl-pyrrolidin-1yl)propoxy)phenyl)-5H-thieno[2,3-d]pyridazin-4-one) (52 mg, 42percent): Mp 123-4° C.; MS m/z 412 (M+H).
  • 8
  • [ 1005402-33-4 ]
  • [ 41720-98-3 ]
  • 2,6-dimethyl-5-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of the product of step 3 (481 mg, 1.65 mmol), K2CO3 (3.5 eq, 795 mg), 50 mg of NaI, and R-2-methylpyrrolidine hydrochloride (2.0 eq., 773 mg) in acetonitrile (10 mL) was heated to 80° C. for 2 days. The reaction was then filtered, washed with CH2Cl2 (2.x.20 mL) and concentrated. The residue was dissolved in 30 mL of CH2Cl2 and washed with saturated NaHCO3, saturated NaCl solution, dried with Na2SO4 and then concentrated. The residue was purified by preparative TLC (10percent MeOH: 90percent CH2Cl2:0.5 mL 2-aminopropane) to give the product. The product was dissolved in 10 mL of MeOH, and was added 2.5 mL of 1N HCl in EtOH. The solvents were evaporated and the product crystallized from MeOH:Et2O to give example 86 as the HCl salt (231 mg, 41percent): Mp 176-8° C.; MS m/z 342 (M+H).
  • 9
  • [ 41720-98-3 ]
  • [ 627-30-5 ]
  • [ 862314-38-3 ]
YieldReaction ConditionsOperation in experiment
33% With potassium carbonate; potassium iodide; In butanone; at 100℃; To 3-chloro-1-propanol (1.00 g, 10.6 mmol) in 2-butanone (10.00 mL) was added R-2-methyl-pyrrolidine hydrochloride (1.93 g, 15.9 mmol), potassium carbonate (3.65 g, 26.44 mmol), and potassium iodide (1.76 g, 10.6 mmol). After overnight stirring at 100° C., the reaction was filtered, partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated under vacuum to obtain 495 mg product (33percent); MS m/z 144 (M+H).
  • 10
  • [ 1005402-79-8 ]
  • [ 41720-98-3 ]
  • [ 1005402-80-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide; In acetonitrile; at 90℃; for 48h; The product from step 1 (3.1 g, 10.4 mmol), R-2-methylpyrrolidine HCl (2.5 g, 21 mmol), KI (0.9 g) and K2CO3 (4.1 g, 2.9 mmol) in acetonitrile (75 mL) was stirred at 90° C. for 2 days. The reaction was cooled, filtered and concentrated. The residue was dissolved in Et2O (75 mL) and washed with water and NaCL solution, dried (MgSO4) and concentrated to an oil; MS m/e 348 (M+H).
  • 11
  • [ 1005402-83-4 ]
  • [ 41720-98-3 ]
  • [ 1005402-84-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide; In acetonitrile; at 90℃; for 48h; The product from step 3 (0.75 g, 2.4 mmol), R-2-methylpyrrolidine benzene sulfonic acid salt (1.0 g, 5 mmol), K2CO3 (1 g, 7 mmol) and KI (0.1 g) in acetonitrile (25 mL) were heated at 90° C. for 2 days. The reaction was filtered, concentrated, dissolved in Et2O and washed with water, NaCl solution and dried (MgSO4) to give 0.7 g as an oil; MS m/z 376 (M+H).
  • 14
  • [ 338945-22-5 ]
  • [ 41720-98-3 ]
  • 15
  • [ 791614-74-9 ]
  • [ 41720-98-3 ]
  • [ 791784-75-3 ]
YieldReaction ConditionsOperation in experiment
1.9 g (100%) With triethylamine; In dichloromethane; acetonitrile; Example 2F 5-Bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole A solution of 2-(5-bromo-benzothiazol-2-yl)-ethanol (1.50 g, 5.8 mmol) and triethylamine (1.33 g, 11.6 mmol) in CH2Cl2 was cooled to 0° C., and mesyl chloride was added dropwise. The mixture was warmed to room temperature and stirred for 1 hr. The solvent was removed under vacuum, and to the residue was added acetonitrile (20 mL), triethylamine (1.33 g, 11.6 mmol) 2-(R)-methylpyrrolidine hydrochloride (2.83 g, 23.2 mmol) to the mixture, and the mixture was stirred at 60° C. for 1 hr. Solvents were removed under vacuum, and the residue was dissolved in 20 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride extracts were concentrated to give a crude product yield 1.9 g (100percent)
  • 16
  • [ 791614-75-0 ]
  • [ 41720-98-3 ]
  • 5-Bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In tetrahydrofuran; acetonitrile; at 60℃; for 18h; A solution of 2-(5-bromo-benzothiazol-2-yl)-ethanol and triethylamine in THF was cooled to -20° C., and mesyl chloride was added at -20 to -10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate, 2-(R)-methylpyrrolidine hydrochloride and acetonitrile were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and chromatographed (silica gel, 10:90 MeOH:CHCl3) to give 5-Bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole.
  • 17
  • 2-(6-bromobenzo[d]thiazol-2-yl)ethyl methanesulfonate [ No CAS ]
  • [ 41720-98-3 ]
  • 6-bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.3% With potassium carbonate; In tetrahydrofuran; acetonitrile; at 60℃; for 18h; A solution of 2-(6-bromo-benzothiazol-2-yl)-ethanol (2.23 g, 8.6 mmol) and triethylamine (2.19 g, 21.6 mmol) in THF (45 mL) was cooled to -20° C., and mesyl chloride (1.58 g, 13.8 mmol) was added at -20 to -10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate (1.79 g, 13 mmol), 2-(R)-methylpyrrolidine hydrochloride (2.1 g, 17.2 mmol) and acetonitrile (40 mL) were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and chromatographed (silica gel, 10:90 MeOH:CHCl3) to give 6-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (2.48 g, 88.3percent yield). 1H NMR (CDCl3, 400 MHz) delta 1.12 (d, 3H, J=7 Hz), 1.41-1.50 (m, 1H), 1.68-1.87 (m, 2H), 1.91-1.99 (m, 1H), 2.24 (q, 1H, J=7 Hz), 2.39-2.48 (m, 1H), 2.56-2.64 (m, 1H), 3.19-3.33 (m, 4H), 7.52 (dd, 1H, J=8, 4 Hz), 7.79 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=4 Hz); 13C NMR(CDCl3, 400 MHz) delta 19.3, 22.1, 33.1, 33.9, 52.5, 53.7, 59.9, 117.9, 123.3, 123.7, 128.9, 136.9, 151.3, 170.4; (DCl/NH3) m/z 325, 327 (M+H)+.
  • 18
  • C12H12BrNO3S [ No CAS ]
  • [ 41720-98-3 ]
  • [ 689291-63-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In tetrahydrofuran; acetonitrile; at 60℃; for 20h; The product from Example 62E (0.5 g, 2.0 mmol) and triethylamine (0.5 g, 4.9 mmol) were combined in THF (15 ML) at -15° C. The mixture was treated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at 0-10° C. for 2 hours.The mixture was treated with additional methanesulfonyl chloride (0.2 mmol) and stirred at room temperature for 16 hours.The mixture was treated with <strong>[41720-98-3](2R)-2-methylpyrrolidine hydrochloride</strong> (0.72 g, 6.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) in acetonitrile (25 ML) and then the mixture was heated at 60° C. for 20 hours.The mixture was allowed to cool to room temperature and was concentrated under reduced pressure.The residue was dissolved in 20 ML CH2Cl2, washed with 5 ML of water and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) delta 9.10 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.72 (dd, J=12, 4 Hz, 1H), 7.64 (d, J=12 Hz, 1H), 7.58 (s, 1H), 3.46-3.40 (m, 2H), 3.34-3.29 (m, 2H), 2.91-1.85 (m, 1H), 2.81-2.68 (m, 1H), 2.59-2.49 (m, 1H), 2.11-2.02 (m, 1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 1H), 1.32 (d, J=8 Hz, 3H).13C NMR (CDCl3, 100 MHz) delta 152.5, 150.6, 134.5, 133.6, 129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4, 36.0, 32.4, 21.9, 17.9. MS (DCl/NH3) 319, 321 [M+H]+.
  • 19
  • [ 177948-61-7 ]
  • [ 41720-98-3 ]
  • [ 871489-56-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In tetrahydrofuran; at 70℃; for 24h; The crude mesylate is dissolved in THF (50mL), and triethylamine (22 mL, 156 mmol) is added followed by R-methylpyrrolidine hydrochloride salt (CAS 135324-85-5, 9.49g, 78 mmol), and the reaction mixture heated at 70 °C for 24 hours. The crude reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with saturated sodium bicarbonate, dried (Na2S04), and concentrated in vacuo to give the crude amine. Purification by flash chromatography (1-10percent MeOH in CH2C12) affords the desired amine. MS (ES+) 269.2
  • 20
  • [ 1117949-04-8 ]
  • [ 41720-98-3 ]
  • 4-(3-chloro-4-fluorophenyl)-6-(4-(1-methyl-1H-imidazol-2-yl)-piperazin-1-yl)-2((R)-2-methylpyrrolidin-1-yl)-pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ISOPROPYLAMIDE; at 110℃; for 16h; 2. 4-(3-Chloro-4-fluoro-phenyl)-6-[4-(l-methyl-lH4midazol-2-yl)psiiperazin-l-ylJ methyl-pyrrolidin-l-yl)-pyrimidineHeat a solution of 2-chloro-4-(3-chloro-4-.pound.luoro-phenyl)-6-[4-(l-methyl-lH-imidazol-2- yl)-piperazin-l-yl]-pyrimidine (50 mg, 0.123 mmol) and <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> (prepared essentially as described in US Published Application 2004/0171845; 22 mg, 0.18 mmol) in DMA at 1100C for 16 hours. Partition the cooled mixture between EtOAc and 10percent NaOH and separate the layers. Wash the organic layer with 10percent NaOH solution (2x) followed by brine. Dry the solution (Na2SO4) and concentrate under reduced pressure to give the crude product. Purify using preparative plate silica gel chromatography (1 x 2mm, 5percent MeOH/DCM eluent) to give the title product. Prepare the HCl salt by dissolving in EtOAc and adding excess HCl/ether solution to give the HCl salt as an off-white solid. (M+H) = 456; 1H NMR (300 MHz, CDC13): delta 8.06 (dd, IH), 7.88 (m, IH), 7.26 (s, IH), 7.18 (t, IH), 6.80 (s, IH), 6.70 (s, IH), 6.24 (s, IH), 4.33 (M, IH), 3.80 (m, 4H)5 3.67 (m, 2H), 3.17 (t, 4H), 2.06 (m, 2H), 1.90 (m, IH), 1.70 (m, IH), 1.29 (d, 3H, J=6.3 Hz). The IC50 determined as described in Example 6 is less than 1 micromolar.
YieldReaction ConditionsOperation in experiment
To a suspension of (R)-(+)-2-methylpyrrolidine hydrochloride (5.42 g) which was synthesised in accordance with the method described in the literature (Tetrahedron, 27, 2599 (1971)) and triethylamine (8.46 ml, 60.72 mM) in THF (121 ml) was added the solution containing N-hydroxysuccinimide ester of the compound (46) at room temperature. The reaction mixture was stirred for additional 15 h. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (24.6 g) was subjected to gel filtration column chromatography (MCI Gel CHP-20P, 600 ml). The fractions eluding with 40percent aqueous methanol were collected to give 8.87 g of the crude compound (I-57).
  • 22
  • [ 41720-98-3 ]
  • (2S)-2-((R)-2-methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
General Procedure D: Amide FormationThe carboxylic acid or carboxylic acid Lithium salt (1.1-1.2 eq.) is stirred in 0-50percent DMF/CH2C12 as the EDC-HC1 (1.5 eq.) is added portionwise, then the HOBt (1.5 eq.) and reaction is stirred at room temperature for 30-60 minutes. The DIEA (2.5 eq,) and amine(1 eq.) is added and reaction stirred 8-72 hours. Reaction is diluted with CH2CI2, washedwith aq. NaHCC>3 and brine, dried (IS^SCU) and concentrated in vacuo. The crudemixture is purified by SCX chromatography (MeOH wash, then elution with 2M NH3/MeOH) and/ or silica gel column chromatography (gradient: 100percent CH2CI2 to 10percent 2MNH3 in MeOH/ CH2CI2) to give the desired product.; Intermediate Preparation 1 2-(R)-Methyl-l-(2-(S)-pyrrolidinylmethyl)pyrrolidine (S) BOC proline (CAS 15761-39-4) and 2-(R)Methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to General Procedure D in dichloromethane to give 2(S)-(2(R)-Methyl-pyrrolidine-l-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester(233179). The material is deprotected by stirring in dichloromethane at 5-10 °C while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 hours. Reaction is concentrated and dissolved in H2O. The pH is adjusted to 8-9 with K2CO3, and the aqueous layer is extracted several times with CH2CI2. The extracts are combined, dried (Na2SO,0 and concentrated in vacuo to give (2(R)-Methyl-pyrrolidin-l-yl)-pyrrolidin-2-yl-methanone. AIM Lithium Aluminum Hydride/ THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2. A THF solution of (2(R)-methyl-pyrrolidin-l-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. The reaction is stirred at 40 °C for 45 minutes, then at room temperature 18 hours. Reaction is cooled in an ice bath and is auenched with H?0 ( 3 ea.). 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping reaction temperature less than 15 °C. Reaction is stirred overnight, is filtered and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-l- (2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 169.3 (M+H)+ Intermediate is used as such or is purified by SCX chromatography or distillation.
  • 23
  • [ 41720-98-3 ]
  • [ 876617-01-5 ]
YieldReaction ConditionsOperation in experiment
To a mixture of [2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-acetic acid [CAS 403611-89-2] (2.2 g, 6.8 mmpl) in CH2C12 (40 mL) is added EDC (1.57 g, 8.2 mmol) and HOBT (1.11 g, 8.2 mmol). After a few minutes, <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> [CAS 41720-98-3] (1.0 g, 8.2 mmol) and DIPEA (2.5 mL, 13.6 mmol) are added. The mixture is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2x), and the combined organic phase is washed with brine, dried (Na2SC<4), and concentrated. The residue is purified by flash chromatography [120 g Si02, elute gradient 30percent EtOAc/hexane to 80percent EtOAc/hexane) to yield 1.25 g of the title compound as a yellow oil. MS (m/e):. 391.2 (M+l)
  • 24
  • [ 876617-23-1 ]
  • [ 41720-98-3 ]
  • 1-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-2-(2R-methyl-pyrrolidin-1-yl)-ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With sodium carbonate;potassium iodide; In acetonitrile; at 60℃; Add a solution of 2-bromo-l-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (0.500 g, 0.139 mmol) in 8 mL acetonitrile to a sealed tube containing 2R-methyl-pyrrolidine hydrochloride (See Intermediate 7) (0.507 g, 4.16 mmol), K2CO3 (0.959 g, 6.95 mmol), and KI (0.002 g, 0.01 mmol), and heat at 60 °C overnight. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2S04, filter, and concentrate. Purify on silica gel eluting with 5percent ammoniated methanol in dichloromethane to give l-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-2-(2R-methyl-pyrrolidin-l-yl)-ethanol (0.221 g, 44percent): mass spectrum (m/e): 365 (M+l).
  • 25
  • [ 876618-54-1 ]
  • [ 41720-98-3 ]
  • 1-(4'-{5-methyl-4-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-yl)-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate;potassium iodide; In acetonitrile; at 60℃; Add a solution of methanesulfonic acid 2-[2-(3'-acetyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.233 g, 0.583 mmol) in 3 mL acetonitrile to a sealed tube containing 2R-methylpyrrolidine hydrochloride (See Intermediate 7) (0.142 g, 1.17 mmol), K2CO3 (0.282 g, 2.04 mmol), and KI (0.010 g, 0.058 mmol), and heat at 60°C overnight. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2S04, filter, and concentrate. Purify on silica gel eluting with 8percent ammoniated methanol in dichloromethane to give to give l-(4'-{5-methyl-4-[2-(2R-methyl-pyrrolidin- l-yl)-ethyl]-oxazol-2-yl} -biphenyl-3-yl)-ethanone (0.201 g, 89percent).
  • 26
  • [ 876618-60-9 ]
  • [ 41720-98-3 ]
  • 2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[3-(2R-methyl-pyrrolidin-1-yl)-propyl]-oxazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate;potassium iodide; In acetonitrile; at 60℃; Add a solution of methanesulfonic acid 3-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propyl ester (0.206 g, 0.458 mmol) in 3 mL acetonitrile to a sealed tube containing 2R-methyl-pyrrolidine hydrochloride (See Intermediate 7) (0.111 g, 0.916 mmol), K2CO3 (0.221 g, 1.60 mmol), and KI (0.008 g, 0.05 mmol), and heat at 60 °C overnight. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2S04, filter, and concentrate. Purify on silica gel eluting with 8percent ammoniated methanol in dichloromethane to give to give 2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[3-(2i?-methyl-pyrrolidin-l-yl)-propyl]-oxazole (0.130 g, 65percent): MS (m/e): 439(M+1).
  • 27
  • [ 876616-96-5 ]
  • [ 41720-98-3 ]
  • 2-(4-bromo-phenyl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-oxazole hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
2-(4-Bromophenyl)-5-methyl-oxazoleethanol (0.592 g, 2.1 mrnol) [which is obtained by the method of D. Brooks, J. Med. Chem., 2001, 44, 2061-2064 or see WO 0116120], triethylamine (0.316 mL, 2.27 mmol), and methanesulfonyl chloride (0.176 mL, 2.27 mmol) are dissolved in 12 mL of dichloromethane and stirred at ambient temperature for 1 hour. The mixture is concentrated to a tan residue and redissolved in 4 mL of tetrahydrofuran. Triethylamine (0.585 mL, 4.2 mmol), and 2R-Methyl-pyrrolidine; hydrochloride (See Intermediate 7) (0.510 g, 4.2 mmol) are added and the mixture is heated to reflux for 40 hours. The reaction is concentrated and redissolved in dichloromethane and washed successively with water and aqueous sodium bicarbonate. The organics phase is separated, dried over sodium sulfate, filtered and concentrated to provide the free base of the titled compound (0.586 g) which is converted to the titled compound substantially in accordance with the procedure of Example 2. MS (m/e): 349.1 (M+l)
  • 28
  • [ 876616-96-5 ]
  • [ 41720-98-3 ]
  • [ 876617-65-1 ]
YieldReaction ConditionsOperation in experiment
34% With triethylamine; In tetrahydrofuran; at 60℃; Add methanesulfonyl chloride (0.742 g, 5.14 mmol) to a cool (0 °C) solution of 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-efhanol (1.1 g, 3.95 mmol) and triethylamine 0.999 g, 9.88 mmol) in dichloromethane (10 mL). Warm to room temperature and stir for 1 hour. Remove solvents, transfer residue to a sealed tube, add tetrahydrofuran (30 mL) and 2/?-methyl pyrrolidine hydrochloride (2.4 g, 20 mmol), triethylamine (2.2 g, 22 mmol), and heat at 60°C overnight. Add dichloromethane and wash the crude organic material with saturated sodium chloride solution. Dry the'organic layer over Na2SC>4, filter, and concentrate. Purify on silica gel eluting with 2percent ammoniated methanol in dichloromethane to give 2-(4-bromo-phenyl)-5-methyl-4-[2-(2i?-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (0.471 g, 34percent): MS (m/e): 349 (M +1).
  • 29
  • C18H15ClN2O4S [ No CAS ]
  • [ 41720-98-3 ]
  • [ 876617-04-8 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; In dichloromethane; at 20℃; for 1h; To a stirring solution of Sodium {2-[6-(4-methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-acetate (See Intermediate 20) (1.0 mmol) and oxalyl chloride (3.0 mmol) in dioxane (0.10M), add a catalytic amount of dimethylformamide and heat to reflux for 30 minutes. After this time, remove the heat and concentrate in vacuo. Take the resulting solid into dichloromethane (0.10M) and slowly add a solution of (R)-methyl-pyrrolidine hydrochloride (1.0 mmol) and n-methylmorpholine (2.0 mmol) in dichloromethane. Stir at room temperature for 1 hour. After this time, the reaction appears complete. Wash the reaction with IN hydrochloric acid while extracting with dichloromethane. Concentrate the organic layer in vacuo and purify via radial chromatography eluting with methanol and dichloromethane. MS (m/e): 440.2(M+1)
  • 30
  • [ 876617-10-6 ]
  • [ 41720-98-3 ]
  • 3-methoxy-6-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-oxazol-2-yl}-phenyl)-pyridazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;potassium iodide; In acetonitrile; for 18h;Heating / reflux; To a stirring solution of methanesulfonic acid 2-{2-[4-(6-methoxy-pyridazin-3-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethyl ester (l.Ommol) (see Intermediate 32), potassium carbonate (3.5mmol), potassium iodide (O.lmmol) in acetonitrile (0.1M), add 2R-methylpyrrolidine hydrochloride (1.8mmol) (see Intermediate 7). The reaction is heated to a light reflux for 18 hours. After this time, the heat is removed and the product is extracted into IN HC1 while washing with dichloromethane. The aqueous layer is then made basic with 2N NaOH and extracted with dichloromethane. The organic layer is concentrated in vacuo and purified via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 379.2 (M+l)
  • 31
  • [ 921627-27-2 ]
  • [ 921616-62-8 ]
  • [ 41720-98-3 ]
  • [ 921616-75-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide; In butanone; for 72h;Heating / reflux; A mixture of 1,1 -dimethylethyl 4-{4-[(3-chloropropyl)oxy]phenyl}-3-oxo-1- piperazinecarboxylate and 1 ,1 -dimethylethyl 4-{4-[(3-bromopropyl)oxy]phenyl}-3-oxo-1- piperazinecarboxylate (Intermediate :5) (9:1; 2.58 g) was dissolved in 2-butanone (50 m\\}. Potassium carbonate (2.9 g), potassium iodide (2.32 g) and (2f?)-2-methylpyrrolidine hydrochloride (which can be made as described in US 20040171845 for example)(1.0 g) were added. The mixture was heated at reflux under nitrogen over the weekend (for about 72 h). The reaction mixture was cooled to room temperature and partitioned between DCM and water. The organic phase was dried (MgSO4) and concentrated. The residue was purified by flash chromatography, [100 g silica cartridge; 0percent to 30percent of 1percent triethylamine in methanol - DCM gradient over 60 min], to give the title compound (1.87 g). LCMS RT = 2.2 min, ES+ve m/z 418 (M+H)+.
With potassium carbonate; potassium iodide; In butanone; at 90℃; for 72h; A mixture of 1 ,1-dimethylethyl 4-{4-[(3-chloropropyl)oxy]phenyl}-3-oxo-1- piperazinecarboxylate and 1 ,1-dimethylethyl 4-{4-[(3-bromopropyl)oxy]phenyl}-3-oxo-1- piperazinecarboxylate (D14) (9:1 ; 2.58 g) was dissolved in 2-butanone (50 ml). Potassium carbonate (2.9 g), potassium iodide (2.32 g) and <strong>[41720-98-3](2R)-2-methylpyrrolidine hydrochloride</strong> (which can be prepared as described in US20040171845) (1.0 g) were added. The mixture was heated at 90 0C under nitrogen for 72 h. The reaction mixture was cooled to room temperature and partitioned between DCM and water. The organic phase was dried and concentrated. The residue was purified by flash chromatography, [100 g silica cartridge; 0percent to 30percent (1 percent triethylamine/MeOH) - DCM gradient over 60 min], to give the title compound (1.87 g). LCMS RT = 2.2 min.
  • 32
  • [ 791614-80-7 ]
  • [ 41720-98-3 ]
  • 6-bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.3% With potassium carbonate; triethylamine; In tetrahydrofuran; dichloromethane; acetonitrile; Example 12E 6-Bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole A solution of 2-(6-bromo-benzothiazol-2-yl)-ethanol (2.23 g, 8.6 mmol) and triethylamine (2.19 g, 21.6 mmol) in THF (45 mL) was cooled to -20° C., and mesyl chloride (1.58 g, 13.8 mmol) was added at -20 to -10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate (1.79 g, 13 mmol), 2-(R)-methylpyrrolidine hydrochloride (2.1 g, 17.2 mmol) and acetonitrile (40 mL) were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give 6-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (2.48 g, 88.3percent yield). 1H NMR (CDCl3, 400 MHz) delta 1.12 (d, 3H, J=7 Hz), 1.41-1.50 (m, 1H), 1.68-1.87 (m, 2H), 1.91-1.99 (m, 1H), 2.24 (q, 1H, J=7 Hz), 2.39-2.48 (m, 1H), 2.56-2.64 (m, 1H), 3.19-3.33 (m, 4H), 7.52 (dd, 1H, J=8, 4 Hz), 7.79 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=4 Hz); 13C NMR(CDCl3, 400 MHz) delta 19.3, 22.1, 33.1, 33.9, 52.5, 53.7, 59.9, 117.9, 123.3, 123.7, 128.9, 136.9, 151.3, 170.4; (DCl/NH3) m/z 325, 327 (M+H)+.
  • 33
  • [ 41720-98-3 ]
  • [ 188396-76-1 ]
  • [ 1001333-70-5 ]
YieldReaction ConditionsOperation in experiment
82% Step C: Preparation of Intermediate (i.)-l-(2-Biphenyl-4-yl-ethyl)-2-methyl- pyrrolidine. <n="58"/>To a 250 mL three-neck round-bottomed flask equipped with a condenser was charged sodium carbonate (14.6 g, 137.4 mol) and <strong>[41720-98-3](R)-2-methyl-pyrrolidine hydrochloride</strong> (5.57g, 45.8 mmol) in acetonitrile (30 mL). The mixture was allowed to stir at 25 0C for 10 minutes, and methanesulfonic acid 2-biphenyl-4-yl-ethyl ester (14.5 g, 52.7 mmol) in acetonitrile (50 mL) was added. The mixture was then heated to reflux and stirred for 16 h. The reaction was filtered and concentrated to yield a dark brown oil. This was dissolved in EtOAc (125 mL) and extracted with 1 M HCl (4 x 25 mL). The aqueous layers were combined and made basic by addition of 50percent NaOH (20 mL). The aqueous layer was extracted with DCM (7 x 25 mL), the organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by column chromatography (Biotage column 65M, 2-20percentMeOH/DCM) to afford the title compound (10.1 g, 82percent) as an orange oil. Exact mass calculated for C19H23N: 265.2, Found: LCMS tnlz = 266.1 (M+H+); 1H NMR (400 MHz, CDCl3) delta ppm 1.13 (d, J = 6.06 Hz, 3 H), 1.40 - 1.51 (m, 1 H), 1.66 - 1.78 (m, 1 H), 1.78 - 1.88 (m, 1 H), 1.88 - 1.99 (m, 1 H), 2.21 (q, J = 8.84 Hz, 1 H), 2.28 - 2.39 (m, 2 H), 2.79 - 2.94 (m, 2 H), 3.07 (td, J = I l .24, 6.06 Hz, 1 H), 3.27 (dt, J1 = 8.65, J2 = 2.65 Hz, 1 H), 7.29 (d, J = 8.34 Hz, 2 H), 7.31 - 7.35 (m, 1 H), 7.38 - 7.46 (m, 2 H), 7.49 - 7.54 (m, 2 H), 7.55 - 7.62 (m, 2 H).
  • 34
  • [ 2969-81-5 ]
  • [ 41720-98-3 ]
  • [ 1040724-54-6 ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate; In butanone; for 48h;Heating / reflux; a) 4-((R)-2-Methyl-pyrrolidin-l-yl)-bntyric acid ethyl ester(R)-2-methyl-pypi.Olidine hydrochloride (1.0 g, 8.2 mmol, 1.1 eq) was dissolved in 2-butanone (25 niL) and potassium carbonate (2.2 g, 15.7 mmol, 2.1 eq) was added. Ethyl 4-bromobutyrate (1.07 niL, 7.5 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature and solid was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give 1.5 g of the title compound (yield 99percent) which was used in the next step without further purification.C1 1H21NO2IH-NMR (dmso-d6): 0.95 (3H, d, J=6.0 Hz); 1.15 (3H, t, J=7.2 Hz); 1.20-1.27 (IH, m); 1.56-1.64 (4H, m); 1.77-1.86 (IH, m); 1.91-1.99 (2H, m); 2.15-2.22 (lH,m); 2.25-2.30 (2H, m); 2.62-2.69 (IH, m); 2.97-3.01 (IH, m); 4.01 (2H, q, J=7.2 Hz).
  • 35
  • [ 41720-98-3 ]
  • [ 1018966-12-5 ]
YieldReaction ConditionsOperation in experiment
Example 4 Production of 3-[(4-[2-[(2R)-2-methylpyrrolidin-1-yl]ethoxy]phenyl)thio-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide Using <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong>, the entitled compound was obtained as a pale yellow solid in the same method as in Example 1 (step 2) or in accordance with the method or by combining it with an ordinary method. 1H-NMR (CDCl3) delta: 1.18 (3H, d, J=6.1 Hz), 1.49 (1H, m), 1.80 (1H, m), 1.85 (1H, m), 1.97 (1H, m), 2.35 (1H, m), 2.52 (1H, m), 2.60 (1H, m), 2.61 (3H, s), 3.26 (2H, m), 3.73 (3H, s), 4.18 (2H, m), 7.00 (2H, d, J=8.8 Hz), 7.04 (1H, d, J=8.8 Hz), 7.12 (1H, d, J=8.8 Hz), 7.44 (2H, d, J=8.8 Hz), 8.41 (1H, s). ESI-MS (m/e): 569[M+H]+.
  • 36
  • [ 957061-13-1 ]
  • [ 41720-98-3 ]
  • [ 1005403-35-9 ]
YieldReaction ConditionsOperation in experiment
84% With potassium carbonate; In acetonitrile; at 78℃; for 36h; 2-[4-(3-Bromopropoxy)phenyl]-4,4,5,5-tetramethyl-[l,3,2]-dioxaborolane (20.47 g, 60 mmol), (i?)-2-methylpyrrolidine hydrochloride (7.663 g, 63 mmol) and dry, pulverized K2CO3 (24.96 g, 180 mmol) were mixed in dry CH3CN (650 mL). After stirring for 12h at 78°C under a nitrogen atmosphere, the reaction mixture was cooled and further (R)-2- methylpyrrolidine hydrochloride (10.0 g, 82 m mol) was introduced and heating at 78°C was continued for 24 h. The reaction mixture was cooled, filtered and the filtrate was evaporated. Chromatography on silica gel, eluting initially with CH2Cl2, then with a mixture of CH2Cl2 /EtOH/ aq. NH3 (290:10:1) and later with a (90:10:1) and (40:10:1) mixture of these solvents <n="29"/>provided the title compound (17.44 g, 84percent). The material crystallized on seeding. A sample was converted into a hydrochloride salt, m.p. 212-214°C.
  • 37
  • [ 41720-98-3 ]
  • [ 140-88-5 ]
  • [ 23348-84-7 ]
YieldReaction ConditionsOperation in experiment
In a round-bottom flask, R-2-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was analyzed by GC until the Area percent of ethyl acrylate was less than 1percent (approximately 2 h). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl, t-butyl ether and H2O were added and all solids dissolved. The organic was washed a second time with H2O and then distilled to dryness to yield 5.6 g of the title compound. The oil product was used in the next step without further purification
  • 38
  • [ 791614-74-9 ]
  • [ 41720-98-3 ]
  • [ 124-63-0 ]
  • [ 791784-75-3 ]
YieldReaction ConditionsOperation in experiment
100% A solution of 2-(5-bromo-benzothiazol-2-yl)-ethanol (1.50 g, 5.8 mmol) and triethylamine (1.33 g, 11.6 mmol) in CH2Cl2 was cooled to 0° C., and mesyl chloride was added dropwise. The mixture was warmed to room temperature and stirred for 1 hr. The solvent was removed under vacuum, and to the residue was added acetonitrile (20 mL), triethylamine (1.33 g, 11.6 mmol) 2-(R)-methylpyrrolidine hydrochloride (2.83 g, 23.2 mmol) to the mixture, and the mixture was stirred at 60° C. for 1 hr. Solvents were removed under vacuum, and the residue was dissolved in 20 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride extracts were concentrated to give a crude product yield 1.9 g (100percent)
  • 39
  • [ 791614-80-7 ]
  • [ 41720-98-3 ]
  • [ 124-63-0 ]
  • [ 791614-81-8 ]
YieldReaction ConditionsOperation in experiment
88.3% A solution of 2-(6-bromo-benzothiazol-2-yl)-ethanol (2.23 g, 8.6 mmol) and triethylamine (2.19 g, 21.6 mmol) in THF (45 mL) was cooled to -20° C., and mesyl chloride (1.58 g, 13.8 mmol) was added at -20 to -10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate (1.79 g, 13 mmol), 2(R)-methylpyrrolidine hydrochloride (2.1 g, 17.2 mmol) and acetonitrile (40 mL) were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give 6-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (2.48 g, 88.3percent yield). 1H NMR (CDCl3, 400 MHz) delta 1.12 (d, 3H, J=7 Hz), 1.41-1.50 (m, 1H), 1.68-1.87 (m, 2H), 1.91-1.99 (m, 1H), 2.24 (q, 1H, J=7 Hz), 2.39-2.48 (m, 1H), 2.56-2.64 (m, 1H), 3.19-3.33 (m, 4H), 7.52 (dd, 1H, J=8, 4 Hz), 7.79 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=4 Hz); 13C NMR(CDCl3, 400 MHz) delta 19.3, 22.1, 33.1, 33.9, 52.5, 53.7, 59.9, 117.9, 123.3, 123.7, 128.9, 136.9, 151.3, 170.4; (DCl/NH3) m/z 325, 327 (M+H)+.
  • 40
  • [ 41720-98-3 ]
  • [ 140-88-5 ]
  • [ 791614-87-4 ]
YieldReaction ConditionsOperation in experiment
In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area percent of ethyl acrylate was less than 1percent (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification.
  • 41
  • [ 689291-62-1 ]
  • [ 41720-98-3 ]
  • [ 689291-63-2 ]
YieldReaction ConditionsOperation in experiment
The product from Example 15E (0.5 g, 2.0 mmol) and triethylamine (0.5 g, 4.9 mmol) were combined in THF (15 mL) at -15° C. The mixture was treated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at 0-10° C. for 2 hours. The mixture was treated with additional methanesulfonyl chloride (0.2 mmol) and stirred at room temperature for 16 hours. The mixture was treated with <strong>[41720-98-3](2R)-2-methylpyrrolidine hydrochloride</strong> (0.72 g, 6.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) in acetonitrile (25 mL) and then the mixture was heated at 60° C. for 20 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in 20 mL CH2Cl2, washed with 5 mL of water and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) delta 9.10 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.72 (dd, J=12, 4 Hz, 1H), 7.64 (d, J=12 Hz, 1H), 7.58 (s, 1H), 3.46-3.40 (m, 2H), 3.34-3.29 (m, 2H), 2.91-1.85 (m, 1H), 2.81-2.68 (m, 1H), 2.59-2.49 (m, 1H), 2.11-2.02 (m, 1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 1H), 1.32 (d, J=8 Hz, 3H). 13C NMR (CDCl3, 100 MHz) delta 152.5, 150.6, 134.5, 133.6, 129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4, 36.0, 32.4, 21.9, 17.9. MS (DCl/NH3) 319, 321 [M+H]+.
Example 15F 7-Bromo-3-[2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl]isoquinoline The product from Example 15E (0.5 g, 2.0 mmol) and triethylamine (0.5 g, 4.9 mmol) were combined in THF (15 mL) at -15° C. The mixture was treated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at 0-10° C. for 2 hours. The mixture was treated with additional methanesulfonyl chloride (0.2 mmol) and stirred at room temperature for 16 hours. The mixture was treated with <strong>[41720-98-3](2R)-2-methylpyrrolidine hydrochloride</strong> (0.72 g, 6.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) in acetonitrile (25 mL) and then the mixture was heated at 60° C. for 20 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in 20 mL CH2Cl2, washed with 5 mL of water and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) delta 9.10 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.72 (dd, J=12, 4 Hz, 1H), 7.64 (d, J=12 Hz, 1H), 7.58 (s, 1H), 3.46-3.40 (m, 2H), 3.34-3.29 (m, 2H), 2.91-1.85 (m, 1H), 2.81-2.68 (m, 1H), 2.59-2.49 (m, 1H), 2.11-2.02 (m, 1H), 2.00-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 1H), 1.32 (d, J=8 Hz, 3H). 13C NMR (CDCl3, 100 MHz) delta 152.5, 150.6, 134.5, 133.6, 129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4, 36.0, 32.4, 21.9, 17.9. MS (DCl/NH3) 319, 321 [M+H]+.
  • 42
  • [ 41720-98-3 ]
  • [ 627-18-9 ]
  • [ 862314-38-3 ]
YieldReaction ConditionsOperation in experiment
Preparation of compound DDl; Example 103:2-(4-Benzoyl-piperazin-1-yl)-1-{2-fluoro-4-[3-(2-methyl-pyrrolidin-1yl)- propoxy]-phenyl}-ethanone fumarateTo a suspension of compound CCl (1.51g, 4.40 mmol), triphenylphosphine (2.24 g, 8.80 mmol), and 3-((i?y)-2-methylpyrrolidine)propan-l-ol (1.26g, 8.80 mmol, prepared from corresponding <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> and 3-bromo-l-propanol) in anhydrous THF (20 mL) and anhydrous DMF (5 mL) at room temperature was added diethylazodicarboxylate (1.35 mL, 8.80 mmol) over 5 min. The brown solution was stirred at room temperature under nitrogen for 20 h, diluted with EtOAc (50 mL), and extracted into a citric acid solution (50 mL). The acidic solution was cooled (ice bath), basified with 50percent aq. NaOH solution to pH ~ 11 and extracted with EtOAc (100 mL). The organic layer was washed with water, dried (NaSO4) and concentrated to afford crude product that was purified by chromatography (silica gel; gradient of 5percent 4:1 :0.2CH2Cl2/MeOH/NH4OH in CH2Cl2 to 50percent 4:1 :0.2 CH2Cl2/MeOH/NH4OH in CH2Cl2) to yield 0.57g (28percent) of the DDl as the free base.The free base was then treated with fumaric acid to generate Example 103 fumaric acid salt; mp 98-101 0C. MS: m/z 468 [M+H free base].
  • 43
  • [ 1260099-57-7 ]
  • [ 41720-98-3 ]
  • [ 1260098-21-2 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; sodium iodide; at 180℃; for 0.666667h; Preparation of compound Z, Example 54:2-Methyl-1-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]- phenyl}-2-morpholin-4-yl-propan-1-one fumarateA suspension of compound Y (0.24 g, 0.7 mmol), (i?)-2-methylpyrrolidinehydrochloride (0.107 g, 0.9 mmol), NaI (0.06 g, 0.4 mmol), and diisopropylethylamine(0.52 g, 1.4 mmol) in 2-butanone (2 mL) was subjected to microwave irradiation for 20 min (180 0C). After cooling, an additional amount of (i^-2-methylpyrrolidinehydrochloride (0.107 g, 0.9 mmol) and diisopropylethylamine (0.52 g, 1.4 mmol) were added, and the reaction mixture was resubjected to microwave irradiation for another 20 min (180 0C). The crude reaction mixture was then adsorbed onto silica gel (5 g), and the solvents were removed under reduced pressure. Flash chromatography of the abovematerial (silica gel; 3percent MeOH in CH2Cl2) afforded Example 54 (0.24 g) as a colorless oil. The free base was then converted to the fumaric acid salt to give 0.113g of product as off- white foam; mp 45-50 0C. MS m/z 375 [M+H free-base].
  • 44
  • [ 1311182-40-7 ]
  • [ 41720-98-3 ]
  • 2-ethyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one [ No CAS ]
  • 45
  • [ 1311182-41-8 ]
  • [ 41720-98-3 ]
  • 2-isopropyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one [ No CAS ]
  • 46
  • [ 1311182-42-9 ]
  • [ 41720-98-3 ]
  • 2-phenyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one [ No CAS ]
  • 47
  • [ 1311182-39-4 ]
  • [ 41720-98-3 ]
  • 2-benzyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one [ No CAS ]
  • 48
  • [ 64010-38-4 ]
  • [ 41720-98-3 ]
  • [ 1005403-39-3 ]
  • 49
  • C14H15BrN2O2 [ No CAS ]
  • [ 41720-98-3 ]
  • CEP-19938 [ No CAS ]
  • 50
  • [ 889865-32-1 ]
  • [ 41720-98-3 ]
  • [ 1005403-35-9 ]
  • 51
  • [ 1349798-37-3 ]
  • [ 41720-98-3 ]
  • [ 1349798-32-8 ]
  • 52
  • [ 41720-98-3 ]
  • [ 540-51-2 ]
  • [ 379229-46-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; at 20℃; A mixture of <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> (4 g, 0.03 mol), 2-bromoethanol(3.7 g, 0.029 mmol) and K2CO3 (8.28 g, 0.0618 mol) in acetonitrile (50 mL) was stirred at room temperature overnight. The mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL). The combined filtrate was concentrated and the residue was purified on a silica gel column (MeOH/DCM = 1/50) to give (R)-2-(2-methylpyrrolidin- 1 -yl)ethanol (0.9 g) as a colorless oil. 3/4 NMR (CDC13): delta 3.63 (m, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.44 (m, 1H), 2.24 (dt, 1H), 2.14 (m, 1H), 1.95 (m, 1H), 1.68 (m, 2H), 1.38 (m, 1H), 1.07 (d, 3H); LCMS: 130 (M+H)+.
  • 53
  • 2-(5-bromo-1-oxoisoindolin-2-yl)acetaldehyde [ No CAS ]
  • [ 41720-98-3 ]
  • [ 1131223-25-0 ]
  • 54
  • [ 1388766-13-9 ]
  • [ 41720-98-3 ]
  • [ 1131216-22-2 ]
  • 55
  • [ 1131222-87-1 ]
  • [ 41720-98-3 ]
  • [ 1131216-20-0 ]
  • 56
  • [ 1388765-78-3 ]
  • [ 41720-98-3 ]
  • [ 1131216-26-6 ]
  • 57
  • [ 1260099-53-3 ]
  • [ 41720-98-3 ]
  • [ 1260098-08-5 ]
  • 58
  • [ 1391635-95-2 ]
  • [ 41720-98-3 ]
  • [ 1260098-10-9 ]
  • 59
  • [ 1391635-94-1 ]
  • [ 41720-98-3 ]
  • [ 1260098-14-3 ]
  • 60
  • [ 1391635-93-0 ]
  • [ 41720-98-3 ]
  • [ 1260098-11-0 ]
  • 61
  • [ 1391635-92-9 ]
  • [ 41720-98-3 ]
  • [ 1260098-19-8 ]
  • 62
  • [ 1391635-91-8 ]
  • [ 41720-98-3 ]
  • [ 1260098-27-8 ]
  • 63
  • [ 1372793-30-0 ]
  • [ 41720-98-3 ]
  • [ 1260098-30-3 ]
  • 64
  • [ 1391636-30-8 ]
  • [ 41720-98-3 ]
  • [ 1260098-31-4 ]
  • 65
  • [ 1391636-31-9 ]
  • [ 41720-98-3 ]
  • [ 1260098-33-6 ]
  • 66
  • [ 1391636-32-0 ]
  • [ 41720-98-3 ]
  • [ 1260098-35-8 ]
  • 67
  • [ 1391636-33-1 ]
  • [ 41720-98-3 ]
  • [ 1260098-68-7 ]
  • 68
  • [ 1391636-34-2 ]
  • [ 41720-98-3 ]
  • [ 1260098-47-2 ]
  • 69
  • [ 1391636-36-4 ]
  • [ 41720-98-3 ]
  • [ 1260098-48-3 ]
  • 70
  • [ 1391636-58-0 ]
  • [ 41720-98-3 ]
  • [ 1260098-51-8 ]
  • 71
  • [ 1391636-59-1 ]
  • [ 41720-98-3 ]
  • [ 1260098-91-6 ]
  • 72
  • [ 1391636-60-4 ]
  • [ 41720-98-3 ]
  • [ 1260098-49-4 ]
  • 73
  • [ 1391636-61-5 ]
  • [ 41720-98-3 ]
  • [ 1260098-82-5 ]
  • 74
  • [ 1391636-62-6 ]
  • [ 41720-98-3 ]
  • [ 1260098-98-3 ]
  • 75
  • [ 1391636-63-7 ]
  • [ 41720-98-3 ]
  • [ 1260098-95-0 ]
  • 76
  • [ 1391636-64-8 ]
  • [ 41720-98-3 ]
  • [ 1260099-18-0 ]
  • 77
  • [ 1382182-62-8 ]
  • [ 41720-98-3 ]
  • [ 1005403-35-9 ]
  • 78
  • [ 1382182-68-4 ]
  • [ 41720-98-3 ]
  • [ 1382182-73-1 ]
YieldReaction ConditionsOperation in experiment
45% With potassium carbonate; In acetonitrile; for 22h;Reflux; General procedure: A round bottom flask charged with 6b (2.1 g, 5.6 mmol), <strong>[41720-98-3](R)-2-methyl-pyrrolidine hydrochloride</strong> (1.4 g, 11.1 mmol), K2CO3 (5.0 g, 36.2 mmol) and acetonitrile (35 mL) was stirred at reflux for 22 h. After cooling to ambient temperature, the reaction was filtered and the residue was concentrated. The produce was purification by column chromatography (2percent MeOH in CH2Cl2) to give 900 mg (45percent) of 7b. 1H NMR (DMSO-d6, delta): 0.99 (m, 6H), 1.07 (m, 2H), 1.27 (s, 12H), 1.63 (m, 2H), 1.85 (m, 1H), 2.03 (m, 2H), 2.17 (m, 1H), 2.53 (m, 1H), 3.02 (m, 1H), 3.78-3.94 (m, 2H), 6.92 (m, 2H), 7.59 (m, 2H). LCMS m/z: 360 (M+1).
  • 79
  • [ 1382182-65-1 ]
  • [ 41720-98-3 ]
  • [ 1382182-76-4 ]
YieldReaction ConditionsOperation in experiment
48% With potassium carbonate; In acetonitrile; for 22h;Reflux; General procedure: A round bottom flask charged with 6b (2.1 g, 5.6 mmol), <strong>[41720-98-3](R)-2-methyl-pyrrolidine hydrochloride</strong> (1.4 g, 11.1 mmol), K2CO3 (5.0 g, 36.2 mmol) and acetonitrile (35 mL) was stirred at reflux for 22 h. After cooling to ambient temperature, the reaction was filtered and the residue was concentrated. The produce was purification by column chromatography (2percent MeOH in CH2Cl2) to give 900 mg (45percent) of 7b.
  • 80
  • [ 1384850-39-8 ]
  • [ 41720-98-3 ]
  • [ 1394972-96-3 ]
YieldReaction ConditionsOperation in experiment
72% With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 70℃; for 3h; -Methyl 3-(2-methylpyrrolidin-l-yl)-2-oxo-l,2-dihydroquinoxaline-6-carboxylateTo a solution of methyl 3-chloro-2-oxo-l,2-dihydroquinoxaline-6-carboxylate (250 mg, 1.05 mmol) in DMSO (2 rriL) was added DIEA (850 mg, 4.2 mmol), and (/?)-2-methylpyrrolidine hydrochloride (300 mg, 2.35 mmol), and the resulting mixture was stirred for 3 h at 70°C. Then the reaction was quenched by the addition of water (10 rriL). The solids were collected by filtration to afford (/?)-methyl 3-(2-methylpyrrolidin-l-yl)-2-oxo-l,2-dihydroquinoxaline- 6-carboxylate as a light yellow solid (216 mg, 72percent).LC/MS (ES, m/z):[M+H]+ 288.0
  • 81
  • [ 1384850-39-8 ]
  • [ 41720-98-3 ]
  • [ 1394972-96-3 ]
YieldReaction ConditionsOperation in experiment
72% EXAMPLE 19 (R)-Methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate Step 1. (R)-Methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (250 mg, 1.05 mmol) in DMSO (2 mL) was added DIEA (850 mg, 4.2 mmol), and <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> (300 mg, 2.35 mmol), and the resulting mixture was stirred for 3 h at 70° C. Then the reaction was quenched by the addition of water (10 mL). The solids were collected by filtration to afford (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (216 mg, 72percent).LC/MS (ES, m/z): [M+H]+ 288.0
  • 82
  • (2R,2'R)-2,2'-((2-iodo-1,3-phenylene)bis(oxy))dipropanoyl chloride [ No CAS ]
  • [ 41720-98-3 ]
  • [ 1611494-88-2 ]
  • 83
  • [ 41720-98-3 ]
  • [ 109-70-6 ]
  • [ 108-95-2 ]
  • (R)-2-methyl-1-(3-phenoxypropyl)pyrrolidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Phenol 7a (5.0g, 53.1mmol), 1-bromo-3-chloropropane (5.5mL, 55.8mmol), and potassium carbonate (22.0g, 106mmol), in acetonitrile (100mL) was stirred at reflux for 15h. After cooling to rt <strong>[41720-98-3](R)-2-methyl-pyrrolidine hydrochloride</strong> (12.9g, 106mmol) and sodium iodide (8.0g, 53.1mmol) were then added and the reaction was heated again to reflux for 24h. After cooling to rt, the mixture was filtered and concentrated. The product was purified by silica gel chromatography (5percent MeOH in CH2Cl2) to give a white solid (9.02g, 77percent). 1H NMR (400MHz, CDCl3) delta: 7.27 (m, 2H), 6.91 (m, 3H), 4.04 (m, 2H), 3.23 (m, 1H), 2.41 (m, 1H), 3.02 (m, 1H), 2.25 (m, 2H), 2.00 (m, 3H), 1.78 (m, 2H), 1.48 (m, 1H), 1.15 (d, 3H, J=6.2Hz).
  • 84
  • ethyl 1-[5-({5-(acetoxymethyl)-4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]piperidine-4-carboxylate [ No CAS ]
  • [ 41720-98-3 ]
  • ethyl 1-{5-[(4-[4-chloro-3-(trifluoromethyl)phenyl]-5-[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperidine-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; Preparation Example 24 To a solution of ethyl 1-[5-({5-(acetoxymethyl)-4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]piperidine-4-carboxylate (160 mg) in tetrahydrofuran (1.6 mL) were added <strong>[41720-98-3](2R)-2-methylpyrrolidine hydrochloride</strong> (64 mg) and diisopropylethylamine (0.18 mL), followed by stirring at 150°C for 1 hour under irradiation with microwaves. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 1-{5-[(4-[4-chloro-3-(trifluoromethyl)phenyl]-5-[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperidine-4-carboxylate (117 mg) as an oily substance.
117 mg With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 150℃; for 1h;Microwave irradiation; To ethyl 1-[5-({5-(acetoxymethyl)-4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]piperidine-4-carboxylate (160 mg) tetrahydrofuran (1.6 ml) solution, <strong>[41720-98-3](2R)-2-methylpyrrolidine hydrochloride</strong> (64 mg) and diisopropylethylamine (0.18 ml) were mixed, followed by stirring at 150 °C for 1 hour under microwave irradiation. Concentrated within a pressure reduced to reaction mixture, residue silica gel column chromatography (cyclohexan-acetic acid ethyl) for purifying the, ethyl 1-{5-[(4-[4-chloro-3-(trifluoromethyl)phenyl]-5-[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperidine-4-carboxylate (117 mg) obtained as oily a.
  • 85
  • (6-bromo-imidazo[1,2-a]pyridine)-3-sulfonyl chloride [ No CAS ]
  • [ 41720-98-3 ]
  • (R)-6-bromo-3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% With triethylamine; In dichloromethane; at 20℃; for 2h; TEA (0.42 mL, 3.0453 mmol) was added to a room temperature stirred solution of <strong>[41720-98-3](R)-2-methylpyrrolidine hydrochloride</strong> (0.185 g, 1.5226 mmol) in DCM (5 mL), followed by the addition of a solution of Intermediate 3 (0.3 g, 1.0151 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2 h and, after completion, was concentrated under reduced pressure. The product obtained was purified by silica gel chromatography using a gradient of 50-70percent ethyl acetate in hexane as eluent. The fractions were combined and concentrated to afford the title compound (0.07 g, 20percent). MH+ 346.19;
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