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[ CAS No. 51387-90-7 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 51387-90-7
Chemical Structure| 51387-90-7
Chemical Structure| 51387-90-7
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Product Details of [ 51387-90-7 ]

CAS No. :51387-90-7 MDL No. :MFCD00003175
Formula : C7H16N2 Boiling Point : -
Linear Structure Formula :- InChI Key :PNHGJPJOMCXSKN-UHFFFAOYSA-N
M.W :128.22 Pubchem ID :98388
Synonyms :

Calculated chemistry of [ 51387-90-7 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.17
TPSA : 29.26 Ų

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) : -6.92 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.96
Log Po/w (XLOGP3) : 0.23
Log Po/w (WLOGP) : 0.05
Log Po/w (MLOGP) : 0.57
Log Po/w (SILICOS-IT) : 0.57
Consensus Log Po/w : 0.68

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.65
Solubility : 28.8 mg/ml ; 0.225 mol/l
Class : Very soluble
Log S (Ali) : -0.4
Solubility : 50.5 mg/ml ; 0.394 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.89
Solubility : 16.4 mg/ml ; 0.128 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.7

Safety of [ 51387-90-7 ]

Signal Word:Danger Class:8
Precautionary Statements:P501-P210-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 UN#:2735
Hazard Statements:H314-H227 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 51387-90-7 ]

* 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 [ 51387-90-7 ]

[ 51387-90-7 ] Synthesis Path-Downstream   1~80

  • 1
  • [ 20028-68-6 ]
  • [ 51387-90-7 ]
  • [ 76004-38-1 ]
  • 2
  • [ 369-58-4 ]
  • [ 51387-90-7 ]
  • 3-<2-(1-Methylpyrrolidin-2-yl)ethyl>-1-phenyltriazene [ No CAS ]
  • 3
  • [ 61049-67-0 ]
  • [ 51387-90-7 ]
  • [ 362598-70-7 ]
  • 4
  • [ 51387-90-7 ]
  • [ 163594-14-7 ]
  • 4-[2-(1'-methylpyrrolidin-2-yl)ethylamino]-1H-pyrrole-2-carboxylic acid benzyl ester [ No CAS ]
  • 5
  • [ 400-94-2 ]
  • [ 51387-90-7 ]
  • 4-fluoro-<i>N</i>-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-3-nitro-benzamide [ No CAS ]
  • 6
  • [ 785795-15-5 ]
  • [ 51387-90-7 ]
  • [ 785795-16-6 ]
  • 7
  • [ 64248-58-4 ]
  • [ 51387-90-7 ]
  • (3,4-difluoro-phenyl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine [ No CAS ]
  • 8
  • [ 3622-38-6 ]
  • [ 51387-90-7 ]
  • [ 939795-73-0 ]
  • 9
  • [ 51387-90-7 ]
  • [ 98776-99-9 ]
  • [ 479411-49-9 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; at 0℃; for 1h; (Example 10) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[2-(1-methylpyrrolidin-2-yl)ethyl)docosahexaenoamide (Compound 10) Crude docosahexaenoic acid (DHA) (2.1 g) and 10 ml of toluene were mixed.. With the mixture being cooled with ice, 0.93 ml (10.6 mmols) of (COCl)2 was added, and the mixture was stirred for 2 hours at room temperature.. The reaction mixture was concentrated under reduced pressure on a 40C water bath and, after addition of toluene, was concentrated again under reduced pressure to obtain a crude DHA acid chloride as a yellow liquid.. After combining 3 ml (21 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine with 20 ml of CH2Cl2, the total of the crude DHA acid chloride was added under cooling with ice.. The mixture was stirred for 1 hour while being cooled with ice, and 30 ml of CH2Cl2 and 50 ml of iced water were added..
  • 10
  • [ 101-39-3 ]
  • [ 51387-90-7 ]
  • (E)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-3-phenylprop-2-en-1-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% [0097] 0.5 g of 2- (1-methyl-prrolidin-2-yl)-ethylamine (3.89 MMOL) and 0.56 g of 2-methyl-3-phenyl-propenal were combined in 20 ml of anhydrous dichloromethane. The mixture was stirred under nitrogen on 5 g of magnesium sulfate. After two days, thin layer chromatography (TLC) using a 9: 1: 0.1 DICHLOROMETHANE/METHANOL/AMMONIUM hydroxide eluent showed an absence of the starting material. The reaction mixture was filtered, and the collected solid was washed with dichloromethane. The resultant organic layer was then concentrated under vacuum. Ten ml of dry methanol was added to the residual mixture under nitrogen and the solution was cooled to 0C. To this mixture was added 0.14 g of sodium borohydride. TLC showed an absence of starting material after about 15 minutes. The reaction was then quenched with acetone (1 ML), and the solvent was removed by distillation. The mixture was partitioned between 5 mi of water in chloroform and the layers were separated. The aqueous layer was then extracted 3 times with 30 mi chloroform. The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. Concentration under vacuum gave 0.78 g of a pale yellow solid. Yield: 77%. [0098] LC-MSD, m/z for C17H26N2 [M+H] +: 259, [M+2H] +: 260 [0099] H NMR (400 MHz, CDCI3) : 8 1.4-1. 6 (m, 2H), 1.67-1. 82 (m, 3H), 1.9-2. 0 (m, 3 H), 2. 02- 2. 20 (m, 2H), 2.38 (s, 3H), 2. 58- 2. 79 (m, 2, H), 3.02-3. 08 (m, 1 H), 3.39 (s, 2H), 7.16-7. 39 (m, 5H).
  • 11
  • 2-ethoxy-3-ethyl-6-[(2-fluorophenyl)sulfonyl]amino}benzoic acid [ No CAS ]
  • [ 51387-90-7 ]
  • 2-ethoxy-3-ethyl-6-([2-({2-[1-methyl-2-pyrrolidinyl]ethyl}amino)phenyl]sulfonyl}amino)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
50.3% With triethylamine; In acetonitrile; at 120℃; for 48h; EXAMPLE 406 2-ethoxy-3-ethyl-6-([2-({2-[1-methyl-2-pyrrolidinyl]ethyl}amino)phenyl]sulfonyl}amino)benzoic acid [0729] A solution of Example 3851 (120 mg, 0.33 mmol), triethylamine (0.24 mL) and N-methyl-2-(2'-aminoethyl)pyrrolidine (217 mg, 1.7 mmol) in acetonitrile (3 mL) was heated to 120 C. in a sealed vial for 2 days, concentrated, and purified using a reverse phase HPLC, giving the desired product, 79 mg, 50.3%. 1H NMR (DMSO-d6) delta 1.08 (t, 3H), 1.28 (t, 3H), 1.60-1.70 (m, 1H), 1.80-2.00 (m, 3H), 2.12-2.30 (m, 2H), 2.53 (q, 2H), 2.68 (s, 3H), 2.90-3.04 (m, 1H), 3.20-3.32 (m, 3H), 3.50-3.60 (m, 1H), 3.90 (q, 2H), 5.98 (br s, 1H), 6.60 (d, 1H), 6.68 (t, 1H), 6.85 (d, 1H), 7.15 (d, 1H), 7.40 (t, 1H), 7.58 (d, 1H), 9.68 (s, 1H), 10.48 (br s, 1H); MS (ESI(+)) m/e 476 (M+H)+.
  • 12
  • [ 681247-35-8 ]
  • [ 51387-90-7 ]
  • 2-[(2-[({2-[1-methyl-2-pyrrolidinyl]ethyl}amino)carbonyl]amino}phenyl)sulfonyl]amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
29% EXAMPLE 418D 2-[(2-[({2-[1-methyl-2-pyrrolidinyl]ethyl}amino)carbonyl]amino}phenyl)sulfonyl]amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid [0748] A solution of Example 418C (145.6 mg, 0.404 mmol) in THF (0.25 mL) was treated with carbonyldiimidazole (65.5 mg, 0.404 mmol), heated to 50 C. for 1.5 hours, cooled to room temperature, treated with 2-(2-aminoethyl)-1-methylpyrrolidine. (58 muL, 0.404 mmol), stirred for 24 hours, and concentrated. The residue was dissolved in pyridine (0.5 mL), treated with LiI (162.2 mg, 1.212 mmol), heated in a microwave reactor at 150 C. for 25 minutes, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. (58.7 mg, 29%). MS (ESI(-)) m/e 499 (M-H)-; 1H NMR (300 MHz, DMSO-d6) delta 9.74 (s, 1H), 8.21 (m, 1H), 7.66 (dd, 1H), 7.53 (ddd, 1H), 7.32 (t, 1H), 7.07 (td, 1H), 6.96 (d, 1H), 6.53 (d, 1H), 3.18 (m, 3H), 3.01 (m, 2H), 2.78 (s, 3H), 2.66 (m, 4H), 2.30 (m, 2H), 1.92 (m, 2H), 1.67 (m, 4H), 1.28 (m, 1H), 0.87 (m, 1H).
  • 13
  • [ 681247-57-4 ]
  • [ 51387-90-7 ]
  • 3-[(1E)-3-({2-[1-methyl-2-pyrrolidinyl]ethyl}amino)-3-oxo-1-propenyl]-2-[(phenylsulfonyl)amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 476E 3-[(1E)-3-({2-[1-methyl-2-pyrrolidinyl]ethyl}amino)-3-oxo-1-propenyl]-2-[(phenylsulfonyl)amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid [0829] A mixture of Example 476D (20 mg, 0.05 mmol) in DMF (1.0 mL) was treated with macroporous polystyrene bound DCC resin (105 mg, 0.14 mmol), 1-hydroxybenzotriazole hydrate (7 mg, 0.05 mmol), diisopropylethylamine (0.026 mL, 0.15 mmol) and 2-(aminoethyl)-1-methylpyrrolidine (0.010 mL, 0.07 mmol), heated to 55 C. for 16 hours, and concentrated. The concentrate was dissolved in 0.5 mL 2:1 dioxane/water, treated with LiOH (13 mg, 0.3 mmol), and heated to 160 C. for 27.5 minutes in a microwave reactor. The reaction mixture was concentrated and the residue was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 512 (M+H)+; 1H NMR (500 MHz, DMSO-d6) delta 12.89 (br s, 1H), 9.37 (br s, 1H), 7.99 (t, 1H), 7.61 (d, 2H), 7.54 (t, 1H), 7.46-7.43 (m, 3H), 7.31 (s, 1H), 6.28 (d, 1H), 3.23 (m, 4H), 3.08 (m, 1H), 2.84 (d, 3H), 2.75 (m, 2H), 2.65 (m, 2H), 2.30 (m, 1H), 2.04 (m, 2H), 1.90 (m, 1H), 1.71-1.63 (m, 6H).
  • 14
  • [ 51387-90-7 ]
  • [ 334893-11-7 ]
  • 4-[2-Methyl-5-(3-morpholinobenzamido)anilino]-2-[2-(N-methylpyrrolidin-2-yl)ethylamino]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 18h; A mixture of 2-chloro-4-[2-methyl-5-(3-morpholinobenzamido)anilino]pyrimidine (0.64 g), 2-(N-methylpyrrolidin-2-yl)ethylamine (0.44 ml), N,N-di-isopropylethylamine (0.52 ml) and n-butanol (7 ml) was stirred and heated to 100C for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound as a solid (0.33 g); NMR Spectrum: (DMSOd6) 1.44 (m, 2H), 1.62 (m, 2H), 1.88 (m, 2H), 2.15 (s, 3H), 2.31 (m, 4H), 3.04 (m, 2H), 3.17 (m, 5H), 3.74 (m, 4H), 5.88 (d, 1H), 6.5 (m, 1H), 7.13 (m, 2H), 7.34 (m, 2H), 7.44 (m, 2H), 7.77 (d, 1H), 7.9 (m, 1H), 8.37 (s, 1H), 10.04 (s, 1H); Mass Spectrum: M+H+ 516.
  • 15
  • [ 957134-37-1 ]
  • [ 51387-90-7 ]
  • 4-bromo-5-(2-chloro-benzoylamino)-1H-pyrazole-3-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
The pyrazole acid, prepared as described in Procedure 8, was coupled with 2-(2-aminoethyl)-1-methylpyrrolidine (Aldrich, 13,950-5) using the method of Procedure 17. MS+ = 454.2 A solution of 1.0 eq. of acid 7,1. 0 eq. of amine 2, and 8.1 eq. OF ET3N in DMF was prepared. While stirring, a solution of 1.0 eq. of HATU dissolved in DMF was added. After stirring at rt for a time sufficient for reaction completion, 6.0 eq. OF MP- carbonate resin and 6.0 eq. ofPS-trisamine resin (both from Argonaut Technologies, Inc.) were added. The mixture was stirred at rt for 16 hrs, filtered, and washed with DMF and MeOH. The crude material was purified by reverse-phase HPLC using a mixture of acetonitrile-water as eluant. The purified material was concentrated and dried to afford amide 44.
  • 16
  • C3H4BrO2Pol [ No CAS ]
  • [ 51387-90-7 ]
  • C10H19N2O2Pol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dimethyl sulfoxide; at 20℃; for 24h; EXAMPLE 19 Preparation of carbamic acid, [3-[2-(1-methyl-2-pyrrolidinyl)ethyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester The Merrifield resin-bound -bromoacetate ester (3 g, loading 0.67 mmol/g) is treated with DMSO (60 ML) and 2-(2-aminoethyl)-1-methylpyrrolidine (1.42 g, 10 mmol) and allowed to shake for 24 hours at room temperature.. Washing two times each with DMF, MeOH, DCM affords the resin.. This is then treated with boc-hydrazinecarbonylimidazole (10 mmol) in 60 ML of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n=0, X=O, R1=2-(1-methyl-2-pyrrolidinyl)ethyl).. The resin is then placed in a flask with 50 ML of DMF and heated to 60-70 C. for 8 hours.. After cooling, the resin is filtered, washed with small amount of DMF, DCM and MeOH and the combined filtrates concentrated.. The residue is dissolved in 30 ML of MeOH and filtered, concentrated in vacuo to give desired product (445 mg, 69%).
  • 17
  • [ 869105-84-0 ]
  • [ 51387-90-7 ]
  • [ 869105-85-1 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h; 4-(2-Chlorophenyl)-6-methyl-1,3-dioxo-1,2,3,6-tetrahydro-2,6-diaza-as-indacene-7-carboxylic acid pentafluorophenyl ester (200 mg, 0.38 mmol), prepared as described in Example 84, triethylamine (78 mg, 0.77 mmol) and 2-(1-methylpyrrolidin-2-yl)-ethylamine (54 mg, 0.42 mmol) were dissolved in dimethylformamide (1 mL) and stirred at room temperature for 3 h. The reaction mixture was then poured into water (10 mL) and the yellow precipitate collected by filtration. The solid was washed with water (10 mL) and dried to produce 126 mg of the title compound as a yellow solid; 1H NMR (400 MHz, CDCl3) delta ppm 1.76 (s, 3H) 1.86 (m, 1H) 1.92 (m, 2H) 2.26 (s, 1H) 2.43 (d, J=3.91 Hz, 3H) 2.55 (s, 1H) 3.23 (s, 1H) 3.53 (s, 1H) 3.69 (m, 1H) 4.16 (d, J=8.79 Hz, 3H) 7.39 (m, 3H) 7.44 (s, 1H) 7.49 (s, 1H) 7.51 (m, 1H) 8.88 (s, 1H); Elemental Analysis for C25H25ClN4O3.0.42H2O, % C (calc/found) 64.31/63.92, % H 5.44/5.13, % N 12.00/11.80.
  • 18
  • [ 869106-86-5 ]
  • [ 51387-90-7 ]
  • [ 869106-03-6 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In DMF (N,N-dimethyl-formamide); for 3h; To a solution of 8-bromo-4-(2-chlorophenyl)-6-methyl-1,3-dioxo-1,2,3,6-tetrahydro-2,6-diaza-as-indacene-7-carboxylic acid pentafluorophenyl ester (100 mg, 0.17 mmol), prepared as described in Example 97, in DMF (1 mL) were added triethylamine (51 mg, 0.50 mmol) and 2-(1-methylpyrrolidin-2-yl)ethylamine (32 mg, 0.25 mmol). The reaction mixture was stirred in a sealed vial for 3 h. The reaction mixture was poured into water (25 mL) and filtered. The title compound was isolated as a yellow solid (48 mg); 1H NMR (400 MHz, DMSO-D6) delta ppm 1.45 (m, 2H) 1.63 (m, 2H) 1.93 (m, 2H) 2.07 (s, 1H) 2.23 (s, 4H) 2.94 (d, J=5.13 Hz, 1H) 3.35 (m, 2H) 3.83 (s, 3H) 7.45 (m, 3H) 7.55 (ddd, J=4.76, 3.17, 1.59 Hz, 1H) 7.88 (s, 1H) 8.91 (t, J=5.74 Hz, 1H) 11.05 (s, 1H); HPLC (Altima C18, 3mu, 53*7.0 mm column, gradient method 5-95% acetonitirile/water eluent (0.1% trifluoroacetic acid) in 10 min with 3 min hold, UV254 nm detection) 95% at 5.61 min; LCMS (Phenomenex Develosil Combi RP3 50*4.6 mm column, gradient method 50-2% acetonitrile/water eluent (0.1% formic acid) in 2.0 min with 2 min hold, MSD in ESI positive mode) 35% at 1.35 min, 63% at 1.48 min (broad, sloping peak) (UV254 nm); API-ES 542.9 (75), 544.9 (100), 546.9 (25).
  • 19
  • [ 871793-28-1 ]
  • [ 51387-90-7 ]
  • C22H26F3N5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)- pyrimidine-2-carbonitrile (50mg) in methanol (1 mL) was added 2-(2-Aminoethyl)-1- methylpyrrolidine (48pL) and acetic acid (12muL). The mixture was stirred at room temperature for five minutes then solid supported cyanoborohydride (77mg, 257mmol/g) was added and stirring continued overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to yield crude product. Purification by preparative-HPLC afforded the TFA salt of 4-{3-[2-(1-methyl-pyrrolidin- 2-yl)-ethylamino]-propyl}-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile. ¹H NMR (MeOD) : No. 8.52 (s, 1 H), 8.48 (d, 1 H), 8.25 (s, 1 H), 7.90 (d, 1 H), 7.79 (t, 1 H), 3.75 (m, 1 H), 3.38 (m, 1 H), 3.19 (m, 5H), 3.12 (t, 2H), 2.96 (s, 3H), 2.40 (m, 2H), 2.27 (t, 2H), 2.15 (m, 2H), 2.05 (m, 1 H), 1.82 (m, 1 H). MS m/z418.3 (M+1 ), 100%.
  • 20
  • [ 5381-20-4 ]
  • [ 51387-90-7 ]
  • [ 862494-47-1 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; Step 1: Benzo[b]thiophen-3-ylmethyl-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine Experimental condition analogous to Example 5, from benzo[b]thiophen-3-carbaldehyde 0.16 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL Dichloromethane. Purification using silica chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 140 mg of compound.
  • 21
  • [ 885024-24-8 ]
  • [ 51387-90-7 ]
  • 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% In ethylene glycol; at 85℃; for 12h; The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (159 mg, 0.278 mmol) was dissolved in ethylene glycol (2 mL) containing 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (400 muL, 2.78 mmol) and heated to 85 C. for 12 h. The reaction was poured into water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (5×10 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative thin layer chromatography to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (60 mg, 32%) as a faint yellow solid. MS (ES+) 668.4 (M+H)+(100%). This material (60 mg, 0.089 mmol) was combined with 2-pyridone (17 mg, 0.18 mmol), anhydrous potassium carbonate (49 mg, 0.36 mmol), copper(I) iodide (3.4 mg, 0.018 mmol), 1,10-phenanthroline (3.2 mg, 0.018 mmol), and dry-degassed dimethylsulfoxide (1.0 mL) and heated to 140 C. for 6 h. The mixture was cooled to ambient temperature and diluted with 6N ammonium hydroxide and ethyl acetate. The phases were separated, and the aqueous phase extracted once with ethyl acetate. The combined organic extracts were washed successively with water (2×) and 3N ammonium hydroxide, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 635.5 (M+H)+(100%).
  • 22
  • [ 880264-88-0 ]
  • [ 51387-90-7 ]
  • C29H28FN5O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With aluminum (III) chloride; In dichloromethane; for 0.5h; To a solution of the quinolone ester (60 mg, 0.13 mmol) and 2-(2-aminoethyl)-1-methylpyrrolidine (30 muL, 0.19 mmol) in methylene chloride (1.0 mL) was added aluminum chloride (25 mg, 0.19 mmol) and the reaction mixture was allowed to stir for 30 minutes. The solvent was removed in vacuo and saturated L-tartaric acid (1.0 mL) was added, stirring for 45 minutes, until all of the solid dissolved. The aqueous solution was washed with methylene chloride (1.0 mL), basified with 1N NaOH and extracted with methylene chloride. The resulting extract was washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The resulting yellow material was purified on preparative TLC (Alumina, 2% Methanol in CH2Cl2) to afford the product as a yellowish solid (30 mg, 43%).
  • 23
  • [ 880264-89-1 ]
  • [ 51387-90-7 ]
  • C29H27ClFN5O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With aluminum (III) chloride; In dichloromethane; for 0.5h; To a solution of the quinolone ester (60 mg, 0.11 mmol) and 2-(2-aminoethyl)-1-methylpyrrolidine (25 muL, 0.17 mmol) in methylene chloride (1.0 mL) was added aluminum chloride (23 mg, 0.17 mmol) and the reaction mixture was allowed to stir for 30 minutes. The solvent was removed in vacuo and saturated L-tartaric acid (1.0 mL) was added, stirring for 45 minutes, until all of the solid dissolved. The aqueous solution was washed with methylene chloride (1.0 mL), basified with 1N NaOH and extracted with methylene chloride. The resulting extract was washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The resulting yellow material was purified on preparative TLC (Alumina, 2% Methanol in CH2Cl2) to afford the product as a yellowish solid (30 mg, 46%).
  • 24
  • [ 880264-90-4 ]
  • [ 51387-90-7 ]
  • C30H30FN5O3S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With aluminum (III) chloride; In dichloromethane; for 0.5h; To a solution of the quinolone ester (75 mg, 0.15 mmol) and 2-(2-aminoethyl)-1-methylpyrrolidine (32 muL, 0.22 mmol) in methylene chloride (1.0 mL) was added aluminum chloride (29 mg, 0.22 mmol) and the reaction mixture was allowed to stir for 30 minutes. The solvent was removed in vacuo and saturated L-tartaric acid (1.0 mL) was added, stirring for 45 minutes, until all of the solid dissolved. The aqueous solution was washed with methylene chloride (1.0 mL), basified with 1N NaOH and extracted with methylene chloride. The resulting extract was washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The resulting yellow material was purified on preparative TLC (Alumina, 2% Methanol in CH2Cl2) to afford the product as a yellowish solid (30 mg, 34%).
  • 25
  • [ 880264-93-7 ]
  • [ 51387-90-7 ]
  • C29H29N5O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
5% With aluminum (III) chloride; In dichloromethane; for 0.5h; To a solution of the quinolone ester (146 mg, 0.65 mmol) and 2-(2-aminoethyl)-1-methylpyrrolidine (1 mmol) in methylene chloride (1.0 mL) was added aluminum chloride (1 mmol) and the reaction mixture was allowed to stir for 30 minutes. The solvent was removed in vacuo and saturated L-tartaric acid (1.0 mL) was added, stirring for 45 minutes, until the entire solid dissolved. The aqueous solution was washed with methylene chloride (1.0 mL), basified with 1N NaOH and extracted with methylene chloride. The resulting extract was washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The resulting yellow material was purified on preparative TLC (Alumina, 2% Methanol in CH2Cl2) to afford the product as a yellowish solid (1.7 mg, 5%).
  • 26
  • [ 904688-49-9 ]
  • [ 51387-90-7 ]
  • 4-hexyloxy-N-[(S)-1-[[[2-(1-methyl-pyrrolidin-2-yl)ethyl]amino]carbonyl]butyl]-benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 15h; (3) To a solution of the compound (64 rag) obtained in the above (2), 2-(l-methylpyrrolidin-2-yl)ethylamine (0.030 ml) and 1-hydroxybenzo- triazole (27 mg) in chloroform (3 ml) were added l-(3-dimethylamino- propyl)-3-ethylcarbodiimide hydrochloride (58 mg) and triethylamine (0.028 ml) in this order, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water (3 ml), and the mixture was vigorously stirred for 10 minutes and extracted with ethyl acetate. The organic layer was washed with water, 1 % aqueous potassium carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [NH] [solvent: methanol-chloroform (1:30)] to obtain 4-(hexyloxy)-N-[(lS)- l-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]amino]- carbonyl] butyl] benzamide (68 mg, the compound of Example 3.001 listed in Table as described hereinafter)
  • 27
  • [ 541-41-3 ]
  • [ 51387-90-7 ]
  • [ 473706-95-5 ]
YieldReaction ConditionsOperation in experiment
With carbon disulfide; sodium bicarbonate; In water; EXAMPLE 7 A mixture of carbon disulfide (0.996 mL, 16.57 mmol) in water (5 mL) was cooled to 0 C. Then 2-(2-aminoethyl)-1-methylpyrrolidine (2.4 mL, 16.57 mmol) was added over 45 minutes. The resulting mixture was maintained at 0 C. for an additional 30 minutes and then the cooling was discontinued. Next, ethyl chloroformate (1.58 mL, 16.57 mmol) was added over a 1 h period. The resulting mixture was maintained at room temperature for an additional 30 minutes and then made basic with saturated sodium hydrogen carbonate in water. The mixture was extracted with diethyl ether (2*50 mL). The extracts were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by vacuum distillation to give 1.22 g of 2-(2-isothiocyanatoethyl)-1-methylpyrrolidine.
  • 28
  • C27H22FN5O5 [ No CAS ]
  • [ 51387-90-7 ]
  • C32H32FN7O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With aluminum (III) chloride; In dichloromethane; at 20℃; for 3h; The pyrazine substituted annulated phenoxazine (53mg, 0.1028 mmol), 2- aminoethylpyrolidine (132mg, 1.03 mmol) and aluminum chloride (51mg, 0.255 mmol) were added to dichloromethane (ImI) and stirred at room temperature under argon for 3h. The mixture was then evaporated to a residue and was then washed with saturated aqueous sodium potassium tartaric acid. The resulting mixture was extracted with 3 x 1 OmI dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the pyrazine pyrrolidine amide (30mg, 50%) as a yellow solid.
  • 29
  • C27H20FN5O4 [ No CAS ]
  • [ 51387-90-7 ]
  • C32H30FN7O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With aluminum (III) chloride; In dichloromethane; at 20℃; for 16h; The pyrazine nitrile (94mg, 0.19mmol), 2-(aminoethyl)- 1 -methlypyrrolidine (4IuL, 0.19 mmol) and aluminum chloride (17mg, 0.13 mmol) were added to dichloromethane (2ml) and stirred at room temperature under argon for 16h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the methyl pyrazine nitrile 24mg as a yellow solid.
  • 30
  • [ 913537-95-8 ]
  • [ 51387-90-7 ]
  • C33H31N5O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With aluminum (III) chloride; In dichloromethane; at 20℃; for 22h; The pyrazine substituted annulated phenoxazine (43mg, 0.08677 mmol), 2- (aniinoethyl)-l-methlypyrrolidine (2OuL, 0.138 mmol) and aluminum chloride (17mg, 0.13 mmol) were added to dichloromethane (ImI) and stirred at room temperature under argon for 16h. A further 20mg of aluminum chloride was then added and the mixture stirred for a further 6 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the pyrazine methylpyrrolidine (20mg, 40%) as a yellow solid.
  • 31
  • C29H21NO4S [ No CAS ]
  • [ 51387-90-7 ]
  • C34H31N3O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With aluminum (III) chloride; In dichloromethane; for 1h; Benzyl phenoxazine (20mg, 0.0417mmol), 2-(2-aminoethyl)-l-methylpyrrolidine (12ul, 0.083mmol) and aluminum chloride (1 lmg, 0.0825mmol) were mixed in anhydrous dichloromethane (ImI) and stirred for Ih. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in Dichloromethane) to yield the benzyl methylpyrrolidine (18mg, 77%) as a yellow solid.
  • 32
  • C27H20N2O5S [ No CAS ]
  • [ 51387-90-7 ]
  • C32H30N4O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With aluminum (III) chloride; In dichloromethane; for 1h; Isoxazole phenoxazine (14mg, 0.1 ldeltalmmol), 2-(2-aminoethyl)-l-methylpyrrolidine (20ul, 0.138mmol) and aluminum chloride (25mg, 0.1874mmol) were mixed in anhydrous dichloromethane (ImI) and stirred for Ih. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in Dichloromethane) to yield the isoxazole methylpyrrolidine (19mg, 77%) as a yellow solid.
  • 33
  • C28H20N2O4S [ No CAS ]
  • [ 51387-90-7 ]
  • C33H30N4O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With aluminum (III) chloride; In dichloromethane; for 1h; 4-Pyridinyl phenoxazine (13mg, 0.118 lmmol), 2-(2-aminoethyl)-l - methylpyrrolidine (22ul, O.1518mmol) and aluminum chloride (27mg, 0.2025mmol) were mixed in anhydrous dichloromethane (ImI) and stirred for Ih. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 4-pyridinyl methylpyrrolidine (1 lmg) as a yellow solid.
  • 34
  • C28H20N2O4S [ No CAS ]
  • [ 51387-90-7 ]
  • C33H30N4O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With aluminum (III) chloride; In dichloromethane; for 1h; 2-Pyridinyl phenoxazine (28mg,), 2-(2-aminoethyl)-l-methylpyrrolidine (17ul, 0.1173mmol) and aluminum chloride (21mg, 0.1575mmol) were mixed in anhydrous dichloromethane (ImI) and stirred for Ih. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 2-pyridinyl methylpyrrolidine (17.5mg) as a yellow solid.
  • 35
  • C24H19N3O4S [ No CAS ]
  • [ 51387-90-7 ]
  • C29H29N5O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With aluminum (III) chloride; In dichloromethane; for 1h; 2-Pyridinyl phenoxazine (46mg,), 2-(2-aminoethyl)-l-methylpyrrolidine (20ul, 0.13mmol) and aluminum chloride (21mg, 0.1575mmol) were mixed in anhydrous dichloromethane (ImI) and stirred for Ih. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3 x 10ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 2-pyridinyl methylpyrollidine (25mg) as a yellow solid.
  • 36
  • [ 912665-91-9 ]
  • [ 912665-93-1 ]
  • [ 51387-90-7 ]
  • [ 912666-01-4 ]
  • [ 912666-03-6 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 16h; Example 2:; (3S, 4R)-2-{4-[(4-Chloro-3-methylbenzenesulfonyl)-(2-ethylbutylamino]-3-hydroxy-2,2- dimethylchroman-6-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]acetamide; A) A mixture (4.0 g) of (3S, 4R)-(4-fert-butoxycarbonylamino-3-hydroxy-2,2-dimethyl- chroman-6-yl)acetic acid and (3S, 4R)-(4-fert-butoxycarbonylamino-3-fert-butoxy- carbonyloxy-2,2-dimethylchroman-6-yl)acetic acid (for preparation see example 1 F) above) was dissolved in dichloromethane (50 ml). DIC (1.68 ml), HOBT (1.46 g) and 2-(2-aminoethyl)-1-methylpyrrolidine (1.37 g) was added and the reaction shaken at room temperature for 16 hours. The solution was concentrated in vacuo and the obtained mixture of (3S, 4R)-(3-hydroxy-2,2-dimethyl-6-[2-(1-methylpyrroli- din-2-yl)ethylcarbamoyl]methyl}chroman-4-yl)carbamic acid fe/t-butyl ester (mono- protected product) and (3S, 4R)-carbonic acid 4-fe/t-butoxycarbonylamino-2,2- dimethyl-6-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoyl]methyl}chroman-3-yl ester fe/t-butyl ester (di-protected product) purified by column chromatography using a EPO <DP n="31"/>solvent gradient from dichloromethane:ethyl acetate (4:1) to dichloromethane: ethyl acetate (1 :1) and then increased to ethyl acetate: MeOH (1 :1).HPLC-MS (ES+): mono-protected Rt = 1.05 mins 462.51 (M+, 100%); di-protected Rt = 1.46 mins 562.47 (M+, 100%).
  • 37
  • [ 31265-81-3 ]
  • [ 51387-90-7 ]
  • 5,11-Dihydro-11-[3-[[2-(1-methyl-2-pyrrolidinyl)ethyl]amino]propionyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In N-methyl-acetamide; EXAMPLE 8 5,11-Dihydro-11-[3-[[2-(1-methyl-2-pyrrolidinyl)ethyl]amino]propionyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 3.85 g (0.03 mol) of 2-(2-aminoethyl)-1-methyl-pyrrolidine were added dropwise to a solution of 7.1 g (0.024 mol) of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3 g of triethylamine in 70 ml of dimethylformamide at ambient temperature and the resulting mixture was stirred at this temperature for a further 2 hours. After the solvent had been evaporated off, the residue was purified by column chromatography on silica gel (mobile phase: ethylene chloride/methanol/ammonia 100/20/2 by volume). The amorphous solid substance obtained was not crystalline. Yield: 2.93 g (31% of theory) RF =0.23 (Merck ready-made plates, silica gel F 254; eluant: ethyl acetate/methanol/conc. ammonia 70/30/5 by volume).
  • 38
  • [ 51387-90-7 ]
  • [ 374776-34-8 ]
  • [ 382592-28-1 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; Step 10 2-Methyl-4-{5-[2-(1-methyl-pyrrolidin-2-yl)-ethylsulfamoyl]-2-propoxy-benzoylamino}-5-propyl-2H-pyrazole-3-carboxamide: To a solution of 3-(5-carbamoyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-4-propoxy-benzenesulfonyl chloride (2.12 g, 4.8 mmol) and dry triethylamine (0.5 g, 4.8 mmol) in dichloromethane (20 mL), was added 2-(2-aminoethyl)-1-methylpyrrolidine (0.6 g, 4.8 mmol) at 0 C. The reaction was warmed to ambient temperature, stirred for 1 hour at ambient temperature, and diluted with dichloromethane (40 mL). Following standard extractive work up, the solvent was evaporated under reduced pressure to yield the title compound (2.2 g) which was used directly in the next step. LC-MS: m/z=535 (M+H)+
In dichloromethane; at 0℃; In Step 2, 4-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amido- sulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole is prepared from the pyrazole compound prepared in the above step 1. For preparation, a predetermined amount of 2-(2-aminoethyl)-l-methylpyrrolidine is added at O0C to a dichloromethane solution containing a predetermined amount of4-[2-propyloxy-5-(chlorosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole of step 1, followed by stirring. Upon completion of the reaction, the reaction solution is diluted with dichloromethane. The organic layer is washed, dried, concentrated and filtered to obtain 4-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amido- sulfonyl)benzamido]- l-methyl-3-propyl-5-carbamoyl pyrazole.
In dichloromethane; at 0℃; In step 2, 4-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl ami- dosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole is prepared from the pyrazole compound produced in the above step 1. Precisely, the proper amount of 2-(2-aminoethyl)-l -methyl pyrrolidine is added at 0 0C to dichloromethane solution containing the proper amount of 4-[2-propyloxy-5-(chlorosulfonyl)benzamido] - l-methyl-3-propyl-5-carbamoyl pyrazoleof step 1, followed by stirring. Upon completion of reaction, the reaction solution is diluted with dichloromethane. The organic layeris washed, dried, concentrated and filtered to give 4-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amidosulfonyl)benzamido] - l-methyl-3-propyl-5-carbamoyl pyrazole.
  • 39
  • 4-(4-chlorophenyl)thiazole-2-carboxylic acid hydrochloride [ No CAS ]
  • [ 51387-90-7 ]
  • 4-(4-Chloro-phenyl)-thiazole-2-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48h; Compound 45, 4-(4-Chloro-phenyl)-thiazole-2-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide (B250120) 2-(1-Methyl-pyrrolidin-2-yl)-ethylamine (37 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), followed by addition of 4-(4-Chloro-phenyl)-thiazole-2-carboxylic acid hydrochloride salt (80 mg, 0.29 mmol), HOBt (53 mg, 0.39 mmol), EDC [N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride] (72 mg, 0.38 mmol) and diisopropylethylamine (70 uL). The mixture was stirred at RT for two days. After diluted with dichloromethane (30 mL), the mixture was washed with water (30 mL). The water solution was extracted with dichloromethane (30 mL,). The combined dichloromethane was washed with water (30 mL) and dried over sodium sulfate. After passing through a pad of alumina eluted with 1% MeOH in chloroform and concentration, the residue was purified by chromatotron (alumina) eluted with hexane-chloroform to afford a yellow semisolid (70 mg, Y=69%). Rf0.33 (alumina, 1% MeOH in chloroform). The structure of the compound was confirmed by NMR and MS.
  • 40
  • [ 51387-90-7 ]
  • (+/-)-4-[4-((1R*,2S*)-2-isopropylcarbamoylcyclopentylamino)-5-trifluoromethylpyrimidin-2-ylamino]-N-[2-(1-methylpyrridine-2-yl)ethyl]benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% EXAMPLE 31 (+-)-4-[4-((1R*,2S*)-2-isopropylcarbamoyl-cyclopentylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-N-[2-(1-methyl-pyrridine-2-yl)-ethyl]-benzamide (synthesis scheme D) 80 mg (0.18 mmol) D-4c is dissolved in 2.4 mL DMF, 179 muL (1.03 mol, 1.5 eq) Huenig base is added and the solution is combined with 83 mg (0.25 mmol, 1.4 eq) TBTU. The solution is stirred for 40 min at RT, then 38.5 muL (0.27 mmol, 1.5 eq) 2-(2-aminoethyl)-1-methylpyrrolidine is added and the mixture is stirred for 2 days. Then silica gel is added to the reaction mixture and the volatile constituents are eliminated in vacuo. The purification is carried out by column chromatography through a normal phase chromatography (DCM/MeOH/NH3(aq) 5/1/0.1). 70 mg (0.125 mmol, 70%) of compound 31 is obtained.
  • 41
  • 2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • [ 51387-90-7 ]
  • C33H39N5O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; b) Alkylation of Examples 2 to 79 The amines below, in solution in dimethylformamide at a concentration of 90 mumol per 0.5 ml of dimethylformamide, are placed in tared and labeled glass tubes (1.2×10 cm). The compound 2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is dissolved in dimethylformamide at a concentration of 30 mumol per 0.5 ml of solvent. MW Weight Ex Name or reagent Formula (g/mol) (mg) 2 2-(2-aminoethyl)-1-methylpyrrolidine C7H16N2 128.22 11.540 3 2-(aminomethyl)-1-ethylpyrrolidine C7H16N2 128.22 11.540 4 n-(2-aminoethyl)pyrrolidine C6H14N2 114.19 10.280 5 furfurylamine C5H7NO 97.12 8.741 6 I-methioninol C5H13NOS 135.23 12.170 7 imidazole C3H4N2 68.08 6.127 8 3-pyrroline C4H7N 69.11 6.220 9 pyrrolidine C4H9N 71.12 6.401 10 tetrahydrofurfurylamine C5H11NO 101.15 9.104 11 1-piperonylpiperazine C12H16N2O2 220.27 19.820 12 3,4-methylenedioxybenzylamine C8H9BO2 151.17 13.610 13 2-methylpiperazine C3H12N2 100.16 9.014 14 1-phenylpiperazine C10H14N2 162.24 14.600 15 1-(2-methoxyphenyl)piperazine C11H16N2O 192.26 17.300 16 n-(3-trifluoromethylphenyl)piperazine C11H13F3N2 230.23 20.720 17 1-(4-fluorophenyl)piperazine C10H13FN2 180.23 16.220 18 1-ethoxycarbonylpiperazine C7H14N2O2 158.2 14.240 19 1-methylpiperazine C5H12N2 100.16 9.014 20 1-benzylpiperazine C11H16N2 176.26 15.860 21 n-(2-hydroxyethyl)piperazine C6H14N2O 130.19 11.720 22 2,6-dimethylmorpholine C6H13NO 115.18 10.370 23 1,4-dioxa-8-azaspiro[4.5]decane C7H13NO2 143.19 12.890 24 piperidine C5H11N 85.15 7.664 25 2-piperidineethanol C7H15NO 129.2 11.630 26 3,3-dimethylpiperidine C7H15N 113.2 10.190 27 3,5-dimethylpiperidine C7H15N 113.2 10.190 28 4-hydroxy-4-phenylpiperidine C11H15NO 177.25 15.950 29 4-methylpiperidine C6H13N 99.18 8.926 30 4-piperidineethanol C7H15NO 129.2 11.630 31 1-(2-pyridyl)piperazine C9H13N3 163.22 14.690 32 4-piperidinopiperidine C10H20N2 168.28 15.150 33 40-amino-1-benzylpiperidine C12H18N2 190.29 17.130 34 1-(2-aminoethyl)piperidine C7H16N2 128.22 11.540 35 2-amino-2-methyl-1-propanol C4H11NO 89.14 8.023 36 2-amino-5-diethylaminopentane C9H22N2 158.29 14.250 37 benzylamine C7H9N 107.16 9.644 38 N,N-diethylethylenediamine C6H16N2 116.21 10.460 39 ethanolamine C2H7NO 61.08 5.497 40 N,N-dimethyl-1,3-propanediamine C5H14N2 102.18 9.196 41 1-(3-aminopropyl)imidazole C6H11N3 125.17 11.270 42 (s)-(+)-2-(methoxymethyl)pyrrolidine C6H13NO 115.18 10.370 43 (s)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine C9H18N2 154.26 13.880 44 3-hydroxypiperidine C5H11NO 101.15 9.104 45 1-(3-aminopropyl)-4-methylpiperazine C8H19N3 157.26 14.150 46 N1,N1-dimethyl-1,2-propanediamine C5H14N2 102.18 9.196 47 N,N-diisopropylethylenediamine C8H20N2 144.26 12.980 48 3-(2-methylpiperidin-1-yl)propylamine C9H20N2 156.27 14.06 49 dl-2-amino-1-propanol C3H9NO 75.11 3.756 50 tryptamine hydrochloride C10H13ClN2 196.68 9.834 51 (s)-(+)-2-(anilinomethyl)pyrrolidine C11H16N2 176.26 8.813 52 (+/-)-nornicotine C9H12N2 148.21 7.411 53 2-(2-aminoethyl)pyridine C7H10N2 122.17 6.109 54 4-benzyl-4-hydroxypiperidine C12H17NO 191.28 9.564 55 N-aminopropylpiperidine C8H18N2 142.25 7.112 56 N-(2-aminoethyl)-n-ethyl-m-toluidine C11H18N2 178.28 8.914 57 1-(4-methoxyphenyl)piperazine C11H16N2O 192.26 9.613 58 1-(2-phenylethyl)piperazine C12H18N2 190.29 9.515 59 1-(4-pyridyl)piperazine C9H13N3 163.22 8.161 60 1-(2-hydroxyphenyl)piperazine 2 HBr C10H16Br2N2O 340.06 17.00 61 adenine C5H5N5 135.13 6.757 62 N,N-2,2-tetramethyl-1,3-propanediamine C7H18N2 130.23 6.512 63 1-cyclohexylpiperazine C10H20N2 168.28 8.414 64 N-methylhomopiperazine C6H14N2 114.19 5.710 65 d-prolinol C5H11NO 101.15 5.058 66 (s)-(+)-2-amino-1-butanol C4H11NO 89.14 4.457 67 dimethylamine C2H7N 45.08 1.352 68 diethylamine C4H11N 73.14 2.194 69 1-(3-pyrrolidinopropyl)homopiperazine C12H25N3 211.35 6.340 70 2-(1H-pyrrol-1-yl)-1-ethanamine C6H10N2 110.16 3.305 71 2-(1-benzyl-piperidinyl)ethylamine C14H22N2 218.34 6.550 72 diethanolamine C4H11NO2 105.14 12.620 73 2-(2-methylaminoethyl)pyridine C8H12N2 136.2 16.340 74 N-ethylmethylamine C3H9N 59.11 7.093 75 N,N,N'-trimethylethylenediamine C5H14N2 102.18 12.260 76 N-methylisobutylamine C5H13N 87.17 10.460 77 4-(ethylaminomethyl)pyridine C8H12N2 136.2 16.340 78 bis(2-methoxyethyl)amine C6H15NO2 133.19 15.980 79 3-methylamino-1,2-propanediol C4H11NO2 105.14 12.620 0.5 ml of each of the solutions prepared above is distributed into reactors suitable for parallel synthesis, along with 0.5 ml per well of the solution of 2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in dimethylformamide described above, and then from 0.01 to 0.015 g of potassium carbonate is added. Since the reactors are closed by means of a septum, they are placed at 80 C. for 16 hours, with orbital shaking. After returning to ambient temperature, the content of the reactors is filtered and then purified by reverse-phase liquid chromatography mass spectrometry (method B). After evaporation of the fractions...
  • 42
  • [ 947513-10-2 ]
  • [ 51387-90-7 ]
  • C33H40ClN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; To a solution of 3-chloro-4-(1-(2,2-diphenylethyl)piperidin-4-yloxy)benzoic acid (100 mg, 0.23 mmol), 2-(1-methylpyrrolidin-2-yl)ethanamine (29 mg, 0.23 mmol), and HOBT (102 mg, 0.75 mmol) in DCM (5 ml) is added EDAC (48 mg, 0.25 mmol) and the reaction is stirred overnight. The reaction mixture is diluted with DCM (20 ml) and extracted with 1 N HCI (2 x 15 ml). The HCI washings were combined and made basic with aqueous NaOH, then extracted with DCM (3 x 10 ml). The combine organic phases are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material is purified by preparative HPLC to obtain the product as the free base, which is converted to the hydrochloride salt. The final product is obtained as a white solid (110 mg, 77% yield).
  • 43
  • [ 51387-90-7 ]
  • [ 102-83-0 ]
  • [ 245421-04-9 ]
  • C31H56N8 [ No CAS ]
  • 44
  • methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)propenyl]benzoate [ No CAS ]
  • [ 51387-90-7 ]
  • (Z)-methyl 4-(3-(2-(1-methylpyrrolidin-2-yl)ethylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With triethylamine; In acetonitrile; at 0 - 20℃; for 4h; Methyl 4-[2-bromomethyl-3-(naphthalen-l-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved acetonitrile (5 ml) in a 100 ml vessel at 0C, and thereto triethylamine (0.21 ml, 1.5 mmol, 1.5 eq.) and 2-(l- methylpyrrolidin-2-yl)ethylamine (R]111NH2; 0.22 ml, 1.5 mmol, 1.5 eq.) were added while stirring. The resulting mixture was heated from 0C to room temperature, and then reacted for 4 hours. After the completion of reaction, the solvent was distilled off, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue thus obtained was subjected to a silica gel column chromatography to obtain 220 mg of the title compound as pale yellow oil(yield 48%).1H-NMR (200MHz, CDCl3) delta 1.61(m, 2H), 1.95(m, 4H), 2.25(m, IH), 2.37(s, 3H), 2.58(m, IH), 2.81(m, 2H), 3.22(m, IH), 3.67(s, 2H), 3.89(s, 3H), EPO <DP n="190"/>4.86(s, 2H), 6.71(d, J=7.4Hz, IH), 6.91(s, IH), 7.28-7.58(m, 6H), 7.79(m, IH), 7.97(d, J=8.6Hz, 2H), 8.22(m, IH) LCZMS(MhH): 459
  • 45
  • [ 940870-46-2 ]
  • [ 51387-90-7 ]
  • [ 940870-65-5 ]
YieldReaction ConditionsOperation in experiment
11% With sodium carbonate; In ethanol; at 60℃; for 19h; Example 201-(2-(2-(2-(1-methylpyrrolidin-2-yl)ethylamino)pyrimidin-4-yloxy)benzyl)-3-(3-t-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea [Show Image] To a solution of 1-(2-(2-chloropyrimidin-4-yloxy)benzyl)-3-(3-t-butyl-1-p-tolyl-1 H-pyrazol-5-yl)urea (143 mg) in ethanol (1.0 mL), 2-(2-aminoethyl)-1-methylpyrrolidine (52 mg) and sodium carbonate (93 mg) were added, and the resulting mixture was stirred at 60 C for 19 hours. The reaction mixture was evaporated under reduced pressure, and distilled water (3 mL) was added thereto, after which the mixture was extracted with dichloromethane (5 mL×3). The obtained organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was purified by amine-silica gel column chromatography (ethyl acetate/n-hexane = 97/3 - 100/0, ethyl acetate/methanol = 40/1) to obtain the desired product (18 mg, yield: 11%). 1H-NMR (CDCl3 ):delta 8.09 (d 1H J = 5.7Hz) 7.38-7.04 (m 8H) 6.23 (s 1H) 6.18 (s 1H) 6.01 (d 1H J = 5.7 Hz) 5.51 (br 1H) 4.36-4.29 (m 3H) 3.25-3.19 (m 2H) 2.95-2.89 (m 2H) 2.37 (s 6H) 2.20 (br 5H) 2.14-2.02 (m 2H) 1.33 (s 9H) MS (ESI):583 (M+H+)
  • 46
  • [ 940870-49-5 ]
  • [ 51387-90-7 ]
  • [ 940871-23-8 ]
YieldReaction ConditionsOperation in experiment
67% With N-ethyl-N,N-diisopropylamine; In ethanol; at 20 - 65℃; for 25.5h; Example 781-(5-t-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(2-(6-(2-(1-methylpyrrolidin-2-yl)ethylamino)pyrimidin-4-yloxy)benzyl)urea [Show Image] To a solution of 1-(2-(6-chloropyrimidin-4-yloxy)benzyl)-3-(3-t-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (191 mg) in ethanol (2.0 mL), 2-(1-methylpyrrolidin-2-yl)ethylamine (141 mg) and N,N-diisopropylethylamine (0.050 mL) were added, and the resulting mixture was stirred at room temperature for 3.5 hours and then at 65C for 22 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and was dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained residue was purified by amine silica gel column chromatography (ethyl acetate) to obtain the desired product (151 mg, yield: 67%). 1H-NMR (CDCl3):delta 8.04 (s, 1H), 7.36-7.17 (m, 7H), 7.03 (d, 1H, J=7.4Hz), 6.21 (s, 1H), 6.12 (bs, 2H), 5.67 (s, 1H), 5.49 (t, 1H, J=5.9Hz), 4.34 (d, 2H, J=5.9Hz), 3.30 (br, 2H), 3.07 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.27 (m, 1H), 2.20-1.70 (m, 6H), 2.15 (m, 1H), 1.32 (s, 9H) MS (ESI):583 (M+H+)
  • 47
  • [ 97-00-7 ]
  • [ 51387-90-7 ]
  • [ 925216-69-9 ]
YieldReaction ConditionsOperation in experiment
67.4% EXAMPLE 3 Preparation of the Compounds of Formula 30-36 Preparation of 31: Chloro-2,4-dinitrobenzene 1 (1.00 g, 4.937 mmol) was dissolved in anhydrous EtOH (20 mL) in a small argon purged flask and warmed in an oil bath to 40 C. Addition of 2-(1-methylpyrrolidin-2-yl)ethanamine 30 (0.696 g, 5.431 mmol) occurred dropwise. The reaction was stirred at 65-70 C. for 24 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and ethyl acetate and 1M ammonium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine (twice), dried over magnesium sulphate, filtered and then concentrated. Recrystallization of the crude solid from EtOH yielded a yellow powder 31 (2,4-Dinitro-phenyl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine Yield: 0.979 grams (67.4%). 1H NMR (DMSO) 8-1.51-1.71 (m, 3H), 1.78-1.96 (2*m, 3H), 2.06-2.14 (m, 1H), 2.26 (s, 3H), 2.26-2.36 (m, 1H), 2.93-3.03 (m, 1H), 3.48-3.53 (m, 2H), 7.18 (d, 1H, J=9.6), 8.27 (dd, 1H, J=9.7, 2.7), 8.86 (d, 1H, J=2.8), 9.50 (br s, 1H); MS (ESI): 295 (MH+, 100%)
  • 48
  • [ 7154-73-6 ]
  • [ 27578-60-5 ]
  • [ 140-31-8 ]
  • [ 2038-03-1 ]
  • [ 25560-00-3 ]
  • [ 123-00-2 ]
  • [ 5036-48-6 ]
  • [ 7663-77-6 ]
  • [ 34035-03-5 ]
  • [ 1761-71-3 ]
  • [ 6864-37-5 ]
  • [ 2213-43-6 ]
  • [ 63234-71-9 ]
  • [ 5906-35-4 ]
  • [ 59983-39-0 ]
  • [ 1664-40-0 ]
  • [ 6530-09-2 ]
  • [ 108-00-9 ]
  • [ 109-55-7 ]
  • [ 51387-90-7 ]
  • [ 102-83-0 ]
  • [ 849908-66-3 ]
  • C15H17ClN2O [ No CAS ]
  • [ 849908-70-9 ]
  • [ 940358-24-7 ]
  • C16H19ClN2O [ No CAS ]
  • C19H19ClN2O [ No CAS ]
  • [ 849908-71-0 ]
  • C17H21ClN2O2 [ No CAS ]
  • [ 849908-67-4 ]
  • C17H21ClN2O [ No CAS ]
  • [ 880815-24-7 ]
  • C17H22ClN3O [ No CAS ]
  • C18H21ClN2O [ No CAS ]
  • [ 849908-65-2 ]
  • [ 932172-19-5 ]
  • [ 875001-79-9 ]
  • [ 849908-68-5 ]
  • [ 849908-69-6 ]
  • [ 849908-81-2 ]
  • [ 849908-75-4 ]
YieldReaction ConditionsOperation in experiment
With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS); All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis.
  • 49
  • [ 4795-29-3 ]
  • [ 7154-73-6 ]
  • [ 2038-03-1 ]
  • [ 4572-03-6 ]
  • [ 27757-85-3 ]
  • [ 109-12-6 ]
  • [ 3731-53-1 ]
  • [ 107-10-8 ]
  • [ 7663-77-6 ]
  • [ 6628-04-2 ]
  • [ 2620-50-0 ]
  • polystyrene carboxaldehyde resin [ No CAS ]
  • [ 5071-96-5 ]
  • [ 617-89-0 ]
  • [ 28466-26-4 ]
  • [ 42185-03-5 ]
  • [ 453-71-4 ]
  • [ 19293-58-4 ]
  • [ 75-04-7 ]
  • [ 62-53-3 ]
  • [ 1003-03-8 ]
  • [ 51387-90-7 ]
  • [ 74-89-5 ]
  • [ 100-46-9 ]
  • [ 4152-90-3 ]
  • [ 68-41-7 ]
  • C9H8FN2O3Pol [ No CAS ]
  • C10H10FN2O3Pol [ No CAS ]
  • C11H12FN2O3Pol [ No CAS ]
  • C14H10FN2O3Pol [ No CAS ]
  • C11H8FN4O3Pol [ No CAS ]
  • C12H8FN4O3Pol [ No CAS ]
  • C13H10FN2O4Pol [ No CAS ]
  • C15H12FN2O3Pol [ No CAS ]
  • C14H11FN3O3Pol [ No CAS ]
  • C13H14FN2O3Pol [ No CAS ]
  • C13H10FN2O3PolS [ No CAS ]
  • C13H16FN2O4Pol [ No CAS ]
  • C13H14FN2O4Pol [ No CAS ]
  • C16H14FN2O4Pol [ No CAS ]
  • C11H9FN3O5Pol [ No CAS ]
  • C15H11ClFN2O3Pol [ No CAS ]
  • C17H17FN3O3Pol [ No CAS ]
  • C14H17FN3O3Pol [ No CAS ]
  • C14H17FN3O4Pol [ No CAS ]
  • C15H19FN3O3Pol [ No CAS ]
  • C16H12FN2O5Pol [ No CAS ]
  • C18H13FN3O3Pol [ No CAS ]
  • C15H17FN3O4Pol [ No CAS ]
  • C16H22FN4O3Pol [ No CAS ]
YieldReaction ConditionsOperation in experiment
A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature.
  • 50
  • [ 106-32-1 ]
  • [ 51387-90-7 ]
  • [ 479411-50-2 ]
YieldReaction ConditionsOperation in experiment
(Example 3) Synthesis of N-[2-(1-methylpyrrolidin-2-yl)ethyl]caprylamide (Compound 3) toluene (1.0 ml), dried using MS 4A, was mixed with 1.48 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.25 ml (1.16 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes.. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.5 ml of a toluene solution of 0.2 g (1.16 mmols) of caprylic acid ethyl ester was added dropwise over 1 minute.. After stirring for 2 hours at 70C, the mixture was cooled with ice, and 10 ml of 1N NaOH was added dropwise.. The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30C water bath to obtain the captioned compound (yield 0.22 g).. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:19:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
  • 51
  • [ 1191-41-9 ]
  • [ 51387-90-7 ]
  • [ 479411-53-5 ]
YieldReaction ConditionsOperation in experiment
(Example 7) Synthesis of (9Z,12Z,15Z)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]linolenamide (Compound 7) toluene (0.6 ml), dried using MS 4A, was mixed with 1.99 ml of an n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.23 ml (1.56 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 1 minute.. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.2 ml of a toluene solution of 0.2 g (0.65 mmol) of linolenic acid ethyl ester was added dropwise over 1 minute.. After stirring for 2 hours at 70C, the mixture was cooled with ice, and 10 ml of a 1N NaOH solution was added dropwise.. The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30C water bath to obtain the captioned compound (yield 0.13 g).. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:19:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
  • 52
  • [ 112-62-9 ]
  • [ 51387-90-7 ]
  • [ 479411-51-3 ]
YieldReaction ConditionsOperation in experiment
62% (Example 5) Synthesis of 9Z-N-[2-(1-methylpyrrolidin-2-yl)ethyl]oleamide (Compound 5) toluene (18 ml), dried using MS 4A, was mixed with 12.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 2.42 ml (16.7 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 5 minutes.. The 2-(2-aminoethyl)-1-methylpyrrolidine was finally washed using 2 ml of toluene.. After stirring for 20 minutes, the temperature was raised to room temperature, and 7 ml of a toluene solution of 5.0 g (16.9 mmols) of oleic acid methyl ester was added dropwise over 2 minutes.. After stirring for 2.5 hours at 70C, the mixture was cooled with ice, and 30 ml of 0.67N hydrochloric acid was added dropwise.. An aqueous solution of 1N NaOH (about 100 ml) was added, and the mixture was extracted with about 100 ml of ethyl acetate.. At this time, the PH of the aqueous layer was 9 to 10.. The organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32C water bath to obtain the captioned compound.. This compound was subjected to silica gel column chromatography (BW·80S 150 g, FUJISILYSIA, mobile phase: CHCl3:MeOH (9:14:13:1 (V/V))) for purification.. The purified compound was concentrated under reduced pressure on a 35C water bath to obtain 4.09 g of a pale yellow liquid (10.4 mmols, yield 62%). NMR confirmed this product to have the following structure:
  • 53
  • [ 124-06-1 ]
  • [ 51387-90-7 ]
  • [ 410080-19-2 ]
YieldReaction ConditionsOperation in experiment
(Example 4) Synthesis of N-[2-(1-methylpyrrolidin-2-yl)ethyl]myristamide (Compound 4) toluene (1.00 ml), dried using MS 4A, was mixed with 1.00 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.17 ml (0.78 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes.. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.5 ml of a toluene solution of 0.2 g (0.78 mmol) of <strong>[124-06-1]myristic acid ethyl ester</strong> was added dropwise over 1 minute.. After stirring for 2 hours at 70C, the mixture was cooled with ice, and a 1N NaOH solution was added dropwise.. The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30C water bath to obtain the captioned compound (yield 0.25 g).. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:19:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
  • 54
  • [ 544-35-4 ]
  • [ 51387-90-7 ]
  • [ 479411-52-4 ]
YieldReaction ConditionsOperation in experiment
(Example 6) Synthesis of (9Z,12Z)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]linoleamide (Compound 6) toluene (0.7 ml), dried using MS 4A, was mixed with 0.83 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.14 ml (0.98 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes.. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.4 ml of a toluene solution of 0.2 g (0.65 mmol) of linoleic acid ethyl ester was added dropwise over 1 minute.. After stirring for 2 hours at 70C, the mixture was cooled with ice, and 10 ml of a 1N NaOH solution was added dropwise (inner temperature 12?27C).. The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30C water bath to obtain the captioned compound (yield 0.114 g).. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:19:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
  • 55
  • [ 81926-94-5 ]
  • [ 51387-90-7 ]
  • [ 479411-49-9 ]
YieldReaction ConditionsOperation in experiment
(Example 2) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]docosahexaenoamide (Compound 2) toluene (15 ml), dried using MS 4A, was mixed with 10.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 2.03 ml (14.1 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes (inner temperature -7+8C).. The 2-(2-aminoethyl)-1-methylpyrrolidine was finally washed using 2 ml of toluene.. After stirring for 20 minutes, the temperature was raised to room temperature, and 6 ml of a toluene solution of 5.0 g (14.0 mmols) of DHA ethyl ester was added dropwise over 2 minutes (inner temperature 28?29C).. After stirring for 2 hours at 70C, the mixture was cooled with ice, and 24 ml of 0.67N hydrochloric acid was added dropwise (inner temperature 12?27C).. The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was filtered through Celite, the filtrate was separated into respective layers with the addition of a small amount of NaOH, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32C water bath to obtain the captioned compound (yield 4.7 g).. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:19:1)) for purification. NMR confirmed the purified compound to have the following structure:
  • 56
  • [ 86227-47-6 ]
  • [ 51387-90-7 ]
  • [ 479411-54-6 ]
YieldReaction ConditionsOperation in experiment
57% (Example 8) Synthesis of (5Z,8Z,11Z,14Z,17Z)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]eicosapentaenoamide (Compound 8) toluene (18 ml), dried using MS 4A, was mixed with 12.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 2.42 ml (16.7 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 5 minutes.. After stirring for 20 minutes, the temperature was raised to room temperature, and 7 ml of a toluene solution of 4.5 g (13.6 mmols) of eicosapentaenoic acid ethyl ester was added dropwise over 2 minutes.. After stirring for 2.5 hours at 70C, the mixture was cooled with ice, and 30 ml of 0.67N hydrochloric acid was added dropwise.. An aqueous solution of 1N NaOH (about 100 ml) was added, and the mixture was extracted with about 100 ml of ethyl acetate.. At this time, the PH of the aqueous layer was 9 to 10.. The organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32C water bath to obtain the captioned compound.. This compound was subjected to silica gel column chromatography (BW·80S 150 g, FUJISILYSIA, mobile phase: CHCl3:MeOH (9:14:13:1 (V/V))) for purification.. The purified compound was concentrated under reduced pressure on a 35C water bath to obtain 3.2 g (yield 57%) of a pale yellow liquid. NMR confirmed this product to have the following structure:
  • 57
  • [ 881633-88-1 ]
  • [ 51387-90-7 ]
  • [ 881634-34-0 ]
YieldReaction ConditionsOperation in experiment
85% With aluminum (III) chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 45℃; for 5h; EXAMPLE 23 Ester (1.0 eq, 312 mg, 0.73 mmol) and 2-(1-methylpyrrolidin-2-yl)ethanamine (2.0 eq, 0.21 ml, 1.45 mmol) were mixed with DBU (4.0 eq, 0.44 ml, 2.94 mmol) in CH2Cl2 (5 ml). Aluminum chloride was added (2.0 eq, 196 mg, 1.47 mmol) and the reaction was stirred at 45 C. for 5 hours. The solvent was removed in vacuo and the solid treated with a saturated aqueous solution of tartaric acid for one hour. After addition of water, the pH was adjusted to 12-14 by adding NaOH. The product was extracted with CH2Cl2 (4×). The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent removed in vacuo. The residue was triturated in a mixture of AcOEt and hexanes, filtered and dried to afford desired compound as an off-white solid (318 mg, 85% yield). LCMS (ES): 95% pure, m/z 507 [M+1]+.
  • 58
  • [ 1138544-08-7 ]
  • [ 51387-90-7 ]
  • [ 1138544-09-8 ]
YieldReaction ConditionsOperation in experiment
83% With aluminum (III) chloride; In dichloromethane; at 20℃; for 1h; EXAMPLE 17 To a solution of ester (700 mg, 1.64 mmol) and 2-(1-methylpyrrolidin-2-yl)ethanamine (0.70 mL, 4.83 mmol) in DCM (25 mL) was added AlCl3 (645 mg, 4.84 mmol). The reaction mixture was stirred at rt for 1 h. The reaction was diluted with DCM (150 mL), 6N NaOH (50 mL), and saturated sodium potassium tartrate (50 mL) and stirred for 10 min. The layers were separated and the organic layer was washed with H2O (2×50 mL), brine (50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting solid was triturated in Et2O/EtOAc (1:1) to give the desired product as a white solid (690 mg, 83%). 1H NMR (CDCl3) delta: 10.45 (t, 1H), 9.41 (d, 1H), 8.29 (d, 1H), 7.76 (dd, 1H), 7.50 (m, 1H), 7.49 (m, 1H), 3.96 (t, 4H), 3.85 (t, 4H), 3.55 (m, 2H), 3.06 (m, 1H), 2.34 (s, 3H), 2.17 (m, 1H), 2.08 (m, 3H), 1.80 (m, 2H), 1.56 (m, 2H). LCMS (ES): m/z 510 [M+1]+.
  • 59
  • [ 898537-71-8 ]
  • [ 51387-90-7 ]
  • [ 898536-41-9 ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide; at 70℃; for 5h; To a solution of 1-[5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(6-chloro-pyrimidin-4-yloxy)-phenyl]urea (30 mg, 0.062 mMol) in DMF is added 2-(2-aminomethyl)-1-methyl pyrrolidine (52 mL, 0.37 mMol) and the reaction mixture is stirred at 70 C. for 5 h. After cooling and removal of all volatiles the crude product is purified by HPLC RtB: 2.38 min; MS: [M+1]+=573.1
  • 60
  • [ 1062243-48-4 ]
  • [ 51387-90-7 ]
  • [ 1201691-95-3 ]
YieldReaction ConditionsOperation in experiment
(I-112) A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.12 mmole) 2-(1-methyl-pyrrolidin-2-yl)-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluding with water-acetonitrile (gradient, 0:100-80:20) to give 0.046 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (I-112) as a white solid.
  • 61
  • [ 1694-92-4 ]
  • [ 51387-90-7 ]
  • [ 944691-85-4 ]
  • 62
  • [ 51387-90-7 ]
  • [ 98-74-8 ]
  • [ 944678-85-7 ]
YieldReaction ConditionsOperation in experiment
81% In tetrahydrofuran; at 0 - 20℃; REFERENCE EXAMPLE 4; 4-Amino-W-[2-(1-methylpyrrolidin-2-yS)ethyI]benzenesulfonamide; a) Lambdaf-[2-(1-MethySpyrrolidm-2-yl)ethyl]-4-?strobenzenesulfo?amide 1.0 g of 4-nitrobenzenesuifony. chloride (4.51 mmol) in THF (5 mL) were slowiy added at 0 0C over a solution of 2-(1-methylpyrroiidin-2~yl)ethylamine (3.2 mL, 27 mmol) in THF (23 mL). The reaction mixture was stirred at room temperature overnight. The crude product obtained was diluted with a saturated aqueous solution of NaCi and extract thrice with EtOAc. The combined organic phases were separated, dried over Na2SC>4 and the solvent was evaporated to dryness. 1.18 g of the desired compound were obtained (yield: 81 %). LC-MS (Method 2): tR - 1.33 min; m/z = 314 (MH+).
  • 63
  • [ 1228304-26-4 ]
  • [ 51387-90-7 ]
  • [ 1228303-48-7 ]
YieldReaction ConditionsOperation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; EXAMPLE 56; 2-(4-Chlorophenyl)-3-(hydroxymethyl)-N-[2-(l-methylpyrrolidin-2- yl)ethyl]imidazo[l,2-a]pyridine-6-carboxamide; Diisopropylethylamine (52 muL, 0.3 mmol) and 1 -propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 90 muL, 0.15 mmol) were added to a solution of sodium 2-(4- chlorophenyl)-3-(hydroxymethyl)imidazo[l,2-a]pyridine-6-carboxylate (Intermediate 1; 10 mg, 0.03 mmol) in DMF (0.3 mL). 2-(l-Methylpyrrolidin-2-yl)ethanamine (9 muL, 0.06 mmol) was added and the reaction mixture was left at rt overnight. Water (0.2 mL) and methanol (0.5 mL) were added and the mixture was purified by preparative HPLC (Xterra Cl 8, 50 raM NH4HCO3 (pH 10) - CH3CN) to give the title compound as a white solid (6 mg). HRMS (ESI+) calcd for C22H25ClN4O2 412.1666, found 412.1671.
  • 64
  • [ 1234356-90-1 ]
  • [ 51387-90-7 ]
  • [ 1234356-76-3 ]
YieldReaction ConditionsOperation in experiment
50% In N,N-dimethyl-formamide; at 200℃; for 0.666667h;Microwave irradiaion; A solution of 2-chloro-6-(3 ,4-dichlorophenyl)-5 ,6- dihydrobenzo[fjisoquinoline-l-carbonitrile (156 mg, 0.405 mmol) in N5N- dimethylformamide (3.5ml) and 2-(l-methylpyrrolidin-2-yl)ethanamine (250 ul) was heated under microwave conditions at 200C for 40 minutes. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The aqueous layer was removed and the organic layer was washed with water (3 x 30 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using a gradient of dichloromethane-methanol as eluent to afford 6-(3 ,4-dichlorophenyl)-2-(2-( 1 -methylpyrrolidin-2-yl)ethylamino)-5 ,6- dihydrobenzo[fjisoquinoline-l-carbonitrile as a yellow solid (96 mg, 50%). M.p. = 131- 1340C. 400 MHz 1H NMR (DMSO-d6) delta 8.30 (m, IH), 8.14 (s, IH), 7.49 (m, 5H), 7.13 (m, IH), 7.00 (dd, J= 8 and 2 Hz, IH), 4.30 (m, IH), 3.43 (m, 2H), 3.08 (dd, J= 15.2 and 7.2 Hz, IH), 2.92 (dd, J= 15.2 and 5.6 Hz, IH), 2.37 (m, 6H), 1.97 (m, IH), 1.89 (m, IH), 1.68 (m, 3H), 1.55 (m, IH). LCMS m/e 477 [M+H].
  • 65
  • [ 253870-02-9 ]
  • [ 51387-90-7 ]
  • [ 1196537-28-6 ]
YieldReaction ConditionsOperation in experiment
50.2% Example 3. Synthesis of N-[(1-methylpyrrolidin-2-yl)ethyl]-5-formyl-2,4 -dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were sequentially added to DMF (500mL) with stirring at about 0C, and stirred for 1.5 hrs, then (1-methylpyrrolidin-2-yl) ethylamine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mLx3), the combined organic phase was washed with saturated salt water (300mL*3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 139.1g (502mmol) of N-[(1-methylpyrrolidin-2-yl)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 50.2%, m.p. 143-149C.
  • 66
  • [ 563-76-8 ]
  • [ 51387-90-7 ]
  • C10H19BrN2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.3% In dichloromethane; at 0 - 20℃; 2-Bromopropionyl bromide (9.2g, 40mmol) was added dropwise to a solution of 2-(1-methylpyrrolidin-2-yl) ethylamine (5.68g, 40mmol) in dichloromethane (50mL) with stirring at about 0C. Afterwards, the reaction was warmed to room temperature and stirred until thin layer chromatography (TLC) indicated complete reaction. The solvent was distilled off to afford an oily residue 7.96g (36.52mmol). Yield 91.3%.
  • 67
  • [ 79-04-9 ]
  • [ 51387-90-7 ]
  • [ 1196538-03-0 ]
YieldReaction ConditionsOperation in experiment
89.6% In dichloromethane; at 0 - 20℃; Chloroacetic chloride (4.52g, 40mmol) was added dropwise to a solution of 2-(1-methylpyrrolidin-2-yl) methylamine (5.68g, 40mmol) in dichloromethane (50mL) with stirring at about 0C. Afterwards, the reaction was warmed to room temperature and stirred until completion was indicated by thin layer chromatography (TLC). The solvent was distilled off to give 7.33g (35.84mmol) of an oily residue. Yield 89.6%.
  • 68
  • [ 51387-90-7 ]
  • [ 422545-95-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: ethanol; water / 0.5 h / 65 °C / Inert atmosphere; Industry scale 2.1: hydrogenchloride / water; tert-butyl methyl ether / 0.75 h 2.2: 1.17 h
  • 69
  • [ 32634-68-7 ]
  • [ 51387-90-7 ]
  • [ 1332848-72-2 ]
YieldReaction ConditionsOperation in experiment
44% In ethanol; water; at 65℃; for 0.5h;Inert atmosphere; Industry scale; Example 1 Preparation of (-)-2-(2-Aminoethyl)-1-methylpyrrolidine, 0, 0 -Di-p-toluoyl-D-tartaric acid saltA stock solution of aqueous ethanol was prepared by mixing ethanol (10370 mL) and water (2080 mL). A mixture of O,O'-di-p-tolouyl-D-tartaric acid (1624 g, 4.203 mol) and a portion of the above described stock solution of aqueous ethanol (9050 mL) was stirred at around 65C under a nitrogen atmosphere. Separately, racemic 2-(2- aminoethyl)-1-methylpyrrolidine (700 g, 5.35 mol) was dissolved in a portion of the aqueous ethanol stock solution (3400 mL). The amine solution was then added drop- wise to the tartaric acid solution so that the temperature was maintained at about 65C and no solids formed during the addition. The reaction was held at about 65C for no less than 30 min before being cooled to about 0C. The precipitate was collected by filtration. A stream of nitrogen was pulled through the collected solid until no longer wet. The solid was recrystallized from ethanol (15950 mL)/water (2457 mL) affording the desired product as a colorless solid: 1322.4 g (44%), >99.5% ee.
  • 70
  • [ 1332759-75-7 ]
  • [ 51387-90-7 ]
  • [ 1332760-11-8 ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; The acid f and Hunig's base (15muIota) was dissolved in DMF (2 ml). After a few minutes TBTU (21 .2 mg) was added. To this mixture was added the amin (0.07 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was purified by chromatography.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; The acid f and Huenig's base (150 was dissolved in DMF (2 ml). After a few minutes TBTU (21.2 mg) was added. To this mixture was added the amin (0.07 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was purified by chromatography.
  • 71
  • [ 1344708-45-7 ]
  • [ 51387-90-7 ]
  • [ 1344707-97-6 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;Wheaton tubes; The amines (150 muiotaetaomicron, 3 eq) were weighed into individual 16 x 100 Wheaton tubes. Next stock solutions were made: (R/5)-2-hydroxy-2-(4-(5-(l-phenyl- 5-(trifluoromethyl)-lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int- VII, 494.5 mg, 50 muiotaetaomicron per reaction, 1 eq) was dissolved in DMF (3 mL), and separately, HATU (541 mg, 100 muiotaetaomicron per reaction, 2 eq) was dissolved in DMF (3.8 mL). To each Wheaton tube containing an amine was added (R/S)-2-hydroxy-2-(4- (5-(l-phenyl-5-(trifluoromethyl)-lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII) solution (130 mu), followed by HATU solution (165 mu) and N-ethyl- N-isopropylpropan-2-amine (35 mu^, 200 muiotaetaomicron, 4 eq). The reactions were agitated at 400 rpm on an INNOVA platform shaker overnight at rt. After 16 hours, the reactions were transferred to prep LCMS as solutions in DMF. Samples were purified on a Waters Xbridge 19 x 100 mm C18 column over a 20 min gradient from 0% B to 100% B (solvent A = 5:95 MeOH:H20 with 10 mM NH4OAc, solvent B = 95:5 MeOH:H20 with 10 mM NH4OAc). Fractions containing the desired product were combined and dried for 16 hours in a Genevac at 45 C to provide Examples 135-158 as racemic mixtures (see Table 2).
  • 72
  • [ 1264751-36-1 ]
  • [ 51387-90-7 ]
  • [ 1264752-37-5 ]
YieldReaction ConditionsOperation in experiment
56% In methanol; at 140℃; for 1h;Microwave irradiation; Example 133 (5Z)-5-[(4-[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methoxyphenyl)methylidene]-4-[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-1,5-dihydro-2H-imidazol-2-one; [Show Image] A suspension of (5Z)-4-amino-5-[(4-[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methoxyphenyl)methylidene]-1,5-dihydro-2H-imidazol-2-one (230 mg) and 2-(1-methylpyrrolidin-2-yl)ethanamine (77 mg) in methanol (5 mL) was stirred under microwave irradiation at 140C for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=50:50?0:100) and recrystallized (ethyl acetate) to give the title compound as a white solid (yield: 160 mg, 56%). 1H-NMR (DMSO-d6, 300 MHz):delta1.32 - 1.73 (4H, m), 1.82-2.14 (4H, m), 2.22 (3H, s), 2.87-2.99 (1H, m), 3.34-3.44 (2H, m), 3.87 (3H, s), 5.36 (2H, s), 6.42 (1H, s), 6.97-7.09 (3H, m), 8.03 (1H, d, J = 8.1 Hz), 8.10 (1H, s), 8.17 (1H, d, J = 8.1 Hz), 8.48 (1H, brs), 9.84 (1H, s).
  • 73
  • [ 1264752-39-7 ]
  • [ 51387-90-7 ]
  • [ 1264752-40-0 ]
YieldReaction ConditionsOperation in experiment
70% In methanol; at 140℃; for 1h;Microwave irradiation; Example 136 (5Z)-5-[(4-[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methoxyphenyl)methylidene]-1-methyl-4-[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-1,5-dihydro-2H-imidazol-2-one; [Show Image] A suspension of (5Z)-4-amino-5-[(4-[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methoxyphenyl)methylidene]-1-methyl-1,5-dihydro-2H-imidazol-2-one (95 mg) and 2-(1-methylpyrrolidin-2-yl)ethanamine (30 mg) in methanol (5 mL) was stirred under microwave irradiation at 140C for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=50:50?0:100) and recrystallized (ethyl acetate and hexane) to give the title compound as a white solid (yield: 80 mg, 70%). 1H-NMR (DMSO-d6, 300 MHz)):delta1.33-1.75 (4H, m), 1.92 (2H, m), 2.08 (2H, m), 2.23 (3H, s), 2.76 (3H, s), 2.95 (1H, brs), 3.34-3.49 (2H, m), 3.81 (3H, s), 5.34 (2H, s), 6.66 (1H, s), 6.86 (1H, dd, J = 8.1, 1.5 Hz), 6.96 (1H, d, J = 1.7 Hz), 7.05 (1H, d, J = 8.3 Hz), 8.05 (1H, d, J = 8.3 Hz), 8.10 (1H, s), 8.14-8.21 (1H, d, J=8.7 Hz), 8.63 (1H, brs).
  • 74
  • [ 51387-90-7 ]
  • [ 4303-29-1 ]
  • [ 796844-14-9 ]
  • [ 1264751-86-1 ]
YieldReaction ConditionsOperation in experiment
27% Example 87 (5Z)-5-[(4-[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methoxyphenyl)methylidene]-4-[2-(1-methylpyrrolidin-2-yl)ethyl]aminol-1,3-thiazol-2(5H)-one; [Show Image] To a solution (3.1 mL) of 4-thioxo-1,3-thiazolidin-2-one (91.4 mg) in ethanol was added 2-(1-methylpyrrolidin-2-yl)ethanamine (0.109 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added 4-[2,4-bis(trifluoromethyl)benzyl]oxy}-2-methoxybenzaldehyde (235.9 mg) and potassium tert-butoxide (84.0 mg), and the mixture was stirred with heating under reflux for 4 hr. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:7?0:1) and recrystallized from acetone/diethylether to give the title compound as a pale-yellow powder (yield: 100.5 mg, 27%). 1H-NMR (DMSO-d6,300 MHz):delta1.36-1.76 (4H, m), 1.86-2.01 (2H, m), 2.02-2.18 (2H, m), 2.24 (3H, s), 2.91-3.00 (1H, m), 3.52 (2H, t, J = 7.4 Hz), 3.86 (2H, s), 5.41 (3H, s), 7.10-7.24 (3H, m), 7.73 (1H, s), 8.04 (1H, d, J = 8.5 Hz), 8.11 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 9.35 (1H, brs).
  • 75
  • [ 1055361-66-4 ]
  • [ 51387-90-7 ]
  • [ 4303-29-1 ]
  • [ 1264751-97-4 ]
YieldReaction ConditionsOperation in experiment
24% Example 93 4-(2-methoxy-4-{(Z)-[4-[2-(1-methylpyrrolidin-2-yl)ethyl]aminol-2-oxo-1,3-thiazol-5(2H)-ylidene]methyl}phenoxy)-3-(trifluoromethyl)benzonitrile; [Show Image] To a solution (90 mL) of 2-(1-methylpyrrolidin-2-yl)ethanamine (4.12 g) in ethanol was added 4-thioxo-1,3-thiazolidin-2-one (4.15 g) and the mixture was stirred at room temperature for 3 hr under a nitrogen atmosphere. To the reaction mixture were added 4-(4-formyl-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (8.85 g) and potassium tert-butoxide (4.11 g), and the mixture was heated under reflux for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=100:0?95:5) to give the title compound as a pale-yellow solid (yield: 3.65 g, 24%). The obtained solid was washed with diethyl ether, and recrystallized from ethyl acetate/n-heptane to give the title compound as a pale-yellow solid (yield: 2.62 g, 17%). 1H-NMR (DMSO-d6, 300 MHz):delta1.37-1.72 (4H, m), 1.86-2.18 (4H, m), 2.24 (3H, s), 2.90-3.02 (1H, m), 3.54 (2H, t, J = 6.9 Hz), 3.80 (3H, s), 6.93 (1H, d, J = 8.9 Hz), 7.24 (1H, dd, J = 8.3, 1.7 Hz), 7.30 (1H, d, J = 1.9 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.82 (1H, s), 8.03 (1H, dd, J = 8. 9, 1.9 Hz), 8.33 (1H, d, J = 1.7 Hz), 9.50 (1H, brs).
  • 76
  • [ 1055361-84-6 ]
  • [ 51387-90-7 ]
  • [ 4303-29-1 ]
  • [ 1264752-00-2 ]
YieldReaction ConditionsOperation in experiment
8% Example 96 4-(2-methoxy-4-{(Z)-[4-[2-(1-methylpyrrolidin-2-yl)ethyl]aminol-2-oxo-1,3-thiazol-5(2H)-ylidene]methyl}phenoxy)naphthalene-1-carbonitrile; [Show Image] To a solution (650 mL) of 4-thioxo-1,3-thiazolidin-2-one (46.0 g) in ethanol was added a solution (100 mL) of 2-(1-methylpyrrolidin-2-yl)ethanamine (45.7 g) in ethanol and the mixture was stirred at room temperature for 3 hr under a nitrogen atmosphere. To the reaction mixture were added 4-(4-formyl-2-methoxyphenoxy)naphthalene-1-carbonitrile (87.3 g) and potassium tert-butoxide (45.6 g), and the mixture was heated under reflux for 0.5 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and filtered by basic silica gel column chromatography, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=100:0?95:5), and washed with diethyl ether. The obtained yellow solid was recrystallized from tetrahydrofuran/n-heptane to give the title compound as a yellow solid (yield: 11.9 g, 8%). 1H-NMR (DMSO-d6, 300 MHz):delta1.40-1.72 (4H, m), 1.86-2.17 (4H, m), 2.24 (3H, s), 2.91-3.00 (1H, m), 3.47-3.63 (2H, m), 3.80 (3H, s), 6.70 (1H, d, J = 8.3 Hz), 7.23-7.30 (1H, m), 7.33 (1H, d, J = 1.9 Hz), 7.42 (1H, d, J = 8.3 Hz), 7.75-7.95 (3H, m), 8.04 (1H, d, J = 8.3 Hz), 8.14 (1H, d, J = 8.3 Hz), 8.45 (1H, d, J = 8.1 Hz), 9.52 (1H, brs).
  • 77
  • [ 1264753-87-8 ]
  • [ 51387-90-7 ]
  • [ 4303-29-1 ]
  • [ 1264752-18-2 ]
YieldReaction ConditionsOperation in experiment
16% Example 114 (5Z)-5-[(4-[2,4-bis(trifluoromethyl)benzyl]oxy}-2-chloro-5-methoxyphenyl)methylidene]-4-[2-(1-methylpyrrolidin-2-yl)ethyl]aminol-1,3-thiazol-2(5H)-one; [Show Image] To a solution (2 mL) of 4-thioxo-1,3-thiazolidin-2-one (107 mg) in ethanol was added 2-(1-methylpyrrolidin-2-yl)ethanamine (0.126 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added 4-[2,4-bis(trifluoromethyl)benzyl]oxy}-2-chloro-5-methoxybenzaldehyde (300 mg) and potassium tert-butoxide (98 mg) and the mixture was stirred with heating under reflux for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol-ethyl acetate=0:100?5:95) and recrystallized from ethyl acetate/hexane to give the title compound as a pale-yellow powder (yield: 72 mg, 16%). 1H-NMR (DMSO-d6, 300 MHz):delta1.29 - 2.18 (8H, m), 2.24 (3H, s), 2.96 (1H, dt, J = 9.3, 4.7 Hz), 3.54 (2H, t, J = 7.5 Hz), 3.82 (3H, s), 5.42 (2H, s), 7.23 (1H, s), 7.35 (1H, s), 7.80 (1H, s), 8.04 (1H, d, J = 8.3 Hz), 8.12 (1H, s), 8.19 (1H, d, J = 8.7 Hz), 9.74 (1H, brs).
  • 78
  • [ 1264752-41-1 ]
  • [ 51387-90-7 ]
  • [ 1264752-42-2 ]
YieldReaction ConditionsOperation in experiment
43% In methanol; at 140℃; for 1h;Microwave irradiation; Example 138 4-{2-methoxy-4-[(Z)-(5-[2-(1-methylpyrrolidin-2-yl)ethyl]aminol-2-oxo-2,3-dihydro-4H-imidazol-4-ylidene)methyl]phenoxy}-3-(trifluoromethyl)benzonitrile; [Show Image] A suspension of 4-{4-[(Z)-(5-amino-2-oxo-2,3-dihydro-4H-imidazol-4-ylidene)methyl]-2-methoxyphenoxy}-3-(trifluoromethyl)benzonitrile (130 mg) and 2-(1-methylpyrrolidin-2-yl)ethanamine (49 mg) in methanol (5 mL) was stirred under microwave irradiation at 140C for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=50:50?0:100) and the obtained yellow solid was washed with diethylether to give the title compound as a white solid (yield: 70 mg, 43%). 1H-NMR (DMSO-d6, 300 MHz):delta1.36-1.75 (4H, m), 1.83-2.15 (4H, m), 2.23 (3H, s), 2.95 (1H, brs), 3.38-3.46 (2H, m), 3.81 (3H, s), 6.49 (1H, s), 6.85 (1H, d, J = 8.9 Hz), 7.09-7.31 (3H, m), 8.03 (1H, dd, J = 8.8, 2.0 Hz), 8.31 (1H, d, J = 1.3 Hz).
  • 79
  • [ 14371-10-9 ]
  • [ 51387-90-7 ]
  • C16H22N2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium sulfate; In dichloromethane; at 20℃; for 24h;Inert atmosphere; General procedure: The amine, the aldehyde and MgSO4 (or Na2SO4) were mixed with dry DCM. The mixture was stirred at room temperature for the indicated time (TLC and NMR were used to monitor imine formation). The reaction mixture was filtered and the collected solid was washed with DCM. The filtrate was concentrated in vacuo. MeOH was added to the residue and the mixture was cooled to 0 C. NaBH4 was added to reduce the imine. The mixture was stirred at 0 C for the indicated time. The reaction mixture was quenched with acetone, stirred for 10 min at room temperature and concentrated in vacuo. Extraction was performed with H2O/DCM (2x) ensuring that the pH of the water layer is >10 by addition of aq. 10% K2CO3-solution. The combined organic layers were washed with brine (1x), dried over Na2SO4, filtered and concentrated in vacuo. If indicated, the crude product was purified.
  • 80
  • [ 125265-16-9 ]
  • [ 51387-90-7 ]
  • C17H23FN2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With magnesium sulfate; In dichloromethane; at 20℃; for 120h;Inert atmosphere; General procedure: The amine, the aldehyde and MgSO4 (or Na2SO4) were mixed with dry DCM. The mixture was stirred at room temperature for the indicated time (TLC and NMR were used to monitor imine formation). The reaction mixture was filtered and the collected solid was washed with DCM. The filtrate was concentrated in vacuo. MeOH was added to the residue and the mixture was cooled to 0 C. NaBH4 was added to reduce the imine. The mixture was stirred at 0 C for the indicated time. The reaction mixture was quenched with acetone, stirred for 10 min at room temperature and concentrated in vacuo. Extraction was performed with H2O/DCM (2x) ensuring that the pH of the water layer is >10 by addition of aq. 10% K2CO3-solution. The combined organic layers were washed with brine (1x), dried over Na2SO4, filtered and concentrated in vacuo. If indicated, the crude product was purified.
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