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[ CAS No. 132958-72-6 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 132958-72-6
Chemical Structure| 132958-72-6
Chemical Structure| 132958-72-6
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Product Details of [ 132958-72-6 ]

CAS No. :132958-72-6 MDL No. :MFCD00191347
Formula : C6H14N2 Boiling Point : -
Linear Structure Formula :- InChI Key :AVAWMINJNRAQFS-ZCFIWIBFSA-N
M.W : 114.19 Pubchem ID :2758521
Synonyms :

Calculated chemistry of [ 132958-72-6 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.45
TPSA : 15.27 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.98 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.89
Log Po/w (XLOGP3) : 0.03
Log Po/w (WLOGP) : -0.47
Log Po/w (MLOGP) : 0.21
Log Po/w (SILICOS-IT) : 0.34
Consensus Log Po/w : 0.4

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.5
Solubility : 36.0 mg/ml ; 0.316 mol/l
Class : Very soluble
Log S (Ali) : 0.1
Solubility : 143.0 mg/ml ; 1.25 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.86
Solubility : 15.6 mg/ml ; 0.137 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.63

Safety of [ 132958-72-6 ]

Signal Word:Danger Class:8,3
Precautionary Statements:P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 UN#:2734
Hazard Statements:H225-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 132958-72-6 ]

* 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 [ 132958-72-6 ]

[ 132958-72-6 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 624-28-2 ]
  • [ 132958-72-6 ]
  • [ 868661-92-1 ]
YieldReaction ConditionsOperation in experiment
70.1% With toluene-4-sulfonic acid at 110℃; for 1h; Inert atmosphere; 69 (3R)- 1 -(5 -Bromo-2-pyridyl)-N,N-dimethyl-pyrrolidin-3 -amine 4-Methylbenzenesulfonic acid (0.080 g, 0.42 mmol) was added to 2,5-dibromopyridine (lg, 4.22 mmol) and (3R)-N,N-dimethyl-3-pyrrolidinamine (0.964 g, 8.44 mmol) and stirred at 110 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with saturated sodium hydrogencarbonate, water and saturated brine. The organic layer was dried over Na2SO4, filtered andevaporated to afford the desired product (0.800 g, 70.1 %) as a brown oil.NMR Spectrum: ‘H NMR (400MHz, DMSO) ö 1.65-1.80 (1H, m), 2.05-2.20 (8H, m)2.60-2.72 (1H, m), 2.98-3.10 (1H, m), 3.49-3.60 (2H, m), 6.43 (1H, d), 7.61 (1H, d) 8.10(1H, d).Mass Spectrum: mlz (ES+) [M+H]+ = 270
With toluene-4-sulfonic acid at 130℃; for 20h;
  • 2
  • [ 949556-71-2 ]
  • [ 132958-72-6 ]
  • [ 949558-86-5 ]
YieldReaction ConditionsOperation in experiment
84% With 18-crown-6 ether; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In tetrahydrofuran at 40℃; for 72h; 104.A Step A: Preparation of (R)-1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine: To a stirred suspension of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (49 mg, 0.1 mmol) (prepared according to Example 7, step B) and (R)-N,N-dimethylpyrrolidin-3-amine (23 mg, 0.2 mmol) in 300 μL THF at ambient temperature in a capped reaction vial was added racemic Binap (9 mg, 0.015 mmol) followed by NaOtBu (14 mg, 0.15 mmol) and 18-crown-6 (40 mg, 0.1499 mmol). The reaction purged with nitrogen gas and then held under a balloon of nitrogen. Pd(dba)2 (6 mg, 0.01 mmol) was then added and the reaction was sealed and heated to 40° C. After stirring for 72 hours, the reaction was cooled to ambient temperature, diluted to 30 mL with dichloromethane and washed with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The brown residue was dissolved in a minimum of dichloromethane and loaded onto a Biotage 12S column. The column was eluted with 95/5 dichloromethane/MeOH to provide the product as a tan foam (40 mg, 84%).
  • 3
  • [ 2417-72-3 ]
  • [ 132958-72-6 ]
  • [ 953434-75-8 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In 1,2-dimethoxyethane at 20℃; for 18h; 1a.4 Step 4: (R)-M ethyl 4-((3-(dimethylamino)pyrrolidin-l-yl)methyl)benzoate (6); [0681] Methyl 4-(bromomethyl)benzoate 5 (0.5 g, 2.2 mmol), (R)-N,JV-dimethylpyrrolidin-3- amine (0.523 g, 4.6 mmol) and potassium carbonate (0.392 g, 2.8 mmol) were stirred at room temperature for 18 h in ethyleneglycol dimethylether (3 mL) then diluted with DCM (20 mL), washed with brine, dried over MgSO4 and concentrated to give title compound 6 (0.57 g, 96% yield).[0682] 1H NMR (DMSO-de) δ (ppm): 7.88 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 3.82(s, 3H), 3.60 (abq, J= 44.0, 13.5 Hz, 2H), 2.69 to 2.61 (m, 2H), 2.58 to 2.50 (m, IH), 2.48 to 2.39(m, IH), 2.26 to 2.23 (m, IH), 2.05 (s, 6H), 1.85 to 1.81 (m, IH), 1.62 to 1.56 (m, IH).
  • 4
  • [ 956907-14-5 ]
  • [ 132958-72-6 ]
  • [ 956904-90-8 ]
YieldReaction ConditionsOperation in experiment
36% With potassium carbonate In isopropyl alcohol at 60℃; for 0.166667h; Microwave irradiation; 11 Method 11: A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (50 mg, 0.15 mmol), potassium carbonate (81 mg, 0.59 mmol), and (R)-N,N-dimethylpyrrolidine-3-amine (50 mg, 0.44 mmol) in 2-propanol (1.5 mL) was heated in the microwave at 60° C. for 10 min. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography eluting with chloroform/7N ammonia in methanol (0.1-3.5%) followed by a second column eluting with chloroform/methanol (1-7%) to afford the desired product (21 mg, 36%).
  • 5
  • [ 3430-18-0 ]
  • [ 132958-72-6 ]
  • [ 960289-39-8 ]
YieldReaction ConditionsOperation in experiment
99% With toluene-4-sulfonic acid at 100℃; 48 Preparation 48; [(R)-l-(5-Bromo-3-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine; Combine 2,5-dibromo-3-methyl-pyridine (2.00 g, 7.97 mmol) with dimethyl-(R)- pyrrolidin-3-yl-amine (2.40 g, 20.72 mmol) andp-toluenesulfonic acid monohydrate (0.39 g, 2.07 mmol) in a sealed tube and heat at 100 0C overnight. Dilute with EtOAc (100 mL), wash with saturated NaHCO3 (3 x 40 mL), dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography, eluting with 2%NH3 H2O in 1: 1 CH3OHiEtOAc to give 2.09 g (99%) of the title compound. LC-MS/ES m/z (79Br) 284.3 [M+H]+.
  • 6
  • [ 1000068-33-6 ]
  • [ 132958-72-6 ]
  • [ 1000067-64-0 ]
YieldReaction ConditionsOperation in experiment
48% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 3h; 218 4-[5-(l//-Indol-2-yl)pyridin-3-yl]amino}-3-methoxybenzoic acid (10.0 mg, 0.03 mol), TBTU (44.7 mg, 0.14 mmol), TEA (19.0 μL, 0.14 mmol) and (3R)-N,N- dimethylpyrrolidin-3-amine (15.9 mg, 0.14 mmol) in DMF (1 mL) were shaken at ambient temperature for 3h and purified using preparative HPLC system A. Yield 4.4 mg (48%). HPLC 100%, Rτ: 1.523 (10-97% MeCN over 3min). MS 456 (M+H)+. MS (electronspray) M+H+ m/z calcd 455.2321 found 455.2316.
  • 7
  • [ CAS Unavailable ]
  • [ 132958-72-6 ]
  • [ 596794-52-4 ]
YieldReaction ConditionsOperation in experiment
43% With thionyl chloride; triethylamine 27.a (3R)-1-[(7-Chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-N,N-dimethylpyrrolidin-3-amine Example 27(a) (3R)-1-[(7-Chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-N,N-dimethylpyrrolidin-3-amine This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.214 g, 1.0 mmole) by treatment with thionyl chloride followed by reaction of the resultant acyl chloride with (3R)-N,N-dimethylpyrrolidin-3-amine (0.114 g, 1.0 mmole) and Et3N (0.139 ml, 1.0 mmole), in a manner as previously described for example 9d to give a brown solid (0.134 g, 43%). 1H NMR (300 MHz, CD3OD) δ7.24 (1H, d, J=5.1 Hz), 6.57 (1H, d, J=8.48 Hz), 6.15 (1H, d, J=5.1 Hz), 2.70 (1H, m), 2.51 (2H, m), 2.24 (1H, m), 2.04 (1H, m), 1.49 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.52 (1H, m); ESIMS (MH+): 310.10.
32% With triethylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.25h; 8.a.i Step (i) Step (i) 7-Chloro-2-[3(R)-(dimethylamino)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine HATU (4.99 g, 26.25 mmol) and Et3N (7.23 mL, 52.50 mmol) was added to a solution of (3R)-N,N-dimethylpyrrolidin-3-amine (1.0 g, 17.5 mmol) and 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (3.85 g, 17.5 mmol) in 30 mL DMF at 0° C. The reaction mixture was stirred at 0° C. for 15 min and solvent was concentrated. The residue was partition between H2O and 10% CH3OH in EtOAC. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (5-7% CH3OH in CH2Cl2) to give a white solid (1.74 g, 32%). 1H NMR (CD3OD) δ8.57 (1H, d, J=5.2 Hz), 7.90 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=5.2 Hz), 4.11-3.97 (1H, m), 3.90-3.36 (3H, m), 2.99-2.90 (1H, m), 2.30 (3H, s), 2.26 (3H, s), 1.97-1.72 (2H, m). ESIMS (MH+): 310.10.
  • 8
  • [ 132958-72-6 ]
  • [ 254972-84-4 ]
  • [ 461045-01-2 ]
YieldReaction ConditionsOperation in experiment
65% With Ki; potassium carbonate In butanone 164.D 4'-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1'-biphenyl-4-carbonitrile EXAMPLE 164D 4'-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1'-biphenyl-4-carbonitrile The product from Example 164C (0.31 g, 1.08 mmol), (3R)-N,N-dimethyl-3-pyrrolidinamine (1.30 mmol, 149 mg), K2CO3 (1.62 mmol, 224 mg) and KI (1.62 mmol, 268 mg) were combined in 2-butanone (20 mL) and heated at 110° C. After 4 days, the solution was allowed to cool to room temperature, filtered, and the fitrate evaporated under reduced pressure. The residue was purified using silica gel chromatography (CHCl3:MeOH:NH4OH, 90:10:1) to provide a white solid (65% yield). 1H-NMR (300 MHz, CDCl3) δ 1.60 (m, 2H), 1.80 (bs, 2H), 2.00-2.80 (m, 15H), 2.75 (m, 1H), 4.10 (bs, 2H), 6.90-7.64 (m, 7H); MS (ESI) m/z 364 (M+H)+.
65% With Ki; potassium carbonate In butanone 164.D 4'-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1'-biphenyl-4-carbonitrile EXAMPLE 164D 4'-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1'-biphenyl-4-carbonitrile The product from Example 164C (0.31 g, 1.08 mmol), (3R)-N,N-dimethyl-3-pyrrolidinamine (1.30 mmol, 149 mg), K2CO3 (1.62 mmol, 224 mg) and KI (1.62 mmol, 268 mg) were combined in 2-butanone (20 mL) and heated at 110° C. After 4 days, the solution was allowed to cool to room temperature, filtered, and the fitrate evaporated under reduced pressure. The residue was purified using silica gel chromatography (CHCl3:MeOH:NH4OH, 90:10:1) to provide a white solid (65% yield). 1H-NMR (300 MHz, CDCl3) δ1.60 (m, 2H), 1.80 (bs, 2H), 2.00-2.80 (m, 15H), 2.75 (m, 1H), 4.10 (bs, 2H), 6.90-7.64 (m, 7H); MS (ESI) m/z 364 (M+H)+.
  • 9
  • [ 874959-68-9 ]
  • (R)-(+)-3-(dimethylamino)pyrrolidine [ No CAS ]
  • (3R)-1-[(5-bromo-pyridin-2-yl)sulfonyl]-N,N-dimethyl-pyrrolidin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With triethylamine; In dichloromethane; at 0 - 20℃; for 18h; Intermediate A5(iii): (3R)-1-[(5-bromopyridin-2-yl)sulfonyl]-N,N-dimethylpyrrolidin-3-amine To a solution of A5(ii) (7.62 g, 30 mmol) in anhydrous CH2CI2 (120 mL) at 0 0C was added (R)-N, N- dimethylpyrrolidin-3-amine (3.43 g, 30 mmol) and triethyiamine (12.5 mL, 90 mmol). The mixture was allowed to reach ambient temperature and stirred for 18 hours. The reaction mixture was diluted withCH2Cl2 (100 mL) and water (50 mL), and extracted with CH2CI2 (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (SiO2) eluting with 2-10% methanol in CH2CI2 to give desired product A5(iii) (4.43 g, yield48%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.75 (d, J=1.8 Hz, 1 H) 8.04 (dd, J=8.3, 2.3 Hz, 1 H)7.85 (d, J=8.3 Hz, 1 H) 3.67 - 3.79 (m, 2 H) 3.46 (td, J=10.1 , 7.1 Hz, 1 H) 3.17 (t, J=9.1 Hz, 1 H) 2.67 -2.75 (m, 1 H) 2.19 - 2.22 (m, 6 H) 2.03 - 2.12 (m, 1 H) 1.69 - 1.82 (m, 1 H).
  • 10
  • [ 878198-42-6 ]
  • [ 132958-72-6 ]
  • [ 878198-41-5 ]
YieldReaction ConditionsOperation in experiment
86% In acetonitrile at 70℃; for 15h; 35 A solution of (8S)-Λ/-[(5-fluoroimidazo[1 ,2-a]pyridin-2-yl)methyl]-Λ/-{(1 S)-1-[4- (methyloxy)phenyl]ethyl}-5,6,7,8-tetrahydro-8-quinolinamine (5.64 g, 13.1 mmol) in acetonitrile (65 ml_) was treated with (3R)-(+)-3-dimethylaminopyrrolidine (7.48 g, 65.5 mmol) and heated at 7O0C for 15 hours. The reaction mixture was concentrated, diluted with dichloromethane, washed with saturated aqueous sodium carbonate, separated, and extracted with additional dichloromethane. The organic layers were combined, dried over magnesium sulfate, concentrated, and purified by flash chromatography (0-10% ammonium hydroxide in acetonitrile) to yield (8S)-N- ({5-[(3/?)-3-(dimethylamino)-1 -pyrrolidinyl]imidazo[1 ,2-a]pyridin-2-yl}methyl)-Λ/-{(1 S)- 1-[4-(methyloxy)phenyl]ethyl}-5,6,7,8-tetrahydro-8-quinolinamine (5.94 g, 86% yield) as a pink solid. 1H NMR (400 MHz1 CDCI3) δ 8.47 (d, J = 4.2 Hz, 1 H), 7.91 (s, 1 H), 7.55 (d, J = 8.5 Hz, 2 H), 7.20 (d, J ~ 7.4 Hz, 1 H), 7.08-7.00 (m, 2 H), 6.95 (dd, J = 7.6, 4.7 Hz, 1 H), 6.82-6.80 (m, 2 H), 6.05 (d, J = 6.7 Hz, 1 H), 4.04 (m, 1 H), 4.87 (m, 1 H), 3.86 (m, 2 H), 3.75 (s, 3 H)1 3.58-3.51 (m, 2 H), 3.45 (m, 1 H), 3.34 (m, 1 H), 2.91 (m, 1 H), 2.63 (m, 1 H), 2.52 (m, 1 H), 2.34 (s, 6 H), 2.26 (m, 1 H), 2.06-1.98 (m, 2 H), 1.84-1.77 (m, 2 H), 1.48 (m, 1 H), 1.29 (d, J = 7.1 Hz, 3 H); MS m/z 525 (M+1).
  • 11
  • [ 644971-09-5 ]
  • [ 132958-72-6 ]
  • [ 644972-64-5 ]
YieldReaction ConditionsOperation in experiment
67% Stage #1: With N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene In dichloromethane at 20℃; for 0.25h; Stage #2: 5-chloro-2-[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-[(4-methoxybenzyl)oxy]benzoic acid hydrochloride In 1-methyl-pyrrolidin-2-one; dichloromethane for 0.5h; Stage #3: (R)-(+)-3-(dimethylamino)pyrrolidine In 1-methyl-pyrrolidin-2-one; dichloromethane at 20℃; 214.V Step V:; (2S)-1-{4-chloro-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-5-[(4-methoxybenzyl)oxy]phenoxy}-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)propan-2-ol A mixture of PS-carbodiimide (380 mg, 0.49 mmol) and dichloromethane (3 mL) was stirred at room temperature for 15 minutes, a solution of 5-chloro-2-[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-[(4-methoxybenzyl)oxy]benzoic acid hydrochloride (150 mg, 0.24 mmol) in NMP (0.5 mL) and dichloromethane (2.5 mL) was added. The mixture was stirred for 30 minutes, and a mixture of (3R)-N,N-dimethylpyrrolidin-3-amine (56 mg, 0.49 mmol) in dichloromethane (2.5 mL) was added. The mixture was stirred at room temperture overnight and filtrated. Volatiles were removed in vacuo, the residue was purified by HPLC (acetonitrile/water, 0.025% ammonium hydroxid) and gave 110 mg, (67%) of the subtitle compound. APCI-MS: m/z 684 (MH+)
  • 12
  • [ 23474-34-2 ]
  • [ 132958-72-6 ]
  • [ 589-15-1 ]
  • [ 1089128-95-9 ]
YieldReaction ConditionsOperation in experiment
20% Stage #1: (R)-(+)-3-(dimethylamino)pyrrolidine; 1-bromomethyl-4-bromobenzene In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: 7(S)-7-deoxy-7-mercaptolincomycin With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 130℃; for 0.333333h; Microwave irradiation; S1.vii Step (vii) of Example S1: 7-Deoxy-7-(4-(((R)-3-(dimet hylamino)pyrrolidin-1-yl)methyl)phenylthio)-7-epilincomycin (c ompound 75) (R)-N,N-Dimethylpyrrolidin-3-amine (56.9 mg, 4.98 mmol) was added to a solution (0.8 ml) of 83 mg (0.332 mmol) of 4-bromobenzyl bromide in dimethylformamide, and the mixture was stirred at room temperature for 20 min. The title compound (70 mg, 0.166 mmol) in step (v) of Example S1, 7.6 mg (0.0083 mmol) of tris(dibenzylideneacetone)dipalladium, 9.61 mg (0.0166 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylsantene, and 0.0578 ml (0.322 mmol) of diisopropylethylamine were added to the reaction solution, and the mixture was stirred with a microwave reaction apparatus at 130°C for 20 min. The reaction solution was diluted with ethyl acetate, and the diluted solution was then washed with an aqueous sodium hydrogencarbonate solution, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform : methanol : 28% aqueous ammonia = 90 : 10 : 1) to give 41 mg (yield 20%) of the title compound. 1H-NMR (400 MHz, CD3OD) δ: 0.89-0.97 (3H, m), 1.28 (3H, d, J = 6.8 Hz), 1.30-1.40 (4H, m), 1.67-1.77 (1H, m), 1.80-1.91 (1H, m), 1.95-2.24 (13H, m), 2.27-2.35 (1H, m), 2.40 (3H, s), 2.47-2.55 (1H, m), 2.69-2.89 (3H, m), 2.99 (1H, dd, J = 10.5, 4.6 Hz), 3.25 (1H, dd, J = 8.3, 5.6 Hz), 3.56 (1H, d, J = 12.7 Hz), 3.58 (1H, dd, J = 10.0, 3.4 Hz), 3.63 (1H, d, J = 12.7 Hz), 3.74 (1H, d, J = 3.4 Hz), 3.85 (1H, dq, J = 2.4, 6.8 Hz), 4.10 (1H, dd, J = 10.0, 5.6 Hz), 4.34 (1H, d, J = 9.7 Hz), 4.40 (1H, dd, J = 10.0, 2.4 Hz), 5.26 (1H, d, J = 5.6 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.3 Hz) MS (FAB) m/z 625 [M+H]+
  • 13
  • [ 1229607-38-8 ]
  • [ 132958-72-6 ]
  • [ 1885-14-9 ]
  • [ 1229607-75-3 ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: 4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-amine; phenyl chloroformate With triethylamine In tetrahydrofuran at 20℃; for 1h; Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In tetrahydrofuran at 20℃; for 16h; 54 To a solution of 4-(4-nιtronaphthalen-1-yloxy)pyrιdιn-2-amιne (200 mg, 0.71 mmol) and Et3N (0.20 ml_, 1.42 mmol) in dry THF was added phenyl carbonochloridate (98 μl_, 0.78 mmol) and the reaction mixture maintained at RT for 1 hr. An aliquot of (R)-Λ/,Λ/-dιmethylpyrrolιdιn-3-amιne (270 μl_, 2.13 mmol) was added to this mixture and after 15 hr at RT a second aliquot of (R)- Λ/,Λ/-dιmethylpyrrolιdιn-3-amιne (100 μl_, 0.79 mmol) was added and the mixture was maintained at RT for a further 1 hr. The resulting mixture was partitioned between aq. NH4CI (10 ml.) and DCM (10 ml.) and the aqueous layer was separated and extracted with DCM (3 x 10 ml.) The combined organic extracts were dried (MgSO4) and evaporated in vacuo The residue was purified by flash column chromatography (SiO2, 40 g, [5% MeOH in DCM] in DCM, 0-100%, gradient elution and then, 10% [2% NH3 (7 M in MeOH) in MeOH] in DCM, isocratic elution and finally, 30% MeOH in DCM, isocratic elution) to afford (R)-3-(dιmethylamιno)-Λ/-(4- (4-nιtronaphthalen-1-yloxy)pyrιdιn-2-yl)pyrrolιdιne-1-carboxamιde, Intermediate K1 , as a yellow/brown solid (250 mg, 81 %); R1 1.54 mm (Method 2); m/z 422 (M+H)+ (ES+).
81% Stage #1: 4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-amine; phenyl chloroformate With triethylamine In tetrahydrofuran at 20℃; for 1h; Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In tetrahydrofuran at 20℃; for 16h; 60 To a solution of (77) (200 mg, 0.71 mmol) and Et3N (0.20 mL, 1.42 mmol) in dry THF was added phenyl carbonochloridate (98 μL, 0.78 mmol) and the reaction mixture maintained at RT for 1 hr. An aliquot of (R)-N,N-dimethylpyrrolidin-3-amine (270 μL, 2.13 mmol) was added to this mixture and after 15 hr at RT a second aliquot of (R)-N,N-dimethylpyrrolidin-3-amine (100 μL, 0.79 mmol) was added and the mixture was maintained at RT for a further 1 hr. The resulting mixture was partitioned between aq. NH4Cl (10 mL) and DCM (10 mL) and the aq layer was separated and extracted with DCM (3×10 mL) The combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, [5% MeOH in DCM] in DCM, 0-100%, gradient elution and then, 10% [2% NH3 (7M in MeOH) in MeOH] in DCM, isocratic elution and finally, 30% MeOH in DCM, isocratic elution) to afford (R)-3-(dimethylamino)-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide, (78), as a yellow/brown solid (250 mg, 81%); Rt 1.54 min (Method 2); m/z 422 (M+H)+ (ES+).
With ammonia; triethylamine In tetrahydrofuran; methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 60 (R)-N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide To a solution of (77) (200 mg, 0.71 mmol) and Et3N (0.20 mL, 1.42 mmol) in dry THF was added phenyl carbonochloridate (98 μL, 0.78 mmol) and the reaction mixture maintained at RT for 1 hr. An aliquot of (R)-N,N-dimethylpyrrolidin-3-amine (270 μL, 2.13 mmol) was added to this mixture and after 15 hr at RT a second aliquot of (R)-N,N-dimethylpyrrolidin-3-amine (100 μL, 0.79 mmol) was added and the mixture was maintained at RT for a further 1 hr. The resulting mixture was partitioned between aq. NH4Cl (10 mL) and DCM (10 mL) and the aq layer was separated and extracted with DCM (3*10 mL) The combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, [5% MeOH in DCM] in DCM, 0-100%, gradient elution and then, 10% [2% NH3 (7M in MeOH) in MeOH] in DCM, isocratic elution and finally, 30% MeOH in DCM, isocratic elution) to afford (R)-3-(dimethylamino)-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide, (78), as a yellow/brown solid (250 mg, 81%); Rt 1.54 min (Method 2); m/z 422 (M+H)+ (ES+).
  • 14
  • [ 1337931-94-8 ]
  • [ 132958-72-6 ]
  • [ 1885-14-9 ]
  • [ 1337931-99-3 ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: phenyl chloroformate With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-(2,3-dichloro-4-nitrophenoxy)pyridin-2-amine In dichloromethane at 0 - 20℃; for 1.5h; Stage #3: (R)-(+)-3-(dimethylamino)pyrrolidine To a solution of triethylamine (700 μ, 5.00 mmol) in dry DCM (10.0 mL) at 0°C was added phenyl carbonochloridate (520 μ, 4.17 mmol) and after an interval of 10 min Intermediate C3 (500 mg, 1 .7 mmol) was added and the mixture allowed to warm to RT. After 1 .5 hr the reaction mixture was re-cooled to 0°C and a solution of (R)-/V,/V-dimethylpyrrolidin-3-amine (500 μ, 3.93 mmol) in DCM (1 .0 mL) was added and the mixture warmed to RT for 4 hr. An additional aliquot of (R)-/V,/V-dimethylpyrrolidin-3-amine (250 μ, 1 .97 mmol) was added and after a further 16 hr the reaction mixture was quenched by the addition of NH3 in MeOH (1 % solution, 6.0 mL) and evaporated in vacuo. The residue was partitioned between EtOAc (20 mL) and saturated aq NaHC03 (20 mL) and the organic layer was separated, washed with brine (5.0 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 80 g, MeOH in DCM, 0-20%, gradient elution) to afford (R)-N- (4-(2,3-dichloro-4-nitrophenoxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1 -carboxamide as a yellow solid (510 mg, 68 %); Rl 1.39 min (method 2); m/z 440/442 (M+H)+, (ES+).
68% Stage #1: phenyl chloroformate With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-(2,3-dichloro-4-nitrophenoxy)pyridin-2-amine In dichloromethane at 0 - 20℃; Stage #3: (R)-(+)-3-(dimethylamino)pyrrolidine In dichloromethane at 0 - 20℃; for 20h; To a solution of triethylamine (700 μL, 5.00 mmol) in dry DCM (10.0 mL) at 0° C. was added phenyl carbonochloridate (520 μL, 4.17 mmol) and after an interval of 10 min Intermediate C3 (500 mg, 1.7 mmol) was added and the mixture allowed to warm to RT. After 1.5 hr the reaction mixture was re-cooled to 0° C. and a solution of (R)-N,N-dimethylpyrrolidin-3-amine (500 μL, 3.93 mmol) in DCM (1.0 mL) was added and the mixture warmed to RT for 4 hr. An additional aliquot of (R)-N,N-dimethylpyrrolidin-3-amine (250 μL, 1.97 mmol) was added and after a further 16 hr the reaction mixture was quenched by the addition of NH3 in MeOH (1% solution, 6.0 mL) and evaporated in vacuo. The residue was partitioned between EtOAc (20 mL) and saturated aq NaHCO3 (20 mL) and the organic layer was separated, washed with brine (5.0 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, MeOH in DCM, 0-20%, gradient elution) to afford (R)-N-(4-(2,3-dichloro-4-nitrophenoxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide as a yellow solid (510 mg, 68%); Rt 1.39 min (method 2); m/z 440/442 (M+H)+, (ES+).
  • 15
  • [ 1307230-13-2 ]
  • [ 132958-72-6 ]
  • [ 530-62-1 ]
  • [ 1307230-12-1 ]
YieldReaction ConditionsOperation in experiment
70% Stage #1: (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride; 1,1'-carbonyldiimidazole With triethylamine In dichloromethane at 20℃; for 15h; Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In dichloromethane at 20℃; for 6.5h; 20 [0305] (R)-N-( ( R )-5-( 5-( 3-cyano-4-isopropoxyphenyl)-l, 2, 4-oxadiazol-3-yl)-l,2, 3, 4- tetrahydronaphthalen-l-yl)-3-(dimethylamino)pyrrolidine-l-carboxamide (Compound 20)[0306] Prepared using General Procedure 3: To a stirring solution of CDI ((9.5 mg, 0.06 mmol) in DCM (1 mL) were added dropwise a solution of (R)-5-(3-(5-amino-5,6,7,8- tetrahydronaphthalen-l-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HC1 salt 3 (20 mg, 0.05 mmol) and Et3N (20.3 xL, 0.15 mmol) in DCM (1 mL). After stirring for 15 h at room temperature, this solution was added dropwise to another solution containing (R)-3- dimethylaminopyrrolidine (18.6 mg, 0.15 mmol)) in DCM (1 mL) at room temperature. The reaction was stirred at room temperature for 6.5 h. The solvent was evaporated and the pure product was isolated by preparative HPLC to afford 17.5 mg (70%) of (R)-N-((R)-5-(5-(3- cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)- 1 ,2,3,4- tetrahydronaphthalen- l-yl)-3- (dimethylamino) pyrrolidine- 1-carboxamide 20. LCMS-ESI (m/z) calculated for C29H34N603: 514.6; found 515.3 [M+H]+, tR = 2.56 min. NMR (400 MHz, CDC13) δ 8.39 (d, J = 2.2 Hz, 1H), 8.31 (dt, J = 8.7, 4.3 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 5.13 (d, J = 6.9 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.64 (d, J = 8.2 Hz, 1H), 3.91 (dd, J = 10.4, 7.3 Hz, 1H), 3.80 - 3.56 (m, 3H), 3.41 (dd, J = 17.5, 8.3 Hz, 1H), 3.15 (d, J = 18.0 Hz, 1H), 3.10 - 2.93 (m, 1H), 2.85 (s, 6H), 2.46 (m, 2H), 2.05 (dd, J = 9.2, 4.8 Hz, 1H), 1.88 (m, 3H), 1.45 (dd, J = 13.9, 6.1 Hz, 6H).
  • 16
  • [ 1421372-34-0 ]
  • [ 132958-72-6 ]
  • [ 1421373-28-5 ]
YieldReaction ConditionsOperation in experiment
84% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 140℃; for 0.5h; Microwave irradiation; 165 Intermediate 165: N-{4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine (3R)-N,N-Dimethylpyrrolidin-3-amine (92 mg, 0.81 mmol) was added to a mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 404 mg, 0.73 mmol) and DIPEA (0.256 mL, 1.46 mmol) in DMA 3mL. The mixture was then heated in a microwave at 140°C for 0.5h. Part-purification was achieved by ion-exchange chromatography, using an SCX column (20 g) and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (291 mg, 84%) as an orange solid ; 1H NMR: 1.82 (1H, dt), 2.12-2.20 (1H, m), 2.22 (6H, s), 2.73-2.83 (1H, m), 3.12-3.22 (2H, m), 3.22-3.27 (1H, m), 3.41-3.51 (1H, m), 3.97 (3H, s), 6.58 (1H, s), 7.07 (1H, t), 7.18 (1H, t), 7.26 (1H, d), 7.45 (1H, d), 8.00 (1H, s), 8.28-8.31 (2H, m), 8.35 (1H, d), 8.57 (1H, s), 11.78 (1H, s); m/z: ES+ MH+ 474.30.
  • 17
  • [ 1421372-44-2 ]
  • [ 132958-72-6 ]
  • [ 1421372-60-2 ]
YieldReaction ConditionsOperation in experiment
96% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 140℃; for 0.5h; Microwave irradiation; 94 Intermediate 94: 5-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine (R)-(+)-3-(dimethylamino)pyrrolidine (0.1 1 1 mL, 0.87 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) in DMA (3 mL) and the mixture was heated at 140°C in a microwave for 0.5h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated and further purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (353 mg, 96%) as an orange foam; 1H NMR: 1.78-1.91 (1H, m), 2.16-2.27 (7H, m), 2.70-2.85 (1H, m), 3.12-3.29 (3H, m), 3.41-3.55 (1H, m), 3.89 (3H, s), 6.57 (1H, s), 6.95 (1H, t), 7.17 (1H, t), 7.46 (1H, d), 8.09 (1H, s), 8.24 (1H, br s), 8.37 (1H, s), 8.50 (1H, d), 8.54 (1H, s), 1 1.88 (1H, s); m/z: ES+ MH+ 508.5.
  • 18
  • [ 1421372-92-0 ]
  • [ 132958-72-6 ]
  • [ 1421372-98-6 ]
YieldReaction ConditionsOperation in experiment
79% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 140℃; for 1h; Microwave irradiation; Sealed tube; 135 Intermediate 135: N-{4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (3R)-N,N-dimethylpyrrolidin-3-amine (64 mg, 0.56 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 267 mg, 0.53 mmol) and DIPEA (0.186 mL, 1.07 mmol) were suspended in DMA (2 mL), sealed into a microwave tube and then heated to 140°C for1h in a microwave reactor. After cooling to r.t. the mixture was part-purified by ion exchange chromatography, using an SCX column. The column was first washed with CH3OH and then eluted with 0.7M methanolic ammonia. Clean fractions were concentrated in vacuo to give crude material as an orange gum. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (201 mg, 79%) as a orange gum; 1H NMR (CDCl3): 1.89-1.98 (3H, m), 2.05-2.12 (2H, m), 2.16-2.23 (1H, m), 2.30 (6H, s), 2.78-2.87 (1H, m), 3.14-3.37 (5H, m), 3.54 (1H, td), 3.96 (3H, s), 4.20 (2H, t), 6.34 (1H, s), 6.85 (1H, d), 7.33 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 479.60.
  • 19
  • [ 1421373-18-3 ]
  • [ 132958-72-6 ]
  • [ 1421373-17-2 ]
YieldReaction ConditionsOperation in experiment
86% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 85℃; for 1h; 154 Intermediate 154: N-[4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (3R)-N,N-Dimethylpyrrolidin-3-amine (0.166 mL, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.227 mL, 1.31 mmol) in DMA (3.2 mL) and the mixture was heated at 85°C for1h. Part purification was achieved by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (443 mg, 86%) as an orange solid; 1H NMR: 1.77-1.88 (1H, m), 2.13-2.20 (1H, m), 2.23 (6H, s), 2.75-2.84 (1H, m), 3.14-3.26 (3H, m), 3.43-3.51 (1H, m), 3.96 (3H, s), 6.58 (1H, s), 7.08 (1H, td), 7.27 (1H, d), 7.34-7.39 (1H, m), 8.24 (1H, s), 8.35 (1H, d), 8.40 (1H, s), 8.49 (1H, d), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 475.31.
  • 20
  • [ 137054-46-7 ]
  • [ 132958-72-6 ]
  • [ 1338706-30-1 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid With triethylamine In N,N-dimethyl acetamide at -10℃; for 0.0833333h; Stage #2: With methanesulfonyl chloride In N,N-dimethyl acetamide at -10℃; for 0.5h; Stage #3: (R)-(+)-3-(dimethylamino)pyrrolidine In N,N-dimethyl acetamide at -10℃; for 0.5h; 20.1 Step (1): Compound 20a + Compound 2d → Compound 20b To a solution of Compound 2d (2.14 g, 5 mmol) in N,N-dimethylacetamide (20 mL) triethylamine (0.83 ml, 6 mmol) was added, and then stirred at -10°C for 5 minutes. Methanesulfonyl chloride (0.51 ml, 6.5 mmol) was added in one portion, and then stirred at -10°C for 30 minutes. Subsequently, Compound 20a (0.57 g, 5 mmol) was added thereto, and then stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and then washed with aqueous saturated sodium hydrogen carbonate solution, water, then saturated brine. The organic layer was then dried with magnesium sulfate. After magnesium sulfate was filtered, the filtrate was concentrated in vacuo, and then subjected to silica gel column chromatography, eluting with chloroform - methanol. Fractions containing the desired compound were concentrated under reduced pressure to yield Compound 20b (2.3 g, 88%).MS: 525.83 (M+H)1H-NMR (CDCl3) δ: 1.69-1.86 (2H, m), 2.71-2.78 (1H, m), 2.94 (3H, s), 3.01 (3H, s), 3.16-3.38 (2H, m), 3.51-3.61 (1H, m), 3.79 (3H, s), 3.83 (3H, s), 3.87-4.16 (1H, m), 4.97 (2H, s), 5.06 (2H, s), 6.81 (2H, d, J=6.8), 6.89-6.99 (4H, m), 7.31-7.36 (4H, m).
88% Stage #1: 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid With methanesulfonyl chloride; triethylamine In N,N-dimethyl-formamide at -10℃; for 0.5h; Inert atmosphere; Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In N,N-dimethyl acetamide; N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; [Method B] General procedure: To a solution of 1.0 equivalent of the acid derivative in DMF were added 1.1 equivalent of Et3N. To this solution was added 1.1 equivalent of MsCl at one portion at-10°C and stirred for 30min. To this resulting mixture were added 1.1 equivalent of Et3N and 1.1 equivalent of amine, and stirred for 1hat 0°C. The solvent was evaporated in vacuo, the resulting residue was diluted with a mixture of aq. 2mol/L NaOH and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was subjected to silica gel chromatography, eluting with EtOAc (containing 5% of Et3N)-MeOH. The eluted fractions containing the desired compound were concentrated in vacuo to afford a target amide derivative.
  • 21
  • [ 1442471-00-2 ]
  • [ 132958-72-6 ]
  • [ 1442473-87-1 ]
YieldReaction ConditionsOperation in experiment
45% With 1-Methylpyrrolidine In tetrahydrofuran at 55℃; for 16h; 84 Example 84 A solution of Example A50 (0.098 g, 0.183 mmol) in THF (3 mL) was treated with (3R)-(+)-3-(dimethylamino)pyrrolidine (0.047 g, 0.549 mmol) and 1-methylpyrrolidine (2.088 mg, 0.018 mmol) and heated at 55° C. for 16 h. The mixture was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford (R)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (48 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.57 (d, J=11.0 Hz, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.68 (m, 2H), 3.39 (m, 1H), 3.20 (m, 1H), 2.19 (br s, 6H), 2.07 (m, 2H), 1.72 (m, 1H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 592.2 [M+H]+.
45% With 1-Methylpyrrolidine In tetrahydrofuran at 55℃; for 16h; 84 Example 84: A solution of Example A50 (0.098 g, 0.183 mmol) in THF (3 mL)was treated with (3R)-(+)-3-(dimethylamino)pyrrolidine (0.047 g, 0.549 mmol) and 1-methylpyrrolidine (2.088 mg, 0.018 mmol) and heated at 55°C for 16 h. The mixture wasconcentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford(R)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido )phenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1 ,6-naphthyridin-7 -yl)-3-( dimethylamino )pyrrolidine-1-carboxamide ( 48 mg, 45% yield). 1 HNMR (400 MHz, DMSO-d6): 8 9.10 (s, 1 H), 9.08 (s, 1 H), 8.72 (s, 1 H), 8.65 (s, 1 H), 8.21(d, J = 8.6 Hz, 1 H), 8.11 (s, 1 H), 7.94 (s, 1 H), 7.57 (d, J = 11.0 Hz, 1 H), 7.41 (dd, J = 8.3,1.2 Hz, 2 H), 7.26 (t, J = 7.8 Hz, 2 H), 6.97 (t, J = 7.4 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 3.68(m, 2 H), 3.39 (m, 1 H), 3.20 (m, 1 H), 2.19 (br s, 6 H), 2.07 (m, 2 H), 1.72 (m, 1 H), 1.24 (t,J = 7.1 Hz, 3 H); MS (ESI) m/z: 592.2 [M+H(
  • 22
  • [ 622-46-8 ]
  • (R)-(+)-3-(dimethylamino)pyrrolidine [ No CAS ]
  • (R)-3-(dimethylamino)pyrrolidine-1-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% Example 68 A solution of phenyl carbamate (2 g, 14.58 mmol) in dioxane (15 mL) was treated with (R)-N,N-dimethylpyrrolidin-3-amine (2.498 g, 21.88 mmol), stirred at RT for 3 h and concentrated to dryness. The residue was dissolved in Et2O, treated with HCl (2M in Et2O, 3 mL), stirred for 1 h and concentrated to dryness. The material was dissolved in EtOAc, treated slowly with Hex until solids formed, sonicated and the resulting solid collected via filtration to afford (R)-3-(dimethylamino)pyrrolidine-1-carboxamide hydrochloride (1.8 g, 79%). MS (ESI) m/z: 158.1 (M+H+).
  • 23
  • [ 1307869-27-7 ]
  • [ 132958-72-6 ]
  • [ 530-62-1 ]
  • [ 1307870-07-0 ]
YieldReaction ConditionsOperation in experiment
62% Stage #1: (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride; 1,1'-carbonyldiimidazole With triethylamine In dichloromethane at 20℃; for 2h; Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In dichloromethane at 20℃; for 16h; (R)-N-((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (Compound 56) Prepared using General Procedure 19: To a CDI ((13.4 mg, 0.08 mmol) in DCM (0.5 mL) was added a suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 5 (20.0 mg, 0.04 mmol) and Et3N (14.7 mg, 0.14 mmol) in DCM (0.5 mL) and the mixture stirred for 2 h at room temperature. The resulting solution was added to the preparative solution of azetidin-3-ol hydrochloride (15.9 mg, 0.14 mmol)) at room temperature. The reaction was stirred at room temperature for 16 h. The solvent was evaporated and the crude material was purified by preparative HPLC to afford 15 mg of (62%) of (R)-N-((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide 56. LCMS-ESI (m/z) calculated for C28H32N6O2S: 516.2. found 517.2 [M+H]+, tR=2.43 min. 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=2.4 Hz, 1H), 8.32 (dd, J=9.0, 2.4 Hz, 1H), 7.99-7.76 (m, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.49-7.34 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 5.32 (d, J=8.2 Hz, 1H), 5.09-4.80 (m, 1H), 3.86 (dd, J=14.3, 7.0 Hz, 1H), 3.75 (dd, J=11.0, 7.5 Hz, 1H), 3.63-3.48 (m, 1H), 3.45-3.22 (m, 3H), 3.10 (dt, J=16.5, 8.3 Hz, 1H), 2.82 (t, J=5.1 Hz, 6H), 2.56-2.40 (m, 1H), 2.32 (dd, J=9.8, 2.5 Hz, 1H), 2.15-2.02 (m, 1H), 2.00-1.81 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.10, 165.84, 161.80, 145.94, 142.30, 133.54, 133.36, 128.86, 127.82, 126.94, 126.41, 122.72, 115.78, 114.01, 103.72, 72.71, 64.71, 55.95, 46.76, 44.20, 42.04, 34.06, 31.45, 27.30, 21.90, 21.89.
  • 24
  • [ 2048186-96-3 ]
  • [ 132958-72-6 ]
  • [ 2048185-88-0 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dimethyl sulfoxide at 120℃; for 3h; Sealed tube; 30 7-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]-9-methyl- 2-(2-methyl-[l,2,4]triazolo[l,5-b]pyridazin-6-yl)pyrido[l,2-a]pyrimidin-4-one In a sealed tube, 7-fluoro-9-methyl-2-(2-methyl-[l,2,4]triazolo[l,5-b]pyridazin-6-yl)-4H- pyrido[l,2-a]pyrimidin-4-one (Intermediate (VT3), 20 mg, 0.065 mmol), TEA (32.6 mg, 44.9 μ, 0.322 mmol, 5 eq.) and (R)-N,N-dimethylpyrrolidin-3-amine (22.1 mg, 0.193 mmol, 3 eq.) were stirred in DMSO (1.2 ml) at 120°C for 3 hours. The precipitating product was filtered and triturated with diethylether to afford the title product (20.7 mg, 80%) as a yellow solid. MS m/z 405.3 [M+H]+.
  • 25
  • [ 1807763-14-9 ]
  • [ 132958-72-6 ]
  • [ 1807763-17-2 ]
YieldReaction ConditionsOperation in experiment
79% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h; Inert atmosphere; 11.1 Step 1
(R)-N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(quinolin-3-yl)pyrimidin-2-amine (compound 11-7) Step 1 (R)-N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(quinolin-3-yl)pyrimidin-2-amine (compound 11-7) (R)-N,N-dimethylpyrrolidin-3-amine (80 mg, 0.70 mmol, commercially available) and potassium carbonate (193 mg, 1.40 mmol) were added to a solution of compound 10-3 (200 mg, 0.47 mmol) in 4 ml of DMF, and vigorously stirred at 100° C. for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, 10 ml of water was added, extracted with EA/water system for three times, and the organic layer was separated, and concentrated under reduced pressure to give compound 11-7 (180 mg, 79%). MS m/z (ESI): 486.2 [M+H]+.
  • 26
  • [ 2080364-44-7 ]
  • [ 132958-72-6 ]
  • [ 2080364-47-0 ]
YieldReaction ConditionsOperation in experiment
70.7% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h; 250.3 [Step 3] Methyl (R)-4-((N-(3-chloro-2-fluorophenyl)-3-(dimethylamino)pyrrolidine-l-carboxamido)me thyl)-3-fluorobenzoate [3433] A solution of methyl 4-(((3-chloro-2-fluorophenyl)((4-niti phenoxy)carbonyl)amino)methyl)-3-fluorobenzo ate (0.300 g, 0.629 mmol), (R)-N,N-dimethylpyrrolidin-3-amine (0.216 g, 1.888 mmol) and potassium carbonate (0.435 g, 3.146 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80 °C for 5 hr and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgSOj), filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 24 g cartridge; methanol / dichloromethane = 0 % to 10 %) to give methyl (R)-4-((N-(3-chloro-2-fluorophenyl)-3-(dimethylamino)pyrrolidine-l-carboxamido)me thyl)-3-fluorobenzoate as yellow oil (0.201 g, 70.7 %).
  • 27
  • [ 2080364-51-6 ]
  • [ 132958-72-6 ]
  • [ 2080364-56-1 ]
YieldReaction ConditionsOperation in experiment
58.7% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 7h; 254.1 [Step 1] Methyl (R)-4-((N-(2-chloro-4-fluoiOphenyl)-3-(dimethylamino)pyn lidine- l -carboxamido)me thyl)-3-fluorobenzoate [3480] A solution of methyl 4-(((2-chloiO-4-tluorophenyl)((4-nitrophenoxy)carbonyl)amino)methyl)-3-fluorobenzo ate (0.300 g, 0.629 mmol), ( R)-N,N-dimethylpyrrolidin-3-amine (0.216 g, 1 .888 mmol) and potassium carbonate (0.435 g, 3. 146 mmol) in N,N-dimethylformide (5 mL) was stirred at 80 °C for 7 hr and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous gS0 ), fi ltered, and concentrated in vacuo. The residue was chromatographed (SiO>, 1 2 g cartridge; methanol / dichloromethane = 0 % to 100 % ) to give methyl (R)-4-((N-(2-chloro-4-fluorophenyl)-3-(dimethylamino)pyrrolidine- l -carboxamido)me thyl)-3-fluorobenzoate as yellow oil (0. 167 g, 58.7 %).
  • 28
  • [ 32315-10-9 ]
  • [ 2080363-37-5 ]
  • [ 132958-72-6 ]
  • [ 2080365-01-9 ]
YieldReaction ConditionsOperation in experiment
94% Stage #1: bis(trichloromethyl) carbonate; methyl 3-fluoro-4-(((1-methyl-1H-indazol-6-yl)amino)methyl)benzoate With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In dichloromethane at 20℃; for 18h; 276.1 [Step 1] Methyl (R)-4-((3-(dimethylamino)-N-( 1 -methyl- 1 H-indazol-6-yl)pyrrolidine- 1 -carboxamido) methyl)-3-fluorobenzoate A solution of methyl 3-fluoro-4-((( l -methyl- l H-indazol-6-yl)amino)methyl)benzoate (0.157 g, 0.500 mmol), N.N-diisopropylethylamine (0.523 mL, 3.000 mmol) and triphosgene (0.074 g, 0.250 mmol) in dichloromethane (3 mL) was stirred at the room temperature for 30 min, and mixed with (R)-N,N-dimethylpyrrolidin-3-amine (0.063 mL, 0.500 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatogiaphed (Si02, 12 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give methyl (R)-4-((3-(dimethylamino)-N-( 1 -methyl- 1 H-indazol-6-yl)pyrrolidine- 1 -carboxamido) methyl)-3-fluorobenzoate as colorless oil (0.213 g, 94.0 %).
  • 29
  • [ 2080362-70-3 ]
  • [ 132958-72-6 ]
  • [ 2080367-22-0 ]
YieldReaction ConditionsOperation in experiment
61.1% With potassium carbonate In acetonitrile at 20℃; for 17h; 367.1 [Step 1] (R)-N-(4-((3-(dimethylamino)pyriOlidin-l-yl)methyl)phenyl)thiomorpholine-4-carboxamide 1,1-dioxide [4940] A solution of N-(4-(chloi methyl)phenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide - (0.500 g, 1.65 1 mmol), (R)-N,N-dimethylpyixolidin-3-amine (0.377 g, 3.303 mmol ) and potassium carbonate (0.685 g, 4.954 mmol) in acetonitrile (30 mL) prepared at the room temperature was stined at the same temperature for 17 nr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSOj, filtered, and concentrated in vacuo. The residue was diluted with ethyl acetate ( 10 mL) and stirred. The resulting precipitates were collected by filtration, washed by ethyl acetate, and dried to give (R)-N-(4-((3-(dimethylamino)pyrrolidin- l -yl)methyl)phenyl)thiomorpholine-4-carbox amide 1 , 1 -dioxide as pale yellow solid (0.384 g, 61 . 1 % ).
  • 30
  • [ 33149-25-6 ]
  • (R)-(+)-3-(dimethylamino)pyrrolidine [ No CAS ]
  • (R)-N,N-dimethyl-1-(5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 16h; R)-N,N-Dimethyl-1-(5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-amine ((R)-ZINC-3573) To a solution of 7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (0.069 g, 0.3 mmol) in dioxane (2 ml) was added DIEA (0.19 ml, 0.6 mmol), followed by (R)-(+)-3-(dimethylamino)pyrrolidine (0.038 g,0.33 mmol). The resulting solution was stirred for 16 h at room temperature before being concentrated and purified by silica gel column to provide the title compound (0.070 g, 76%). 1H NMR (600 MHz, CDCl3) δ 8.02 - 7.97 (m, 2H),7.95 (d, J = 2.3 Hz, 1H), 7.51 - 7.40 (m, 3H), 6.48 (d, J = 2.3 Hz, 1H),6.12 (s, 1H), 4.30 (t, J = 8.8 Hz, 1H), 4.23 (t, J = 9.8 Hz, 1H), 4.02 (q, J = 9.4 Hz,1H), 3.83 (t, J = 9.5 Hz, 1H), 2.90 - 2.82 (m, 1H), 2.36 (s, 6H), 2.29 - 2.21 (m, 1H),2.01 - 1.91 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 157.5, 151.8, 147.9,143.8, 139.2, 129.6, 128.7 (2C), 127.3 (2C), 94.9, 86.2, 65.2, 55.0, 50.1, 44.5(2C), 30.1. HRMS (ESI-TOF) m/z: [M+H]+ calculated for C18H22N5, 308.1875; found: 308.1871.
  • 31
  • [ 2101837-19-6 ]
  • [ 132958-72-6 ]
  • [ 2101837-53-8 ]
YieldReaction ConditionsOperation in experiment
70% With N-ethyl-N,N-diisopropylamine In butan-1-ol at 100℃; for 3h; Sealed tube; 39.1 Step 1: A mixture of compound 39-5 (200 mg, 0.62 mmol, 1.0 eq), (R)-(÷)-3- (dimethylamino)pyrrolidine (280 mg, 2.5 mmol, 4.0 eq) and N,N-diisopropylethylamine (320 mg, 2.5 mmol, 4.0 eq) in n-butanol (5 mL) was stirred at 100 °C for 3 hr in a sealed tube. The reaction mixture was concentrated and the residue was partitioned into DCM (20 mL) and water (20 mL). The aqueous fraction was extracted with DCM (20 mL) and the combined organic fractions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (5-10% MeOH in DCM) to afford compound 39-6 (180 mg, 0.41 mmol, 70% yield) as a yellow solid: ES m/z 400.1, 402.1 [M÷1].
  • 32
  • [ 2238851-51-7 ]
  • [ 132958-72-6 ]
  • [ 2238851-58-4 ]
YieldReaction ConditionsOperation in experiment
75% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; 156 Example 1566’-[(6-[(3R)-3-(Dimethylamino)pyrrolid in-i -yl]carbonyl}th ieno[2,3-d]pyri midin-4- yl)amino]-8’-methyl-2’H-spiro[cyclobutane-i ,3’-imidazo[i ,5-a] pyridi ne]-i ‘,S’-dione A mixture of 50 mg (126 pmol) 4-[(8-methyl- 1 ,5-dioxo-1 ,5-dihydro-2H-spiro[cyclobutane- 1 ,3-im idazo[1 ,5-a]pyridin]-6-yl)am ino]thieno[2,3-d]pyrim idine-6-carboxylic acid (prepared according to example 150), 2.0 mL N,N-dimethylacetamide, 175 pL N-ethyl-Nisopropylpropan-2-amine, 57.5 mg (3R)-N,N-dimethylpyrrolidin-3-amine and 225 pL 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in N,Ndimethylformamide) was stirred at RT overnight. The mixture was concentrated, and theresidue purified by flash chromatography (Biotage SNAP cartridge NH 11 g and silica lOg,methanol:dichloromethane) to give 49 mg (75%) of the title compound.LC-MS: m/z = 494.3 [M÷H].1HNMR (400 MHz, DMSO-d6), 6 [ppm]= 1.72-1.99 (2H), 2.05-2.22 (2H), 2.22+2.23 (6H),2.37 (2H), 2.45 (3H), 2.76+2.84 (1H), 3.22-3.55 (3H), 3.65-4.13 (3H), 8.45 (1H), 8.50+8.53(1H), 8.68+8.69 (1H), 9.54÷9.55 (1H), 10.19 (1H)
  • 33
  • [ 2238850-43-4 ]
  • [ 132958-72-6 ]
  • [ 2238850-49-0 ]
YieldReaction ConditionsOperation in experiment
48% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; 63 Example 636’-[(6-[(3R)-3-(Dimethylamino)pyrrolid in-i -yl]carbonyl}th ieno[2,3-d]pyri midin-4-yl)amino]-8’-methyl-2’H-spiro[cyclopentane-i ,3’-i midazo[i ,5-a] pyridi ne]-i ‘,5’-dione A mixture of 50 mg (122 pmol) 4-[(8-methyl-1 ,5-dioxo- 1 ,5-dihydro-2H-spiro[cyclopentane-1 ,3-im idazo[1 ,5-a]pyridin]-6-yl)am ino]thieno[2,3-d]pyrim idine-6-carboxylic acid (preparedaccording to example 58), 1 .9 mL N,N-dimethylacetamide, 169 pL N-ethyl-N15 isopropylpropan-2-amine, 56mg (3R)-N,N-dimethylpyrrolidin-3-amine and 217 pL 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in N,Ndimethylformamide) was stirred at RT overnight. The mixture was concentrated, and the residue purified by flash chromatography (Biotage SNAP cartridge NH 11 g, ethanol:dichloromethane) to give 33 mg (48%) of the title compound.LC-MS: m/z = 508.3 [M÷H].1HNMR (400 MHz, CHLOROFORM-d), 6 [ppm]= 1.76-2.06 (5H), 2.20 (3H), 2.30+2.33 (6H),2.63 (3H), 2.72-2.91 (1H), 3.02-3.12 (2H), 3.45-4.07 (4H), 6.84 (1H), 7.80+7.83 (1H),8.73+8.76 (1 H), 8.79 (1 H), 8.85+8.89 (1 H).
  • 34
  • [ 2238850-66-1 ]
  • [ 132958-72-6 ]
  • [ 2238850-73-0 ]
YieldReaction ConditionsOperation in experiment
83% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; 86 Example 866’-[(6-[(3R)-3-(Dimethylamino)pyrrolid in-i -yl]carbonyl}th ieno[2,3-d]pyri midin-4- yl)amino]-4,4-difl uoro-8’-methyl-2’H-spiro[cyclohexane-i ,3’-imidazo[i ,5-a] pyrid‘,5’-dione A mixture of 50mg (108 pmol) 4-[(4,4-difluoro-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[cyclohexane- 1 ,3-imidazo[1 ,5-a]pyridin]-6-yl)am ino]thieno[2,3-d]pyrim idine-6-carboxylicacid (prepared according to example 80), 1 .7 mL N,N-dimethylacetamide, 151 pL N-ethyl-Nisopropylpropan-2-amine, 49mg (3R)-N,N-dimethylpyrrolidin-3-amine and 194 pL 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in N,Ndimethylformamide) was stirred at RT overnight. The mixture was concentrated and purified by flash chromatography (Biotage SNAP cartridge silica 10 g + NH 11 g, methanol:dichloromethane) to give 53 mg (83%) of the title compound.LC-MS: m/z = 558.3 [M÷H].1HNMR (400 MHz, DMSO-d6), 6 [ppm]= 1 .69 (2H), 1 .74-1 .95 (1 H), 2.03-2.36 (6H), 2.22(6H), 2.53 (3H*), 2.71 -2.88 (1H), 3.25-3.54 (3H), 3.66-3.97 (2H), 4.07 (1H), 8.41 +8.43 (1H), 8.53+8.57 (1H), 8.68+8.70 (1H), 9.46+9.47 (1H), 10.43 (1H);*: at least partially hidden by solvent or water signal
  • 35
  • [ 2412796-92-8 ]
  • [ 132958-72-6 ]
  • [ 2370015-20-4 ]
YieldReaction ConditionsOperation in experiment
87.4% With potassium carbonate In dimethyl sulfoxide at 22 - 50℃; for 5h; Inert atmosphere; 52 Procedure for the preparation of compound 52a : To a solution of compound 36b (200 mg, 0.429 mmol) and K 2CO 3 (119 mg, 0.858 mmol) in DMSO (3 mL) was added (R) -N,N-dimethylpyrrolidin-3-amine (59 mg, 0.515 mmol). The reaction mixture was stired at 22-30°C for 4 h, then 50°C for 1 h while color changed from brown to deep orange. The reaction mixture was added drop wise into H2O (40 mL) under ice water bath. The precipitated solid was collected by filtration and washed with H2O (15 mL 3), the filter cake was dissolved with CH 2Cl 2 (20 mL), dried over Na 2SO 4 and concentrated in vacuum to give compound 52a (210 mg, 87.4% yield) as an orange solid. LCMS: R t =0.677 min in 5-95AB_220&254. lcm chromatography (MERCK RP18 2.5-2mm), MS (ESI) m/z=559.9 [M+H] +. 1H NMR (400MHz, Methanol-d 4) δ 8.42 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 7.24 (d, J=10.8 Hz, 1H), 6.50 (s, 1H), 6.15 (d, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.54 (dt, J=6.4, 10.4 Hz, 1H), 3.36 (t, J=9.2 Hz, 1H), 3.28 -3.24 (m, 1H), 3.09 (dd, J=6.8, 10.0 Hz, 1H), 2.93 -2.81 (m, 1H), 2.33 (s, 6H), 2.30 -2.25 (m, 1H), 1.97 -1.82 (m, 1H), 1.59 (d, J=3.6 Hz, 6H).
  • 36
  • [ 2370014-92-7 ]
  • [ 132958-72-6 ]
  • [ 2370015-18-0 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In dimethyl sulfoxide at 23 - 29℃; for 4h; Inert atmosphere; 51 Procedure for the preparation of compound 51a : To a mixture of compound 41e (200 mg, 0.43 mmol) in DMSO (5 mL) was added K 2CO 3 (178 mg, 1.29 mmol) and (R) -N,N-dimethylpyrrolidin-3-amine (59 mg, 0.51 mmol). The resulting orange mixture was stirred at 23-29°C for 4h. The mixture was poured into water (25 mL) and the orange precipitated solid was collected by suction filtration. The solid was dried in vacuum to afford compound 51a (230 mg, 95% yield). LCMS: R t = 0.778 min in 5-95AB_220&254 chromatography (MERCK RP18 2.5-2mm), MS (ESI) m/z = 583.0 [M+Na] +. 1H NMR: (400MHz, CDCl 3) δ 10.06 (br. s, 1H), 8.92 (br. s, 1H), 8.46-8.25 (m, 2H), 7.35 (br. s, 1H), 7.26 (s, 1H), 6.31 (s, 1H), 3.95 (s, 3H), 3.61-3.52 (m, 1H), 3.39-3.32 (m, 1H), 3.25-3.12 (m, 2H), 2.89-2.78 (m, 1H), 2.31 (s, 6H), 2.02-1.81 (m, 2H), 1.71 (d, J = 5.2 Hz, 6H).
  • 37
  • [ 2370015-09-9 ]
  • [ 132958-72-6 ]
  • [ 2370015-12-4 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In dimethyl sulfoxide at 23 - 29℃; for 0.5h; Inert atmosphere; 48 Procedure for the preparation of compound 48a : To a solution of compound 48a (200 mg, 0.43 mmol) and K 2CO 3 (119 mg, 0.86 mmol) in DMSO (5 mL) was added compound (R) -N,N-dimethylpyrrolidin-3-amine (60 mg, 0.52 mmol). The resulting mixture was stirred at 23-29°C for 0.5 h. The reaction mixture was added drop wise into H2O (100 mL) under ice water bath with stirring, the precipitated solid was filtered and the filter cake was dissolved with CH 2Cl 2 (45 mL), then dried and concentrated in vacuum to give compound 48b (230 mg, 96% yield) as an orange solid. LCMS: R t = 0.722 min in 5-95AB_220&254. lcm chromatography (MERCK RP18 2.5-2 mm), MS (ESI) m/z=559.2 [M+H] +.
  • 38
  • [ 2370015-57-7 ]
  • [ 132958-72-6 ]
  • [ 2370015-58-8 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate In dimethyl sulfoxide at 16 - 21℃; for 12h; Inert atmosphere; 68 Procedure for the preparation of compound 68c : To a solution of compound 68b (200 mg, 0.41 mmol) and K 2CO 3 (113 mg, 0.82 mmol) in DMSO (5 mL) was added (R) -N,N-dimethylpyrrolidin-3-amine (56 mg, 0.49 mmol). The resulting mixture was stirred at 16-21 °C for 12h while the color changes from pale yellow to deep yellow. The reaction mixture was pour into ice water (50 mL) and yellow solid was precipitated out. The solid was collected by filtration and dissolved with CH 2Cl 2 (20 mL), then dried over anhydrous Na 2SO 4 and concentrated under reduced pressure to give compound 68c (200 mg, 85% yield) as yellow solid. LCMS: R t = 0.867 min in 5-95AB_1.5 min_220&254 chromatography (MERCK RP18e 25-2mm), MS (ESI) m/z= 576.0 [M+H] +.
  • 39
  • [ 2370015-75-9 ]
  • [ 132958-72-6 ]
  • [ 2370015-76-0 ]
YieldReaction ConditionsOperation in experiment
92.8% With potassium carbonate In dimethyl sulfoxide at 80℃; for 5h; Inert atmosphere; 74 Procedure for the preparation of compound 74c : The mixture of compound 74b (150 mg, 0.3 mmol), (R) -N,N-dimethylpyrrolidin-3-amine (41.1 mg, 0.36 mmol) and K 2CO 3 (83.0 mg, 0.6 mmol) in DMSO (2 mL) was stirred at 80°C for 5 h (brown suspension). The reaction was combined with previous batch and added into H2O (10 mL) while solid was precipitated out. The solid was collected by filtration and washed with H2O (5 mL), dried in high vacuum to give compound 74c (220 mg, 92.8% yield) as a brown solid. LCMS: R t = 0.709 min in 5-95AB_220&254. lcm chromatography (MERCK RP-18e 25-2mm), MS (ESI) m/z= 594.1 [M+H] +.
  • 40
  • [ 2370015-83-9 ]
  • [ 132958-72-6 ]
  • [ 2370015-84-0 ]
YieldReaction ConditionsOperation in experiment
68.6% With potassium carbonate In dimethyl sulfoxide at 50℃; for 3h; Inert atmosphere; 76; 77 Procedure for the preparation of compound 76f : To an orange solution of compound 76e (160 mg, 0.33 mmol) in DMSO (3 mL) was added K 2CO 3 (92 mg, 0.67 mmol) and (R) -N,N-dimethylpyrrolidin-3-amine (46 mg, 0.40 mmol). The resulting mixture was stirred at 50°C for 3h. The mixture was poured into ice water (30 mL) and an orange solid was precipitated out, it was separated by suction filtration and dried in vacuo to afford compound 76f (130 mg, 68.6% yield). LCMS: R t = 0.674 min in 5-95AB_220&254 chromatography (MERCK RP18 2.5-2mm), MS (ESI) m/z = 574.1 [M+H] +. 1H NMR: (400MHz, CDCl 3) δ 8.98 (d, J = 4.8 Hz, 1H), 8.88 (d, J = 10.8 Hz, 1H), 7.98 (dd, J = 6.0, 1.6 Hz, 1H), 7.90-7.82 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.96 (dd, J = 10.8, 2.0 Hz, 1H), 6.22 (s, 1H), 6.06 (dd, J = 6.0, 3.6 Hz, 1H), 3.85 (s, 3H), 3.52-3.42 (m, 1H), 3.30-3.23 (m, 1H), 3.12-3.02 (m, 2H), 2.78-2.69 (m, 1H), 2.22 (d, J = 3.2 Hz, 6H), 2.16-2.07 (m, 1H), 1.90-1.75 (m, 3H), 1.55 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H).
  • 41
  • [ 2370016-40-1 ]
  • [ 132958-72-6 ]
  • [ 2370016-43-4 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In dimethyl sulfoxide at 80℃; for 18h; Inert atmosphere; 84 Procedure for the preparation of compound 84d : A solution of compound 84c (300 mg, 0.56 mmol) in DMSO (4 mL) was added (R) -N,N-dimethylpyrrolidin-3-amine (64 mg, 0.56 mmol) and K 2CO 3 (233 mg, 1.69 mmol). The mixture was stirred at 80°C for 18 hours. The reaction was pour into ice water (50 mL) and yellow solid was precipitated out. The yellow solid was filtered and dissolved with CH 2Cl 2 (60 mL), then dried over anhydrous Na 2SO 4 and concentrated under reduced pressure to give compound 84d (280 mg, 80% yield) as a yellow solid. LCMS: R t = 0.773 min in 5-95AB_1.5MIN_220&254 chromatography (XBrige Shield RP18 2.1*50mm), MS (ESI) m/z= 628.4 [M +H] +.
  • 42
  • [ 2370016-55-8 ]
  • [ 132958-72-6 ]
  • [ 2370016-59-2 ]
YieldReaction ConditionsOperation in experiment
66.4% With potassium carbonate In dimethyl sulfoxide at 80℃; for 20h; Inert atmosphere; 85 Procedure for the preparation of compound 85d : A mixture of compound 85c (240 mg, 0.489 mmol), (R) -N,N-dimethylpyrrolidin-3-amine (66.3 mg, 0.586 mmol) and K 2CO 3 (135.0 mg, 0.978 mmol) in DMSO (3 mL) was stirred at 80°C for 20 h (brown suspension). The reaction was quench with H2O (10 mL) and diluted with EtOAc (10 mL), stirred for 3 hr and then filtered, the filter cake was washed with H2O (5 ml) and then dried in high vacuum to give the title compound 85d (190 mg, 66.4% yield) as a brown solid. LCMS: R t = 0.760 min in 5-95AB_220&254. lcm chromatography (MERCK RP-18e 25-2mm), MS (ESI) m/z= 607.2 [M+Na] +.
  • 43
  • [ 2370014-06-3 ]
  • [ 132958-72-6 ]
  • [ 2370014-71-2 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In dimethyl sulfoxide at 24 - 27℃; for 1h; Inert atmosphere; 33 Procedure for the preparation of compound 33a : To a solution of compound 11c (200 mg, 0.43 mmol) and K 2CO 3 (119 mg, 0.86 mmol) in DMSO (4 mL) was added compound (R) -N,N-dimethylpyrrolidin-3-amine (59 mg, 0.51 mmol). The resulting mixture was stirred at 24-27°C for 1h. The reaction mixture was pour into water (50 mL) and yellow solid was precipitated. The yellow solid was collected by filtration and dissolved with CH 2Cl 2 (20 mL), dried over anhydrous Na 2SO 4 and concentrated under reduced pressure to give the title product 33a (220 mg, 91% yield) as yellow solid. LCMS: R t = 0.789 min in 5-95AB_1.5 min_220&254 chromatography (MERCK RP18e 25-2mm), MS (ESI) m/z= 583.1 [M+Na] +. 1H NMR (400MHz, CDCl 3) δ 9.69 (br s, 1H), 8.91 (br s, 1H), 8.38 (br s, 2H), 7.35 (br s, 1H), 7.08 (d, J=10.4 Hz, 1H), 6.28 (s, 1H), 3.92 (s, 3H), 3.59-3.51 (m, 1H), 3.37-3.31 (m, 1H), 3.23-3.18 (m, 1H), 3.15-3.07 (m, 1H), 2.86-2.75 (m, 1H), 2.29 (s, 6H), 2.25-2.15 (m, 1H), 1.99-1.88 (m, 1H), 1.69 (s, 6H).
  • 44
  • [ 2370013-68-4 ]
  • [ 132958-72-6 ]
  • [ 2370014-54-1 ]
YieldReaction ConditionsOperation in experiment
87% With potassium carbonate In dimethyl sulfoxide at 24 - 27℃; for 2h; Inert atmosphere; 27 Procedure for the preparation of compound 27a : To a solution of compound 1d (180 mg, 0.40mmol), K 2CO 3 (110.6 mg, 0.80 mmol) in DMSO (4 mL) was added (R) -N,N-dimethylpyrrolidin-3-amine (54.8 mg, 0.48 mmol). The resulting mixture was stirred at 24-27°C for 2 h. The reaction mixture was combined with that of bath 1359-035 and poured into water (50 mL) carefully with stirring, yellow solid was precipitated. The precipitated solid was collected by filtration and dissolved with CH 2Cl 2 (20 mL), dried over anhydrous Na 2SO 4 and concentrated under reduced pressure to give compound 27a (210 mg, 87% yield) as a yellow solid. LCMS: R t = 0.705 min in 5-95AB_1.5 min_220&254 chromatography (MERCK RP18e 25-2mm), MS (ESI) m/z= 545.1 [M+H] +.
  • 45
  • [ 39856-50-3 ]
  • [ 132958-72-6 ]
  • [ 2447110-68-9 ]
YieldReaction ConditionsOperation in experiment
78% With triethylamine In dimethyl sulfoxide at 120℃; 1.1 Step1: Synthesis of 87b: (Part in Ref: WO 20180072707 Al): To a stirred mixture of compound 90a (5.0 g, 44 mmol) and bromo compound 80b (8.4 g, 42 mmol) in DMSO (25 mL) was added triethylamine (31 mL, 220 mmol) at room temperature and stirred at 120°C for overnight. The reaction mixture was cooled and diluted with water (300 mL) and extracted with EtOAc (3 x 150 mL). The organic layer was washed with brine solution (100 mL), dried(Na2504), and concentrated to provide crude residue. The crude residue was further purified by silica-gel column using 0-20% MeOH in DCM to give 87bc as yellow solid (8.0 g, 78% yield). MS (ESI) m/z 237.2 [M+H].
78% With triethylamine In dimethyl sulfoxide at 120℃; 1.1 Stepl : Synthesis of 87b: (Part in Ref: WO 20180072707 A1 ): To a stirred mixture of compound 90a (5.0 g, 44 mmol) and bromo compound 80b (8.4 g, 42 mmol) in DMSO (25 ml.) was added triethylamine (31 ml_, 220 mmol) at room temperature and stirred at 120°C for overnight. The reaction mixture was cooled and diluted with water (300 ml.) and extracted with EtOAc (3 x 150 ml_). The organic layer was washed with brine solution (100 ml_), dried (Na2S04), and concentrated to provide crude residue. The crude residue was further purified by silica-gel column using 0-20% MeOH in DCM to give 87bc as yellow solid (8.0 g, 78% yield). MS (ESI) m/z 237.2 [M+H] +.
78% With triethylamine In dimethyl sulfoxide at 120℃; 1.1 Stepl : Synthesis of 87b : (Part in Ref: WO 20180072707 A1): To a stirred mixture of compound 90a (5.0 g, 44 mmol) and bromo compound 80b (8.4 g, 42 mmol) in DMSO (25 ml.) was added triethylamine (31 ml_, 220 mmol) at room temperature and stirred at 120°C for overnight. The reaction mixture was cooled and diluted with water (300 ml.) and extracted with EtOAc (3 x 150 ml_). The organic layer was washed with brine solution (100 ml_), dried (Na2S04), and concentrated to provide crude residue. The crude residue was further purified by silica-gel column using 0-20% MeOH in DCM to give 87bc as yellow solid (8.0 g, 78% yield). MS (ESI) m/z 237.2 [M+H]
78% With triethylamine In dimethyl sulfoxide at 120℃; 1.1 Stepl : Synthesis of 87b: To a stirred mixture of compound 90a (5.0 g, 44 mmol) and bromo compound 80b (8.4 g, 42 mmol) in DMSO (25 ml.) was added triethylamine (31 ml_, 220 mmol) at room temperature and stirred at 120°C for overnight. The reaction mixture was cooled and diluted with water (300 ml.) and extracted with EtOAc (3 x 150 ml_). The organic layer was washed with brine solution (100 ml_), dried (Na2S04), and concentrated to provide crude residue. The crude residue was further purified by silica-gel column using 0-20% MeOH in DCM to give 87bc as yellow solid (8.0 g, 78% yield). MS (ESI) m/z 237.2 [M+H] +.

  • 46
  • [ 1521892-76-1 ]
  • [ 132958-72-6 ]
  • [ 2704559-14-6 ]
YieldReaction ConditionsOperation in experiment
61% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 16h; 1.1.3 Synthesis of Compound (R)-1-(5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)-N,N-dimethylpyrrolidin-3-amine intermediate product 4) Dissolve 100 mg of intermediate product 3 (0.38 mmol) into 2 mL of dioxane solution, add 0.19 mL of DIEA (0.6 mmol),Then another 44 mg (0.38 mmol) of (R)-3-(dimethylamino)pyrrolidine was added.The resulting solution was stirred at room temperature for 16 hours, concentrated and purified by a silica gel column to obtain intermediate product 4. The yield was 61%.
  • 47
  • [ CAS Unavailable ]
  • [ 132958-72-6 ]
  • [ 2760809-40-1 ]
YieldReaction ConditionsOperation in experiment
87% With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; The third step: Synthesis of (R)-4-(6-chloro-5-fluoro-3,3-dimethylindoline-1-yl)-N-(4-(3-(dimethylamino)pyrrole-1-yl)-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine In 4-(6-chloro-5-fluoro-3,3-dimethylindoline-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)- To a solution of 1,3,5-triazin-2-amine (660mg, 1.42mmol, 1eq.) in N,N-dimethylformamide (20mL) was added (R)-N,N-dimethylpyrrolidine -3-amine (161 mg, 1.42 mmol, 1 eq.) and potassium carbonate (587 mg, 4.26 mmol, 3 eq.). The reaction was stirred at 90°C for 2 hours. Layer with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography [dichloromethane:methanol=10:1] to obtain (R)-4-(6-chloro- 5-Fluoro-3,3-dimethylindoline-1-yl)-N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5- nitrophenyl)-1,3,5-triazin-2-amine (690 mg, yield: 87%).
87% With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; The third step: Synthesis of (R)-4-(6-chloro-5-fluoro-3,3-dimethylindoline-1-yl)-N-(4-(3-(dimethylamino)pyrrole-1-yl)-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine In 4-(6-chloro-5-fluoro-3,3-dimethylindoline-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)- To a solution of 1,3,5-triazin-2-amine (660mg, 1.42mmol, 1eq.) in N,N-dimethylformamide (20mL) was added (R)-N,N-dimethylpyrrolidine -3-amine (161 mg, 1.42 mmol, 1 eq.) and potassium carbonate (587 mg, 4.26 mmol, 3 eq.). The reaction was stirred at 90°C for 2 hours. Layer with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography [dichloromethane:methanol=10:1] to obtain (R)-4-(6-chloro- 5-Fluoro-3,3-dimethylindoline-1-yl)-N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5- nitrophenyl)-1,3,5-triazin-2-amine (690 mg, yield: 87%).
  • 48
  • [ 2401931-72-2 ]
  • [ 132958-72-6 ]
  • [ 2760808-95-3 ]
YieldReaction ConditionsOperation in experiment
86% In acetonitrile at 80℃; for 1h; The fifth step: synthesis of (R)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitropyridin-3-yl)acetamide To a solution of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 3.4 mmol, 1 eq.) in acetonitrile (20 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (581 mg, 5.1 mmol, 1.5 eq.). The reaction solution was stirred at 80°C for 1 hour. After removing the solvent, silica gel column chromatography [dichloromethane:methanol=10:1] gave (R)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy yl-5-nitropyridin-3-yl)acetamide (864 mg, yield: 86%).
86% In acetonitrile at 80℃; for 1h; The fifth step: synthesis of (R)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitropyridin-3-yl)acetamide To a solution of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 3.4 mmol, 1 eq.) in acetonitrile (20 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (581 mg, 5.1 mmol, 1.5 eq.). The reaction solution was stirred at 80°C for 1 hour. After removing the solvent, silica gel column chromatography [dichloromethane:methanol=10:1] gave (R)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy yl-5-nitropyridin-3-yl)acetamide (864 mg, yield: 86%).
  • 49
  • [ 1075705-01-9 ]
  • [ 132958-72-6 ]
  • [ 2756855-28-2 ]
YieldReaction ConditionsOperation in experiment
60% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Intermediate A1: Preparation of (R)-1-(4-amino-5-methoxy-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine 4-Fluoro-2-methoxy-5-nitroaniline (500 mg, 2.69 mmol) was dissolved in N,N-dimethylformamide (10 mL). To the solution were added (R)-N,N-dimethylpyrrolidin-3-amine (367 mg, 3.22 mmol) and potassium carbonate (742 mg, 5.38 mmol) at room temperature. The reaction was stirred at room temperature for 16 hours. Water was added to the solution, which was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography [dichloromethane:methanol=10:1] gave (R)-1-(4-amino-5-methoxy-2-nitrophenyl)-N,N- Dimethylpyrrolidin-3-amine (480 mg, yield: 60%).
60% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Intermediate A1: Preparation of (R)-1-(4-amino-5-methoxy-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine 4-Fluoro-2-methoxy-5-nitroaniline (500 mg, 2.69 mmol) was dissolved in N,N-dimethylformamide (10 mL). To the solution were added (R)-N,N-dimethylpyrrolidin-3-amine (367 mg, 3.22 mmol) and potassium carbonate (742 mg, 5.38 mmol) at room temperature. The reaction was stirred at room temperature for 16 hours. Water was added to the solution, which was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography [dichloromethane:methanol=10:1] gave (R)-1-(4-amino-5-methoxy-2-nitrophenyl)-N,N- Dimethylpyrrolidin-3-amine (480 mg, yield: 60%).
  • 50
  • [ 2758518-64-6 ]
  • [ 132958-72-6 ]
  • [ 2758514-09-7 ]
YieldReaction ConditionsOperation in experiment
72% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 18h; 467 [Step 2] Synthesis of compound 4466 General procedure: The 4-(l-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-lH-l,2,3- triazol-4-yl)benzaldehyde (0.040 g, 0.100 mmol) prepared in step 1 and azetidine hydrochloride (0.019 g, 0.200 mmol) were dissolved in dichloromethane (1.5 mL) at room temperature, after which sodium triacetoxyborohydride (0.106 g, 0.501 mmol) was added to the resulting solution and stirred at the same temperature. Sodium triacetoxy borohydride (0.106 g, 0.501 mmol) was poured into the reaction mixture, and further stirred at room temperature for 18 hours. Saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, and an extraction was performed with dichloromethane. An organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (S1O2, 4 g cartridge; dichloromethane/methanol = 100 to 70%) and concentrated to obtain 2-(4-((4-(4-(azetidin-l-ylmethyl)phenyl)-lH-l,2,3- triazol-l-yl)methyl)-3-fhiorophenyl)-5-(difluoromethyl)-l,3,4-oxadiazole (0.030 g, 68.0%) in a white solid form.
72% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 18h; 467 [Step 2] Synthesis of compound 4466 General procedure: The 4-(l-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-lH-l,2,3- triazol-4-yl)benzaldehyde (0.040 g, 0.100 mmol) prepared in step 1 and azetidine hydrochloride (0.019 g, 0.200 mmol) were dissolved in dichloromethane (1.5 mL) at room temperature, after which sodium triacetoxyborohydride (0.106 g, 0.501 mmol) was added to the resulting solution and stirred at the same temperature. Sodium triacetoxy borohydride (0.106 g, 0.501 mmol) was poured into the reaction mixture, and further stirred at room temperature for 18 hours. Saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, and an extraction was performed with dichloromethane. An organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (S1O2, 4 g cartridge; dichloromethane/methanol = 100 to 70%) and concentrated to obtain 2-(4-((4-(4-(azetidin-l-ylmethyl)phenyl)-lH-l,2,3- triazol-l-yl)methyl)-3-fhiorophenyl)-5-(difluoromethyl)-l,3,4-oxadiazole (0.030 g, 68.0%) in a white solid form.
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