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Chemical Structure| 150349-65-8 Chemical Structure| 150349-65-8

Structure of 150349-65-8

Chemical Structure| 150349-65-8

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Product Details of [ 150349-65-8 ]

CAS No. :150349-65-8
Formula : C13H26N2O2
M.W : 242.36
SMILES Code : O=C(N1CCC(CCCN)CC1)OC(C)(C)C
MDL No. :MFCD08234497
InChI Key :QZYIDMYWRACBRQ-UHFFFAOYSA-N
Pubchem ID :22990164

Safety of [ 150349-65-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H335-H314
Precautionary Statements:P260-P264-P270-P271-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P403+P233-P405-P501
Class:8
UN#:2735
Packing Group:

Application In Synthesis of [ 150349-65-8 ]

* 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 [ 150349-65-8 ]

[ 150349-65-8 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 150349-65-8 ]
  • [ 229006-96-6 ]
  • [ 307301-62-8 ]
  • 2
  • [ 150349-65-8 ]
  • ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate sulfuric acid salt [ No CAS ]
  • [ 203867-81-6 ]
YieldReaction ConditionsOperation in experiment
62.1% With triethylamine; In ethanol; EXAMPLE 81 4,5-Dihydro-4-[3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one A solution prepared by dissolving 3.59 g (10.66 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine sulfate, 3.10 g (12.79 mM) of 3-(1-tert-butoxycarbonylpiperidin-4-yl)-1-propylamine, and 5.94 ml (42.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of chloroform. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=50:1) to provide 2.55 g (yield 62.1%) of the title compound as yellow oil. 1 H-NMR(200 MHz,CDCl3)delta: 0.97-1.24(2H,m), 1.25-1.39(3H,m), 1.45(9H,s), 1.57-1.81(4H,m), 2.52-2.78(2H,m), 3.57(2H,t,J=7.4 Hz), 3.96-4.18(2H,m), 5.01(2H,s), 6.74(1H,d,J=6.0 Hz), 7.33(1H,dd,J=9.2, 7.0 Hz), 7.59(1H,d,J=9.2 Hz), 8.18(1H,s). IR(Neat): 1678, 1533, 1161 cm-1.
  • 3
  • [ 161975-20-8 ]
  • [ 150349-65-8 ]
YieldReaction ConditionsOperation in experiment
With H2;PtO2; In ethanol; dichloromethane; STR48 3-(N-t-Butyloxycarbonylpiperidin-4-yl)propylamine (2-4) Compound 2-3 (0.89 g, 3.7 mmole) was dissolved in 2 mL CH2 Cl2 and 25 mL EtOH and treated with PtO2 (0.113 g, 0.49 mmole) and H2 at 55 psi for 24 hours. The reaction was filtered and concentrated to give 2-4 as a white solid. 1 H NMR (300 MHz, 5% CD3 OD M CDCl3) delta8.0 (bs, 2H), 4.1 (d, 2H), 2.9 (bs, 2H), 2.7 (t, 2H), 1.7 (m, 4H), 1.5 (s, 9H), 1.4-1.3 (m, 3H), 1.1 (m, 2H).
YieldReaction ConditionsOperation in experiment
d) 3-[N-(tert-butoxycarbonyl)-piperidin-4-yl]propanamine. A mixture of 3.35 g of the tosyloxy-substituetd compound obtained in step c) above in 50 ml of tetrahydrofuran and 100 ml of an aqueous solution of ammonia was stirred at 20 C. for 20 hours in an autoclave. After evaporation of ammonia, the residue was chromatographied on silica gel using first dichloromethane as eluent and then a mixture CH2 Cl2 /MeOH:8/2 (v/v). The desired compound which was isolated in the form of its salt was then taken up in a mixture of dichloromethane and a 1N solution of sodium hydroxide. The mixture was allowed to settle. The organic layer was separated and dried over MgSO4. The solvent was evaporated and 1.5 g of the desired free amine was finally isolated. RMN=(DMSOd6; 200 MHz) 4.4-4 (s, 2H); 3.88 (d, 2H); 2.62 (t, 2H); 2.52 (m, 2H); 1.6-0.81 (m, 16 H).
3) Synthesis of 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propylamine To a solution of 20.24 g (54.34 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propylphthalimide in 350 ml of ethanol was added 7.9 ml (163 mM) of hydrazine monohydrate and the mixture was refluxed for one hour. After cooling to room temperature, the resulting precipitate (phthalide) was filtered off and washed with a small amount of ethanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform and the organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound. Light-yellow oil. Yield 13.08 g (99%) 1H-NMR (200 MHz, CDCl3) delta: 0.96-1.95 (m, 18H), 2.61-2.72 (m, 4H), 4.04-4.10 (m, 2H).
  • 5
  • [ 6066-82-6 ]
  • [ 150349-65-8 ]
  • [ 25952-53-8 ]
  • [ 198895-68-0 ]
  • N-[3-(1-tert-butoxycarbonyl-4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium chloride; In chloroform; acetonitrile; 1) Synthesis of N-[3-(1-tert-butoxycarbonyl-4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide In acetonitrile (120 ml) was suspended 6.55 g (30.0 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid as well as 6.91 g (60.0 mM) of N-hydroxysuccinimide, followed by additino of 11.50 g (60.0 mM) of N-ethyl-N'-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride, and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure and the residue was extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the active ester. To a solution of this active ester in chloroform (100 ml) was added 8.4 ml (60.0 mM) m of triethylamine as well as 8.72 g (36.0 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)propylamine and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was washed with purified water and the organic layer was further washed with saturated m aqueous solution of sodium chloride. After the organic layer was dried over MgSO4, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (ethyl acetate/ethanol=10/1) to provide the title compound. Red solid. Yield 10.16 g (76%) 1H-NMR (200 MHz, CDCl3) delta: 0.95-1.41 (m, 4H), 1.45 (s, 9H), 1.48-1.72 (m, 5H), 2.61-2.73 (m, 2H), 3.28 (m, 2H), 4.05-4.14 (m, 2H), 5.79 (dd, J=2.2, 5.8 Hz, 1H), 6.02 (t, J=5.6 Hz, 1H), 6.63-6.70 (m, 3H), 7.02 (s, 1H). IR (KBr): 1684, 1624, 1278, 1161 cm-1.
  • 6
  • [ 946517-74-4 ]
  • [ 150349-65-8 ]
YieldReaction ConditionsOperation in experiment
95% With water; triphenylphosphine; In tetrahydrofuran; at 20℃; To a solution of 4-(3-azido-propyl)-piperidine-l-cafboxylic acid tert-butyl ester (1.738 g, 6.48 mmol) in dry tetrahydrofuran (50 mL) water (0.49 mL) and triphenyl phosphine (3.4 g, 12.96 mmol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated. The residue was purified by column chromatography using Kieselgel 60 (0.015-0.040 mm) (Merck) as adsorbent, and methanol: ammonium hydroxide = 10:1 as eluent to yield 1.498 g (95 %) of the title compound. MS (EI) 243.2 (MH+).
95% With water; triphenylphosphine; In tetrahydrofuran; at 20℃; To a solution of 4-(3-azido-propyl)-piperidine-l-carboxylic acid tert-butyl ester (1.738 g, 6.48 mmol) in dry tetrahydrofuran (50 mL) water (0.49 mL) and triphenyl phosphine (3.4 g, 12.96 mmol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated. The residue was purified by column chromatography using Kieselgel 60 (0.015-0.040 mm) (Merck) as adsorbent, and methanol: ammonium hydroxide = 10:1 as eluent to yield 1.498 g (95 %) of the title compound. MS (EI) 243.2 (MH+).
83% With triphenylphosphine; In tetrahydrofuran; water; acetonitrile; at 20℃; for 18h; (C). Preparation of 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester; Triphenylphosphine (0.657 g, 2.50 mmol) is added to a stirred solution of 4-(3-azido-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.560 g, 2.09 mmol) in THF (2 mL)/CH3CN (5 mL)/H2O (1 mL) and the mixture is stirred at ambient temperature for 18 hours. After concentration and subsequent chromatography purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-15%, the title compound is obtained as a clear oil (0.420 g, 83% yield).
  • 7
  • [ 150349-65-8 ]
  • [ 1021363-51-8 ]
  • [ 1021361-57-8 ]
YieldReaction ConditionsOperation in experiment
64% To a stirred solution of 4-[2-(4-bromo-2-chloro-phenoxy)-rhohenylsulfamoyl]-benzoic acid (Example 22/c) (41 mg, 0.085 mmol) in a mixture of dicloromethane (2 mL) and dimethylformamide (0.2 mL) 4-(3-amino-propyl)-piperidine-l -carboxylic acid tert-butyl ester (Reference Example 13) (24 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol) and triethylamine (60 muL, 0.4 mmol) were added. The mixture was stirred at room temperature for 24 h, then purified by column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and gradient elution starting with 100% A eluent and processing to 100% B eluent over a period of 20 minutes (eluent A: n-hexane; eluent B: ethyl acetate). The purified compound was dissolved in ethyl acetate (0.5 mL) 2.5 M hydrogen chloride in ethyl acetate (2.0 mL) was added and the mixture was stirred at room temperature for 24 h. The EPO <DP n="46"/>precipitated product was filtered, washed with diethyl ether and dried in vacuum to yield 35 mg (64 %) of the title compound. MS (EI) 608.1 (MH+).
  • 8
  • [ 150349-65-8 ]
  • [ 946517-80-2 ]
  • [ 946519-85-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 95℃; for 34h; EXAMPLE 1222-[5-Fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide; 4-(3-Aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.557 g, 2.30 mmol) is added to a stirred suspension of 2-(2-chloro-5-fluoropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.400 g, 1.15 mmol) and diisopropylethylamine (0.60 mL, 3.5 mmol) in anhydrous 1,4-dioxane (8 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 95 C. for 34 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with CH3OH in dichloromethane: 0-2%, to give 4-{3-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-fluoropyrimidin-2-ylamino]-propyl}-piperidine-1-carboxylic acid tert-butyl ester (0.512 g) as a solid.Triethylsilane (0.7 mL) and TFA (4 mL) are added successively to a stirred suspension of the above product in dichloromethane (20 mL). The resultant yellow solution is stirred for 3 hours. After concentration and subsequent silica gel chromatography, eluting with 2N NH3/CH3OH in dichloromethane: 0-24%, the fractions containing the product are collected and concentrated to give a solid. The solid is dissolved in MeOH (40 mL) and the solution is treated in portions with 2 N LiOH (16 mL) to form a suspension. Methanol is evaporated off under vacuum at room temperature. Water (40 mL) is added to the thick suspension before it is filtered and dried to give the title compound as a yellow solid (0.400 g, 76% yield). ES+(m/z) 454 [M+H].
  • 9
  • [ 150349-65-8 ]
  • [ 946521-38-6 ]
  • C42H49N5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 97℃; for 72h; (B). Preparation of 2-[5-methyl-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide; A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide (1.14 g, 2.15 mmol), <strong>[150349-65-8]4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.04 g, 4.30 mmol) and diisopropylethylamine (1.12 mL, 6.45 mmol) in 1,4-dioxane (10 mL) is heated at 97 C. under a nitrogen atmosphere for 3 days. After concentration and subsequent chromatography on silica gel, eluting with MeOH in dichloromethane 0-2%, the desired product is obtained as a solid. The solid is suspended in dichloromethane (20 mL), followed by the successive addition of triethylsilane (1.5 mL) and TFA (5 mL). The resultant yellow solution is stirred for 2 hours. After concentration the solid is dissolved with stirring in MeOH (30 mL) and dichloromethane (30 mL) and the solution is treated in portions with 1.0 N LiOH (15 mL) to form a suspension. The suspension is concentrated at 45 C. under atmospheric pressure for 30 minutes, then methanol and dichloromethane are evaporated off in vacuo. The suspension is filtered and the yellow solid is dried under vacuum at 45 C. to provide the title compound (0.890 g, 100% yield). ES+(m/z) 410 [M+H].
  • 10
  • [ 150349-65-8 ]
  • [ 1182323-93-8 ]
  • [ 1182324-16-8 ]
YieldReaction ConditionsOperation in experiment
at 150℃; for 24h;Neat (no solvent); Example D5: N-(3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propyl)-6- (methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine. [00146] Step A: 2-Methoxy-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine 17 (0.30 g, 1.17 mmol) in neat tert-bupsilonXy 4-(3-aminopropyl)piperidine-l- carboxylate (0.82 g, 3.38 mmol) is stirred at 150C oil bath for 24 h. The reaction is purified by flash chromatography (SiO2, EtOAc/hexanes 30-80%) to give tert-butyX 4-(3- (6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino) propyl)piperidine-l-carboxylate 26 as a light yellow solid: MS calcd. for C21H36NsO4S [M+H]+: 454.3, found: 454.2
  • 11
  • [ 150349-65-8 ]
  • [ 1410800-33-7 ]
  • 12
  • [ 150349-65-8 ]
  • N-(3-(piperidin-4-yl)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide trifluoroacetate [ No CAS ]
  • 13
  • [ 150349-65-8 ]
  • 1H-pyrrolo [3,2-c] pyridine-2-carboxylic acid [ No CAS ]
  • [ 1410803-71-2 ]
YieldReaction ConditionsOperation in experiment
75% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; To a 100 ml of flask added fert-butyl 4-(3-aminopropyl)piperidine-l -carboxylate (250 mg, 1.032 mmol) and lH-pyrrolo[3,2-c]pyridine-2-carboxylic acid (167 mg, 1.032 mmol) in DMF (10 ml). HATU (510 mg, 1.341 mmol) and DIPEA (0.721 ml, 4.13 mmol) were added. The mixture was stirred at RT for 16 hours. The mixture was dilutated with water and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and washed with water (3 x 20 mL). The organic was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by the Biotage to afford 300 mg of product (75%).¾ NMR (DMSO-d6).8: 12.35 (s, 1H), 9.08 (s, 1H), 8.75 (m, 1H), 3.87-3.91 (m, 2H), 3.23-3.30 (m, 4H), 1.49-1.63(m, 5H), 1.32 (s, 9H), 1.20-1.24(m, 2H), 0.90- 0.98(m, 2H).LC-MS: 387.22 (M+l)
  • 14
  • [ 150349-65-8 ]
  • [ 41972-62-7 ]
  • [ 530-62-1 ]
  • C20H29N5O3S [ No CAS ]
  • 15
  • [ 150349-65-8 ]
  • [ 27631-29-4 ]
  • tert-butyl 4-(3-((2-chloro-6,7-dimethoxyquinazolin-4-yl)amino)propyl)piperidine-1-carboxylate [ No CAS ]
  • 16
  • [ 150349-65-8 ]
  • 6,7-dimethoxy-N-(3-(piperidin-4-yl)propyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine trifluoroacetic acid salt [ No CAS ]
  • 17
  • [ 150349-65-8 ]
  • C27H41N5O4 [ No CAS ]
  • 18
  • [ 150349-65-8 ]
  • 1-((1H-indol-4-yl)methyl)-N<SUP>3</SUP>-methyl-2-oxo-N<SUP>5</SUP>-(3-(piperidin-4-yl)propyl)-1,2-dihydropyridine-3,5-dicarboxamide [ No CAS ]
  • 19
  • [ 150349-65-8 ]
  • 1-((1H-indol-4-yl)methyl)-N<SUP>5</SUP>-(3-(1-acetylpiperidin-4-yl)propyl)-N<SUP>3</SUP>-methyl-2oxo-1,2-dihydropyridine-3,5-dicarboxamide [ No CAS ]
  • 20
  • [ 150349-65-8 ]
  • 1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • tert-butyl 4-(3-(1-benzyl-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)propyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% 1-Benzyl-5-(methylcarbamoyl)-6-oxo- 1,6-dihyd ropyrid ine-3-carboxylic acid (250 mg, 0.873 mmol) was taken up in DMF (4 mL) and HATU (365 mg, 0.961 mmol) followed by DIPEA (0.302 mL,1.747 mmol) were added. The reaction mixture was allowed to stir for 5 mm, then ter1butyl 4-(3- aminopropyl)piperid me- 1-carboxylate (233 mg, 0.961 mmol, commercially available from, for example, Milestone PharmTech) was added and the reaction allowed to stir for 1 h. The solution was concentrated under vacuum and redissolved in ethyl acetate (15 mL) and washed with citric acid (1 M, 3 x 10 mL), saturated NaHCO3 (3 x 10 mL), water (10 mL) and brine (10 mL). Thesolution was dried and concentrated under vacuum to give the desired product (456 mg, 0.893 mmol, quant. yield).LCMS (2 mm Formic): Rt = 1.18 mi [MH] = 511.
  • 21
  • [ 150349-65-8 ]
  • 1-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • C29H40N4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 19h;Sonication; Sealed tube; General procedure: To a stock solution of i-(3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-i,6-d ihydropyrid ine-3- carboxylic acid (300 mg, 1.0 mmol) and HATU (380 mg, 1.0 mmol) dissolved in DMF (5 mL) was added DIPEA (520 pL, 3.0 mmol). The mixture was shaken and sonicated to aid dispersion. Analiquot (0.5 mL) of this mixture was added to the appropriate amine (0.12 mmol) in a vial which was subsequently sealed. Each vial was shaken before being allowed to stand at rt for 18 h.(NOTE: to the reaction containing monomer amine used to prepare example 15 was added further HATU (0.038 g, 0.100 mmol) and DIPEA (0.052 mL, 0.300 mmol) before this mixture was left to stand at rt for 1 h. The samples were injected as is and purified by MDAP (High pH). The solventwas dried under a stream of nitrogen in the plate blowdown apparatus. The products derived from the amine monomers used to prepare example 15 and 16 were dissolved in DCM (0.5 mL). TFA (0.5 mL) was added and the vials were capped and sonicated to aid dispersement. Each mixture was left to stand at rt for 2 h. The solvent was then concentrated to dryness and the residues were redissolved in MeOH (0.5 mL) and applied to the top of a SCX-2 SPE cartridge (100 mg,preconditioned with MeOH (1 mL)). Each cartridge was eluted with further MeOH (1 mL) followed by 2M NH3/MeOH (1 mL). The solvent was removed to dryness to give the required products as shown in the table below.
  • 22
  • [ 150349-65-8 ]
  • (R)-5-(methylcarbamoyl)-6-oxo-1-(1-phenylethyl)-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • C29H40N4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;Sonication; Sealed tube; General procedure: To a stock solution of (R)-5-(methylcarbamoyl)-6-oxo- 1-( 1-phenylethyl)-1,6-d ihydropyridine3-carboxylic acid (30 mg, 0.1 mmol) and HATU (380 mg) in DMF (5 mL) was added DIPEA (520 pL). The mixture was shaken and sonicated to aid dispersion. The mixture was aliquoted (0.5 mL) to a set of preweighed amines (0.100 mmol) in micronic vials. These were capped and shaken and left to stand at rt for 18 h. The samples were purified by MDAP (High pH). The solvent was dried under astream of nitrogen to give the required products. Examples 17 and 18 were dissolved in DCM (0.5 mL) and treated with TFA (0.5 mL) and the solutions left to stand in capped vials at rt for 2 h. The reaction mixtures were evaporated and the residues dissolved in MeOH (0.5 mL). The solutions were applied to MeOH-preconditioned 100 mg SCX-2 cartridges which were then washed with MeOH (1 mL) followed by 2M ammonia in MeOH solution (1 mL). The basic washes were evaporated todryness to give final deprotected compounds as the free base.
  • 23
  • [ 150349-65-8 ]
  • 1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • C29H40N4O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;Sonication; Sealed tube; General procedure: To a stock solution of 1-(3-methoxybenzyl)-5-(methylcarbamoyl)-6-oxo- 1,6-dihyd ropyrid me3-carboxylic acid (316 mg, 1 mmol) and HATU (380 mg) in DMF (5 mL) was added DIPEA (520 pL).The mixture was shaken and sonicated to aid dispersion. The mixture was aliquoted (0.55 mL) to aset of preweighed amines (as shown in table below). These were capped and shaken and left tostand at rt for 18 h. The samples were purified by MDAP (High pH). The solvent was dried under a stream of nitrogen to give the required products. Examples 19 and 20 were dissolved in DCM (0.5 mL) and treated with TFA (0.5 mL) and the solutions left to stand in capped vials at rt for 2 h. The reaction mixtures were evaporated and the residues dissolved in MeOH (0.5 mL). The solutions were applied to MeOH-preconditioned 100 mg SCX-2 cartridges which were then washed with MeOH (1mL) followed by 2M ammonia in MeOH solution (1 mL). The basic washes were evaporated to dryness to give final deprotected compounds as the free base (as shown in the table below).
  • 24
  • [ 150349-65-8 ]
  • 1-(4-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • tert butyl 4-(3-(1-(4-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)propyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
172 mg 1-(4-Fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo- 1,6-d ihydropyridine-3-carboxylicacid (100 mg, 0.314 mmol) was added to a solution of HATU (119 mg, 0.314 mmol) and DIPEA(0.055 mL, 0.314 mmol) in DMF (3 mL). The reaction mixture was left to stir at rt for 5 mi tertButyl 4-(3-aminopropyl)piperidine-1-carboxylate (76 mg, 0.314 mmol) was added to the reaction mixture, which was then left to stir at rt overnight. The reaction mixture was concentrated under vacuum and partitioned between DCM (20 mL) and water (20 mL). The organic layer was concentrated under vacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 10 g silicaflash chromatography using a gradient of O-100% cyclohexane/ethyl acetate. The appropriate fractions were combined and concentrated under vacuum to give the product (172 mg) as a yellow solid.
  • 25
  • [ 150349-65-8 ]
  • 1-(4-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • tert-butyl 4-(3-(1-(4-fluorobenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)propyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% 1-(4-Fluorobenzyl)-5-(methylcarbamoyl)-6-oxo- 1,6-dihydropyrid ine-3-carboxylic acid (100 mg, 0.329 mmol) was added to a solution of HATU (125 mg, 0.329 mmol) and DIPEA (0.057 mL, 0.329 mmol) in DMF (3 mL). The reaction mixture was left to stir at rt for 5 mi tert-Butyl 4-(3-aminopropyl)piperidine-1-carboxylate (80 mg, 0.329 mmol) was added to the reaction mixture which was then left to stir at rt overnight. The reaction mixture was concentrated under vacuum and partitioned between DCM (20 mL) and water (20 mL). The organic layer was concentrated under vacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 10 g silica flash chromatography using a gradient of O-100% cyclohexane/ethyl acetate. The appropriate fractionswere combined and concentrated under vacuum to give the product (195 mg, 0.369 mmol, quant yield) as a yellow solid.LCMS (2 mm Formic): Rt = 1.19 mi [MH] = 529.2.
  • 26
  • [ 150349-65-8 ]
  • 1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • C30H42N4O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With diisobutylaluminium hydride; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;Sonication; General procedure: To a stock solution of 1-(3-(2-hydroxyethoxy)benzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (337 mg, 0.97 mmol) and HATU (374 mg) in DMF (5.5 mL) wasadded DIPEA (550 pL). The solution was shaken and sonicated to aid dispersion and aliquoted (0.55 mL) to a set of preweighed amines (as shown in table below). The samples were injected as is and purified by MDAP (High pH). The solvent was dried under a stream of nitrogen to give the required products. Examples 23 and 24 were dissolved in DCM (0.5 mL) and treated with TFA (0.5 mL) andthe solutions left to stand in capped vials at rt for 2 h. The reaction mixtures were evaporated and examples 23 and 24 were dissolved in MeOH (0.5 mL). The solutions were applied to MeOHpreconditioned 100 mg SCX-2 cartridges which were then washed with MeOH (1 mL) followed by 2M ammonia in MeOH solution (1 mL). The basic washes were evaporated to dryness to give final deprotected compounds as the free base (as shown in table below). Examples 24 was re-purified byMDAP (High pH). The solvent was dried under a stream of nitrogen to give the required product.
  • 27
  • [ 150349-65-8 ]
  • 1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • C29H39FN4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h;Sonication; Sealed tube; General procedure: To a stock solution of 1-(2-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid (350 mg, 1.1 mmol) dissolved in DMF (5.5 mL) was added HATU (502 mg, 2.13 mmol) and DIPEA (570 pL, 3.3 mmol). The mixture was sonicated to aid dispersionand further DMF (5.5 mL) was added. An aliquot (1.0 mL) of this mixture was added to the appropriate amine (0.12 mmol) in DMF (0.3 mL) in a vial, which was subsequently sealed, sonicated and left to stand at rt for 3 h. The samples were reduced to 1 mL, then injected as is and purified by MDAP (High pH). The solvent was removed using a plate dryer to give the required products.
  • 28
  • [ 150349-65-8 ]
  • 1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • tert-butyl 4-(3-(1-((1H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)propyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;Sonication; Sealed tube; General procedure: A stock solution of 1-(( 1 H-indol-4-yl)methyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (358 mg) was prepared in DMF (7.7 mL), along with HATU (502 mg), and DIPEA (0.57 mL), and was then capped and sonicated, before being aliquoted (0.7 mL)into a vial containing the listed amine monomer (0.12 mmol). This was sealed and sonicated, then allowed to stand at rt for 18 h. The sample was then directlyinjected and purified by MDAP (High pH). The solvent was removed using a plate dryer to give the required Boc-protected intermediate. This was dissolved in DCM (0.5 mL), and HCI in dioxane (4M, 0.5 mL) was added to the sample. This was sealed and sonicated before leaving to stand for 2 h. The solvent was removed using ablow down unit, The sample was found to be impure by LCMS. The sample was dissolved in DMSO (1 mL) and purified by MDAP (Formic). The solvent was removed using a plate dryer to give the required example 30 as indicated in the example table.
  • 29
  • [ 150349-65-8 ]
  • 1-benzyl-5-(ethylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • 1-benzyl-N<SUP>3</SUP>-ethyl-2-oxo-N<SUP>5</SUP>-(3-(piperidin-4-yl)propyl)-1,2-dihydropyridine-3,5-dicarboxamide [ No CAS ]
  • 30
  • [ 150349-65-8 ]
  • 1-benzyl-5-(ethylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ No CAS ]
  • tert-butyl 4-(3-(1-benzyl-5-(ethylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)propyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51.2% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h; To a solution of 1-benzyl-5-(ethylcarbamoyl)-6-oxo-1,6-d ihydropyrid ine-3-carboxylic acid(200 mg, 0.666 mmol) in N,N-Dimethylformamide (10 mL) and cooled to 0C, was added DIPEA (0.233 mL, 1.332 mmol), HATU (380 mg, 0.999 mmol) followed by ter1butyl 4-(3- aminopropyl)piperid me- 1-carboxylate (0.161 mL, 0.666 mmol, commercially available from, for example, Fluorochem) was added slowly at 0C. The reaction mixture was stirred for 3 hr at RT. Water was added and extracted with ethyl acetate ( 2 x 75 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to get crude product. This was purified by column chromatography silica gel 100-200 column and was eluted with l8% EtOAc in n-hexane andcollected pure fractions were concentrated under reduced pressure to get tert-butyl 4-(3-(1-benzyl-5-(ethylcarbamoyl)-6-oxo-1,6-d ihydropyrid ine-3-carboxamido)propyl)piperidine- 1-carboxylate (180mg, 0.341 mmol, 51.2 % yield). as a off-white solid.LCMS (10 mm RND-FA-10-MIN=REV): Rt = 5.67 mi [MH] = 525.1.LCMS Conditions: RND-FA- lO-MIN:Column: Acquity BEH C18 (100 mm x 2.1 mm, 1.7 pm)Mobile Phase: A: 0.05% formic acid in ACN; B: 0.05% formic acid in waterTime (mm) /%B: 0/97, 0.4/97, 7.5/2, 9.5/2, 9.6/97, 10/97Column Temp: 35 C, Flow Rate: 0.45 mL/min
  • 31
  • [ 150349-65-8 ]
  • 2-benzyl-6-(methylcarbamoyl)isonicotinic acid [ No CAS ]
  • tert-butyl 4-(3-(2-benzyl-6-(methylcarbamoyl)isonicotinamido)propyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
17.7% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; Example 1: fe -Butyl 4-f3-f2-benzyl-6- (1199) (1200) 2-Benzyl-6-(methylcarbamoyl)isonicotinic acid (50 mg, 0.185 mmol), HATU (112 mg, 0.295 mmol), DIPEA (0.097 mL, 0.555 mmol) and DMF (3 mL) were stirred at rt under N2 then fe/f-butyl 4- (3-aminopropyl)piperidine-l-carboxylate (100 mg, 0.413 mmol) was added and the reaction stirred at rt under N2 for 2 h. The solution was concentrated to give 300 mg of an orange oil. This was purified by chromatography on S1O2 (Biotage SNAP 25 g cartridge, eluting with 0-100% ethylacetate/cyclohexane). The appropriate fractions were concentrated to give 25 mg of a yellow oil. The reaction was purified by MDAP (Formic). The fractions containing the desired product were concentrated to give fe/f-butyl 4-(3-(2-benzyl-6-(methylcarbamoyl)isonicotinamido)propyl)piperidine- 1-carboxylate (18 mg, 0.033 mmol, 17.70 % yield) as an off white solid. (1201) LCMS (2 min Formic): Rt = 1.28 min, [MH]+ = 495.5.
  • 32
  • [ 150349-65-8 ]
  • (2R*,3S*)-2-methyl-7-(methylcarbamoyl)-3-phenyl-2,3-dihydrobenzofuran-5-carboxylic acid [ No CAS ]
  • (2R*,3S*)-N7,2-dimethyl-3-phenyl-N5-(3-(piperidin-4-yl)propyl)-2,3-dihydrobenzofuran-5,7-dicarboxaminde [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% A solution of (2S,3R9-2-methyl-7-(methylcarbamoyl)-3-phenyl-2,3-d ihydrobenzofuran-5- carboxylic acid (180 mg, 0.578 minol) in DMF (2 mL) at room temperature was treated with DIPEA (0.121 mL, 0.694 minol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouroniumhexafluorophosphate(V) (264 mg, 0.694 minol) and ter1butyl 4-(3-aminopropyl)piperidine-1-carboxylate (168 mg, 0.694 minol) and the resulting minxture was stirred at this temperature for 15 min then was treated with TFA (0.89 mL, 12 minol). The resulting minxture was stirred at room temperature for 20 min then was concentrated in vacuo. The residue was co-evaporated with a 2N NH3 solution in MeOH (10 mL) then was loaded onto a 10 g SCX column, eluting with MeOH then witha 2N NH3 solution in MeOH. The aminonia fractions were concentrated in vacuoto give (2S*,3R*) N7, 2-d imethyl-3-phenyl-N5-(3-(piperidin-4-yl)propyl)-2,3-dihydrobenzofuran-5,7-d ica rboxaminde (250 mg, 99%).LCMS (method forminc): Retention time 0.66 min [M+H] = 436.
  • 33
  • [ 150349-65-8 ]
  • (2R*,3S*)-2-methyl-7-(methylcarbamoyl)-3-phenyl-2,3-dihydrobenzofuran-5-carboxylic acid [ No CAS ]
  • (2R,3S)-N7,2-dimethyl-3-phenyl-N5-(3-(piperidin-4-yl)propyl)-2,3-dihydrobenzofuran-5,7-dicarboxaminde [ No CAS ]
  • 34
  • tert-butyl 4-(3-(1,3-dioxoisoindolin-2-yl)propyl)piperidine-1-carboxylate [ No CAS ]
  • [ 150349-65-8 ]
YieldReaction ConditionsOperation in experiment
With hydrazine hydrate; In ethanol; at 90℃; for 3h; To a solution of tert-butyl 4- (3- (1, 3-dioxoisoindolin-2-yl) propyl) piperidine-1-carboxylate (1.3 g, 3.5 mmol) in EtOH (20 mL) was added 85hydrazine hydrate (3 mL) . The mixture was stirred at 90 for 3h and then the solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was suspended in DCM (50 mL) and filtered. The filtrate was concentrated to give the crude tert-butyl 4- (3-aminopropyl) piperidine-1-carboxylate (800 mg, 95) which was used in next step directly. LRMS m/z (M+H) 243.2 found, 243.2 required
  • 35
  • [ 150349-65-8 ]
  • benzyl (3-(piperidin-4-yl)propyl)carbamate [ No CAS ]
 

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