630-580-1088 sales@ambeed.com
Structure Search

List Search MOL Search Structure Search

0
Chemistry
Asymmetric Synthesis >>Chiral Building BlocksChiral Catalysts, Chiral Ligands and Chiral ReagentsChiral Resolution ReagentsBoronic acids/esters >>Aliphatic BoronsAromatic BoronsOther BoronsOxaborolesCatalysis Chemistry >>Achiral Crown LigandsC-H ActivationCarbon-Donor LigandsChiral Carbon LigandsChiral Crown LigandsChiral Olefin LigandsCross-CouplingCross-Coupling Using Transition Metal CatalystsDACH or Trost LigandsChemical Biology >>Conjugation Chemistry
GlycoscienceLinkers and CrosslinkersNucleic Acid ChemistryPEGylationPeptide ChemistryPhotolabile Protecting GroupHeterocyclic Building Blocks >>AcridinesAliphatic HeterocyclesAromatic HeterocyclesAzetidinesBenzimidazolesBenzisoxazolesBenzodioxansBenzofuransBenzothiazolesInorganic reagents >>Inorganic ReagentOrganic Building Blocks >>Acid AnhydridesAcyl Chlorides
AlcoholsAldehydesAliphatic Chain HydrocarbonsAliphatic Cyclic HydrocarbonsAlkenesAlkylsAlkynesOrganometallic Reagents >>Grignard ReagentsOrganoarsenicOrganobismuthOrganoboronOrganogermaniumOrganolithiumOrganomercuryOrganosiliconOrganotinSpecialty Synthesis >>Enzyme-Mediated SynthesisFluorous SynthesisIonic Liquids
Solid Supported SynthesisStains and Dyes >>Acid DyesAzoic DyesBasic DyesDirect DyesDisperse DyesDye IntermediatesMordant DyesOil DyesOther Stains and DyesSynthetic Reagents >>Acids and BasesC-C Bond FormationC-X Bond Formation (Halogen)C-X Bond Formation (Non-Halogen)Chelation and Complexation CompoundsCondensation AgentsCouplingDehydrating ReagentsFluorination Reagent
Pharmaceutical Intermediates
Analgesics >>BenzhydrocodoneBicifadineCapsaicinCelecoxibDebio-0827DexamethasoneElagolix SodiumEsketamine HydrochlorideIbuprofen SodiumAnesthetics >>CiprofolEsketamine HydrochlorideFospropofol Fospropofol DisodiumLevobupivacaine RemimazolamRemimazolam BesilateRemimazolam BesylateRopivacaineAnti-Addiction Agents >>Kakonein
Lofexidine HydrochlorideVarenicline Anti-inflammatory Agents >>ApremilastAsunaprevirATB-346 RelatedBalsalazide BaricitinibBencycloquidium BromideBudesonideCefiderocol Sulfate TosylateCeftaroline Fosamil AcetateAntibacterials >>AFN-1252 RelatedAlatrofloxacin Bedaquiline FumarateBesifloxacin BrilacidinCaspofungin AcetateCefiderocol Sulfate TosylateCefilavancinCeftaroline Fosamil
Anticonvulsants >>BrivaracetamCannabidiolEscitalopram OxalateEslicarbazepine Acetate RelatedFosphenytoinGabapentin EnacarbilJNJ-10234094LacosamideLevetiracetam RelatedAntidementia Agents >>Azeliragon RelatedDavunetideDonepezil HydrochlorideDonepezil RelatedEnsaculinFlorbetaben Flortaucipir F 18Flutemetamol IdalopirdineAntidepressants >>4-Chlorokynurenine
AgomelatineAgomelatine RelatedAllopregnanolone RelatedAmibegronAmitifadineAripiprazole RelatedBasimglurantBefloxatoneAntiemetics >>AprepitantAprepitant RelatedDolasetron RelatedDolasetron Mesylate HydrateFosaprepitant DimeglumineFosaprepitant RelatedOlanzapinePalonosetron RelatedPalonosetron HydrochlorideAntifungals >>Anidulafungin RelatedCabotegravirMore >>
Inhibitors/Agonists
ADC >>ADC AntibodyADC LinkerADC Linker with PayloadADC ToxinAntibody-Drug Conjugates (ADCs)Drug-Linker Conjugates for ADCAngiogenesis >>ALKBcr-AblBTKEGFRFAKFGFRFLT3HER2HIFAnti-infection >>3CLproAntibacterialAntibioticAntifungal
AntiparasiticAntiprotozoalAntiviralArenavirusBVDVApoptosis >>Apoptosis InducerBcl-2Bcl-6BRKc-Mycc-RETC/EBPCARDCaspaseAutophagy >>Atg4ATG4BATTECsAUTACsAutophagyBeclin1
FKBPLC3LRRK2Biochemical Reagent >>Cell Cycle >>AntifolateAPCAurora KinaseBUBCasein KinaseCdc25CDKChkCRISPR/Cas9Cytoskeleton >>ActinArp2/3 ComplexCYTHCytoplasmic DyneinDynaminFAKMore >>
Material Science
Aggregation-Induced Emission >>Other AIE BlocksTetraphenylethylene SeriesCOFs Linkers >>Aldehyde COFs LinkersAlkynyl COFs LinkersAmine COFs LinkersBoric COFs LinkersCyano COFs LinkersMultifunctional COFs linkersOther COFs linkersTriptycene SeriesElectronic Materials >>Battery MaterialsDye-Sensitized Solar Cell (DSSC) MaterialsElectronic MaterialLiquid Crystal (LC) MaterialsMolecular ConductorsOrganic Light-Emitting Diode (OLED) MaterialsOrganic Solar Cell (OPV) MaterialsOrganic Transistor (OFET) MaterialsPerovskite Solar Cell (PSC) MaterialsMagnetic Materials >>Magnetic Ionic LiquidsMagnetic MaterialMagnetic Metal Complexes
Organic Radicals Material Chemical Compounds >>Ligands for Functional Metal ComplexesLiquid Crystal (LC) Building BlocksPhthalocyanine Building BlocksPolymer and Macromolecule Semiconductor Building BlocksSmall Molecule Semiconductor Building BlocksSolubility Enhancing Reagents Supramolecular Host Materials MOF Ligands >>Carboxylic Acid MOF LigandsCarboxylic Acid Nitrogen-Containing Mixed MOF LigandsNitrogen-Containing MOF LigandsOther MOF LigandsNanomaterials >>Carbon NanomaterialsCeramic MembranesDendrimersGold NanoparticlesIron Oxide NanoparticlesMaterials by ApplicationMesoporous MaterialsMetals and Metal AlloysNano Minerals: NanoclaysOLED Materials >>Dopant
HostHTMOLED IntermediatesOther OLED related materialsOptical Materials >>Coumarin DyesCyanine and Squarylium DyesDCM DyesDipyrromethene DyesFluorescence MaterialsFluorescent ProbesHeat and Pressure Sensitive DyesNear-Infrared (NIR) DyesOrganic Non-Linear Optical (NLO) MaterialsOrganic Pigments >>Organic PigmentOther Materials >>Mateial OtherPolymer Science >>MonomersPolymer AdditivesPolymerization ReagentsPolymersResins
Contact Us
Home Cart 0 Sign in  
X
Chemistry
Organic Building Blocks
Piperidines
t-butoxycarbonyl
1-Boc-4-(aminomethyl)piperidine
Chemistry
Organic Building Blocks
Heterocyclic Building Blocks
Piperidines
Amines Amides Esters Carbamates Aliphatic Heterocycles
t-butoxycarbonyl
piperidin-4-ylmethanamine

[ CAS No. 144222-22-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 144222-22-0
Chemical Structure| 144222-22-0
Chemical Structure| 144222-22-0
Structure of 144222-22-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 144222-22-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 144222-22-0 ]

SDS Specification
Alternatived Products of [ 144222-22-0 ]

Product Details of [ 144222-22-0 ]

CAS No. :144222-22-0 MDL No. :MFCD01076207
Formula : C11H22N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :KLKBCNDBOVRQIJ-UHFFFAOYSA-N
M.W : 214.30 Pubchem ID :736817
Synonyms :
Chemical Name :1-Boc-4-(Aminomethyl)piperidine

Calculated chemistry of [ 144222-22-0 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 64.11
TPSA : 55.56 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.95 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.65
Log Po/w (XLOGP3) : 0.92
Log Po/w (WLOGP) : 1.21
Log Po/w (MLOGP) : 1.15
Log Po/w (SILICOS-IT) : 0.69
Consensus Log Po/w : 1.33

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.48
Solubility : 7.03 mg/ml ; 0.0328 mol/l
Class : Very soluble
Log S (Ali) : -1.67
Solubility : 4.55 mg/ml ; 0.0212 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.33
Solubility : 10.1 mg/ml ; 0.0471 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.17

Safety of [ 144222-22-0 ]

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

Application In Synthesis of [ 144222-22-0 ]

* 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 [ 144222-22-0 ]

[ 144222-22-0 ] Synthesis Path-Downstream   1~88

  • 1
  • [ 24424-99-5 ]
  • [ 7144-05-0 ]
  • [ 144222-22-0 ]
YieldReaction ConditionsOperation in experiment
88% In chloroform at 0 - 20℃; for 48h; 5.a To a solution of 4-(aminomethyl)piperidine (100 g, 0.88 mol) in CHCI3 (550 ml_), cooled at 0 °C and under Ar-atmosphere, a solution of di-te/t-butyl dicarbonate (98 g, 0.45 mol) in CHCI3 (350 ml_) was added. The resulting mixture was stirred at room temperature for 48 h, washed with H2O and the aqueous phase extracted with CHCI3. The combined organic phases were dried over Na2SO4 and the solvents were removed to afford 84.5 g of the title compound (88 % yield). 1H NMR (80MHz, CDCI3) δ (TMS): 4.11 (broad d, J = 13.4 Hz, 2 H), 2.69 (m, 4 H), 1.45 (s, 9 H), 1.8-0.8 (complex signal, 7 H).
86.5% Stage #1: 4-Aminomethylpiperidine With benzaldehyde In toluene for 4h; Heating / reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate In toluene at 20℃; Stage #3: With potassium hydrogensulfate; water at 20℃; for 4h; 28 Example 28 Preparation of intermediate 4-aminomethyl-1-(tert-butoxycarbonyl) piperidine Benzaldehyde (8.73 g, 82.3 mmol) was added all at once to a stirred solution of 4- aminomethylpiperidine (9.42 g, 82.3 mmol) in toluene (100 ml). The mixture was heated under reflux for 4 h with a Dean-Stark trap attached to collect the water. The reaction mixture was cooled to room temperature and di-tert-butyldicarbonate (19.75 g, 90.5 mmol) was added in divided portions under continuously stirring. The mixture was stirred overnight, evaporated in vacuo and the residue stirred vigorously with aqueous 1 N KHS04 (100 ml) at room temperature for 4 h. The mixture was extracted with Et20 (3 x 100 ml) and then the aqueous layer was made strongly basic with NaOH. The aqueous layer was extracted with CHzCIz (3 x 100 ml). The combined extracts were dried with Na2504, filtered and the solvent evaporated in vacuo to leave the product as an oil (15.4 g, 86.5 %). H-NMR (200 MHz, DMSO-d6) : 8 4.04-4. 01 (m, 2 H), 2,60 (t, 2 H), 2.50 (d, 2 H), 1.62 (d, 2 H), 1.32 (s, 9 H), 1.31-1. 28 (m, 1 H), 1.06 (br s, 2 H), 1.03-0. 93 (m, 2 H)
36% In chloroform at 20℃; for 18h;
In chloroform for 18h;
With sodium hydroxide; potassium hydrogensulfate; benzaldehyde; sodium chloride In toluene 43 Preparation of 1-tert-butoxycarbonyl-4-aminomethylpiperidine (51) Example 43 Preparation of 1-tert-butoxycarbonyl-4-aminomethylpiperidine (51) 4-Aminomethylpiperidine (2.28 g; 20 mmol) is dissolved in dry toluene (25 mL) at ambient temperature. Benzaldehyde (2.03 mL; 20 mmol) is added in one portion and the solution is heated to azeotropic reflux for 135 minutes (with concommitant removal of water from the reaction medium). The reaction mixture is cooled to ambient temperature then di-tert-butyl dicarbonate (4.8 g; 22 mmol) is added portionwise and the resulting solution is stirred at ambient temperature for 64 hours. The solution is concentrated to dryness in vacuo at 40° C., then 1N KHSO4 (22 mL) is added to the residue and the resulting mixture is stirred rapidly at ambient temperature for 4 hours. The mixture is extracted with ether (3*20 mL), then the aqueous layer is basicified with 1N NaOH (30 mL). Solid NaCl is added to the alkaline aqueous layer, then it is extracted with dichloromethane (3*30 mL). The organic extracts are dried (MgSO4), filtered, and concentrated in vacuo affording the title compound (3.34 g) as a light colored liquid. ESMS: MH+ 215.4
With triethylamine In chloroform 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2) EXAMPLE 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2) A solution of C-piperidin-4-yl-methylamine (1) (5.0 g, 44 mmol) and triethylamine (12 ml 88 mmol) in 150 ml of chloroform was cooled to 0° C. To this solution was added dropwise ditertbutyldicarbonate (8.6 g, 40 mmol) in 100 ml of chloroform. After stirring at room temperature for 24 hours the solution was washed with water, dried over MgSO4, filtered and the solvents removed in vacuo to give the title compound 1 NMR (CDCl3, 400 MHz) 4.20-4.00 (br m, 2H), 2.75-2.62 (br t, 2H), 2.60 (d, 2H), 1.75-1.65 (br m, 2H), 1.50-1.30 (m, 3H), 1.63 (s, 9H), 1.20-1.00 (m, 2H).
In chloroform R.1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine REFERENCE EXAMPLE 1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine To a cooled (0° C.) solution of 4-(aminomethyl)piperidine (40 g, 0.35 mol) in CHCl3 (300 mL) was added a solution of di-tert-butyl dicarbonate (39.2 g, 0.17 mol) in CHCl3 (300 mL) and the reaction mixture was stirred at room temperature for 48 h. The resulting solution was washed with H2 O and the aqueous phase was reextracted with CHCl3. The combined organic phases were dried over sodium sulphate and the solvent was removed to afford 54.1 of a crude product, which was directly used in the next step as obtained. 1 H NMR (80 MHz, CDCl3) δ(TMS): 4.11 (broad d, J=13.4 Hz, 2H), 2.69 (m, 4H), 1.45 (s, 9H), 1.8-0.8 (complex signal, 7H).
With sodium hydroxide; sodium monohydrogen sulfate; benzaldehyde In toluene l 1-[(1,1-Dimethylethoxy)carbonyl]-4-aminomethyl piperidine 1-[(1,1-Dimethylethoxy)carbonyl]-4-aminomethyl piperidine A mixture of 4-aminomethyl piperidine (100 g, 0.88 mol) and benzaldehyde (102 g, 0.96 mmol) in toluene (1.5 L) was heated to reflux with a Dean-Stark trap for 1 hr, cooled to 5oC, and treated with a solution of di-t-butyl-dicarbonate (200 g, 0.92 mol) in toluene (700 mL). The mixture was stirred at room temperature overnight, treated with 1 M sodium hydrogen sulfate (1 L) and stirrred for 3 hr. The layers were separated, and the aqueous layer was washed with ether (3 X 250 mL), made basic with sodium hydroxide (50% solution) and extracted with ether (3 X 500 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give 218.7 g of 1-[(1,1-dimethylethoxy)carbonyl]-4-aminomethyl piperidine as an oil.
In chloroform R.1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine REFERENCE EXAMPLE 1 1-tert-Butoxycarbonyl-4-(aminomethyl)piperidine To a cooled (0° C.) solution of 4-(aminomethyl)piperidine (40 g, 0.35 mol) in CHCl3 (300 mL) was added a solution of di-tert-butyl dicarbonate (39.2 g, 0.17 mol) in CHCl3 (300 mL) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was washed with H2 O and the aqueous phase was reextracted with CHCl3. The combined organic phases were dried and concentrated to a crude product (54.1 g), which was directly used in the next step as obtained. 1 H NMR (80 MHz, CDCl3) δ (TMS): 4.11 (broad d, J=13.4 Hz, 2H), 2.69 (m, 4H), 1.45 (s, 9H), 1.8-0.8 (complex signal, 7H).
In chloroform at 0 - 20℃; for 18h; 4.3 Step 3 tert-Butyloxycarbonyl anhydride (6.69 g, 30.6 mmol) was added to a solution of 4-(aminomethyl)piperidine (7 g, 61.3 mmol) in chloroform (40 ml) at 0° C. The reaction mixture was allowed to warm to room temperature over 3 h and then stirred an additional 15 h.. The reaction mixture was washed with water, the organic layer was separated and dried over magnesium sulfate, filtered and concentrated to provide N-tert-butyloxy-carbonyl-4-(aminomethyl)piperidine (6.55 g) as a pale yellow oil.
In chloroform at 0 - 20℃; 11.A Part AA solution of 4-(aminomethyl)piperidine (10 g, 87.6 mmol) in chloroform (60 mL) was chilled in an ice water bath. A dicarbonate (9.6 g, 43.8 mmol) in chloroform (37 mL) was added dropwise over a period of 30 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature over the weekend. The reaction was quenched with water (10O mL). The organic layer was dried EPO over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 9 g of (erf-butyl 4-(aminomethyl)piperidine-l-carboxylate.
With triethylamine In 1,4-dioxane; water XIII 4-Aminomethyl-1-tert-butyloxycarbonylpiperidine EXAMPLE XIII 4-Aminomethyl-1-tert-butyloxycarbonylpiperidine 19 g of di-tert-butyl dicarbonate and 12 ml of triethylamine are added to 10 g of 4-aminomethylpiperidine in 120 ml of a dioxane/water (1:1) mixture at 0° C. and the mixture is stirred at room temperature for 12 hours. The dioxane is then distilled off in a rotary evaporator, and the aqueous phase is extracted six times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is purified by chromatography on an alumina column with methylene chloride/methanol=50:1. Yield: 7.4 g (39% of theory),; Rf: 0.48 (alumina; methylene chlorid/methanol=10:1) The following compound is obtained in analogy to Example XIII:
In tetrahydrofuran 174.1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester Step 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester To a mixture of 15 g of 4-aminomethylpiperidine in 250 mL of anhydrous tetrahydrofuran cooled to -78° C. was added dropwise over 45 min a solution of 24 g of di-tert-butyl di-carbonate in 100 mL of anhydrous tetrahydrofuran. After stirring for 1 h at -78° C., the mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated to near dryness and diluted with 200 mL of 10% aqueous citric acid. The mixture was extracted with 3*100 mL of ether, then made basic with sodium hydroxide pellets and extracted with 3*200 mL of chloroform. The combined chloroform extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure. The resulting oil was homogeneous by TLC (development with 90:10 chloroform saturated with ammonia: methanol). 1H NMR (400 MHz, CDCl3): 4.1 (br s, 2 H), 2.7 (br m, 2H), 2.6 (d, 2H), 1.7 (m, 3H), 1.42 (s, 9H), 1.1 (m, 2H).

Reference： [1]Current Patent Assignee: PALAU PHARMA SA - WO2008/119792, 2008, A1 Location in patent: Page/Page column 70
[2]Current Patent Assignee: SERODUS - WO2005/61483, 2005, A2 Location in patent: Page/Page column 48
[3]Wijtmans, Maikel; Verzijl, Dennis; van Dam, Cindy M.E.; Bosch, Leontien; Smit, Martine J.; Leurs, Rob; de Esch, Iwan J.P. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2252 - 2257]
[4]Carceller, Elena; Merlos, Manuel; Giral, Marta; Balsa, Dolors; García-Rafanell, Julián; Forn, Javier [Journal of Medicinal Chemistry, 1996, vol. 39, # 2, p. 487 - 493]
[5]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - US6376514, 2002, B1
[6]Current Patent Assignee: MERCK & CO INC - US6143750, 2000, A
[7]Current Patent Assignee: PALAU PHARMA SA - US5747477, 1998, A
[8]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP743320, 1996, A2
[9]Current Patent Assignee: PALAU PHARMA SA - US5705504, 1998, A
[10]Current Patent Assignee: ROCHE HOLDING AG - US6339087, 2002, B1 Location in patent: Page column 57
[11]Current Patent Assignee: 3M CO; PFIZER INC - WO2007/28129, 2007, A1 Location in patent: Page/Page column 65-66
[12]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US5821240, 1998, A
[13]Current Patent Assignee: MERCK & CO INC - US2003/119811, 2003, A1
  • 2
  • [ 325290-50-4 ]
  • [ 144222-22-0 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen In methanol
95% With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 3h; 4.1.22 4.1.14. tert-Butyl 4-(aminomethyl)piperidine-1-carboxylate (7) To a solution of 15 (520 mg, 2.1 mmol) in MeOH (15 mL), a catalytic amount of palladium on carbon 10 wt.% was added under argon atmosphere. The reaction environment was saturated with hydrogen gas. The mixture was stirred at 25 C for 3 h. The suspension was filtered on paper and concentrated in vacuo giving 7 as colorless oil without further purification (427 mg, 95%). 1H NMR(300 MHz, CDCl3) d 3.88 (d, J 13.1 Hz, 2H), 2.50 (d, J 17.4 Hz, 4H),2.45e2.33 (m, 2H), 1.50 (d, J 13.0 Hz, 2H), 1.38e1.27 (m, 1H), 1.27(s, 9H), 0.90e0.45 (m, 2H); 13C NMR (75 MHz, CDCl3) d 155.0, 79.3,48.1, 43.4, 39.7, 29.9, 28.6; MS (ESI) m/z 215 [M H].
79% Stage #1: tert-butyl 4-(azidomethyl)piperidine-1-carboxylate With triphenylphosphine In tetrahydrofuran for 2h; Reflux; Stage #2: With water In tetrahydrofuran for 3h; Reflux; 1.1-1.4 Step 4: Preparation of tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (compound of formula 8) Tertiary butyl 4-(azidomethyl)piperidine-1-carboxylate (30g, 124.8mmol) was dissolved in tetrahydrofuran (300mL), and triphenylphosphine (39.3g, 149.8mmol) was added thereto, followed by stirring under reflux for 2 hours. Water (120mL) was added thereto, followed by stirring under reflux for another 3 hours and concentration under reduced pressure. The resulting residue was extracted with ethyl acetate and a 1N hydrochloride solution, and the aqueous layer was neutralized with a 2N sodium hydroxide solution, followed by re-extraction with dichloromethane. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (21.16g, 79%).1H NMR (CDCl3, 400MHz): δ 4.16-3.98 (m, 2H), 2.69-2.63 (m, 2H), 2.56 (d, J =6.8Hz, 2H), 1.69-1.66 (m, 2H), 1.46-1.38 (m, 10H), 1.10-1.04 (m, 2H).
Reference： [1]Levesque, Sophie; St-Denis, Yves; Bachand, Benoit; Preville, Patrice; Leblond, Lorraine; Winocour, Peter D; Edmunds, Jeremy J; Rubin; Siddiqui [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 24, p. 3161 - 3164]
[2]Vallone, Alessandra; D'Alessandro, Sarah; Brogi, Simone; Brindisi, Margherita; Chemi, Giulia; Alfano, Gloria; Lamponi, Stefania; Lee, Soon Goo; Jez, Joseph M.; Koolen, Karin J.M.; Dechering, Koen J.; Saponara, Simona; Fusi, Fabio; Gorelli, Beatrice; Taramelli, Donatella; Parapini, Silvia; Caldelari, Reto; Campiani, Giuseppe; Gemma, Sandra; Butini, Stefania [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 698 - 718]
[3]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD. - WO2011/132901, 2011, A2 Location in patent: Page/Page column 14
  • 3
  • [ 91419-48-6 ]
  • [ 144222-22-0 ]
Reference： [1]Patent: EP1215208,2002,A2 .Location in patent: Example J(4)
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 757 - 761
  • 4
  • [ 7206-70-4 ]
  • [ 144222-22-0 ]
  • [ 188973-04-8 ]
YieldReaction ConditionsOperation in experiment
96% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;benzotriazol-1-ol; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h; Step 5: Preparation of tertiary butyl 4-((4-amino-5-chloro-2-methoxybenzamido)methyl)piperidine-1-carboxylate (compound of formula 10) <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (compound of formula 9) (16.6g, 82.28mmol) was dissolved in dimethylformamide (166mL) and the solution was cooled to 0. Then, tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (21.16g, 98.74mmol), triethylamine (11.56mL, 246.84mmol), N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC, 20.51g, 106.96mmol), and 1-hydroxybenzotriazole (HOBT, 16.68g, 123.42mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (31.4g, 96%). 1H NMR (CDCl3, 400MHz): delta 8.08 (s, 1H), 7.76-7.70 (m, 1H), 6.27 (s, 1H), 4.37 (s, 2H), 4.16-4.04 (m, 2H), 3.88 (s, 3H), 3.34-3.26 (m, 2H), 2.74-2.60 (m, 2H), 1.80-1.63 (m, 3H), 1.42 (s, 9H), 1.20-1.10 (m, 2H).
64.1% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; To a mixture of 4-aminomethyl-l- (tert-butoxycarbonyl) piperidine (10.0 g, 46.7 mmol) , 4-amino-5-chloro-2~ methoxybenzoic acid (9.41 g, 46.7 mmol) and NEt3 (6.80 ml, 46.7 mmol) in DMF (100 ml) were added l-ethyl-3- [3- (dimethylamino)propyl] carbodiimide hydrochloride (EDC) (9.39 g, 46.7 mmol) and 1-hydroxybenzotriazole (HOBT) (6.62 g, 46.7 mmol) at 00C. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The resulting residue was added H2O (100 ml) and extracted with EtOAc. The combined organic extracts were washed with aqueous K2CO3 and dried over Na2SO4. The solvent was removed in vacuo and the residue separated with flash chromatography (SiO2, EtOAc) to give the expected product as a white solid (11.91 g, 64.1%).1H-NMR (200 MHz, CDCl3) :delta 8.06 (s, 1 H), 7.77 (t, 1 H), 6.33 (s, 1 H), 4.64 (s, 2 H), 4.08 (d, 2 H), 3.86 (s, 3 EPO <DP n="51"/>H) , 3.30 (t, 2 H), 2.67 (t, 2 H), 1.78-1.66 (m, 3 H), 1.43 (s, 9 H) , 1.24-1.11 (m, 2 H)
64.1% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; Example 29 Synthesis of 4-amino-N- (tert-butoxycarbonyl) piperidin-4-ylmethyl]-5-chloro-2- methoxybenzamide A mixture of 4-aminomethyl-1-(tert-butoxycarbonyl) piperidine (10.0 g, 46.7 mmol), 4- amino-5-chloro-2-methoxybenzoic acid (9.41 g, 46.7 mmol) and NEt3 (6.80 ml, 46.7 mmol) in DMF (100 ml) were added 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDC) (9.39 g, 46.7 mmol) and 1-hydroxybenzotriazole (HOBT) (6.62 g, 46.7 mmol) at 0 C. The reaction mixture was stirred to room temperature overnight and concentrated in vacuo. The resulting residue was added H2O (100 ml) and extracted with EtOAc. The combined organic extracts were washed with aqueous K2CO3 and dried over Na2S04. The solvent was removed in vacuo and the residue separated with flash chromatography (SiO2, EtOAc) to give the expected product as a white solid (11.91 g, 64.1 %). 'H-NMR (200 MHz, CDCl3) : 8 8.06 (s, 1 H), 7.77 (t, 1 H), 6.33 (s, 1 H), 4.64 (s, 2 H), 4.08 (d, 2 H), 3.86 (s, 3 H), 3.30 (t, 2 H), 2.67 (t, 2 H), 1.78-1. 66 (m, 3 H), 1.43 (s, 9 H), 1.24-1. 11 (m, 2 H)
1,1'-Carbonyldiimidazole (1.61 g, 9.91 mmol) was added to a solution of <strong>[7206-70-4]4-amino-5-chloro-2-methoxybenzoic acid</strong> (2.0 g, 9.91 mmol) in dimethylformamide (5 ml). After stirring for 5 min. at room temperature, solution of N-tert-butyloxycarbonyl-4-(aminomethyl)piperidine (1.77 g, 8.26 mmol) in dimethylformamide (5 ml) was added and the reaction mixture was heated at 55 C. After 23 h, the product was extracted into ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the crude product with 2:1, ethyl acetate/hexanes as the eluant gave N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (2.63 g) as a foam.

Reference： [1]Patent: WO2011/132901,2011,A2 .Location in patent: Page/Page column 14-15
[2]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 4225 - 4234
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 3172 - 3187
[4]Patent: WO2007/7072,2007,A1 .Location in patent: Page/Page column 49-50
[5]Patent: WO2005/61483,2005,A2 .Location in patent: Page/Page column 49
[6]Patent: US6339087,2002,B1 .Location in patent: Page column 57-58
[7]Journal of Medicinal Chemistry,2009,vol. 52,p. 5330 - 5343
  • 5
  • [ 5381-20-4 ]
  • [ 76-05-1 ]
  • [ 144222-22-0 ]
  • <i>C</i>-(1-benzo[<i>b</i>]thiophen-3-ylmethyl-piperidin-4-yl)-methylamine; compound with trifluoro-acetic acid [ No CAS ]
Reference： [1]European Journal of Organic Chemistry,2004,p. 2723 - 2737
  • 6
  • [ 147624-13-3 ]
  • [ 76-05-1 ]
  • [ 144222-22-0 ]
  • <i>C</i>-[1-(3-fluoro-2-methyl-benzyl)-piperidin-4-yl]-methylamine; compound with trifluoro-acetic acid [ No CAS ]
Reference： [1]European Journal of Organic Chemistry,2004,p. 2723 - 2737
  • 7
  • [ 76-05-1 ]
  • [ 144222-22-0 ]
  • [ 5736-88-9 ]
  • <i>C</i>-[1-(4-butoxy-benzyl)-piperidin-4-yl]-methylamine; compound with trifluoro-acetic acid [ No CAS ]
Reference： [1]European Journal of Organic Chemistry,2004,p. 2723 - 2737
  • 8
  • [ 38871-41-9 ]
  • [ 144222-22-0 ]
  • [ 261767-14-0 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1697 - 1700
  • 9
  • [ 148550-51-0 ]
  • [ 144222-22-0 ]
  • [ 604811-06-5 ]
Reference： [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 597 - 606
  • 10
  • [ 24424-99-5 ]
  • [ 144222-22-0 ]
YieldReaction ConditionsOperation in experiment
78.9% Stage #1: 4-Aminomethylpiperidine With benzaldehyde In toluene for 4h; Heating / reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate In toluene at 20℃; 37 Benzaldehyde (8.73 g, 82.3 itimol) was added all at once to a stirred solution of 4-minomethylpiperidine (9.42 g, 82.3 mmol) in toluene (100 ml) . The mixture was heated under reflux for 4 h with a Dean-Stark trap attached to collect the water. The reaction mixture was cooled to room temperature and di-tert-butyldicarbonate (19.75 g, 90.5 mmol) was added in divided portions under continuous stirring. The mixture was stirred overnight, evaporated in vacuo and the residue stirred vigorously with aqueous 1 N KHSO4 (100 ml) at room temperature for 4 h. The mixture was extracted with Et2O (3 x 100 ml) and then the aqueous layer was made strongly basic with NaOH. The aqueous layer was extracted with CH2Cl2 (3 x 100 ml) . The combined extracts were dried with Na2SO4, filtered and the solvent evaporated in vacuo to leave the product as an oil (15.4 g, 86.5%) EPO 1H-NMR (200 MHz, DMSO-d6):δ 4.04-4.01 (m, 2 H), 2,60 (t, 2 H), 2.50 (d, 2 H), 1.62 (d, 2 H), 1.32 (s, 9 H), 1.31- 1.28 (m, 1 H), 1.06 (br S, 2 H), 1.03-0.93 (m, 2 H)
70% Stage #1: 4-Aminomethylpiperidine With benzaldehyde In toluene for 1 - 2h; Heating / reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate In toluene at 20℃; for 4h; 1.2.1; 2.6 Reference Example 1-2-1; Synthesis of 4-aminomethyl-piperidine-1-carboxylic acidtert-butyl ester; Reference Example 2-6; Preparation of 1-Boc-4-aminomethylpiperidine After dissolving 4-aminomethylpiperidine (5.00 g, 43.8 mmol) in toluene (90 mL), benzaldehyde (4.45 mL, 43.8 mmol) was added, a Dean-Stark trap was fitted, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, di-t-butyl dicarbonate (11.5 mL, 43.8 mmol) was added in 5 divided portions, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction mixture under reduced pressure, an aqueous potassium hydrogen sulfate solution (1.0 M, 70 mL, 70 mmol) was added in an ice bath, and the mixture was vigorously stirred for 1 hour. It was then washed with diethyl ether (30 mL x 2 times), and 2N aqueous sodium hydroxide was added to the aqueous layer to adjust the pH to approximately 7. The aqueous solution was adjusted to a pH of approximately 7 and then washed with ethyl acetate (30 mL x 3 times), and 2N sodium hydroxide was added to the aqueous layer to adjust the pH to approximately 12. The aqueous solution was then adjusted to a pH of approximately 12 and extracted with ethyl acetate (50 mL x 4 times), after which the obtained organic layer was dried over anhydrous magnesium sulfate. It was then concentrated under reduced pressure to obtain 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester. Yield: 6.49 g (70%).
Multi-step reaction with 4 steps 1.1: Et3N 2.1: aq. NaOH 3.1: ClCOO-i-Bu; N-methylmorpholine 3.2: aq. NH3 4.1: LiAlH4
Multi-step reaction with 5 steps 1: 100 percent / CH2Cl2 2: 100 percent / BH3*THF / tetrahydrofuran 3: Et3N / CH2Cl2 / 0 °C 4: NaN3 / dimethylformamide / Heating 5: 100 percent / H2 / 10 percent Pd/C / methanol
Multi-step reaction with 4 steps 1.1: triethylamine / methanol / 2 h / 0 - 20 °C 2.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 3.1: sodium azide / N,N-dimethyl-formamide / 6 h / 120 °C 4.1: triphenylphosphine / tetrahydrofuran / 2 h / Reflux 4.2: 3 h / Reflux

Reference： [1]Current Patent Assignee: SERODUS - WO2007/7072, 2007, A1 Location in patent: Page/Page column 48-49
[2]Current Patent Assignee: TEIJIN LIMITED - EP1502916, 2005, A1 Location in patent: Page 423; 453-454
[3]Itani, Hiromichi; Ito, Harunobu; Sakata, Yoshihiko; Hatakeyama, Yoshifumi; Oohashi, Hiroko; Satoh, Yoshinari [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 757 - 761]
[4]Levesque, Sophie; St-Denis, Yves; Bachand, Benoit; Preville, Patrice; Leblond, Lorraine; Winocour, Peter D; Edmunds, Jeremy J; Rubin; Siddiqui [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 24, p. 3161 - 3164]
[5]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD. - WO2011/132901, 2011, A2
  • 11
  • [ 31872-62-5 ]
  • [ 144222-22-0 ]
  • [ 173604-55-2 ]
YieldReaction ConditionsOperation in experiment
100% In methanol; for 2h;Heating / reflux; [0538] A solution of 643 mg (3.00 mmol) tert. butyl-4-aminomethyl-piperidin-1-carboxylate and 471 mg (3.00 mmol) <strong>[31872-62-5]4-methoxy-3-nitro-pyridine</strong> in 5 mL MeOH was refluxed for 2 hours and then evaporated down i. vac. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 100:0-->19:1 v/v) (Yield: 1.010 g, quantitative). [0539] The intermediate product was added to a suspension of 500 mg Raney nickel in 30 mL MeOH and the mixture was hydrogenated for 6 hours at 50° C. and 50 psi H2-pressure. The catalyst was filtered off and the filtrate evaporated i. vac. The crude product was purified by column chromatography (Alox (neutral, activity II-III), Gradient dichloromethane/MeOH 99:1-->19:1 v/v) purified. [0540] Yield: 0.480 g (53percent of theory) [0541] Rf=0.15 (silica gel, dichloromethane/MeOH 19/1 v/v) [0542] ESI-MS: (M+H)+=307
Reference： [1]Patent: US2003/236282,2003,A1 .Location in patent: Page 23
  • 12
  • [ 519147-96-7 ]
  • [ 144222-22-0 ]
  • tert-butyl 4-([(5-amino-6-chloro-2-ethylimidazo[1,2-a]-pyridin-8-yl)carbonyl]amino}methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 43h; 2.3 Step 3, tert-butyl 4-([(5-amino-6-chloro-2-ethylimidazo[1, 2-a]pyridin-8-yl)carbonyl]amino}methyl)piperidine-1-carboxylate A mixture of 5-AMINO-6-CHLORO-2-ETHYLIMIDAZO [1, 2-A] PYRIDINE-8-CARBOXYLIC acid (EXAMPLE 2, Step 2, LOOOO G, 41. 72 mmol), TERT-BUTYL 4- (aminomethyl) PIPERIDINE-L-CARBOXYLATE (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22,2357-60) (15.20 g, 70.93 mmol), diethyl phosphorocyanidate (10.76 ML, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104-. 4 mmol) in N,N-dimethylformamide (267 ML) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 mL), and extracted with dichloromethane (5 x 100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in VACUO. Flash chromatography of the residue eluting with dichloromethane/methanol (100: 1 to 20: 1) afforded 19.08 g (90%) of the title compound as yellow oil. 1H-NMR (CDC13) 8 : 1.35 (3 H, t, J=7.6 Hz), 1.45 (9 H, s), 1. 88-1. 28 (5 H, m), 2.88- 2.64 (2 H, m), 3.52-3. 38 (2 H, m), 4.30-3. 97 (4 H, m), 5.17 (2 H, br s), 7.21 (1 H, s), 8. 19 (1 H, s), 10.21 (1 H, br s).
90% With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 43h; 4.3 EXAMPLE 4: [5-AMINO-6-CHLORO-N { [1- (3,] 3-DIMETHYL-2- OXOBUTYL) PIPERIDIN-4-YL] [METHYL}-2-ETHYIIMIDAZO] [1,2- a] [PYRIDINE-8-CARBOXAMIDE]; Step 3. tert-butyl [4-([(5-AMINO-6-CHLORO-2-ETHYLIMIDAZO [1, 2-A] PYRIDIN-8-] yl) carbonyl] amino} methyl) piperidine-1-carboxylate A mixture of [5-AMINO-6-CHLORO-2-ETHYLIMIDAZO] [1, 2-a] pyridine-8-carboxylic acid (EXAMPLE 4, Step 2,10. 00 g, 41.72 mmol), tert-butyl [4-(AMINOMETHYL) PIPERIDINE-1-] carboxylate (J. [PRUGH,] L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22,2357-60, 15.20 g, 70.93 mmol), DEPC (10.76 mL, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104.4 mmol) in [N, N-DIMETHYLFORMAMIDE] (267 mL) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 [ML),] and extracted with dichloromethane (5 x 100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue eluting with dichloromethane/methanol (100: 1 to 20: 1) afforded 19.08 [G] (90%) of the title compound as a yellow oil. H-NMR [(CDC13)] 5 : 1.35 (3 H, t, [J=7.] 6 Hz), 1.45 (9 H, s), 1.88-1. 28 (5 H, [M),] 2.88- 2.64 [(2 H, M),] 3.52-3. 38 [(2 H, M),] 4.30-3. 97 (4 H, m), 5.17 (2 H, br s), 7.21 (1 H, s), 8.19 [(1 H,] s), 10.21 [(1 H,] bv).
Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/94418, 2004, A1 Location in patent: Page 31
[2]Current Patent Assignee: PFIZER INC - WO2004/26868, 2004, A1 Location in patent: Page 43-44
  • 13
  • [ 1575-61-7 ]
  • [ 144222-22-0 ]
  • [ 184968-81-8 ]
YieldReaction ConditionsOperation in experiment
84% With pyridine In dichloromethane at 0 - 23℃; for 16h; 2.2A Step 2A: Dissolve the product (19.64 g, 0.0916 mol, 22.84 g of the mixture) of Step 1 in dry CH2Cl2 (350 mL) and cool to 0°C under N2. Add pyridine (10.87 g, 11.1 mL, 0.137 mol) then chlorovaleryl chloride (15.63 g, 13.0 mL, 0.101 mol), warm slowly to 23°C and stir for 16 h. Add saturated aqueous NH4Cl (300 mL), separate layers and extract with CH2Cl2 (2x250 mL). Dry combined organic extracts (MgSO4), filter and concentrate. Purify by chromatography (1000 mL of flash silica gel; eluant: 1:1 EtOAc:hexane, then EtOAc). Combine appropriate fractions and concentrate to give 25.36 g (0.0762 mol, 84%) as a colorless oil. MS (Cl/CH4): m/e 333 (M+1)
Reference： [1]Current Patent Assignee: MERCK & CO INC - EP1032561, 2004, B1 Location in patent: Page 11
  • 14
  • [ 107582-20-7 ]
  • [ 144222-22-0 ]
  • [ 616224-06-7 ]
YieldReaction ConditionsOperation in experiment
91.4% Stage #1: di(1H-imidazol-2-yl)methanethione; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With 1H-imidazole In acetonitrile at 0 - 20℃; for 2h; Stage #2: 2,3-diaminobenzoic acid methyl ester In acetonitrile at 50℃; Stage #3: With diisopropyl-carbodiimide In acetonitrile at 80℃; for 2h; 1.4.5 Reference,Example 1-4-5; Synthesis of 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3.29 g, 15.4 mmol) in acetonitrile (40 ml), the mixture was cooled in an ice bath. A solution of 1,1-thiocarbonyldiimidazole (3.28 g, 18.4 mmol) and imidazole (314 mg, 4.6 mmol) in acetonitrile (30 ml) was added dropwise thereto, and the mixture was stirred for 2 hours while raising the temperature to room temperature. After adding 2,3-diaminobenzoic acid methyl ester (3.07 g, 18.5 mmol) to the reaction mixture, it was stirred at 50°C overnight. Diisopropylcarbodiimide (2.84 ml, 18.5 mmol) was then added and the mixture was stirred at 80°C for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate = 3/2 → ethyl acetate/methanol/triethylamine = 10/1/0.1) to obtain 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester. The compound was identified by LC-MS. Yield: 5.47 g (91.4%), [M+1] = 389.2.
Reference： [1]Current Patent Assignee: TEIJIN LIMITED - EP1502916, 2005, A1 Location in patent: Page 435
  • 15
  • [ 4103-60-0 ]
  • [ 144222-22-0 ]
  • [ 616225-00-4 ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: di(1H-imidazol-2-yl)methanethione; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With 1H-imidazole In acetonitrile at 0 - 20℃; for 4h; Stage #2: 2-(2-aminophenyl)acetamide In acetonitrile at 60℃; 7.1 Reference Example 7-1; Synthesis of 4-[([2-(carbamoylmethyl)phenyl]amino} thioxomethyl)amino]methyl}piperidine carboxylic acid tert-butyl ester After dissolving 1-N-Boc-4-aminomethylpiperidine (869 mg, 4.06 mmol) in acetonitrile (10 mL), a solution of thiocarbonyldiimidazole (794 mg, 4.46 mmol) and imidazole (82.9 mg, 1.22 mmol) in acetonitrile (15 mL) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 4 hours. After then adding 2-(2-aminophenyl)acetamide (670 mg, 4.46 mmol) thereto, the mixture was stirred overnight at 60°C. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (methylene chloride/methanol = 65:1 → 49:1) to obtain the title compound. Yield: 1.41 g (85%), M+1 = 407.2 (found), M = 406.2 (calculated).
Reference： [1]Current Patent Assignee: TEIJIN LIMITED - EP1502916, 2005, A1 Location in patent: Page 469
  • 16
  • [ 144222-22-0 ]
  • [ 3694-52-8 ]
  • [ 616223-97-3 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: di(1H-imidazol-2-yl)methanethione; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With 1H-imidazole In acetonitrile at 0 - 20℃; for 2.5h; Stage #2: 2,3-diamino-nitrobenzene In acetonitrile at 50℃; for 12h; Stage #3: With diisopropyl-carbodiimide In acetonitrile for 3.5h; Heating / reflux; 1.3.1 Reference Example 1-3-1; Synthesis of 4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2 g) in acetonitrile (100 ml), thiocarbonyldiimidazole (2 g) and imidazole (0.2 g) were added at 0°C. The mixture was stirred at room temperature for 2 hours and 30 minutes, 3-nitro-1,2-phenylenediamine (2.1 g) was added, the temperature was raised to 50°C, and the mixture was stirred for 12 hours. Diisopropylcarbodiimide (2.4 g) was added, the mixture was refluxed for 3 hours and 30 minutes, and then the solvent was removed under reduced pressure and the obtained residue was purified by silica gel chromatography (dichloromethane/hexane = 7/3 → 1/0) to obtain 4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester. The compound was identified by LC-MS. Yield: 3.5 g (100%), Purity: 95%, Found: ESI/MS m/e 376.4(M+1).
Reference： [1]Current Patent Assignee: TEIJIN LIMITED - EP1502916, 2005, A1 Location in patent: Page 430
  • 17
  • [ 37466-90-3 ]
  • [ 144222-22-0 ]
  • [ 616224-23-8 ]
YieldReaction ConditionsOperation in experiment
4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.394 g, 1.84 mmol) was dissolved in acetonitrile (3 ml). A solution of thiocarbonyldiimidazole (0.340 g, 1.91 mmol) and imidazole (0.052 g, 0.77 mmol) in acetonitrile (6 ml) was added dropwise over 3 minutes, at 0C. The mixture was stirred at room temperature for 1 hour, <strong>[37466-90-3]3,4-diaminobenzoic acid ethyl ester</strong> (0.371 g, 2.06 mmol) was added to the reaction mixture, and the mixture was stirred at 50C for 5.5 hours. Diisopropylcarbodiimide (0.32 ml) was further added, and the mixture was stirred overnight at 50C. Saturated brine was then added to the obtained reaction mixture, extraction was performed with ethyl acetate (100 ml), and the organic layer was dried overnight over anhydrous sodium sulfate. After filtering out the desiccant and concentrating the filtrate, the obtained light brown oil was'purified by silica gel column chromatography (dichloromethane/methanol = 49/1 ? 19/1) to obtain 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester as a yellow amorphous solid. Yield: 0.838 g ( %), Found: ESI/MS m/e 403.2(M+1).
Reference： [1]Patent: EP1502916,2005,A1 .Location in patent: Page 439
  • 18
  • [ 95-54-5 ]
  • [ 144222-22-0 ]
  • [ 302341-65-7 ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: di(1H-imidazol-2-yl)methanethione; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With 1H-imidazole In acetonitrile at 0 - 20℃; for 1.5h; Stage #2: 1,2-diamino-benzene In acetonitrile at 50℃; for 2h; Stage #3: With diisopropyl-carbodiimide In acetonitrile at 80℃; for 3h; 1.2.2 Reference Example 1-2-2; Synthesis of 4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3.18 g, 14.8 mmol) in acetonitrile (20 mL), a suspension of thiocarbonyldiimidazole (3.17 g, 17.8 mmol) and imidazole (302 mg, 4.45 mmol) in acetonitrile (30 mL) was added dropwise thereto in an ice bath. The temperature was raised to room temperature, the mixture was stirred for 90 minutes, o-phenylenediamine (1.93 g, 17.8 mmol) was added thereto, and the mixture was stirred at 50°C for 2 hours. Diisopropylcarbodiimide (3.4 mL, 22.2 mmol) was further added, and the mixture was stirred at 80°C for 3 hours. The mixture was cooled, concentrated under reduced pressure, and then dissolved in ethyl acetate (200 mL) and washed with water (100 mL x 2 times) and brine (100 mL). It was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol = 19/1 → dichloromethane/methanol/triethylamine = 10/1/1) to obtain 4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester. Yield: 4.33 g (89%).
Reference： [1]Current Patent Assignee: TEIJIN LIMITED - EP1502916, 2005, A1 Location in patent: Page 423-424
  • 19
  • [ 1992-90-1 ]
  • [ 144222-22-0 ]
  • [ 616224-80-7 ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: di(1H-imidazol-2-yl)methanethione; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With 1H-imidazole In acetonitrile at 0 - 20℃; for 2h; Stage #2: 2-amino-5-fluorobenzenesulfonamide With dmap In acetonitrile at 80℃; Stage #3: With diisopropyl-carbodiimide In acetonitrile at 80℃; for 1h; 3.8 Reference Example 3-8; Synthesis of 4-[(7-fluoro-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine carboxylic acidtert-butyl ester After dissolving 1-N-Boc-4-aminomethylpiperidine (1.08 g, 5.04 mmol) in acetonitrile (8.0 mL), the mixture was cooled to 0°C. A solution of 1,1'-thiocarbonyldiimidazole (988 mg, 5.54 mmol) and imidazole (103 mg, 1.51 mmol) in acetonitrile (10 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. Next, 2-amino-5-fluorobenzenesulfonamide (1.25 g, 6.55 mmol) and dimethylaminopyridine (739 mg, 6.05 mmol) were added to the reaction mixture, which was then stirred at 80°C overnight. Diisopropylcarbodiimide (0.233 mL, 1.51 mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). This was washed with water (20 mL) and saturated brine (20 mL), and then dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:2 → 2:3) to obtain 4-[(7-fluoro-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine carboxylic acidtert-butyl ester. Yield: 1.66 g (80%), M-Boc+2H = 313.1.
Reference： [1]Current Patent Assignee: TEIJIN LIMITED - EP1502916, 2005, A1 Location in patent: Page 464-465
  • 20
  • [ 672323-76-1 ]
  • [ 144222-22-0 ]
  • [ 672316-65-3 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 75℃; for 24h; 169; 460.A A. 4-[3-BROMO-5-(2-CHLOROPHENYL) PYRAZOLO [1,5-a] PYRIMIDIN-7- YLAMINO] METHYL} PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER 3-BROMO-7-CHLORO-5-(2-CHLOROPHENYL) PYRAZOLO [1, 5-a] pyrimidine (300mg, 0. 875mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (6.8mL). 4- (AMINOMETHYL) piperidine-1- carboxylic acid tert-butyl ester (225mg, 1. 05mmoles) and diisopropyl ethylamin (0.3055mL, 1. 75mmoles) were added and the mixture was heated at 75 C for 24h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15x5cm) using dichloromethane as the eluant to give 4- { [3-BROMO-5- (2-CHLOROPHENYL) PYRAZOLO [1,5-a] pyrimidin-7- YLAMINO] METHYL} PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ester (461.2mg, 100%): FABMS: m/z 520.1 (MH+) ; HRFABMS: m/z 520.1111 (MH+). CALCD. for C23H28N502BRCI : m/z 520.1115 ; 8H (CDC13) 1.30 (2H, m, CH2), 1.51 (9H,. s, - COOC (CH3) 3), 1.85 (2H, d, CH2), 1.95 (1 H, m, CH), 2. 76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1 H, s, H6), 6.55 (1 H, m, NH), 7.42 (2H, m, Ar-H), 7.52 (1 H, m, Ar-H), 7.76 (1 H, m, Ar-H) and 8. 07 ppm (1 H, s, H2) ; 8C (CDCI3) CH3 :. 28.5, 28.5, 28.5 ; CH2: 29.1, 29. 1, 43.5, 43.5, 47.9 ; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9 ; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.
Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2004/22561, 2004, A1 Location in patent: Page 157; 271-274
  • 21
  • C14H14ClNO2 [ No CAS ]
  • [ 144222-22-0 ]
  • tert-butyl 4-([(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3h; 3.3 To a solution of 1-isopropyl-5-methyl-2-oxo-1, 2-dihydroquinoline-3- carboxylic acid (8.00 g, 32.6 mmol, step 4 in preparation 2) in dichloromethane (200 mL) was added dropwise oxalyl chloride (8.5 mL, 98 mmol) at 0 C. Then, N, N- dimethylformamide (3 drops) was carefully added to the mixture. The resulting mixture was stirred at 0 C for 30 min and at room temperature for 3 h. Then, the mixture was evaporated in vacuo to give crude acid chloride as a yellow solid. Then, to a mixtureof tert-butyl 4-(aminomethyl) piperidine-1-carboxylate (9.08 g, 42.4 mmol) anddiisopropylethylamine (11.4 mL, 65.2 mmol) in dichloromethane (200 mL) was added dropwise a solution of crude acid chloride in dichloromethane(50 mL) at0 C, and the mixture was stirred at room temperature for 3 h. The resulting mixture was poured onto water (300 mL), and the aqueous layer was extracted with dichloromethane (200 mL x 3). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel with ethyl acetate/hexane (1/1.5) and then methanol/dichloromethane(1/40-1/10) to give 15.0 g (quant.) of the title compound as a pale yellow solid. MS(ESI) m/z: 442 (M+H+). H-NMR(CDCl3)6 : 10.07 (1 H, br), 9.13 (1 H, s), 7.53-7. 47 (2 H,m), 7.13 (1 H, t, J=3.6 Hz),4. 20-4. 06 (2 H,m), 3.39 (2 H, t, J=6.3 Hz), 2.78-2. 66 (2 H,m), 2.68 (3 H, s), 1.67 (6 H, d, J=7.1 Hz), 1.45 (9 H, s), 1.85-1. 18 (5 H,m). A signal due toCH (CH3)2 was not observed.
Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/49608, 2005, A1 Location in patent: Page/Page column 61-62
  • 22
  • [ 144222-22-0 ]
  • [ 15174-47-7 ]
  • [ 881833-19-8 ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate; α-methyl-trans-cinnamaldehyde With acetic acid In 1,2-dichloro-ethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 3h; 1 Example 1 A mixture of 4-aminomethyl-1-t-butoxycarbonylpiperidine (3.6 g, 16.8 mmol), (E)-2-methyl-3-phenylpropenal (3.9 g, 26.7 mmol), acetic acid (3.9 g, 65 mmol), and 1,2-dichloroethane (30 mL) was stirred under argon at room temperature for 30 min before sodium triacetoxyborohydride (4.1 g, 19.3 mmol) was added. After 3 h saturated aqueous sodium bicarbonate was added to make the mixture basic, then it was diluted with water and extracted with dichloromethane (three times). The combined extracts were dried (anhydrous sodium sulfate) and evaporated under vacuum prior to column chromatography (silica gel, step-wise gradient of 2% to 4% of (10% concentrated aqueous ammonium hydroxide in methanol) in dichloromethane), which provided 4-(N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)-1-t-butoxycarbonylpiperidine (3.72 g, 64% yield) as a pale yellow oil. A smaller excess of aldehyde over amine may produce optimal desired product yields when other aldehydes are used.
Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2006/79556, 2006, A1 Location in patent: Page/Page column 10
  • 23
  • [ 23165-60-8 ]
  • [ 144222-22-0 ]
  • (1,1-dimethylethyl) acid 4-[3-(4-methoxy-2-nitro-phenyl)-thioureidomethyl]-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% In tetrahydrofuran at 20℃; for 5h; 40.a A mixture of 1 g (4.67 mmoles) of (1,1-dimethylethyl) acid 4-aminomethylpiperidine)-1-carboxylate and 1.08 g (6.06 mmoles) of 4-methoxy-2-nitrophenyl isothiocyanate in 70 ml of tetrahydrofuran is stirred at ambient temperature, under a nitrogen flow for 5 hours. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silicagel with the following eluent: ethyl acetate-heptane from 20-80 to 30-70. 1.66 g (Yield=84%) of expected product is obtained. TLC: Rf=0.4 (silicagel, eluent: ethyl acetate-heptane 50-50) 1H-NMR (CDCl3): δ 1.25 and 1.76 (2m, 4H, N-CH2--CH--CH2); 1.47 (s, 9H, tBu); 1.91 (m, 1H, N-CH2-CH2--CH2-CH2); 2.73 and 4.15 (2m, 4H, N--CH2-CH-CH2-); 3.51 (m, 2H, CH--NH); 3.90 (s, 3H, O-); 6.66 (m, 1H, CH=CH aromatic); 7.22 (m, 1H, CH=CH aromatic); 7.59 (m, 1H, CH=CH aromatic). MS: 425(MH+); 325(MH-COOtBu+).
Reference： [1]Current Patent Assignee: GALAPAGOS - US2006/52398, 2006, A1 Location in patent: Page/Page column 71
  • 24
  • [ 501-53-1 ]
  • [ 144222-22-0 ]
  • [ 155456-33-0 ]
YieldReaction ConditionsOperation in experiment
96% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; 1.5.113.A tert-Butyl 4-(aminomethyl)piperidine-l-carboxylate (0.611 g, 2.851 mmol) and diisopropylethylamine (0.479 g, 3.706 mmol) were dissolved in 30 mis of dry dichloromethane. To this mixture was added benzyl chloro formate (0.552 g, 3.136 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 mis of dichloromethane, washed once with IN aqueous HCl, one with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure to 950 mgs (96%) of the the title compound and used directly without further purification.
81% With dmap; triethylamine In dichloromethane at 20℃; for 16h; Cooling with ice; Inert atmosphere; 4.A Step A Compound 1-Boc-4-aminomethylpiperidine (1.00 g, 4.67 mmol) was dissolved in 50 mL of dichloromethane, triethylamine (2.36 g, 23.3 mmol), 4-dimethylaminopyridine (570 mg, 4.67 mmol), and CbzCl (2.39 g, 14.0 mmol) were added dropwise under an ice bath and nitrogen protection.Stir for 16 hours at room temperature.It was concentrated under reduced pressure, and the compound 1-Boc-4-(((benzyloxycarbonyl)amino)methyl)piperidine (1.32 g, yield 81%) was obtained by silica gel column chromatography
57% With pyridine In dichloromethane at 0 - 20℃; for 4h; 28 Benzyl chloroformate (10.53g, 61.7mmol) in DCM (3OmL) was added dropwise with stirring to an ice-cooled solution of 1 ,1 -dimethylethyl 4- (aminomethyl)-i-piperidinecarboxylate (12.Og, 56.1mmol) and pyridine (6.64g, 84.1 mmol) in DCM (8OmL). After the addition, the solution was stirred at 0- 5°C for 0.5h followed by 3.5h at room temperature. The reaction solution was then washed with 1 M HCI (3 x 3OmL) and brine (3OmL). It was then treated with decolourising charcoal and MgSO4, filtered and evaporated to dryness to leave a pale yellow oil. This was stirred and treated with EtOAc (2OmL), causing crystallisation of the product. Hexane (20OmL) was added and stirring was continued for 0.5h. The resulting solid was filtered and dried to afford 1 ,1- dimethylethyl 4-[([(phenylmethyl)oxy]carbonyl}amino)methyl]-1- piperidinecarboxylate (D28) as a white solid (11.15g, 57%). δH (CDCI3, 400MHz) 1.10 (2H, br.m), 1.45 (9H, s), 1.67 (3H, br.m), 2.68 (2H, br.m), 3.09 (2H, br.m), 4.10 (2H, br.m), 4.82 (1 H, br.m), 5.10 (2H, s) and 7.34 (5H, m).
With 4-methyl-morpholine In tetrahydrofuran at 5℃; for 2h; I.I.A.a 1-tert-Butyloxycarbonyl-4-(aminomethyl)piperidine (14 g; 65.33 mmol; prepared as described by Prugh et al., Synthetic Communications 22 (16), 2361-2365 (1992)) was dissolved in 50 ml of THF and, at 5° C., N-methylmorpholine (6.6 g) and benzyl chloroformate (12.6 g) were added, and the mixture was stirred for about 2 h. It was then concentrated, and the residue was taken up in CH2Cl2, washed with saturated NaCl solution, dried and filtered. The residue after concentration was 23.5 g of a yellow oil which was crystallized from methyl tert-butyl ether. 18 g; ESI-MS [M+H+]=293.15
With sodium carbonate In ethyl acetate 77.2 4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester Step 2 4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (21 g) in 100 mL of ethyl acetate cooled to 0° C. was added 100 mL of saturated sodium carbonate and benzyl chloroformate (17 g). The solution was stirred for 3 h, then separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as an oil: 1H NMR (400 MHz, CDCl3): δ7.35 (m, 5H), 5.3 (d, 1H), 5.1 (s, 2H), 4.1 (br s, 2 H), 3.0 (br m, 2H), 2.6 (br m, 2H), 1.7 (m, 3H), 1.42 (s, 9H), 1.1 (m, 2H).
With sodium carbonate In ethyl acetate 174.2 4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester Step 2 4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester To a solution of 21 g of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester in 100 mL of ethyl acetate cooled to 0° C. was added 100 mL of saturated sodium carbonate and 17 g of benzyl chloroformate. The solution was stirred for 3 h, then separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as an oil: 1H NMR (400 MHz, CDCl3): 7.35 (m, 5H), 5.3 (d, 1H), 5.1 (s, 2H), 4.1 (br s, 2H), 3.0 (br m, 2H), 2.6 (br m, 2H), 1.7 (m, 3H), 1.42 (s, 9H), 1.1 (m, 2H).

Reference： [1]Current Patent Assignee: PFIZER INC; BRISTOL-MYERS SQUIBB CO - WO2011/22508, 2011, A2 Location in patent: Page/Page column 52; 53
[2]Current Patent Assignee: VIVAVISION BIOPHARMA TECH SHANGHAI - CN110724142, 2020, A Location in patent: Paragraph 0114; 0118-0120
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/68739, 2007, A1 Location in patent: Page/Page column 34-35
[4]Current Patent Assignee: ABBVIE INC - US7105508, 2006, B1 Location in patent: Page/Page column 68
[5]Current Patent Assignee: MERCK & CO INC - US2002/165241, 2002, A1
[6]Current Patent Assignee: MERCK & CO INC - US2003/119811, 2003, A1
  • 25
  • [ 389602-62-4 ]
  • [ 68957-94-8 ]
  • [ 144222-22-0 ]
  • [ 389601-23-4 ]
YieldReaction ConditionsOperation in experiment
38% With 4-methyl-morpholine; In dichloromethane; EXAMPLE 18 N-(N-tert.butoxycarbonyl-piperidin-4-yl-methyl)-3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid amide Prepared analogously to Example 7 from 3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid and N-tert.butoxy-carbonyl-piperidin-4-yl-methylamine in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield:38% of theory Rf value:0.68 (silica gel; dichloromethane/ethanol=9:1)
Reference： [1]Patent: US2002/32238,2002,A1
  • 26
  • [ 17794-48-8 ]
  • [ 80029-43-2 ]
  • [ 144222-22-0 ]
  • 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine; In dichloromethane; water; Reference Example 29 Preparation of 1-(tert-Butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine N-{3-(Trifluoromethyl)benzoyl}glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and Et3N (1.72 g) were added to a solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g) in dry CH2Cl2 (200 mL). The reaction mixture was stirred at 25 C. for 20 h. H2O (100 mL) was added to the reaction mixture and the mixture was extracted with CH2Cl2 (2*50 mL). The combined extracts were washed with H2O (2*50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed under reduced pressure to afford an yellow oil which was purified by column chromatography (SiO2, 70% EtOAc-hexane) to give 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (6.39 g, 85%): 1H-NMR (CDCl3, 300 MHz) delta1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J=7.2, 7,2 Hz), 7.79 (d, 1H, J=7,2 Hz), 8.0 (d, 1H, J=7.2 Hz), 8.11 (s, 1H); The purity was determined by RPLc/MS (97); ESI/MS m/e 444.3 (M++H, C21H28F3N3O4).
85% With triethylamine; In dichloromethane; water; [Reference Example 29] Synthesis of 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine N-[3-(Trifluoromethyl)benzoyl]glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and triethylamine (1.72 g) were added to an anhydrous dichloromethane (200 mL) solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g). The resulting reaction mixture was stirred at 25 C for 20 hours, and H2O (100 mL) was then added to the mixture. The obtained mixture was extracted with dichloromethane (50 mL * 2). The extracts were combined, washed with H2O (50 mL * 2) and brine (50 mL), dried (over MgSO4) and concentrated to thereby afford a yellow oil. The obtained crude product was purified by column chromatography (SiO2,70% ethyl acetate-hexane) to provide 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine as a white solid (6.39 g, 85%). 1H NMR(CDCl3, 300MHz) delta 1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J = 7.2, 7.2 Hz), 7.79 (d, 1H, J = 7.2 Hz), 8.0 (d, 1H, J = 7.2 Hz), 8.11 (s, 1H). The purity was determined by RPLC/MS (97%). ESI/MS m/e 444.3 (M++H, C21H28N3O4).
Reference： [1]Patent: US6362177,2002,B1
[2]Patent: EP1179341,2002,A1
  • 27
  • [ 1138-80-3 ]
  • [ 144222-22-0 ]
  • [ 226249-70-3 ]
YieldReaction ConditionsOperation in experiment
94% With sodium hydroxide; benzotriazol-1-ol; triethylamine In dichloromethane R.31 Preparation of 4-[{(N-(Benzyloxycarbonyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine Reference Example 31 Preparation of 4-[{(N-(Benzyloxycarbonyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine A solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (3.54 g, 16.5 mmol) in CH2Cl2 (80 mL) was treated with Et3N (2.8 mL, 20 mmol), N-(benzyloxycarbonyl)glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol). After the reaction mixture was stirred at room temperature for 15 h, 2 N aqueous NaOH solution (100 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate) afforded the desired 4-[{(N-(Benzyloxycarbonyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (6.27 g, 94%) as an amorphous solid.
94% With sodium hydroxide; benzotriazol-1-ol; triethylamine In chloroform [Reference Example 31] Synthesis of 4-[[(N-(benzyloxycarbonyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine [Reference Example 31] Synthesis of 4-[[(N-(benzyloxycarbonyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine Triethylamine (2.8 mL, 20 mmol), N-(benzyloxycarbonyl)glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol) were added to a chloroform (80 mL) solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (3.54 g, 16.5 mmol). The resulting mixture was stirred at room temperature for 15 hours, and a 2 M aqueous solution of NaOH (100 mL) was then added to the mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL* 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO2, ethyl acetate) to provide 4-[[(N-(benzyloxycarbonyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine as an amorphous solid (6.27 g, 94%).
94.5% Stage #1: N-(Benzyloxycarbonyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate In N,N-dimethyl-formamide at 20℃; Stage #3: With sodium hydrogencarbonate In water 1.a A solution of Z-glycine (Aldrich) (1.95 g, 9.32 mmol), HOBt [1- hydroxybenzotriazol] (1.26 g, 9.32 mmol) and EDC hydrochloride [N-(3- dimethylaminopropyl)-iV-ethylcarbodiimide] (1.79 g, 9.32 mmol) in dry dimethylformamide (20 mL) was stirred at 0 0C for ten minutes before 4-aminomethyl- piperidine-1-carboxylic acid tert-butyl ester (Fluka) (2.0 g, 9.32 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, the residue was treated with saturated sodium hydrogencarbonate solution (50 mL), extracted with chloroform (3x50 mL), the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, EPO and chloroform:methanol = 25:1 as eluent to yield 3.57 g (94.5 %) of the title compound as white amorphous solid. MS (EI) 428.2 (M+Na+).
Reference： [1]Current Patent Assignee: TEIJIN LIMITED - US6362177, 2002, B1
[2]Current Patent Assignee: TEIJIN LIMITED - EP1179341, 2002, A1
[3]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2008/50167, 2008, A1 Location in patent: Page/Page column 22-23
  • 28
  • [ 349-88-2 ]
  • [ 144222-22-0 ]
  • [ 301226-37-9 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine In chloroform for 48h;
82% With N-ethyl-N,N-diisopropylamine In dichloromethane 87.A Step A Step A 4-(N-((4-Fluorophenyl)sulfonyl)aminomethyl)-1-tert-butoxycarbonylpiperidine Diisopropylethylamine (DIEA, 0.7 mL, 2 mmol) was added to a solution of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (200 mg, 0.93 mmol) in 5 mL of CH2Cl2 under nitrogen. (4-fluorophenyl)sulfonyl chloride (195 mg, 1 mmol) was then added, and the reaction mixture was stirred at room temperature for 30 min. The solution was diluted with diethyl ether, washed with 1N HCl, 1N NaOH, and brine, and then dried over MgSO4. The solution was then concentrated to afford 284 mg (82% yield) of the title compound, which could be purified by recrystallization from diethyl ether. 1H NMR (300 MHz, CDCl3). δ 1.00-1.13 (m, 1H), 1.42 (s, 9H), 1.61-1.70 (m, 3H), 2.58-2.70 (m, 2H), 2.80-2.84 (m, 2H), 4.02-4.16 (m, 2H), 4.46-4.52 (m, 1H), 7.17-7.22 (m, 2H), 7.82-7.90 (m, 2H).
With triethylamine In dichloromethane at 5 - 20℃; for 0.5h; Inert atmosphere; 4.2.3 General procedure for the synthesis of substituted tert-butyl 4-(methylamino) piperidine-1-carboxylate (7a-o) General procedure: In a dry two necked RBF, equipped with nitrogen source, was charged with solution of commercially available 1-N-BOC-4-(aminomethyl)piperidine (5) (1.39mmol) in dichloromethane (DCM) (2.0mL) and triethylamine (TEA) (2.09mmol). The resulting reaction mixture was cooled at 10°C. Commercially available different substituted aromatic and aliphatic acid chlorides and sulphonyl chlorides (6a-o) (1.39mmol) were dissolved in DCM (1.0mL) and added dropwise to the above solution over the period of 5min using a glass syringe while maintaining temperature 5-10°C. Then, the reaction was moved to room temperature after the complete addition of 6a-o and monitored on TLC. After completion of the reaction, the reaction mixture was concentrated under vacuum to yield semi-solid crude products. Crude products were suspended in a mixture of diethyl ether: hexane (70:30) and cooled at 10°C. After cooling, products were fall out as white to off-white precipitates and filtered using vacuum filtration. This treatment yields high purity of 7a-o, used in the next step as obtained.
Reference： [1]Martini, Elisabetta; Ghelardini, Carla; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Melchiorre, Michele; Norcini, Monica; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1431 - 1443]
[2]Current Patent Assignee: MERCK & CO INC - US6498161, 2002, B1
[3]Gediya, Piyush; Vyas, Vivek K.; Carafa, Vincenzo; Sitwala, Nikum; Della Torre, Laura; Poziello, Angelita; Kurohara, Takashi; Suzuki, Takayoshi; Sanna, Vinod; Raguraman, Varalakshmi; Suthindhiran; Ghosh, Debarpan; Bhatia, Dhiraj; Altucci, Lucia; Ghate, Manjunath D. [Bioorganic Chemistry, 2021, vol. 110]
  • 29
  • [ 86-59-9 ]
  • [ 144222-22-0 ]
  • N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]quinoline-8-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; In dichloromethane; EXAMPLE 8 Quinoline-8-carboxylic acid (0.74 g) and thionyl chloride (10 ml) were stirred and heated together at 50° C. for 2 hours. Excess thionyl chloride was removed in vacuo and the residue was suspended in dichloromethane (20 ml). A solution of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (0.98 g) in dichloromethane (10 ml) was added and the mixture stirred at ambient temperature for 4 hours then poured into aqueous sodium hydrogen carbonate solution (1M; 50 ml). The organic layer was separated and washed with aqueous oxalic acid solution (2M; 2*50 ml) then dried over magnesium sulphate. The solvent was evaporated to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]quinoline-8-carboxamide (0.59 g) as a colourless solid.
Reference： [1]Patent: US5935973,1999,A
  • 30
  • [ 16498-81-0 ]
  • [ 144222-22-0 ]
  • N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-2-methoxypyridine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In thionyl chloride; dichloromethane; ethyl acetate; Petroleum ether; EXAMPLE 26 <strong>[16498-81-0]2-Methoxypyridine-3-carboxylic acid</strong> (4.86 g) was added in portions to thionyl chloride (50 ml) then the mixture stirred and heated under reflux for 2 hours. After cooling, excess thionyl chloride was removed in vacuo and the residue dissolved in dichloromethane (100 ml). A solution of 4-(aminomethyl)-1 -tert-butoxycarbonylpiperidine (7.3 g) in dichloromethane (100 ml) was added and the mixture stirred at ambient temperature for 4 hours then poured into water (200 ml). The organic phase was washed with water (100 ml), aqueous oxalic acid solution (2 M; 2*100 ml), hydrochloric acid (1 M; 100 ml), aqueous sodium hydrogen carbonate solution (2 M; 2*150 ml), then water, and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluding with a 1:1 mixture of ethyl acetate and petroleum ether (b.p. 60-80 C.). Appropriate fractions were combined and the solvent removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-2-methoxypyridine-3-carboxamide (2.06 g)
Reference： [1]Patent: US5935973,1999,A
  • 31
  • [ 7646-93-7 ]
  • [ 24424-99-5 ]
  • [ 7144-05-0 ]
  • [ 144222-22-0 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; benzaldehyde In toluene P.147 PREPARATION EXAMPLE 147 PREPARATION EXAMPLE 147 4-(Aminomethyl)piperidine (137 g) was dissolved in toluene (1200 ml), and benzaldehyde (127 g) was added, and the mixture was stirred at refluxing temperature for 6.5 hr. The reaction mixture was cooled to room temperature, and di-tert-butyl dicarbonate (288 g) was dropwise added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and 1N potassium hydrogensulfate (1200 ml) was added to the obtained residue, which was followed by stirring at room temperature for 4 hr. The reaction mixture was washed 3 times with isopropyl ether and made alkaline with 10% sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give 236.5 g of 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine. 1 H-NMR (CDCl3,ppm) δ: 1.01-1.30(5 H,m), 1.45(9 H,s), 1.65-1.75(2 H,m), 4.07-4.16(2 H,m)
With sodium hydroxide; benzaldehyde In toluene P.1 Preparation Example 1 Preparation Example 1 4-(Aminomethyl)piperidine (137 g) was dissolved in toluene (1200 ml), and benzaldehyde (127 g) was added, and the mixture was stirred at refluxing temperature for 6.5 hr. The reaction mixture was cooled to room temperature, and di-tert-butyl dicarbonate (288 g) was dropwise added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and 1N potassium hydrogensulfate (1200 ml) was added to the obtained residue, which was followed by stirring at room temperature for 4 hr. The reaction mixture was washed 3 times with isopropyl ether and made alkaline with 10% sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give 236.5 g of 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine. 1H-NMR (CDCl3,ppm)δ:1.01-1.30(5H,m), 1.45(9H,s), 1.65-1.75(2H,m), 4.07-4.16(2H,m)
With sodium hydroxide; benzaldehyde In toluene P.1 Preparation Example 1 Preparation Example 1 4-(Aminomethyl)piperidine (137 g) was dissolved in toluene (1200 ml), benzaldehyde (127 g) was added thereto, and the mixture was stirred at refluxing temperature for 6.5 hours. The reaction mixture was cooled to room temperature, and di-tert-butyl dicarbonate (288 g) was dropwise added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 1N potassium hydrogensulfate (1200 ml) was added to the obtained residue, which was followed by stirring at room temperature for 4 hours. The reaction mixture was washed 3 times with isopropyl ether and made alkaline with 10% sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give 236.5 g of 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine. 1H-NMR (CDCl3, ppm)δ:1.01-1.30(5H,m), 1.45(9H,s), 1.65-1.75(2H,m), 4.07-4.16(2H,m)
Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US5864039, 1999, A
[2]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP873990, 1998, A1
[3]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP979818, 2000, A1
  • 32
  • [ 21038-63-1 ]
  • [ 144222-22-0 ]
  • [ 187543-49-3 ]
YieldReaction ConditionsOperation in experiment
In 1,2-dimethoxyethane 2 EXAMPLE 2 A mixture of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (2.0 g) and pyrido[2,3d][1,3]oxazine-2,4-(1H)-dione (1.53 g) in 1,2-dimethoxyethane (30 ml) was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo and the residue purified by flash chromatography on silica eluding with dichloromethane then a 19:1 mixture fo dichloromethane and industrial methylated spirit. Appropriate fractions were combined and the solvent was removed in vacuo to give 2-amino-N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (1.7 g).
Reference： [1]Current Patent Assignee: ABBVIE INC - US5935973, 1999, A
  • 33
  • [ 122-84-9 ]
  • [ 144222-22-0 ]
  • N-[2-(4-Methoxyphenyl)-1-methylethyl]-N-propyl-[1-(tert-butoxycarbonyl)piperidin-4-ylmethy]lamine [ No CAS ]
  • N-[2-(4-methoxyphenyl)-1-methylethyl]-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With sodium cyanoborohydride In methanol 2.A 2A. 2A. N-[2-(4-Methoxyphenyl)-1-methylethyl]-N-propyl-[1-(tert-butoxycarbonyl)piperidin-4-ylmethy]lamine A solution of sodium cyanoborohydride (1.07 grams, 17 mmole), 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine (3.0 grams, 14.3 mole) and 1-(4-methoxyphenyl)propan-2-one (2.35 grams, 14.31 mmole) in methanol (50 ml) was stirred at 22° C. for 17 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The dried (anhydrous magnesium sulfate) organic phase was concentrated under reduced pressure to leave N-[2-(4-methoxyphenyl)-1-methylethyl]-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine as an oil (4.28 grams, 82%); hydrochloride, m.p. 198-199° C. (methanol/ethyl ether), M+H 391.
Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US6319920, 2001, B1
  • 34
  • [ 78756-28-2 ]
  • [ 144222-22-0 ]
  • 3-amino-N-(1-tert-butoxycarbonyl-4-piperidylmethyl)thiophene-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In 1,2-dimethoxyethane; EXAMPLE 16 A solution of <strong>[78756-28-2]2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione</strong> (3.1 g) and 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (3.9 g) in 1,2-dimethoxyethane (50 ml) was stirred at ambient temperature for 5 hours. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluding with ether. Appropriate fractions were combined and the solvent evaporated to give 3-amino-N-(1-tert-butoxycarbonyl-4-piperidylmethyl)thiophene-2-carboxamide as a colourless solid (2.57 g).
Reference： [1]Patent: US5935973,1999,A
  • 35
  • [ 204574-42-5 ]
  • [ 144222-22-0 ]
  • 1-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-N-[4-(N-tert-butoxycarbonylpiperidine)methyl]-4-piperidinecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 19h; 8.2.A 1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-N-[4-(N-tert-butoxycarbonylpiperidine)methyl]-4-piperidinecarboxamide Procedure 2, Step A: 1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-N-[4-(N-tert-butoxycarbonylpiperidine)methyl]-4-piperidinecarboxamide 1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-piperidinecarboxylate (0.5g; 1 equivalent) (prepared as described in Preparative Example 2 below) dissolved in anhydrous DMF (18ml) is added to a solution of 1-N-tert-butoxycarbonyl-4-aminomethylpiperidine (0.1778g; 1 equivalent) (prepared as described in Preparative Example 3, Step C below), DEC (0.2067g; 1.3 equivalents), HOBT (0.1457g; 1.3 equivalents) and N-methylmorpholine (0.1185ml; 1.3 equivalents) in anhydrous DMF (8ml) and the mixture is stirred at 25°C for 19h. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a silica gel column (60X2.5cm) using 0.75% (10% concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (0.4805g; 71% yield), FABMS: m/z 631 (MH+).
Reference： [1]Current Patent Assignee: MERCK & CO INC; LIGAND PHARMACEUTICALS INC - EP931078, 2006, B1 Location in patent: Page/Page column 23-24
  • 36
  • ditertbutyldicarbonate [ No CAS ]
  • [ 7144-05-0 ]
  • [ 144222-22-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In chloroform 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2) EXAMPLE 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2) A solution of C-piperidin-4-yl-methylamine (1) (5.0 g, 44 mmol) and triethylamine (12 ml 88 mmol) in 150 ml of chloroform was cooled to 0° C. To this solution was added dropwise ditertbutyldicarbonate (8.6 g, 40 mmol) in 100 ml of chloroform. After stirring at room temperature for 24 hours the solution was washed with water, dried over MgSO4, filtered and the solvents removed in vacuo to give the title compound 1H NMR (CDCl3) 4.20-4.00 (br m, 2H), 2.75-2.62 (br t, 2H), 2.60 (d, 2H), 1.75-1.65 (br m, 2H), 1.50-1.30 (m, 3H), 1.63 (s, 9H), 1.20-1.00 (m, 2H).
Reference： [1]Current Patent Assignee: MERCK & CO INC - US6214832, 2001, B1
  • 37
  • [ 10132-07-7 ]
  • [ 144222-22-0 ]
  • [ 917021-64-8 ]
YieldReaction ConditionsOperation in experiment
45% In pentan-1-ol; at 120℃; for 12h; N-tert-Butoxycarbonylpiperidinyl-4-methylamine (5.0 g) was slowly added to a stirred solution of <strong>[10132-07-7]2,4-dichloro-6-aminopyrimidine</strong> (5.7 g) in 1-pentanol (20 mL). The solution was stirred at 120 C. for 12 hours. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to give Intermediate 224-I (3.6 g) in a 45% yield. Intermediate 224-I (2.4 g) was then dissolved in CH2Cl2 (80 mL) and 20% TFA/CH2Cl2 (20 mL) was added. The solution was stirred at room temperature overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Intermediate 224-II (1.5 g) in a 90% yield. Intermediate 222-III (3.3 g) prepared in Example 222 was added to a solution of Intermediate 224-II (1.9 g) in MeOH (40 mL). The mixture was stirred at 60 C. for 12 hours. NaBH4 (0.3 g) was then added at 0 C. After the mixture was stirred for 1 hour, an aqueous solution of NH4Cl (10%, 10 mL) was added. The mixture was extracted with EtOAc, dried over anhydrous MgSO4, and filtered. The solution thus obtained was then concentrated. The resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/1) to afford Intermediate 224-III (1.5 g) in a 40% yield. N1-Morpholine-N1-piperazine ethane (370 mg) was added to Intermediate 224-III (300 mg) in 1-pentanol (1 mL). The mixture was stirred at 120 C. for 12 hours. After the solution was concentrated, the residue was treated with water and extracted with CH2Cl2. The organic layer was separated and concentrated. The resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to afford Intermediate 224-IV (281 mg) in a 70% yield. A solution of 20% TFA/CH2Cl2 (3 mL) was added to a solution of Intermediate 224-IV (281 mg) in CH2Cl2 (2 mL). The reaction mixture was stirred for 8 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Compound 224 (200 mg) in a 85% yield. Compound 224 was then treated with 1 M HCl (4 mL) in CH2Cl2 (2 mL) for 0.5 hours. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 224. CI-MS (M++1): 544.4.
Reference： [1]Patent: US2006/281712,2006,A1 .Location in patent: Page/Page column 107-108
  • 38
  • 2-(propan-2-yl)-1H-benzimidazole-4-carboxylic acid [ No CAS ]
  • [ 144222-22-0 ]
  • [ 916075-97-3 ]
YieldReaction ConditionsOperation in experiment
91% With 1-methyl-1H-imidazole; N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate In tetrahydrofuran; water at 20℃; Green chemistry;
78% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16.25h; 1.c To a solution of 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (9.0 g, 44.1 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (9.4 g, 44.1 mmol), followed by N,N-diisopropylethylamine (16.9 mL, 97.0 mmol). The solution was stirred for 15 min at room temperature prior to the addition of hydroxybenzotriazole (5.9 g, 44.1 mmol), N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.4 g, 44.1 mmol), and additional N,N-dimethylformamide (50 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with dichloromethane (300 mL), and washed sequentially with 1M aqueous phosphoric acid, 1M aqueous sodium hydroxide and brine. The solution was then dried over sodium sulfate and concentrated in vacuo to afford a brown oil which solidified upon addition of hexanes. The solid was filtered to give the title intermediate as a beige solid (13.8 g, 36.0 mmol, 78%). (m/z): [M+H]+ calcd for C22H32N4O3 401.26; found 401.5; [M-Boc+H]+ 301.5. Retention time (anal. HPLC: 2-90% MeCN/H2O over 6 min)=3.7 min. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.20 (m, 2H), 1.37 (s, 9H), 1.37 (s, 6H), 1.72 (m, 1H), 1.75 (m, 2H), 2.73 (br s, 2H), 3.22 (septet, 1H), 3.36 (m, 2H), 3.95 (m, 2H), 7.26 (t, 1H), 7.63 (d, 1H), 7.79 (d, 1H), 10.11 (t, 1H).
Reference： [1]Bailey, J. Daniel; Helbling, Edward; Mankar, Amey; Stirling, Matthew; Hicks, Fred; Leahy, David K. [Green Chemistry, 2021, vol. 23, # 2, p. 788 - 795]
[2]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2006/270652, 2006, A1 Location in patent: Page/Page column 14-15
  • 39
  • [ 916076-08-9 ]
  • [ 144222-22-0 ]
  • [ 916076-09-0 ]
YieldReaction ConditionsOperation in experiment
73% With 1,4-diaza-bicyclo[2.2.2]octane; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 18h; 3.c To a solution of 2-tert-butyl-1H-benzoimidazole-4-carboxylic acid hydrochloride (1.11 g, 4.37 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added 1,1'-carbonyldiimidazole (0.77 g, 4.75 mmol). The solution was stirred at 50° C. for 2 h, then 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.94 g, 4.39 mmol) was added, followed by 1,4-diazabicyclo[2,2,2]octane (1.46 g, 13 mmol). The solution was stirred at 50° C. for 16 h, allowed to cool and diluted with water (20 mL) and ethyl acetate (60 mL). The aqueous layer was removed, the organic layer washed with water (20 mL), dried over sodium sulfate and concentrated in vacuo to afford the title intermediate (1.32 g, 3.18 mmol, 73%) which was used without further purification. (m/z): [M+H]+ calcd for C23H34N4O3 415.27; found 415.5.
Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2006/270652, 2006, A1 Location in patent: Page/Page column 15-16
  • 40
  • [ 4487-56-3 ]
  • [ 144222-22-0 ]
  • [ 910815-03-1 ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine; In ethanol; ISOPROPYLAMIDE; for 18h; Example 2 Synthesis of 5-nitro-N4-piperidin-4-ylmethyl-N2-(2-trifluoromethoxy-benzyl)-pyridine-2,4-diamine 2,4-Dichloro-5-nitro-pyridine (500 mg, 2.59 mmol) was dissolved in EtOH-DMA (15 mL, 1:1). To this solution was added diisopropylethyl amine (0.99 mL, 5.7 mmol) followed by 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (611 mg, 2.85 mmol). The reaction was stirred for 18 h, then concentrated in vacuo. The crude residue was rediluted in EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude residue was purified by SiO2 flash chromatography eluding with 2percent CH3OH-CH2Cl2 to afford 4-[(2-chloro-5-nitro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (780 mg, 81percent).
Reference： [1]Patent: US2006/217417,2006,A1 .Location in patent: Page/Page column 13
  • 41
  • [ 144222-22-0 ]
  • [ 132976-78-4 ]
  • [ 941692-17-7 ]
YieldReaction ConditionsOperation in experiment
80% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; 1 A solution of 1 ,1 -dimethylethyl 4-(aminomethyl)-1 -piperidinecarboxylate (1.65g, 7.7mmol; available commercially from e.g. Fluka) in dichloromethane (100ml) was added to a solution of 5-amino-6-chloro-3,4-dihydro-2H- chromene-8-carboxylic acid (may be prepared according to the procedure described in Chem. Pharm. Bull., 1998, 46(12): 1881 ) (1.75g, 0.77mmol) in dichloromethane (100ml). Successive additions of 1-ethyl-3(3- dimethylaminopropyl)carbodiimide hydrochloride (2.45g, 12.8mmol) and A- (N,N-dimethylamino)pyridine (151 mg, 1.23mmol) were then made to the stirred mixture and the whole reaction mixture was left to stir at ambient temperature for 24h. After this time the solvent was evaporated under reduced pressure and the residue dissolved in dichloromethane. This solution was washed with water and the aqueous layer re-extracted with dichloromethane (3 x). The combined organic extracts were washed with saturated sodium hydrogen carbonate solution and then dried (MgSO4) and evaporated under reduced pressure to a solid. This solid was purified by chromatography over silica gel eluting with a solvent gradient of ethyl acetate/hexane to afford the title compound (D1 ) as a solid (2.62g, 6.2mmol, 80%). δH (CD3OD, 400MHz) 1.10-1.20 (2H, m), 1.45 (9H, s), 1.73-1.80 (3H, m), 2.05-2.11 (2H, m), 2.55 (2H, t, J = 6.4Hz), 2.70-2.85 (2H, br, s), 3.27-3.30 (2H, m), 4.06-4.11 (2H, m), 4.27 (2H, t, J = 4.8Hz), 7.71 (1 H, s). Mass Spectrum: C2IH30CIN3O4 requires 423/425; found 424/426 (MH+)
79.9% Stage #1: 5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2h; Stage #2: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate In dichloromethane at 20℃; for 12h; Inert atmosphere; 7.i Step (i): Preparation of 5-Amino-6-chloro-N-[l-(t-butoxycarbonyl)-4-piperidinyl] methyl} chroman-8-carboxamide A solution of 5-amino-6-chloro-chroman-8-carboxylic acid (0.40 gram, 1.758 mmole, obtained in the preparation 1) and carbonyldiimidazole (CDI) (0.427 gram, 2.637 mmole) in DCM (15 mL) was stirred for 2 hours at RT and a solution of tert-butyl 4- aminomethyl piperidine- 1 -carboxylate (0.45 gram, 2.109 mmole) in DCM (10 mL) was added. The reaction -mass was stirred overnight (12 hours) at RT under nitrogen atmosphere and washed with chilled water (20 mL), brine solution (20 mL) and dried over Na2S04. The organic phase was concentrated under vacuum to obtain the crude residue, which was further purified by flash chromatography using EtOAc: n-hexane (80: 20) to afford the title compound. Weight: 0.595 gram (Yield: 79.9%). (0391) - NMR (δ ppm): 1.21 - 1.29 (4H, m), 1.34 (9H, s), 1.51 - 1.70 (3H, m), 1.86 - 1.95 (2H, m), 2.41 - 2.46 (2H, m), 3.09 - 3.12 (2H, m), 3.86 -3.92 (2H, m), 4.15 - 4.17 (2H, m), 5.55 (2H, bs), 7.53 (1H, s), 7.91 - 7.94 (1H, t); Mass (m/z): 424.2 (M+H)+, 426.3 (M+H)+.
Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/68739, 2007, A1 Location in patent: Page/Page column 19-20
[2]Current Patent Assignee: SUVEN LIFE SCIENCES LIMITED - WO2016/128990, 2016, A1 Location in patent: Page/Page column 37-38
  • 42
  • [ 144222-22-0 ]
  • [ 175422-53-4 ]
  • [ 941692-20-2 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: 4-amino-5-chloro-2-methylbenzofuran-7-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2h; Stage #2: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate In dichloromethane at 20℃; for 12h; Inert atmosphere; 15.i Step (i): Preparation of 4-Amino-5-chloro-2-methyI- V-[l-(t-butoxycarbonyl)-4- piperidinyl methyl]benzofu A solution of 4-amino-5-chloro-2-methyl benzofuran-7-carboxylic acid (0.300 gram, 1.330 mmole, obtained from preparation 3) and CDI (0.323 gram, 1.995 mmole) in DCM (6 mL) was stirred for 2 hours at RT and added a solution of tert-butyl 4- aminomethyl piperidine-l-carboxylate (0.341 gram, 1.596 mmole) in DCM (4 mL). The reaction mass was stirred overnight (12 hours) at RT under nitrogen atmosphere and washed with chilled water (20 mL) and brine solution (20 mL) and dried over Na2S04. The organic phase was concentrated on rotavacuum to obtain the crude residue, which was further purified by flash chromatography using EtOAc:n-hexane (50:50) to afford the title compound. (0486) Weight: 0.560 gram (Yield: 100%). (0487) - NMR (δ ppm): 1.19 - 1.29 (2H, m), 1.45 (9H, s), 1.75 - 1.78 (2H, m), 1.82 - 1.87 (1H, m), 2.50 (3H, s), 2.61 - 2.71 (2H, m), 2.43 - 2.48 (2H, m), 4.09 - 4.15 (2H, m), 4.52 (2H, bs), 6.37 (1H, s), 7.29 - 7.31 (1H, t), 7.95 (1H, s); (0488) Mass (m/z): 422.3 (M+H)+, 424.3 (M+H)+.
49% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h; 8 1 ,1 -Dimethylethyl 4-([(4-amino-5-chloro-2-methyl-1 -benzofuran-7- yl)carbonyl]amino}methyl)-1 -piperidinecarboxylate (D8)To a solution of 4-amino-5-chloro-2-methyl-1-benzofuran-7-carboxylic acid (may be prepared according to the procedure described in Chem. Pharm. Bull., 1998, 46, 42) (221 mg, 0.98mmol) in DCM (1OmL) was added 1 ,1- dimethylethyl 4-(aminomethyl)-1 -piperidinecarboxylate (315mg, 1.47mmol; available commercially from e.g. Fluka), EDC (376mg, 1.96mmol) and DMAP (24mg, 0.19mmol). The mixture was stirred under argon at room temperature. The reaction was shown to be complete by LCMS after stirring at room temperature for 3h. The reaction mixture was transferred to a separating funnel. 2OmL DCM and 2OmL sodium bicarbonate were added, and the DCM layer was separated using a phase separation cartridge. The DCM was removed in vacuo and the residue was purified on silica, eluting with 0-95% EtOAc/pentane. The product containing fractions identified were combined, and the solvent was removed in vacuo to yield the desired product as a yellow paste (D8) (202mg, 49%). δH (CDCI3, 400MHz) 1.17-1.32 (2H, m, masked by solvent peak), 1.45 (9H, s), 1.72-1.90 (3H, m), 2.50 (3H, s), 2.65-2.80 (2H, m), 3.43 (2H, br s), 4.06-4.20 (2H, m, masked by solvent peak), 4.54 (2H, br s), 6.37 (1 H, s), 7.30 (1 H, br s), 7.95 (1 H, s). Mass Spectrum: C2IH28CIN3O4 requires 421/423; found 422/424 (MH+).
Reference： [1]Current Patent Assignee: SUVEN LIFE SCIENCES LIMITED - WO2016/128990, 2016, A1 Location in patent: Page/Page column 48-49
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/68739, 2007, A1 Location in patent: Page/Page column 23-24
  • 43
  • [ 106-39-8 ]
  • [ 144222-22-0 ]
  • [ 947139-41-5 ]
YieldReaction ConditionsOperation in experiment
60% With sodium t-butanolate In toluene at 110℃; for 3h; 8 Example 8; ^[(^Chloro-phenylaminoJ-methyll-piperidine-i-carboxylic acid tert-butyl ester (8a); 4-Aminomethyl-piperidine-1-carboxylic acid te/t-butyl ester (10.0 g, 46.7 mmol), A- bromochlorobenzene (10.7 g, 56.0 mmol) and sodium te/t-butoxide (6.73 g, 70.0 mmol) were dissolved in toluene (150 ml_). Argon was bubbled through. 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (Xanthphos) (810 mg, 1.40 mmol) and ths(dibenzylidineacetonedipalladium (Pd2(dba)3) (427 mg, 0.47 mmol) were added and the mixture was stirred at 110°C for 3 hours. Aqueous sodium hydrogen carbonate was added and the mixture was filtrated. The organic layer was washed with brine, died over sodium sulphate in combination with activated charcoal. The mixture was filtered through a pad of kieselguhr and concentrated to give the crude product as an orange sticky oil. 4-[(4-Chloro-phenylamino)-methyl]-piperidine-1-carboxylic acid tert- butyl ester (9.1 g, 60%) was crystallized from ethyl acetate/heptane as a white solid.
Reference： [1]Current Patent Assignee: NEUROSEARCH A/S - WO2007/93603, 2007, A1 Location in patent: Page/Page column 17
  • 44
  • [ 474018-94-5 ]
  • [ 144222-22-0 ]
  • [ 945916-43-8 ]
YieldReaction ConditionsOperation in experiment
56% With triethylamine In ethanol at 75℃; 18.1 Example 18: 2-(2,3-dihydrb-l-benzofuran-5-ylmethyl)-iVVVr-diethyH-(piperidin-4- ylmethyl)-lH-benzimidazole-5-carboxamideStep 1. t&-t-butyl 4-[({4-[(diethylamino)carbonyl]~2-nitrophenyl}amino)methyl]piperidine-l- carboxylate[0199] To a mixture ofN,N-diethyl-4-fluoro-3-nitrobenzamide (0.050 g, 0.21 mmol, 1 equiv) and ethanol (3 mL) were added triethylamine (38 μL, 0.28 mmol, 1.3 equiv) and 1-Boc- 4(aminomethyl)piperidine (0.060 g, 0.25 mmol, 1.3 equiv). The mixture was stirred overnight at 75 °C. Complete consumption of starting material was observed by TLC. Ethanol was removedunder reduced pressure. The resulting residue was dissolved in ethyl acetate. The organic layer was washed once with a 5% aqueous KHSO4 solution, once with a saturated aqueous NaHCO3 solution and once with brine. The combined aqueous layer was extracted once with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. Ethyl acetate was removed under reduced pressure. The resulting residue was purified by chromatography on silica gel (hexanes/EtOAc, 50:50 to 20:80) to afford tert-butyl 4-[({4-[(diethylamino)carbonyl]- 2-nitrophenyl}amino)methyl]piperidine-l-carboxylate (0.051 g) in 56% yield. 1HNMR (400 MHz, CHLOROFORM-D) δppm 1.19 - 1.28 (m, 8 H) 1.47 (s, 9 H) 1.76 - 1.92 (m, 3 H) 2.64 - 2.82 (m, 2 H) 3.25 (t, J=6.05 Hz, 2 H) 3.34 - 3.55 (m, 4 H) 6.88 (d, J=8.98 Hz, 1 H) 7.57 (dd, J=8.59, 2.15 Hz, 1 H) 8.27 - 8.31 (m, 2 H); MS (ESI) m/z 335.1 (M-C5H9O2)4", 379.1 (M- C4Hs)+.
Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/91950, 2007, A1 Location in patent: Page/Page column 73
  • 45
  • [ 941692-27-9 ]
  • [ 144222-22-0 ]
  • [ 941692-28-0 ]
YieldReaction ConditionsOperation in experiment
81% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3.5h; 3 1 ,1 -Dimethylethyl 4-([(5-amino-6-bromo-3,4-dihydro-2/-/-chromen-8- yl)carbonyl]amino}methyl)-1 -piperidinecarboxylate (D3) 5-amino-6-bromo-3,4-dihydro-2H-chromene-8-carboxylic acid (may be prepared as described in Description 2) (1.Og, 3.7mmol) was dissolved in dichloromethane (80ml). 1 ,1 -dimethylethyl 4-(aminomethyl)-1- piperidinecarboxylate (0.78g, 3.7mmol; available commercially from Fluka) was dissolved in dichloromethane (40ml) and added to the reaction mixture. 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (1.17g, 6.1 mmol) then 4-(N,N-dimethylamino)pyridine (72mg, 0.59mmol) were added. The reaction mixture was left to stir at ambient temperature for 3.5 hours. Volatiles were removed in vacuo. The residue was partitioned between DCM and water. The aqueous layer was extracted with DCM x3. Combined organics were washed with NaHCO3 (saturated, aqueous), then brine, and dried over MgSO4. Volatiles were removed in vacuo to yield a yellow solid/oil The crude product was purified by chromatography using silica gel eluting with a solvent gradient of ethyl acetate/hexane (10Og column, 25%→75% EtOAc: hexane). Fractions containing the product were combined and volatiles removed in vacuo to yield a white solid (1.39g, 2.96mmol, 81 %). δH (MeOD, 400MHz) 1.10-1.20 (2H, m), 1.54 (9H, s), 1.70-1.90 (3H, m), 2.05-2.15 (2H, m), 2.60-2.70 (2H, m, masked by solvent peak), 2.70-2.90 (2H, m),3.30 (2H, t, J = 6Hz), 4.00-4.15 (2H, m), 4.30-4.40 (2H, m), 5.67 (2H, br s)7.88 (1 H, s), 8.11 , (1 H, t).Mass Spectrum: C2IH3OBrN3O4 requires 467/469; found 468/470 (MH+).
80% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3.5h; 16 A solution of 1 ,1 -dimethylethyl 4-(aminomethyl)-1 -piperidinecarboxylate (0.78g, 3.7mmol; available commercially from e.g. Fluka) in DCM (40ml) was added to a solution of 5-amino-6-bromo-3,4-dihydro-2H-chromene-8- carboxylic acid (may be prepared as described in Description 15) (1.0g, 3.7mmol) in DCM (80ml). Successive additions of EDC (1.17g, 6.1 mmol) and DMAP (72mg, 0.59mmol) were then made to the stirred mixture and this was left to stir at ambient temperature for 3.5h. After this time the solvent was evaporated under reduced pressure and the residue dissolved in DCM. This solution was washed with water and the aqueous layer re-extracted with DCM (3 x). The combined organic extracts were successively washed with saturated sodium hydrogen carbonate solution and brine then dried (MgSO4) and evaporated under reduced pressure to give an oily solid. This solid was purified by chromatography over silica gel eluting with a solvent gradient of EtOAc/hexane to afford the title compound (D16) as a solid (1.39g, 2.96mmol, 80%). δH (MeOD, 400MHz) 1.15 (2H, m), 1.54 (9H, s), 1.75 (2H, d, J = 13.2Hz), 1.80 (1 H, m), 2.12 (2H, m), 2.80 (2H, m), 3.30 (2H, t, J = 6Hz), 4.17 (2H, m), 4.35 (2H, t, J = 4.8Hz), 7.88 (1 H, s), 8.11 , (1 H, t). Mass Spectrum: C2IH30BrN3O4 requires 467/469; found 468/470 (MH+).
Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/96352, 2007, A1 Location in patent: Page/Page column 20-21
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/68739, 2007, A1 Location in patent: Page/Page column 27-28
  • 46
  • [ 417717-21-6 ]
  • tris (dimethylamino) phosphonium hexafluorophosphate [ No CAS ]
  • [ 144222-22-0 ]
  • [ 417719-60-9 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In <i>N</i>-methyl-acetamide; ethyl acetate 599 tert-Butyl 4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate Example 599 tert-Butyl 4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate 4-(3-Chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)7-methoxy-6-quinolinecarboxylic acid) (171 mg, 0.40 mmol) was dissolved in dimethylformamide (4 ml) under a nitrogen atmosphere, and then tert-butyl 4-aminomethyl-1-piperidinecarboxylate (171 mg, 0.80 mmol), triethylamine (0.2 ml) and 1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphonium hexafluorophosphate (265 mg, 0.60 mmol) were added in that order at room temperature, and the mixture was stirred overnight. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (249 mg, quantitative) as white crystals. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.05 (2H, m), 1.22 (1H, m), 1.37 (9H, s), 1.66 (2H, m), 2.56 (1H, m), 2.67 (2H, m), 3.20 (2H, m), 3.93 (2H, m), 3.99 (3H, s), 6.51 (1H, d, J=5.2 Hz), 7.17-7.24 (2H, m), 7.-46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.97 (1H, s), 8.26 (1H, dd, J=2.8, 8.8 Hz), 8.39 (1H, m), 8.46 (1H, s), 8.64 (1H, d, J=5.2 Hz)
Reference： [1]Current Patent Assignee: EISAI CO LTD; JPARIMOTO ITARU - US2004/53908, 2004, A1
  • 47
  • [ 1071017-49-6 ]
  • [ 144222-22-0 ]
  • [ 1071017-71-4 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In 1,4-dioxane; water; at 100℃; for 48h; 4-[(3-Pyhdin-4-yl-[2, 6]naphthyridin- 1 -ylamino) -methylj-piperidine- 1 -carboxylic acid tert-butyl ester.; To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (50.0 mg, 0.197 mmol) in 1 ,4- dioxane (5 ml_) is added 4-aminomethyl-piperidine-1 -carboxylic acid fert-butyl ester (128 mg, 0.590 mmol) and 40% aqueous NaOH (29.0 μl_, 0.290 mmol) at rt. The reaction mixture is heated to 1000C for 48 h, and then cooled to rt, diluted with EtOAc and filtered through a Florisil plug. The filtrate is evaporated to dryness to yield the title compound as a yellow oil, which is used without further purification for the next step.
Reference： [1]Patent: WO2008/122614,2008,A1 .Location in patent: Page/Page column 30
  • 48
  • [ 928337-00-2 ]
  • [ 144222-22-0 ]
  • [ 1025065-67-1 ]
YieldReaction ConditionsOperation in experiment
53.6% With sodium t-butanolate In toluene for 12h; Heating / reflux; 2.9.10 9. Scheme for the synthesis of Compounds 7-27 and 7-28 .Scheme 510. Synthesis of tert-butyl 4-((3-(3-(trifluoromethoxy) phenyl) imidazof 1,2- blpyridazin-6-ylamino)methyl)piperidine-1-carboxylate (Compound 7-27). [0146] To the toluene solvent was added 7-12 (100 mg, 0.319 mmol), 4-Aminomethyl-1-Boc-piperidine (68.3 mg, 0.319 mmol), ligand (18.8 mg, 0.048 mmol), Pd2(dba)3 (0.05 eq) and NaOfBu (1.5 eq). The resulting reaction mixture was degassed for 10 min under argon and then was heated to reflux overnight (12 h). The crude product was concentration and preparative EPO TLC was performed with 10% MeOH/DCM solvent system afforded 84 mg of 7- 27 (53.6 %).
Reference： [1]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - WO2008/58126, 2008, A2 Location in patent: Page/Page column 53-54
  • 49
  • [ 124-63-0 ]
  • [ 144222-22-0 ]
  • [ 1143517-68-3 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane at 20℃; for 3.25h; 13 Preparation 13: N-Piperidin-4-ylmethyl-methanesulfonamideTo a solution of /-butyl 4-(aminomethyl)tetrahydropyridine-l(2H)-carboxylate (1.50 g, 7.0 mmol, 1 eq) in DCM (anhydrous) (20 mL) is added methanesulfonyl chloride (569 μL, 7.35 mmol, 1.05 eq). To this add triethylamine (2.05 ml, 14.7 mmol, 2.1 eq), dropwise over 15 min. Stir at room temperature for 3 hr. and then add water (20 mL) with stirring. The organic phase is isolated then washed with 2 M aqueous hydrochloric acid (20 mL), and saturated aqueous sodium hydrogen carbonate solution (20 mL). Dry the organic layer (magnesium sulphate) and concentrate to give 4-(methanesulfonyl- aminomethyl)-piperidine-l-carboxylic acid /-butyl ester (2.1 g, 102%). MS (ES): m/z = 315.1 [M+Na]+.
With triethylamine In dichloromethane at 5 - 20℃; for 0.5h; Inert atmosphere; 4.2.3 General procedure for the synthesis of substituted tert-butyl 4-(methylamino) piperidine-1-carboxylate (7a-o) General procedure: In a dry two necked RBF, equipped with nitrogen source, was charged with solution of commercially available 1-N-BOC-4-(aminomethyl)piperidine (5) (1.39mmol) in dichloromethane (DCM) (2.0mL) and triethylamine (TEA) (2.09mmol). The resulting reaction mixture was cooled at 10°C. Commercially available different substituted aromatic and aliphatic acid chlorides and sulphonyl chlorides (6a-o) (1.39mmol) were dissolved in DCM (1.0mL) and added dropwise to the above solution over the period of 5min using a glass syringe while maintaining temperature 5-10°C. Then, the reaction was moved to room temperature after the complete addition of 6a-o and monitored on TLC. After completion of the reaction, the reaction mixture was concentrated under vacuum to yield semi-solid crude products. Crude products were suspended in a mixture of diethyl ether: hexane (70:30) and cooled at 10°C. After cooling, products were fall out as white to off-white precipitates and filtered using vacuum filtration. This treatment yields high purity of 7a-o, used in the next step as obtained.
Reference： [1]Current Patent Assignee: ELI LILLY &amp; CO - WO2009/48765, 2009, A1 Location in patent: Page/Page column 16
[2]Gediya, Piyush; Vyas, Vivek K.; Carafa, Vincenzo; Sitwala, Nikum; Della Torre, Laura; Poziello, Angelita; Kurohara, Takashi; Suzuki, Takayoshi; Sanna, Vinod; Raguraman, Varalakshmi; Suthindhiran; Ghosh, Debarpan; Bhatia, Dhiraj; Altucci, Lucia; Ghate, Manjunath D. [Bioorganic Chemistry, 2021, vol. 110]
  • 50
  • [ 1147099-01-1 ]
  • [ 144222-22-0 ]
  • [ 1147098-97-2 ]
YieldReaction ConditionsOperation in experiment
62% Stage #1: [4-(2-phenylsulfanyl-phenylsulfamoyl)-benzoylamino]-acetic acid; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; Stage #2: With hydrogenchloride In ethyl acetate at 20℃; for 24h; 39 To a stirred solution of [4-(2-phenylsulfanyl-phenylsulfamoyl)-benzoylamino]- acetic acid (Example 2/c) (37.6 mg, 0.085 mmol) in a mixture of dicloromethane (2 mL) and dimethylformamide (0.2 mL) and 4-aminomethyl-piperidine-l-carboxylic acid tert- butyl ester (21.4 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol) and triethylamine (30 μL, 0.2 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 precipitated product was filtered, washed with diethyl ether and dried in vacuum to yield 30 mg (62 %) of the title compound. MS (EI) 539.4 (MH+).
62% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; 39 Example 39 4-(2-Phenylsulfanyl-phenylsulfamoyl)-N-[(piperidin-4-ylmethyl)-carbamoyl]-methyl}-benzamide hydrochloride To a stirred solution of [4-(2-phenylsulfanyl-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 2/c) (37.6 mg, 0.085 mmol) in a mixture of dichloromethane (2 mL) and dimethylformamide (0.2 mL) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (21.4 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol) and triethylamine (30 μL, 0.2 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 precipitated product was filtered, washed with diethyl ether and dried in vacuum to yield 30 mg (62%) of the title compound. MS (EI) 539.4 (MH+).
Reference： [1]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2009/53763, 2009, A1 Location in patent: Page/Page column 36-37
[2]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - US2010/298299, 2010, A1 Location in patent: Page/Page column 14
  • 51
  • [ 519147-88-7 ]
  • [ 144222-22-0 ]
  • tert-butyl 4-([(5-amino-6-chloro-2-methylimidazo[1, 2-a]pyridin-8-yl)carbonyl]amino}methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid With 1,1'-carbonyldiimidazole In DMF (N,N-dimethyl-formamide) at 20 - 60℃; for 2.08333h; Stage #2: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate In DMF (N,N-dimethyl-formamide) at 20℃; for 4h; Stage #3: With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 23℃; for 2h; 1.6 Srep 6, tert-butyl 4-([(5-amino-6-chloro-2-methylimidazo[1, 2-a]pyridin-8-yl)carbonyl]amino}methyl)piperidine-1-carboxylate To a suspension of 5-AMINO-6-CHLORO-2-METHYLIMIDAZO [1, 2-a]pyridine-8- carboxylic acid (EXAMPLE 1, Step 5,12. 0 g, 53.2 mmol) in N,N-dimethylformamide (120 mL) was added 1, 1'-carbonyldiimidazole (17.3 g, 106.4 mmol) at room temperature. After stirring for 5 min, the temperature was raised to 60C and the stirring was continued for 2 h. A solution of N,N-dimethylformamide (50 mL) solution of tert-butyl 4-(ANIINOMETHYL) PIPERIDINE-1-CARBOXYLATE (J. Prugh, L. A. Birchenough and M. S. Egbertson, SYITTLZ. COININUN., 1992,22, 2357-60) (14.8 g, 69.1 mmol) was added at room temperature and the stirring was continued for 4 h. Diisopropylethylamine (12.0 ML, 69.1 mmol) was added to the mixture and stirred at room themperatur further 2h. The mixture was quenched with 0. 5 N aq. NAOH (250 mL) and diluted with ethyl acetate (300 mL). The resulting precipitate was collected by filtration and washed with water (200 mL). The filtrate was extracted with ethyl acetate-hexane (4: 1 mixture, 150 mL x 2) and washed with H2O. The precipitate and the organic extracts were combined and concentrated to give a brown solid. The residal solid was dissolved in hot ethyl acetate and filtered. The filtrate was concentrated and the residual solid was triturated with ethyl acetate to give a pale brown solid (16. 4 g, 73 %) of the title compound. MS (ESI) m/z: 422 (M+H) +, 420 (M-H) +. H-NMFT (DMSO-d6) O : 1.03-1. 20 (2 H, m), 1.38 (9H, s), 1.61-1. 75 (3H, brd, J=11. 5 Hz), 2.37 (3 H, d, J=0.6 Hz), 2.70 (2 H, br), 3.28-3. 35 (2 H, m), 3.85-4. 05 (2H, brd, J=11.5 Hz), 7.59 (2H, brs), 7.85 (1 H, s), 7.87 (1 H, d, J=0.6Hz), 9.93 (1 H, t, J=5.5 HZ)
Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/94418, 2004, A1 Location in patent: Page 29
  • 52
  • [ 862122-49-4 ]
  • [ 144222-22-0 ]
  • [ 862122-65-4 ]
YieldReaction ConditionsOperation in experiment
99% Stage #1: 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 18 - 25℃; for 2h; Stage #2: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With N-ethyl-N,N-diisopropylamine In dichloromethane at 18 - 25℃; for 18h; 6.1 Example 6 5-CHLORO-N-t I l-(CYCLOHEXYLMETHYL) PIPERIDIN-4-YLlMETHYLT-l-ISOPROP YL-6-METHYL-2-OXO-1 2-DIHYDROPYRIDINE-3-CARBOXAMIDE; 6(1) tert-Butyl --( [ (5-chloro-1-isopropyl-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) carbonvllamino} methyl) piper idine-1-carboxylate; To a solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-1, 2-dihydropyridine-3-carboxylic acid as prepared in Example 1 (7) (2.66 g, 11.6 mmol) in dichloromethane (30 mL) were added oxalyl chloride (4.41 g, 34.8 mmol) and a drop of N, N dimethylformamide at room temperature, and the mixture was stirred at room temperature for 2 h. The solvent and excess amounts of oxalyl chloride were removed in vacua. The residue was dissolved in dichloromethane (80 mL). To the resulting solution were added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (3.72 g, 17.4 mmol, prepared according to Carceller, Elena et al., J. Med. Chenu., 1996,39, 487), N, N-diisopropylethylamine (2.25 g, 17.4 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was quenched with saturated sodium hydrogencarbonate aqueous solution (100 mL), and extracted with dichloromethane (100 mL x 4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=l/l) to give 5.27 g (99%) of the title compound as a white solid. MS (ESI) m/z : 426 (M+H) +, 424 (M-H)-. H-NMR (CDCl3) 5 ppm : 9. 81 (1 H, br.), 8. 41 (1 H, s), 4.73 (1 H, br. ), 4.13-4. 06 (2 H, m), 3.33-3. 29 (2 H, m), 2.72-2. 64 (2 H, m), 2.59 (3 H, s), 1.75-1. 71 (3 H, m), 1.63 (6 H, d, J=6. 8 Hz), 1.44 (9 H, s), 1.25-1.11 (2 H, m).
Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/73222, 2005, A1 Location in patent: Page/Page column 40-41
  • 53
  • [ 10242-01-0 ]
  • [ 144222-22-0 ]
  • 4-[(5-methoxy-1H-indole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5330 - 5343
  • 54
  • [ 1193-21-1 ]
  • [ 144222-22-0 ]
  • [ 939986-79-5 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In acetonitrile at 120℃; for 0.5h; Microwave irradiation; 79-C 4,6-Dichloropyrimidine (284 mg, 1.9 mmol), λ/-Boc-4-aminomethyl piperidine (409 mg, 1.9 mmol) and potassium carbonate (317 mg, 2.3 mmol) were dissolved in acetonitrile (5 mL) and the solution was heated for 30 minutes at 1200C using microwave irradiation. The reaction mixture was partitioned between water and dichloromethane and the aqueous5 phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 4-((6-chloropyrimidin-4-ylamino)methyl)- piperidine-1-carboxylate (656 mg, 100%) as a yellow oil which was used without further purification. 0 1H NMR (DMSO-d6, 400MHz) δ 8.26 (s, 1H), 7.80 (br s, 1H), 6.51 (s, 1 H), 3.92 (m, 2H), 3.23 (m, 2H)1 2.68 (br s, 1 H), 2.51 (m, 1H), 1.64 (m, 3H), 1.06-0.97 (m, 2H). LCMS (1) Rt = 1.94 min; m/z (ESI+) 271 , 227 (MH+), (ESI") 325.
Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - WO2009/44162, 2009, A1 Location in patent: Page/Page column 170
  • 55
  • [ 65973-52-6 ]
  • [ 144222-22-0 ]
  • [ 1137475-88-7 ]
YieldReaction ConditionsOperation in experiment
84% With triethylamine; In butan-1-ol; at 120℃; for 1.5h;Microwave irradiation; A solution of <strong>[65973-52-6]methyl 4,6-dichloronicotinate</strong> (1.20 g, 5.8 mmol), terf-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.24 g, 5.8 mmol) and triethylamine (4.09 mL, 29.1 mmol) in n-butanol (13 mL) was heated at 1200C for 90 minutes by microwave irradiation. The solvent was evaporated and the mixture was purified by flash chromatography on silica, eluting with ethyl acetate - hexane (1:4), to give methyl 4-((1- (fert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate as a colourless solid (1.87 g, 84percent).1H NMR (500 MHz, CDCI3) 5 1.14-1.27 (3H, m), 1.46 (9H, s) 1.76-1.78 (3H, m), 2.72 (2H, t, J = 12.3 Hz), 3.10 (2H1 1, J = 5.6 Hz), 3.17 (3H, s), 4.16 (2H, s), 6.53 1H, s), 8.25 (1H, s), 8.66 (1 H, s). LCMS (3) Rt 5.26 min; m/z (ESI+) 386, 384 (MH+).
Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 5221 - 5237
[2]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 157
  • 56
  • [ 1137475-57-0 ]
  • [ 144222-22-0 ]
  • [ 1137475-56-9 ]
YieldReaction ConditionsOperation in experiment
98% With triethylamine; In acetonitrile; for 0.516667h; A solution of 4-(aminomethyl)-1-boc-pipeiotadine (370 mg, 1.73 mmol) in acetonitrile (1 ml_) was added over 1 minute to a solution of <strong>[1137475-57-0]2-bromo-4-chloro-5-nitropyridine</strong> (373 mg, 1.57 mmol) and triethylamine (0.24 mL, 1.73 mmol) in acetonitrile (5 mL). The solution was stirred for 30 minutes then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (x3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 4-((2-bromo-5-nitropyridin-4- ylamino)methyl)piperidine-1-carboxylate as a light brown foam (640 mg, 98%) which was used without further purification.1H NMR (MeOD, 400MHz) delta 8.82 (s, 1 H), 7.25 (s, 1 H), 4.14 (m, 3H), 3.35 (s, 1H), 1.97- 1.88 (m, 1H), 1.80 (m, 3H), 1.27-1.17 (m, 3H). LCMS (1) Rt = 2.35 min; m/z (ESI+) 415, 417 (MH+).
Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 146
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 8328 - 8342
  • 57
  • [ 3934-20-1 ]
  • [ 144222-22-0 ]
  • [ 544696-23-3 ]
YieldReaction ConditionsOperation in experiment
74% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; 20.1 Step 1: Synthesis of tert-butyl 4-[[(2-chloropyrimidin-4-yl)amino]methyl]piperidine-1-carboxylate: Into a 250-mL 3-necked round-bottom flask, was placed a solution of 2,4-dichloropyrimidine (5.0 g, 33.56 mmol, 1 equiv) in N,N-dimethylformamide (50 mL), tert- butyl 4-(aminomethyl)piperidine-1-carboxy late (7.18 g, 33.50 mmol, 1 equiv), potassium carbonate (9.26 g, 2.00 equiv). The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 50 mL of EA, washed with 3x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10-1 :2). The collected fractions were combined and concentrated under vacuum. This resulted in 8.1 g (74%) of the title compound as colorless oil. Analytical Data: (ES, m/z): RT = 1.449 min, LCMS 28: m/z = 327 [M+l]. H-NMR: (400 MHz, Methanol-c 4) δ 8.83 - 8.68 (m, 1H), 7.26 (d, J = 5.8 Hz, 1H), 5.01 - 4.56 (m, 2H), 4.06 - 3.80 (m, 2H), 3.49 (s, 2H), 2.58 - 2.37 (m, 3H), 2.20 (s, 9H), 1.95 - 1.69 (m, 2H).
With potassium carbonate In N,N-dimethyl-formamide
Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2017/181177, 2017, A1 Location in patent: Paragraph 0517-0519
[2]Location in patent: scheme or table Tester, Richland; Tan, Xuefei; Luedtke, Gregory R.; Nashashibi, Imad; Schinzel, Kurt; Liang, Weiling; Jung, Joon; Dugar, Sundeep; Liclican, Albert; Tabora, Jocelyn; Levy, Daniel E.; Do, Steven [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2560 - 2563]
  • 58
  • [ 1187591-17-8 ]
  • [ 144222-22-0 ]
  • [ 1236121-05-3 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3540 - 3544
  • 59
  • [ 7579-20-6 ]
  • [ 144222-22-0 ]
  • [ 1237526-05-4 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3545 - 3549
  • 60
  • [ 30683-23-9 ]
  • [ 144222-22-0 ]
  • [ 1237526-04-3 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3545 - 3549
  • 61
  • [ 108-37-2 ]
  • [ 144222-22-0 ]
  • 4-[(3-Chloro-phenylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 110℃; for 3h;Inert atmosphere; 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 14.0 mmol), 3-bromochlorobenzene (2.0 mL, 16.8 mmol) and sodium tert-butoxide (2.06 g, 21.0 mmol) were dissolved in toluene (150 mL) and argon was bubbled through. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xanthphos) (251 mg, 0.42 mmol) and tris(dibenzylidineacetone)dipalladium (Pd2(dba)3) (128 mg, 0.14 mmol) were added and the mixture was stirred at 110 C. for 3 hours. Aqueous sodium hydrogencarbonate was added and the mixture was filtrated. The organic layer was washed with brine, dried over sodium sulphate in combination with activated charcoal. The mixture was filtrated through a pad of celite and concentrated in vacuo to give the crude product as an orange sticky oil. 4-[(3-Chloro-phenylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.95 g, 65%) was crystallised from ethyl acetate/heptane to give a white solid.
Reference： [1]Patent: US2010/204275,2010,A1 .Location in patent: Page/Page column 5
  • 62
  • [ 85740-98-3 ]
  • [ 144222-22-0 ]
  • [ 1235473-74-1 ]
YieldReaction ConditionsOperation in experiment
A solution of the compound prepared in Example 10 (1.44 g) in dichloromethane (8.04 mL)-trifluoroacetic acid (1.46 mL) was stirred for 18 hours. The reaction was concentrated and the excess trifluoroacetic acid was removed via azeotropic distillation from toluene and diethyl ether. The resulting oil solidified upon treatment with (diethyl ether: hexane = 5: 1) and the solids were collected by filtration to obtain the title compound (1.36 g) having the following physical data.1H NMR (DMSOd6): delta 8.68 (t, J = 5.8 Hz, IH), 8.58-8.42 (m, IH), 8.22-8.08 (m, IH), 7.53- 7.44 (m, 3H), 3.91 (s, 3H), 3.28-3.16 (m, 4H), 2.87-2.75 (m, 2H), 1.83-1.75 (m, 3H), 1.32 (d, J = 11.9 Hz, 2H); Mass data (ESI, Pos.): m/z 283 (M + H)+.
Reference： [1]Patent: WO2010/80864,2010,A1 .Location in patent: Page/Page column 109-110
  • 63
  • [ 1188914-98-8 ]
  • [ 144222-22-0 ]
  • [ 1246203-61-1 ]
YieldReaction ConditionsOperation in experiment
91% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; 4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]methyl}-6-(4-morpholinyl)-1,3,5-triazin-2-amine (87) Reaction of 8 with tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate, as for the synthesis of 62a, gave tert-butyl 4-([4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}methyl)-1-piperidinecarboxylate (87a) in 91% yield: mp (CH2Cl2/MeOH) 203-205°C; 1H NMR (DMSO-d6) δ 8.10-7.60 (m, 3H), 7.41-7.36 (m, 1H), 6.94 (dd, J = 7.8, 3.8 Hz, 1H), 3.974 and 3.970 (2s, 3H), 3.95-3.92 (m, 2H), 3.78-3.77 (m, 4H), 3.69 (m, 4H), 3.34-3.24 (m, 2H), 2.69 (m, 2H), 1.77-1.67 (m, 3H), 1.389 and 1.381 (2s, 9H), 1.12-1.00 (m, 2H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5; Found: C 56.1; H, 6.3; N, 19.6%.
Reference： [1]Gamage, Swarna A.; Giddens, Anna C.; Tsang, Kit Y.; Flanagan, Jack U.; Kendall, Jackie D.; Lee, Woo-Jeong; Baguley, Bruce C.; Buchanan, Christina M.; Jamieson, Stephen M.F.; Shepherd, Peter R.; Denny, William A.; Rewcastle, Gordon W. [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5859 - 5874]
  • 64
  • [ 530-62-1 ]
  • [ 35034-22-1 ]
  • [ 144222-22-0 ]
  • [ 856418-16-1 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: 2-methylimidazole-4(5)-carbaldehyde; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 15h; Stage #2: With sodium hydroxide; water In 1,2-dichloro-ethane Stage #3: 1,1'-carbonyldiimidazole With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 15h; 85.a 85a) 85a) tert-butyl 4-((5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)methyl)-1-piperidinecarboxylate To a solution of tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate (K. Ito et al., Eur. J. Med. Chem., 34, 977 (1999); 3.7 g), 2-methylimidazole-4-carbaldehyde (1.9 g) and acetic acid (1 ml) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride (5.6 g), and mixed at room temperature for 15 hours. pH of the aqueous layer was adjusted to about 12 by adding a 1 N aqueous sodium hydroxide solution to the reaction solution, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dichloromethane (100 ml), DBU (2.6 ml) and N,N'-carbonyldiimidazole (2.8 g) were added thereto, and mixed at room temperature for 15 hours. The reaction mixture was diluted with water and chloroform and the organic layer was collected by separation, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate: ethanol = 5: 1) to obtain the title compound as a yellow oil (3.5 g, 59%). NMR (CDCl3) δ: 1.16-1.30 (2H, m), 1.45 (9H, s), 1.69 (2H, d, J=12.6), 1.83-1.91 (1H, m), 2.61 (3H, s), 2.70 (2H, t, J=11.9), 3.34 (2H, d, J=7.2), 4.08-4.15 (2H, m), 4.35 (2H, s), 6.69 (1H, s).
Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1695961, 2006, A1 Location in patent: Page/Page column 88-89
  • 65
  • [ 454-78-4 ]
  • [ 144222-22-0 ]
  • [ 1266244-60-3 ]
YieldReaction ConditionsOperation in experiment
65% With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 80℃; 6 g (23.12 mmoles) of 2-bromo-l-chloro-4- trifluoromethyl-benzene are placed in the presence of 8.65 mL (41.61 mmoles) of l-BOC-4-aminomethyl- piperidine, 3.05 g (31.67 mmoles) of sodium tertio- butylate, 1.06 g (2.24 mmoles) of X-Phos and 1.06 g (2.24 mmoles) of Pd2(dba)3 in 75 mL de toluene. The reaction medium is agitated overnight at 800C then filtered through celite and concentrated to dryness. The residue obtained is purified by silica gel flash chromatography (petroleum ether-AcOEt, gradient 100:0 to 80:20 over 45 min) . 5.96 g of yellow oil are obtained (yield 65%) . TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 80:20, Rf=O.68.
Reference： [1]Patent: WO2011/15629,2011,A1 .Location in patent: Page/Page column 39
  • 66
  • [ 454-78-4 ]
  • [ 144222-22-0 ]
  • (2-chloro-5-trifluoromethyl-phenyl)-piperidin-4-ylmethyl-amine hydrochloride [ No CAS ]
Reference： [1]Patent: WO2011/15629,2011,A1
  • 67
  • [ 16588-74-2 ]
  • [ 144222-22-0 ]
  • [ 1274835-24-3 ]
YieldReaction ConditionsOperation in experiment
88% In dichloromethane at 0℃; for 4h; 4 Example 4: Synthesis of l-(3,5-bis(trifluoromethyl)phenyl)-3-(piperidin-4- ylmethyl)urea (14)[00152] To a solution of tert-butyl 4-(aminomethyl)piperidine-l-carboxylate (11) (2.05 g, 9.57 mmol) in CH2C12 (1 10 mL) at 0 °C was added slowly l-isocyanato-3,5- bis(trifluoromethyl)benzene (12)(1.65 mL, 9.57 mmol). The reaction was stirred for 4 hours; at this time, the reaction was concentrated and purified by automated flash chromatography ( f = 0.6 in 1 : 1 PE:EtOAc) to provide the title compound as a white solid (3.93 g, 88%). NMR (300 mHz, CDC13) δ 1.12 (m, 2 H), 1.47 (s, 9 H), 1.72 (m, 4 H), 2.74 (t, 2 H, J = 12.8 Hz), 3.20 (m, 2 H), 4.13 (d, 2 H, J - 11.7 Hz), 5.74 (br s, 1 H), 7.45 (s, 1 H), 7.88 (s, 2 H). LRMS (ESI) calcd for C15Hi7F6N30 [M - Boc + 2] 370.3, found 370.0, calcd for C2oH25F6N303 [M + Na] 492.4, found 492.0].
Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/32291, 2011, A1 Location in patent: Page/Page column 45
  • 68
  • [ 6299-85-0 ]
  • [ 144222-22-0 ]
  • C17H25ClN4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 72h; Example 226 (Z)-methyl 2-(((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)amino)pyrimidine-4-carboxylate was prepared as follows.Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared as follows: A 40 mL round-bottomed vial was charged with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.76 mmol, 1.1 equiv.), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 equiv.), <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (1.58 mmol, 1 equiv.), and then shaken at 85 C. for 72 h. The reaction mixture was concentrated under reduced pressure and purified on SiO2 using a Biotage and a 10-50% EtOAc/hexanes gradient to provide the desired protected amine (233 mg, 552 mg theoretical, 42%). Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared using the general TFA de-protection procedure and used directly in the general displacement procedure to provide the title compound (4 mg, 73.4 mg theoretical, 5%). LC-MS m/z 456.1 (M+1).
Reference： [1]Patent: US2011/152235,2011,A1 .Location in patent: Page/Page column 115
  • 69
  • [ 1329119-35-8 ]
  • [ 144222-22-0 ]
  • [ 1329118-35-5 ]
YieldReaction ConditionsOperation in experiment
59% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; 141 Example 141: Preparation of 4-([7-chloro-2-(2-chloro-6-fluoro-phenyl)-lH- benzimidazoIe-5-carbonyl]-amino}-methyl)-piperidine-l-carboxylic acid tert-butyl ester; To a solution of 4-aminomethyl-piperidine-l-carboxylic acid tert-butyl ester (0.11 ml, 0.55 mmol) in DMF was added EDC(0.14 g, 0.59 mmol) and hydroxyl benzotriazole (0.06 g, 0.50 mmol), 7-chloro-2-(2-chloro-6-fiuorophenyl)-l H- benzimidazole-5-carboxylic acid (0.15 g, 0.46 mmol). This reaction mixture was stirred overnight at r.t, then the solvent was evaporated, and the residue stirred with sat- NaHC03(aq) solution was added, and the mixture was then extracted with ethyl acetate. The organic phase was separated, dried over Na2S04 and concentrated in vacuo. Purification of the residue by silica gel chromatography (Hex/EA=l/3) to give the title compound: 0.14 g (59 %)1H NMR (DMSO-d6, 300MHz) : 5(ppm) 8.63-7.45 (m, 5H) 4.40 (s, 2H) 3.80- 2.30 (m, 8H) 1.20 (s, 9H)
Reference： [1]Current Patent Assignee: CRYSTAL GENOMICS INC.; KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - WO2011/99832, 2011, A2 Location in patent: Page/Page column 131-132
  • 70
  • [ 625-92-3 ]
  • [ 144222-22-0 ]
  • [ 1289153-25-8 ]
YieldReaction ConditionsOperation in experiment
64% With sodium t-butanolate In toluene at 100℃; for 1h; Inert atmosphere; 2.A Tris(dibenzylideneacetone)dipalladium (0.193 g, 0.21 mmol), 2,2-bis-(diphenylphosphino)-1,1-naphthalene (0.26 g, 0.42 mmol), sodium tert-butylate (0.51 g, 5.27 mmol), 3,5-dibromopyridine (0.5 g, 2.11 mmol) and tert-butyl-4-(aminomethyl)piperidine-1-carboxylate (0.41 g, 1.9 mmol) were mixed into a dry Schlenk flask. The flask was evacuated under vacuum and then backfilled with argon. Then, through the septum 40 mL of toluene were added and the mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (50 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using the Biotage flash chromatography system (ethyl acetate/n-heptane (4/1)) to afford the coupling product as a yellowish solid (0.5 g, 64%).1H-NMR (400 MHz, CDCl3): =1.22-1.19 (m, 2H), 1.47 (s, 9H), 1.76-1.71 (m, 3H), 2.70 (dd, 2H), 3.01 (m, 2H), 4.14 (brs, 2H), 6.98 (dd, 1H), 7.91 (d, 1H), 7.97 (d, 1H).MS (ESI): m/z=369.91 (M-H)+, 371.89 (MH)+.
64% With sodium t-butanolate In toluene at 100℃; for 1h; Inert atmosphere; 2.A Preparative Example 2 Step A [Show Image] Tris(dibenzylideneacetone)dipalladium (0.193 g, 0.21 mmol), 2,2-bis-(diphenylphosphino)-1,1-naphthalene (0.26 g, 0.42 mmol), sodium tert-butylate (0.51 g, 5.27 mmol), 3,5-dibromopyridine (0.5 g, 2.11 mmol) and tert-butyl-4-(aminomethyl)piperidine-1-carboxylate (0.41 g, 1.9 mmol) were mixed into a dry Schlenk flask. The flask was evacuated under vacuum and then backfilled with argon. Then, through the septum 40 mL of toluene were added and the mixture was heated at 100 °C for 1 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (50 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using the Biotage flash chromatography system (ethyl acetate/n-heptane (4/1)) to afford the coupling product as a yellowish solid (0.5 g, 64 %). 1H-NMR (400 MHz, CDCl3): δ = 1.22-1.19 (m, 2H), 1.47 (s, 9H), 1.76-1.71 (m, 3H), 2.70 (dd, 2H), 3.01 (m, 2H), 4.14 (brs, 2H), 6.98 (dd, 1H), 7.91 (d, 1H), 7.97 (d, 1H) MS (ESI): m/z = 369.91 (M-H)+, 371.89 (MH)+.
Reference： [1]Current Patent Assignee: AC IMMUNE SA - US2011/256064, 2011, A1 Location in patent: Page/Page column 20
[2]Current Patent Assignee: AC IMMUNE SA - EP2377860, 2011, A1 Location in patent: Page/Page column 27
  • 71
  • [ 98-60-2 ]
  • [ 144222-22-0 ]
  • [ 1352012-63-5 ]
YieldReaction ConditionsOperation in experiment
72% With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h;
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; 7.1 Example 7 (compound No. 120)2,2,2-Trifluoro-1 -(trifluoromethyl)ethyl 4-[(4-chlorobenzenesulphonylamino)methyl]- 7.1 . ie f-Butyl 4-[(4-chlorobenzenesulphonylamino)methyl]piperidine-1 -carboxylate; A solution of 0.844 g (4 mmol) of 4-chlorobenzenesulphonyl chloride in 5 ml of dichloromethane is added dropwise to a solution of 0.857 g (4 mmol) of ie f-butyl 4-(aminomethyl)piperidine-1 -carboxylate, 0.99 ml (6 mmol) of diisopropylethylamine and 0.024 g (0.2 mmol) of 4-dimethylaminopyridine in 9 ml of dichloromethane. The mixture is stirred at ambient temperature overnight. The organic phase is washed with 10 ml of water and then 4 ml of a 1 N aqueous hydrochloric acid solution, 2 times 14 ml of water, 2 times 14 ml of a 1 N aqueous sodium hydroxide solution, 3 times 14 ml of water and 14 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness in order to obtain 1 .371 g (3.52 mmol) of product in the form of an orange paste used as is in the following stage.
With triethylamine In dichloromethane at 5 - 20℃; for 0.5h; Inert atmosphere; 4.2.3 General procedure for the synthesis of substituted tert-butyl 4-(methylamino) piperidine-1-carboxylate (7a-o) General procedure: In a dry two necked RBF, equipped with nitrogen source, was charged with solution of commercially available 1-N-BOC-4-(aminomethyl)piperidine (5) (1.39mmol) in dichloromethane (DCM) (2.0mL) and triethylamine (TEA) (2.09mmol). The resulting reaction mixture was cooled at 10°C. Commercially available different substituted aromatic and aliphatic acid chlorides and sulphonyl chlorides (6a-o) (1.39mmol) were dissolved in DCM (1.0mL) and added dropwise to the above solution over the period of 5min using a glass syringe while maintaining temperature 5-10°C. Then, the reaction was moved to room temperature after the complete addition of 6a-o and monitored on TLC. After completion of the reaction, the reaction mixture was concentrated under vacuum to yield semi-solid crude products. Crude products were suspended in a mixture of diethyl ether: hexane (70:30) and cooled at 10°C. After cooling, products were fall out as white to off-white precipitates and filtered using vacuum filtration. This treatment yields high purity of 7a-o, used in the next step as obtained.
Reference： [1]Wang, Changning; Placzek, Michael S.; Van De Bittner, Genevieve C.; Schroeder, Frederick A.; Hooker, Jacob M. [ACS Chemical Neuroscience, 2016, vol. 7, # 4, p. 484 - 489]
[2]Current Patent Assignee: SANOFI - WO2011/151808, 2011, A1 Location in patent: Page/Page column 30
[3]Gediya, Piyush; Vyas, Vivek K.; Carafa, Vincenzo; Sitwala, Nikum; Della Torre, Laura; Poziello, Angelita; Kurohara, Takashi; Suzuki, Takayoshi; Sanna, Vinod; Raguraman, Varalakshmi; Suthindhiran; Ghosh, Debarpan; Bhatia, Dhiraj; Altucci, Lucia; Ghate, Manjunath D. [Bioorganic Chemistry, 2021, vol. 110]
  • 72
  • [ 1137475-57-0 ]
  • [ 144222-22-0 ]
  • [ 1351533-49-7 ]
Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8328 - 8342
  • 73
  • [ 1386398-83-9 ]
  • [ 144222-22-0 ]
  • [ 1386398-91-9 ]
YieldReaction ConditionsOperation in experiment
85.3% With triethylamine In isopropyl alcohol for 15h; Reflux; 14 Example 14; 4-{ [3-(2-Methylsulfanyl-pyrimidin-4-yl)- lH-pyrazolo[3,4-d]pyrimidin-6-ylamino]- methyl}-piperidine- l-carboxylic acid tert-butyl ester; To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)- lH-pyrazolo[3,4- d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(aminomethyl)piperidine- l-carboxylate (420 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted withdichloromethane (3 x 30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{ [3-(2-methylsulfanyl-pyrimidin-4-yl)- lH-pyrazolo[3,4- d]pyrimidin-6-ylamino] -methyl }-piperidine-l-carboxylic acid tert-butyl ester. (Yield 700 mg, 85.3 %).LC-MS: [M+H]+ 457.
85.3% With triethylamine In isopropyl alcohol for 15h; Reflux; 14 Example 14 4-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (420 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3*30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 700 mg, 85.3%). LC-MS: [M+H]+ 457.
Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2012/98068, 2012, A1 Location in patent: Page/Page column 40
[2]Current Patent Assignee: ROCHE HOLDING AG - US2012/184508, 2012, A1 Location in patent: Page/Page column 18
  • 74
  • [ 42926-52-3 ]
  • [ 1341104-70-8 ]
  • [ 144222-22-0 ]
  • [ 1414263-88-9 ]
Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 56,p. 348 - 360,13
  • 75
  • [ 85262-50-6 ]
  • [ 1711-07-5 ]
  • [ 144222-22-0 ]
  • [ 1414264-00-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With polystyrene carboxaldehyde resin; sodium cyanoborohydride; acetic acid In N,N-dimethyl-formamide at 60℃; for 24h; Stage #2: 3-fluorobenzoyl chloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; Stage #3: 1-bromo-2-(2,5-dichlorophenoxy)ethane Further stages;
Reference： [1]Zajdel, Pawel; Grychowska, Katarzyna; Pawlowski, MacIej; Kurczab, Rafal; Satala, Grzegorz; Bojarski, Andrzej J. [European Journal of Medicinal Chemistry, 2012, vol. 56, p. 348 - 360,13] Zajdel, Paweł; Kurczab, Rafał; Grychowska, Katarzyna; Satała, Grzegorz; Pawłowski, MacIej; Bojarski, Andrzej J. [European Journal of Medicinal Chemistry, 2012, vol. 56, p. 348 - 360]
  • 76
  • [ 144222-22-0 ]
  • [ 310400-38-5 ]
  • [ 1415824-86-0 ]
YieldReaction ConditionsOperation in experiment
91.2% With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 90℃; for 17h;
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 150℃; for 2h; microwave irradiation; 2; B Into a 10-mL vial was placed 5,6-dichloropyrimidin-4-amine (250.00 mg; 1 .52 mmol), tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (653.40 mg; 3.05 mmol), and N,N- diisopropylethylamine (1 .01 ml; 6.10 mmol) suspended in NMP (2.50 ml). The reaction mixture was run in the microwave at 150 °C for 2 hours. The reaction mixture was allowed to cool to rt. The mixture was purified using Biotage column chromatography eluting from 50-100 % EtOAc/Hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford tert-butyl 4-[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1 -carboxylate as a yellow viscous oil.
Reference： [1]Askew, Ben C.; Bender, Andrew T.; Brugger, Nadia; Caldwell, Richard D.; Camps, Montserrat; Dhanabal, Mohanraj; Dutt, Vikram; Eichhorn, Thomas; Follis, Ariele Viacava; Gardberg, Anna S.; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Healey, Brian; Hodous, Brian L.; Huck, Bayard R.; Johnson, Theresa L.; Jones, Christopher; Jones, Reinaldo C.; Liu-Bujalski, Lesley; Meyring, Michael; Mochalkin, Igor; Morandi, Federica; Nguyen, Ngan; Potnick, Justin R.; Qiu, Hui; Santos, Dusica Cvetinovic; Schmidt, Ralf; Sherer, Brian; Shutes, Adam; Urbahns, Klaus; Wegener, Ansgar A.; Zimmerli, Simone C. [Journal of Medicinal Chemistry, 2019]
[2]Current Patent Assignee: MERCK KGAA - WO2012/170976, 2012, A2 Location in patent: Page/Page column 33-35
  • 77
  • [ 16114-05-9 ]
  • [ 144222-22-0 ]
  • [ 1225218-70-1 ]
YieldReaction ConditionsOperation in experiment
0.46 g With toluene-4-sulfonic acid In toluene for 10h; Reflux; A.12.a Example A.12 a) Preparation of intermediate (27) Example A.12 a) Preparation of intermediate (27)A mixture of 4-aminomethyl-l-N-(tert-butoxycarbonyl)piperidine (3.5 mmol), intermediate (26) (4.2 mmol) and p-toluenesulphonic acid (catalytic quantity) in toluene (50 ml) was stirred and refluxed for 10 hours. After evaporation, the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH 10/1). The product fraction were collected and the solvent was evaporated, yielding 0.46 g of intermediate (27).
Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2013/21052, 2013, A1 Location in patent: Page/Page column 27
  • 78
  • [ 97997-76-7 ]
  • [ 144222-22-0 ]
  • [ 1332527-88-4 ]
YieldReaction ConditionsOperation in experiment
29% In dichloromethane for 2h; Cooling with ice; 1 2,4,5,6-tetramethylbenzenedisulfonyldichloride (1.2 g, 3.6 mmol) was dissolved in dichloromethane (18 ml), and the mixture was stirred under ice-cooling. Then, a solution (18 ml) of 1-Boc-4-(aminomethyl)piperidine (620 μl, 2.90 mmol) in dichloromethane was added, and the mixture was stirred under ice-cooling for 2 hr. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (2:1)) to give compound Y321 (yield; 533 mg, 29%). Compound Y321 (88 mg, 0.17 mmol) was dissolved in dichloromethane (3 ml), tert-butylaniline (40 μl, 0.26 mmol) and triethylamine (72 μl, 0.52 mmol) were added, and the mixture was stirred at room temperature for 4 hr. Then, the solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (40:1)) to give the title compound (yield; 86 mg, 80%). 1H NMR (500 MHz, CDCl3) δ7.21 (dd, 2H, J=8.5, 3.0 Hz), 7.1 (bs, 1H), 6.85 (dd, 2H, J=8.5, 3.0 Hz), 4.70 (dd, 1H J=7.0, 6.0 Hz), 4.06 (bs, 2H), 2.86 (s, 3H), 2.64-2.60 (m, 9H), 2.25 (s, 3H), 1.60-1.50 (m, 3H), 1.43 (s, 9H), 1.23 (s, 9H), 1.04-0.96 (m, 2H) 13C NMR (125 MHz, CDCl3) δ154.9, 148.8, 141.9, 141.5, 139.6, 139.2, 138.3, 136.6, 133.4, 126.4, 121.6, 79.7, 77.5, 48.4, 36.7, 34.5, 31.4, 29.7, 28.6, 21.0, 20.4, 20.1, 17.4 HRMS (FAB-) m/z: [M-H]- calcd for C31H46N3O6S2, 620.2828. found, 620.2977
Reference： [1]Current Patent Assignee: KYOTO UNIVERSITY - US2013/45977, 2013, A1 Location in patent: Paragraph 0207; 0208; 0209; 0210
  • 79
  • [ 97997-76-7 ]
  • [ 144222-22-0 ]
  • [ 1332527-52-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloromethane / 2 h / Cooling with ice 2: triethylamine / dichloromethane / 4 h / 20 °C
Reference： [1]Current Patent Assignee: KYOTO UNIVERSITY - US2013/45977, 2013, A1
  • 80
  • [ 1349744-81-5 ]
  • [ 144222-22-0 ]
  • [ 1437715-67-7 ]
YieldReaction ConditionsOperation in experiment
81% With quinoline In isopropyl alcohol at 90℃; for 18h; 1D Tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate (0.802 g, 3.74 mmol), 1-chloro-4- methoxy-5-nitro-2-vinylbenzene (0.4 g, 1.87 mmol), quinol (0.082 g, 0.749 mmol) in I PA (16 mL) was heated at 90°C for 18 hours. The reaction mass was allowed to cool to room temperature, diluted with water (80 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with brine (50 ml), dried(Na2S04) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 1.0% MeOH/DCM as the eluent to afford tert-butyl 4-((2-chloro-5-methoxy-4-nitrophenethylamino) methyl) piperidine-1-carboxylate (0.65 g, 81 %).
81% With hydroquinone In isopropyl alcohol at 90℃; for 18h; 1.D 1D.
tert-Butyl 4-((2-chloro-5-methoxy-4-nitrophenethylamino)methyl)piperidine-1-carboxylate
Tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.802 g, 3.74 mmol), 1-chloro-4-methoxy-5-nitro-2-vinylbenzene (0.4 g, 1.87 mmol), quinol (0.082 g, 0.749 mmol) in IPA (16 mL) was heated at 90° C. for 18 hours. The reaction mass was allowed to cool to room temperature, diluted with water (80 mL) and extracted with ethyl acetate (3*40 mL). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 1.0% MeOH/DCM as the eluent to afford tert-butyl 4-((2-chloro-5-methoxy-4-nitrophenethylamino)methyl) piperidine-1-carboxylate (0.65 g, 81%).
Reference： [1]Current Patent Assignee: SENTINEL ONCOLOGY - WO2013/72502, 2013, A1 Location in patent: Page/Page column 78; 79
[2]Current Patent Assignee: SENTINEL ONCOLOGY - US2014/323484, 2014, A1 Location in patent: Paragraph 0586
  • 81
  • [ 90417-53-1 ]
  • [ 144222-22-0 ]
  • [ 1452520-72-7 ]
YieldReaction ConditionsOperation in experiment
96% 1 -Hydroxybenzotriazole (HOBt, 24.3 g, 142 mmoles) and Nu,Nu'- dicyclohexylcarbodiimide (DCC, 29.3 g, 142 mmoles) were added to a solution of 5-methoxy-1 H-indazole-3-carboxylic acid (30 g, 129 mmoles) in DMF (400 ml_) at 0C. After 1 hour, a solution of ethyl [4- (aminomethyl)piperidin-1 -yl]acetate (26 g, 129 mmoles) in DMF (250 ml_) was added at the same temperature. The mixture was stirred at 0 C for 2 hours then was left to reach room temperature during the night. The mixture was diluted with EtOAc and the solid was removed by filtration. The solution was extracted three times with hydrochloridric acid (HCI) 2N. The pH of the acid phase was increased (about 13) with 5N NaOH and the solution was extracted three times with dichloromethane (DCM). The organic phase was dried over anhydrous Na2S04 and the solvent was filtered and evaporated under reduced pressure providing Tert-butyl 4-([(5-methoxy-1 H-indazol-3- yl)carbonyl]amino}methyl)piperidine-1 -carboxylate 7a (96% yield). MS: 389 m/z (M+H)+.
96% 7a) Tert-butyl 4-([(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate 1-Hydroxybenzotriazole (HOBt, 24.3 g, 142 mmoles) and N,N'-dicyclohexylcarbodiimide (DCC, 29.3 g, 142 mmoles) were added to a solution of <strong>[90417-53-1]5-methoxy-1H-indazole-3-carboxylic acid</strong> (30 g, 129 mmoles) in DMF (400 mL) at 0 C. After 1 hour, a solution of ethyl[4-(aminomethyl)piperidin-1-yl]acetate (26 g, 129 mmoles) in DMF (250 mL) was added at the same temperature. The mixture was stirred at 0 C. for 2 hours then was left to reach room temperature during the night. The mixture was diluted with EtOAc and the solid was removed by filtration. The solution was extracted three times with hydrochloridric acid (HCl) 2N. The pH of the acid phase was increased (about 13) with 5N NaOH and the solution was extracted three times with dichloromethane (DCM). The organic phase was dried over anhydrous Na2SO4 and the solvent was filtered and evaporated under reduced pressure providing Tert-butyl 4-([(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate 7a (96% yield). MS: 389 m/z (M+H)+.
Reference： [1]Patent: WO2013/124169,2013,A1 .Location in patent: Page/Page column 31
[2]Patent: US2014/378455,2014,A1 .Location in patent: Paragraph 0179; 0180
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 8920 - 8937
  • 82
  • [ 20826-04-4 ]
  • [ 144222-22-0 ]
  • tert-butyl 4-((5-bromonicotinamido)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 80℃; for 2h; Microwave irradiation; 1 Preparation of tert-bulyl 4-((5-bromonicotinamido)methyl)piperidine-] -carboxylate (104) Preparation of tert-bulyl 4-((5-bromonicotinamido)methyl)piperidine-] -carboxylate (104)5-Bromo-3-pyridinecarboxylic acid (98) (2.25g, lOmmol), 4-aminomethyl- 1 -Bocpiperidine (103) (2.13g, lOmmol), HATU (4.5g, lOmmol) and DIPEA (5m1, 3Ommol) were dissolved in DMF (lOml). The reaction mixture was heated at 80 °C for two hours in the microwave reactor. The reaction mixture was diluted with ethyl acetate (50m1) and washed withwater (50 ml) and brine (50 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated. The crude material was purified by automated column chromatography using petroleum ether and ethyl acetate as eluents to give tert-butyl 4-((5- bromonicotinamido)methyl)piperidine- 1 -carboxylate (104) (3. 98g) as an off white solid. Yield:100%. Synthesis confimed by LCMS and MS (positive ion mode).
Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2013/131018, 2013, A1 Location in patent: Page/Page column 66
  • 83
  • [ 1358040-29-5 ]
  • [ 144222-22-0 ]
  • tert-butyl 4-((9-pentyl-9H-carbazole-3-carboxamido)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; Inert atmosphere; Cooling with ice; 4.1.12 tert-Butyl 4-((9-pentyl-9H-carbazole-3-carboxamido)methyl)piperidine-1-carboxylate (12) Carboxylic acid 3 (700mg, 2.49mmol), HOBt (404mg, 2.99mmol), DIPEA (847μL, 4.98mmol), DMAP (365mg, 2.99mmol), and EDC (573mg, 2.99mmol) were added upon stirring to DCM (50mL) under nitrogen. The obtained solution was cooled down on an ice-water bath. tert-Butyl 4-(aminomethyl)piperidine-1-carboxylate (749mg, 2.99mmol) was added in one portion, and the resulting reaction mixture was then allowed to warm to room temperature and stirred for 16h. The solvent was removed in vacuo, and the obtained residue was extracted with EtOAc (100mL). The organic layer was washed consecutively with 5% citric acid solution (50mL×3), concentrated sodium bicarbonate (50mL×3), and brine (50mL). The organic layer was then separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with heptane/EtOAc (gradient elution) to give 1.096g (92%) of 14 as a yellow glass. 1H NMR (400MHz, CDCl3) δ 8.56 (d, J=1.1Hz, 1H), 8.08 (d, J=7.7Hz, 1H), 7.90 (dd, J=8.6, 1.4Hz, 1H), 7.47 (ddd, J=8.3, 7.1, 1.2Hz, 1H), 7.40 (d, J=8.2Hz, 1H), 7.36 (d, J=8.6Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 6.64 (br. s, 1H), 4.26 (t, J=7.2Hz, 2H), 4.07 (br. m, 2H), 3.39 (br. s, 2H), 2.68 (t, J=12.1Hz, 2H), 1.91-1.79 (m, 3H), 1.75 (br. d, J=13.2Hz, 2H), 1.45 (s, 9H), 1.37-1.29 (m, J=8.9, 5.2Hz, 4H), 1.20 (qd, J=12.5, 4.3Hz, 2H), 0.86 (t, J=6.8Hz, 3H). 13C and DEPT NMR (101MHz, CDCl3) δ 168.49 (C=O), 154.76 (C), 142.05 (C), 140.86 (C), 126.12 (CH), 125.05 (C), 124.86 (CH), 122.76 (C), 122.43 (C), 120.43 (CH), 119.80 (CH), 119.38 (CH), 108.96 (CH), 108.19 (CH), 79.24 (C), 45.45 (CH2), 43.00 (CH2), 36.48 (CH), 29.91 (CH2), 29.20 (CH2), 28.50 (CH2), 28.41 (CH3), 22.33 (CH2), 13.87 (CH3). ESI: m/z 478.2 (M+H)+. HRMS calcd for C29H40N3O3 (M+H)+ 478.3070, found 478.3007.
Reference： [1]Petrov, Ravil R.; Knight, Lindsay; Chen, Shao-Rui; Wager-Miller, Jim; McDaniel, Steven W.; Diaz, Fanny; Barth, Francis; Pan, Hui-Lin; Mackie, Ken; Cavasotto, Claudio N.; Diaz, Philippe [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 881 - 907]
  • 84
  • [ 36082-50-5 ]
  • [ 144222-22-0 ]
  • [ 1289114-86-8 ]
YieldReaction ConditionsOperation in experiment
92% With trimethylamine In acetonitrile at 20℃; for 2h;
75% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 50℃; for 2h; Inert atmosphere; 37 Intermediate 37: 4-[(5-Bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1- carboxylic acid tert-butyl ester 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3.39 g; 15.80 mmol; 1.20 eq.) and 5-Bromo-2,4-dichloro-pyrimidine (3.00 g; 13.17 mmol; 1.00 eq.) were dissolved in THF (30 mL) and DIPEA (6.9 mL). The mixture was stuffed under N2 at 50°C for 2h. The reaction mixture was then diluted with water (150 mL) and EtOAc (75 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x 50 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to afford a colorless oil. Purification by flash chromatography on silica (EtOAc:Hexane, gradient from 10 to 30%) afforded the title compound as a white solid (4.Og, 75%). ‘H NMR (400 MHz, DMSOd6) ö 8.24 (s, 1H), 7.75 (t, 1H), 3.92 (d, 2H), 3.27 (t, 2H), 2.79 - 2.59 (bs, 2H), 1.81 (m, 1H), 1.60 (dd, 2H), 1.40 (s, 9H), 1.02 (qd, 2H). LC/ MS: 349 ((M-tBu) + H).
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 80℃; for 0.333333h; Microwave irradiation;
Reference： [1]Jin, Tingting; Wang, Peipei; Long, Xiubing; Jiang, Kailong; Song, Pinrao; Wu, Wenbiao; Xu, Gaoya; Zhou, Yubo; Li, Jia; Liu, Tao [ChemMedChem, 2021, vol. 16, # 9, p. 1477 - 1487]
[2]Current Patent Assignee: MERCK KGAA - WO2016/81679, 2016, A1 Location in patent: Paragraph 00232
[3]Zhang, Weihe; Zhang, Dehui; Stashko, Michael A.; DeRyckere, Deborah; Hunter, Debra; Kireev, Dmitri; Miley, Michael J.; Cummings, Christopher; Lee, Minjung; Norris-Drouin, Jacqueline; Stewart, Wendy M.; Sather, Susan; Zhou, Yingqiu; Kirkpatrick, Gregory; Machius, Mischa; Janzen, William P.; Earp, H. Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, Xiaodong [Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9683 - 9692]
  • 85
  • [ 2363-16-8 ]
  • [ 144222-22-0 ]
  • [ 1552311-93-9 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 954 - 962
  • 86
  • [ 61953-04-6 ]
  • [ 144222-22-0 ]
  • [ 1552310-65-2 ]
YieldReaction ConditionsOperation in experiment
62% With triethylamine In dichloromethane at 20℃; 11.11a Step 11a. Step 11a. tert-Butyl 4-((3-chloro-4-(methoxycarbonyl)phenylsulfonamido)methyl)piperidine-1- carboxylate (compound 9001) To a mixture of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (570 mg, 2.6 mmol) and 3003 (600 mg, 2.2 mmol) in dichloromethane (10 mL) was added triethylamine (0.6 mL, 4.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl. The ethyl acetate layer was concentrated in vacuo and purified by column chromatography (hexanes:ethyl acetate=5:1) to give compound 9001 as a white solid (610 mg, 62% yield). LCMS: m/z 445.1 [M-1]-. 1H NMR (400 MHz, DMSO-d6): δ 0.87-0.98 (m, 2H), 1.37 (s, 9H), 1.49-1.60 (m, 3H), 2.62-2.70 (m, 4H), 3.86 (br, 2H), 3.90 (s, 3H), 7.84 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.94 (t, J=5.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H).
Reference： [1]Current Patent Assignee: CURIS INC; ROCHE HOLDING AG - US2014/18368, 2014, A1 Location in patent: Paragraph 0162; 0229
  • 87
  • 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine [ No CAS ]
  • [ 144222-22-0 ]
  • tert-butyl 4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 90℃; for 2h; Preparation of tert-butyl4-(((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate(S10) To a solution ofcompound S9 (500 mg, 1.98 mmol1.0 equiv) in isopropanol (10 mL) was added 1-Boc-4-(aminomethyl)piperidine (1.1 equiv) and DIPEA (2 equiv). The mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by flashchromatography (SiO2, 60-90 oC PE : EtOAc = 3:1) to give compound S10 (white solid, 700 mg, 82%). 1H NMR (400 MHz, CDCl3)δ 8.46 (s, 1H), 7.13 (s, 1H), 5.69 (t, J = 5.8 Hz, 1H), 4.20-3.99 (m,2H), 3.69-3.42 (m, 4H), 2.78-2.58 (m, 2H), 1.93-1.82 (m, 1H), 1.81-1.71 (m,2H), 1.44 (s, 9H), 1.29-1.11 (m, 2H). MS (ESI) : m/z431.1 (M+H)+.
80% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 2h; 7 Representative Procedure for the Synthesis of Compounds from Subscaffold 5 tert-Butyl 4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate. To a solution of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (50 mg, 0.20 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (52 μL, 0.30 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (51 mg, 0.30 mmol). The solution was heated to 80° C. for 2 hours. The solution was diluted with EtOAc (10 mL) and washed with 10% NaHCO3 (2*5 mL). The organic phase was dried Na2SO4 and evaporated in vacuo to give the product as a clear oil (103 mg, 80% yield) which was used without further purification. LC-MS: 2.49 min, 431.2 m/z [M+H]+, 375.1 m/z [M-t-Bu+H]+
Reference： [1]Ren, Jing; Xu, Wei; Tang, Le; Su, Minbo; Chen, Danqi; Chen, Yue-Lei; Zang, Yi; Li, Jia; Shen, Jingkang; Zhou, Yubo; Xiong, Bing [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4472 - 4476]
[2]Current Patent Assignee: UNIVERSITY OF MICHIGAN - US2014/275070, 2014, A1 Location in patent: Paragraph 0236; 0237
  • 88
  • [ 100-52-7 ]
  • [ 144222-22-0 ]
  • N-(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-N-benzylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: benzaldehyde; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With methanol; magnesium sulfate at 20℃; for 12h; Stage #2: With sodium tetrahydroborate at 0 - 20℃; for 1h;
69% Stage #1: benzaldehyde; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate In methanol at 20℃; for 8h; Stage #2: With sodium tris(acetoxy)borohydride In methanol at 20℃; 5.1 Step 1: Preparation of tert-Butyl 4-((benzylamino)methyl)piperidine-1-carboxylate (3): To a solution of benzaldehyde (1 , 13.70 g, 64.0 mmol) in methanol (200 mL) was added the primary amine (2, 6.53 mL, 64.0 mmol). This solution was stirred for 8 h at room temperature (RT). Then sodium triacetoxyborohydride (27.14 g, 128.0 mmol) was added in three solid portions over 20 min. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 2.5 M NaOH until pH 1 1 was obtained. This mixture was stirred for 30 min. The reaction mixture was then extracted with ethyl acetate (3 x 300 mL). The combined organics were washed with brine (1 x 200 mL), dried over Na2S04 (sodium sulfate), filtered, the volatiles were removed, and the crude oil was purified using flash column chromatography (40: 1 DCM:MeOH). The product 3 was isolated as an oil (13.50 g, 69% yield).
Reference： [1]Martín-Gago, Pablo; Fansa, Eyad K.; Klein, Christian H.; Murarka, Sandip; Janning, Petra; Schürmann, Marc; Metz, Malte; Ismail, Shehab; Schultz-Fademrecht, Carsten; Baumann, Matthias; Bastiaens, Philippe I. H.; Wittinghofer, Alfred; Waldmann, Herbert [Angewandte Chemie - International Edition, 2017, vol. 56, # 9, p. 2423 - 2428][Angew. Chem., 2017, vol. 129, # 9, p. 2463 - 2468,6]
[2]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES; STANFORD UNIVERSITY - WO2014/152869, 2014, A2 Location in patent: Page/Page column 40
Same Skeleton Products
Related Products
Categories
Chemistry
Organic Building Blocks
Esters
t-butoxycarbonyl
Chemistry
Heterocyclic Building Blocks
Piperidines
piperidin-4-ylmethanamine
Chemistry
Organic Building Blocks
Amines
piperidin-4-ylmethanamine
Chemistry
Organic Building Blocks
Amides
Chemistry
Organic Building Blocks
Carbamates
Chemistry
Heterocyclic Building Blocks
Aliphatic Heterocycles
Historical Records

Related Functional Groups of
[ 144222-22-0 ]

Amides

Chemical Structure| 162167-97-7

[ 162167-97-7 ]

tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 146667-84-7

[ 146667-84-7 ]

tert-Butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 236406-39-6

[ 236406-39-6 ]

8-Boc-2,8-Diazaspiro[4.5]decane

Similarity: 0.98

Chemical Structure| 1279866-58-8

[ 1279866-58-8 ]

tert-Butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride

Similarity: 0.98

Chemical Structure| 896464-16-7

[ 896464-16-7 ]

tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate

Similarity: 0.98

Amines

Chemical Structure| 162167-97-7

[ 162167-97-7 ]

tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 140645-23-4

[ 140645-23-4 ]

(R)-1-Boc-3-(Aminomethyl)piperidine

Similarity: 0.98

Chemical Structure| 1017356-25-0

[ 1017356-25-0 ]

1-Boc-3-((Methylamino)methyl)piperidine

Similarity: 0.98

Chemical Structure| 896103-62-1

[ 896103-62-1 ]

tert-Butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 146093-46-1

[ 146093-46-1 ]

4-(Aminoethyl)-1-N-Boc-piperidine

Similarity: 0.98

Related Parent Nucleus of
[ 144222-22-0 ]

Aliphatic Heterocycles

Chemical Structure| 162167-97-7

[ 162167-97-7 ]

tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 146667-84-7

[ 146667-84-7 ]

tert-Butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 236406-39-6

[ 236406-39-6 ]

8-Boc-2,8-Diazaspiro[4.5]decane

Similarity: 0.98

Chemical Structure| 1279866-58-8

[ 1279866-58-8 ]

tert-Butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride

Similarity: 0.98

Chemical Structure| 896464-16-7

[ 896464-16-7 ]

tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate

Similarity: 0.98

Piperidines

Chemical Structure| 162167-97-7

[ 162167-97-7 ]

tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 146667-84-7

[ 146667-84-7 ]

tert-Butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 236406-39-6

[ 236406-39-6 ]

8-Boc-2,8-Diazaspiro[4.5]decane

Similarity: 0.98

Chemical Structure| 1279866-58-8

[ 1279866-58-8 ]

tert-Butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride

Similarity: 0.98

Chemical Structure| 896464-16-7

[ 896464-16-7 ]

tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate

Similarity: 0.98