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  
Chemistry
Heterocyclic Building Blocks
Piperazines
Piperazines ∩ Amides
(R)-tert-Butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate
Chemistry
Heterocyclic Building Blocks
Organic Building Blocks Asymmetric Synthesis
Piperazines
Amides Ketones Other Aromatic Heterocycles Aliphatic Cyclic Hydrocarbons Chiral Building Blocks Aromatic Heterocycles
Piperazines ∩ Amides
Chiral Building Blocks ∩ Piperazines Aromatic Heterocycles ∩ Ketones Amides ∩ Ketones Chiral Building Blocks ∩ Ketones Aromatic Heterocycles ∩ Amides Piperazines ∩ Other Aromatic Heterocycles Chiral Building Blocks ∩ Amides Aromatic Heterocycles ∩ Other Aromatic Heterocycles Other Aromatic Heterocycles ∩ Ketones Chiral Building Blocks ∩ Other Aromatic Heterocycles Other Aromatic Heterocycles ∩ Amides Piperazines ∩ Ketones cyclopentane Piperazines ∩ Aromatic Heterocycles

[ CAS No. 1001180-21-7 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 1001180-21-7
Chemical Structure| 1001180-21-7
Structure of 1001180-21-7 * 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 [ 1001180-21-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1001180-21-7 ]

SDS Specification
Alternatived Products of [ 1001180-21-7 ]

Product Details of [ 1001180-21-7 ]

CAS No. :1001180-21-7 MDL No. :MFCD28987390
Formula : C17H24N4O3 Boiling Point : -
Linear Structure Formula :- InChI Key :FYSLHZSJYXKKMC-LLVKDONJSA-N
M.W : 332.40 Pubchem ID :59580350
Synonyms :

Calculated chemistry of [ 1001180-21-7 ]

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.65
Num. rotatable bonds : 4
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 97.09
TPSA : 75.63 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.11 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.86
Log Po/w (XLOGP3) : 1.72
Log Po/w (WLOGP) : 1.46
Log Po/w (MLOGP) : 0.98
Log Po/w (SILICOS-IT) : 1.52
Consensus Log Po/w : 1.71

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.91
Solubility : 0.413 mg/ml ; 0.00124 mol/l
Class : Soluble
Log S (Ali) : -2.92
Solubility : 0.396 mg/ml ; 0.00119 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.18
Solubility : 0.219 mg/ml ; 0.000659 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.62

Safety of [ 1001180-21-7 ]

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 [ 1001180-21-7 ]

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

  • Downstream synthetic route of [ 1001180-21-7 ]

[ 1001180-21-7 ] Synthesis Path-Downstream   1~88

  • 1
  • [ 1001180-18-2 ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
82.3% A solution of DMSO (5.45 mL, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a -78C solution of oxalyl chloride (3.35 mL, 38.4 mmol) in DCM <n="56"/>(150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4- (7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at -78C, after which neat triethylamine (18.0 mL, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H2O was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1:4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yi)piperazine- 1-carboxylate (7.5 g, 82.3% yield) as a foam. The foam was concentrated (3 X) from DCM/hexanes, which gave a foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.
82.3% With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -78 - 20℃; Step 10: A solution of DMSO (5.45 mL, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a -78C solution of oxalyl chloride (3.35 mL, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-l -carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at -78C, after which neat triethylamine (18.0 mL, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H2O was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1 :4 DCM:EtOAc eluted product to give (R)-tert- butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 -carboxylate (7.5 g, 82.3% yield) as a foam. The foam was concentrated from DCM/hexanes (3 X), which also gave a foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.
82.3% With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -78 - 20℃; Step 14: A solution of DMSO (5.45 mL, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a -78C solution of oxalyl chloride (3.35 mL, 38.4 mmol) in DCM <n="34"/>(150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4- (7-hydroxy-5-methyl-6s7-dmydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at -78C, after which neat triethylamine (18.0 mL, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H2O was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product elutibag, then 1:4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-memyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrirnidin-4-yl)piperazine-l- carboxylate (7.5 g, 82.3% yield) as a foam. The foam was concentrated fom DCM/hexanes (3 X), which also gave a foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.
82.3% Step 8: A solution of DMSO (5.45 ml, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a -78C solution of oxalyl chloride (3.35 ml, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-l -carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at -78C, after which neat triethylamine (18.0 ml, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H20 was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2S04), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4: 1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1 :4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 - carboxylate (7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3 X) from DCM/hexanes, which gave a very light brown foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.
82.3% Step 8: A solution of DMSO (5.45 ml, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a -78C solution of oxalyl chloride (3.35 ml, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine- 1 -carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at -78C, after which neat triethylamine (18.0 ml, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H20 was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2S04), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1 : 1 DCM:ethyl acetate until product eluting, then 1 :4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 - carboxylate (7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3 X) from DCM/hexanes, which gave a very light brown foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.
82.3% Step 8:; A solution of DMSO (5.45 ml, 76.8 mmol) in DCM (50 mL) was added dropwise by addition funnel to a -780C solution of oxalyl chloride (3.35 ml, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes, and then a solution of (5R)-tert-butyl 4- (7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred another 1 hour at -78C, after which neat triethylamine (18.0 ml, 129 mmol) was added to the mixture. The reaction mixture was then allowed to warm to room temperature, and then it was stirred for 30 minutes. H2O was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1:4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 - carboxylate (7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3 X) from DCM/hexanes, which gave a very light brown foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.
79.6 - 82.3% Step 3: To a -78 0C solution of oxalyl chloride (0.203 mL, 2.33 mmol) in 10 mLDCM was added dropwise by syringe a solution of DMSO (0.330 mL, 4.66 mmol) in 3 mL DCM. The reaction mixture was stirred 35 minutes, then a solution of (R)-tert-butyl 4-(7-hydroxy-5- methyl-^-dihydro-SH-cyclopentafdJpyrimidin^-y^piperazine-l-carboxylate (0.556 g, 1.66 mmol) in 5 mL DCM was added slowly by syringe. The reaction mixture was stirred another 1 hour at -78 0C, after which neat TEA (1.09 mL, 7.81 mmol) was added. The reaction mixture was then allowed to warm to room temperature, stirred 30 minutes, and H2O was added. The mixture was extracted with 3 x 75 mL DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 40M): the column was flushed with about 300 mL 4:1 DCM:EtOAc, then gradient to 1:4 DCM: EtOAc to give (R)-tert- butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 -carboxylate (0.440 g, 79.6% yield) as a brown foam. MS (APCI+) m/z 333 [M+H]+. 1H NMR (CDCl3, 400 MHz) delta 8.73 (s, IH), 3.93-3.82 (m, 2H), 3.74-3.48 (m, 7H), 2.96 (dd, J = 19.6, 7.3 Hz, IH), 2.34 (dd, J= 19.6, 1.5 Hz, IH), 1.50 (s, 9H), 1.32 (d, J= 6.8 Hz, 3H).; Step 8: A solution of DMSO (5.45 mL, 76.8 mmol) in DCM (50 m) was added dropwise by addition funnel to a -78C solution of oxalyl chloride (3.35 mL, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 35 minutes. A solution of (5R)-tert-butyl 4-(7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 -carboxylate (9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel. The reaction mixture was stirred for another 1 hour at -78C, after which neat NEt3 (18.0 mL, 129 mmol) was added. The reaction mixture was then allowed to warm to room temperature, stirred 30 minutes, and then H2O was added. The mixture was extracted with DCM (3 X 200 mL), and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc, then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1:4 DCM:EtOAc eluted product to give (R)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 -carboxylate (7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3 X) from DCM/hexanes, which gave a very light brown foam. HPLC >95% area. LC/MS (APCI+) m/z 333 [M+H]+.

Reference： [1]Patent: WO2009/6567,2009,A2 .Location in patent: Page/Page column 53-54
[2]Patent: WO2009/89453,2009,A1 .Location in patent: Page/Page column 34
[3]Patent: WO2009/89459,2009,A1 .Location in patent: Page/Page column 32-33
[4]Patent: WO2012/135750,2012,A1 .Location in patent: Page/Page column 75-76
[5]Patent: WO2012/135779,2012,A1 .Location in patent: Page/Page column 38
[6]Patent: WO2008/6040,2008,A1 .Location in patent: Page/Page column 101
[7]Patent: WO2008/6032,2008,A1 .Location in patent: Page/Page column 104; 109
[8]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[9]Organic Process Research and Development,2014,vol. 18,p. 1641 - 1651
  • 2
  • [ 1001180-21-7 ]
  • [ 1001180-24-0 ]
YieldReaction ConditionsOperation in experiment
34.5% With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 0.75h; Step 4: (Reaction run in a 20-mL plastic bottle): To a solution of (R)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (0.250 g, <n="107"/>0.752 mmol) in 5 mL DCM was added DAST (0.795 mL, 6.02 mmol). The reaction mixture was capped and stirred at room temperature for 45 hours, after which it poured into ice saturated NaHCO3. The mixture was extracted with 2 x 40 mL DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 40S) eluting with 6:1 to 3:1 hexanes:EtOAc to give (R)-tert-butyl 4-(7,7-difluoro-5-methyl-6,7-dihydro- SH-cyclopenta^pyrimidin^-ytypiperazine-l-carboxylate (0.092 g, 34.5% yield) as a yellow oil. MS (APCI+) m/z 355 [M+H]+.
28% With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 42h; (R)-tert-Butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (1.0 g, 3.0 mmol, see Example 3) was dissolved in DCM (15 mL) in a plastic bottle, and then DAST was added neat over approximately 5 minutes. The reaction was quenched after 42 hours at room temperature by pouring into saturated aqueous sodium bicarbonate solution mixed with ice. The organic layer was diluted with EtOAc, washed 3 times with water, once with brine and then dried over sodium sulfate. After filtration, the residue was concentrated and purified via column chromatography (70:30 hexane/ethyl acetate, then 1:1 hexane/ethyl acetate) to give (R)-tert-butyl 4-(7,7-difluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-l-carboxylate (300 mg, 28%).
Reference： [1]Patent: WO2008/6032,2008,A1 .Location in patent: Page/Page column 104-105
[2]Patent: WO2009/6567,2009,A2 .Location in patent: Page/Page column 78
  • 3
  • [ 1001180-21-7 ]
  • [ 1001180-45-5 ]
YieldReaction ConditionsOperation in experiment
95.3% With formic acid; triethylamine;Ru catalyst; In dichloromethane; for 18h;Product distribution / selectivity; Step 9:; Triethylamine (4.33 ml, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 ml, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1 :4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (minor) (9.35 g, 95.3% yield) as a beige <n="104"/>foam. LC/MS (APCI+) m/z 335 [M+H]+. IH NMR (CDC13) shows 88% de by integration of carbinol methine.
82% With NADP; In aq. phosphate buffer; isopropyl alcohol; at 40℃; for 22h;Inert atmosphere; Example 13aTert-butyl 4- [(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopentaldl pyrimidin-4- yllpiperazine-1-carboxylate mM Potassium dihydrogen phosphate pH 7.2), 78 g 2-Propanol and 50 mg NAD (75iimol) was formed under vigorous stirring. The reduction started by the addition of 500 mg KRED-X1.1- P1 FO 1. The reaction mixture is sparged with nitrogen and heated to 40C for 22 hours. After reaction completion 174 g isopropylacetate are added, agitated, phases were split and the5 aqueous phase removed. The aqueous phase was extracted again with 174 g isopropylacetate. The aqueous phase was removed and the organic phases were combined and concentrated at 35C in vacuo to a final volume of 115 mL. At the same temperature 212 g Heptane are added within 1 hour, the suspension is aged for 1 hour and cooled to 10C within 6 hours. The suspension is filtered and washed with 68g heptane. After drying of the filter cake for 4 hours at10 50C and 41.1 g (82% yield, purity 100% area) white crystals are obtained.
76.3% With nicotinamide adenine dinucleotide phosphate; In aq. phosphate buffer; at 30 - 37℃; for 6h;pH 6.8 - 7.1;Inert atmosphere; Large scale; Enzymatic reaction; A 3000 L glass-lined reactor was evacuated and filled with nitrogen to normal pressure 3 times. Water (660.0 kg) was added into the reactor while maintaining the temperature in the range of 20-30 C. The stirrer was started, followed by the addition of potassium dihydrogen phosphate (9.2 kg), dipotassium phosphate (23.7 kg) and glucose (78.5 kg). The mixture was stirred until solid dissolved completely. Then 30.1 kg of this buffer mixture was discharged into a 50 L drum for future use. To the reactor was added <strong>[1001180-21-7](R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate</strong> (66.0 kg) and PEG400 (732.6 kg) and the mixture was heated to about 30-35 C. Maintaining the temperature at 30-35 C., a mixture of buffer solution (20.0 kg), KRED-101 (2.4 kg), GDH (3.4 kg) and NADP (2.2 kg) was added into the mixture. The mixture was then maintained at 32-37 C. for reaction while controlling the pH at 6.8-7.1. After about 6 h, the mixture was monitored by TLC and HPLC until ketone starting substrate was ?1.0%. During the reaction, potassium hydroxide solution (total 46.2 kg) and extra enzyme buffer solution prepared with purified water (5.0 kg), KRED-101 (0.24 kg), GDH (0.34 kg) and NADP (0.22 kg) were added. To a glass-lined reactor, isopropyl acetate (1148.6 kg) was added. The reaction mixture from the previous paragraph was added to the reactor in three portions. Each time, it was stirred for 15-20 min and held for at least 0.5 h before separation at 20-30 C. This extraction process was repeated three times. The organic phases were combined. At 20-30 C., the combined organic phases were washed with purified water (329.3 kg). It was stirred for 25-30 min and held for at least 30 min before separation. The organic phase was left in the reactor and the washing process was repeated. The organic phase was decolorized with active carbon (6.6 kg) and stirred for 1-1.5 h. The mixture was filtered via a Nutsche filter. The cake was washed with isopropyl acetate (57.5 kg). The filtrates were combined. The filtrate was then transferred into a thin film evaporator and concentrated at ?55 C. under reduced pressure until 500-600 L remained. The concentrated mixture was filtered and transferred into a glass-lined reactor, then concentrated at ?55 C. under reduced pressure until 50-60 L remained. The mixture was then heated to 50-55 C. and stirred at this temperature for 0.5-1.5 h under nitrogen. n-Heptane (277.2 kg) was added into the mixture at the rate of 20-30 kg/h while maintaining the temperature at 50-55 C. The mixture was then cooled to 20-30 C. at the rate of 5-10 C./h. The mixture was stirred at 20-30 C. for 1 h, then heated to 50-55 C. and stirrer for 1-2 h, and then cooled to 15-20 C. at a rate of 5-10 C./h for crystallization. It was sampled to be analyzed by HPLC every 1-2 h until wt % of the mother liquid was ?3% or the change of the wt % between consecutive samples was ?0.5%. The mixture was then filtered with a centrifuge. The filter cake was washed with n-heptane (45.0 kg). The filtrate was transferred into a glass-lined reactor and concentrated at ?45 C. under reduced pressure (?-0.06 MPa) until no more distillate was observed (approximately 20 L remained). Isopropyl acetate (20.0 kg) was added, the mixture was heated to 45-55 C. and stirred for 0.5-1 h. The mixture was dried at 40-50 C. to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as grey solid (50.65 kg, 76.3% yield), HPLC rt=18.93 min, 99.9% pure, 100% de, 100% ee. The HPLC conditions are given in Table 1 below.
With formic acid; triethylamine; In dichloromethane;Inert atmosphere; A flask was equipped with a thermocouple, mechanic stirrer, a nitrogen inlet and drying tube. To the flask was added (R)-tert-buty 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[i ]pyrimidin-4-yl)piperazine-l -carboxylate (46.0 g, 139 mmol) followed by dichloromethane (1.10 L) and RuCl(TsDACH) catalyst (1.50 g, 2.80 mmol) with nitrogen degassing (gas dispersion tube) and agitation at room temperature. To the mixture was added triethylamine (23.0 mL, 167 mmol) with degassing. Formic acid (7.40 mL, 195 mmol) was slowly added to the mixture at a rate of about 1 mL/min. Good agitation with stirring was maintained until complete consumption of starting material (about 8-12 hr) as determined by HPLC analysis. The reaction was quenched with saturated sodium bicarbonate (2.00 vol., 100 mL), the layers were separated and the aqueous layer was discarded. The organic layer was washed with saturated sodium bicarbonate, saturated ammonium chloride and brine (2.00 vol., 100 mL each). The organics were dried over sodium sulfate, filtered and solvent exchanged into methanol. The methanolic solution (5.00 vol.) of crude product was charged with 50 wt % SiliaBond Thiol (Silicycle, Inc.) and 20 wt% Charcoal. The mixture was heated to about 50 C and maintained at that temperature with good stirring overnight. The mixture was cooled to room temperature, filtered over a pad of Celite and then polish filtered through a 0.45 micron filter. The mixture was distilled to a minimum working volume and concentrated under reduced pressure to afford the product (44.0 g, 95 % yield), as a 96:4 mixture of trans/cis diastereomers) as solid. Trace amount of Ru metal was measured by ICP-EOS and found that the product contained less than about 20 ppm Ru. The product was purified by preparative HPLC under the following conditionsor crystallization from ethyl acetate/heptane to yield 98.4 % pure product, 97.7 % de with about 100% ee.
With formic acid; triethylamine;Ru catalyst; In dichloromethane; for 18h;Product distribution / selectivity; Step 9: Triethylamine (4.33 mL, 31.1 mmol) (degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol) (degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The reaction mixture was stirred for 5 minutes, and then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on a high vacuum. 1H NMR of the crude looked like 85% diastereoselectivity. The crude was flashed on Biotage 65M (loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1:4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (major) and tert- butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l- carboxylate (minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335 [M+H]+. 1U NMR (CDC13) shows 88% diastereoselectivity by integration of carbinol methine.

Reference： [1]Patent: WO2008/6040,2008,A1 .Location in patent: Page/Page column 101-102
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[3]Organic Letters,2017,vol. 19,p. 4806 - 4809
[4]Patent: WO2015/73739,2015,A1 .Location in patent: Page/Page column 58; 59
[5]Patent: US2015/99880,2015,A1 .Location in patent: Paragraph 0070-0071
[6]Patent: WO2013/173736,2013,A1 .Location in patent: Page/Page column 34-35
[7]Patent: WO2008/6032,2008,A1 .Location in patent: Page/Page column 109
  • 4
  • [ 1001180-21-7 ]
  • [ 917-54-4 ]
  • [ 1001270-91-2 ]
YieldReaction ConditionsOperation in experiment
69% In tetrahydrofuran; diethyl ether; at -78℃; for 1h; A solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (40 mg, 0.120 mmol; see Example 3, Step 8) in THF (4 mL) was added to a 1.5M solution of methyllithium in diethyl ether (0.088 mL, 0.132 mmol) at -78C. The resulting mixture was stirred at -780C for 1 hour and quenched by saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2 X). The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-l-carboxylate as a solid (29 mg, 69%). LCMS (APCI+) [M-Boc+H]+ 349.1; Retention time: 2.49 minutes.
69% Example 40; 2-(4-chlorophenyl)-l-('4-((5R)-7-hydroxy-5,7-diniethyl-6,7-dihvdro-5H-cvclopenta[dlpyrimidin-4- vDpiperazin- 1 -ylV S-fisopropylamino'propan- 1 -one; Step 1 :; A solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (40 nig, 0.120 mmol) in THF (4 niL) was added to a 1.5M solution of methyllithium in diethyl ether (0.088 mL, 0.132 mmol) at -780C. The resulting mixture was stirred at -78C for 1 hour and quenched by saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2 X). The organic layer was dried (MgSO^ and concentrated. The residue was purified by a silica catridge (5.0 g) eluted by EtOAc to give tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1-carboxylate as an off-white solid (29 mg, 69%). LCMS (APCI+) [M-Boc+H]+ 349.1; Rt: 2.49 min.
Reference： [1]Patent: WO2009/6567,2009,A2 .Location in patent: Page/Page column 45
[2]Patent: WO2008/6040,2008,A1 .Location in patent: Page/Page column 123
  • 5
  • [ 1001180-21-7 ]
  • [ 1001180-45-5 ]
  • [ 1001201-61-1 ]
YieldReaction ConditionsOperation in experiment
Triethylamine (4.33 mL, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1 :4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (minor) (9.35 g, 95.3% yield) as a foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) shows 88% diastereoselectivity by integration of carbinol methine.
With formic acid; triethylamine;Ru catalyst; In dichloromethane; Step 11: Triethylamine (4.33 mL, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol; degassed with nitrogen 30 minutes <n="37"/>prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, and then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1 :4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (major) and tert-butyl 4-((5R,7S)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (minor) (9.35 g, 95.3% yield) as a foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) showed 88% diastereoselectivity by integration of carbinol methine.
With formic acid; triethylamine; In dichloromethane; Step 15: Triethylamine (4.33 mL, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]p;yrimidm-4-yl)piperazme4-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, and then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1:4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopentafdjpyrimidin^-yl^iperazine-l-carboxylate (minor) (9.35 g, 95.3% yield) as a foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) showed 88% diastereoselectivity by integration of carbinol methine.
With formic acid; triethylamine;Ru catalyst; In dichloromethane; for 18h;Inert atmosphere; Step 9: Triethylamine (4.33 ml, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 ml, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1 : 1 DCM:ethyl acetate 500 mL flushed, then 1 :4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy- 5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine- 1 -carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-l -carboxylate (minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDC13) shows 88% de by integration of carbinol methine.
With formic acid; triethylamine;ruthenium; In dichloromethane; for 18h;Inert atmosphere; Step 9: Triethylamine (4.33 ml, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 ml, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1 : 1 DCM:ethyl acetate 500 mL flushed, then 1 :4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy- 5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-l -carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-l -carboxylate (minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDC13) shows 88% de by integration of carbinol methine.

Reference： [1]Patent: WO2009/6567,2009,A2 .Location in patent: Page/Page column 54
[2]Patent: WO2009/89453,2009,A1 .Location in patent: Page/Page column 34-35
[3]Patent: WO2009/89459,2009,A1 .Location in patent: Page/Page column 33
[4]Patent: WO2012/135750,2012,A1 .Location in patent: Page/Page column 76
[5]Patent: WO2012/135779,2012,A1 .Location in patent: Page/Page column 38-39
[6]Organic Letters,2017,vol. 19,p. 4806 - 4809
  • 6
  • [ 89-82-7 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Patent: WO2012/135750,2012,A1
[4]Patent: WO2012/135750,2012,A1
[5]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[6]Patent: WO2008/6032,2008,A1
[7]Patent: WO2008/6032,2008,A1
  • 7
  • [ 623935-92-2 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Patent: WO2012/135750,2012,A1
[4]Patent: WO2012/135750,2012,A1
[5]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[6]Patent: WO2008/6032,2008,A1
[7]Patent: WO2008/6032,2008,A1
  • 8
  • [ 85440-74-0 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Patent: WO2012/135750,2012,A1
[4]Patent: WO2012/135750,2012,A1
[5]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[6]Patent: WO2008/6032,2008,A1
[7]Patent: WO2008/6032,2008,A1
  • 9
  • [ 1001178-85-3 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Patent: WO2008/6032,2008,A1
  • 10
  • [ 1001180-40-0 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[3]Patent: WO2008/6032,2008,A1
  • 11
  • [ 1001180-15-9 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135779,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Patent: WO2008/6040,2008,A1
[5]Patent: WO2008/6032,2008,A1
  • 12
  • [ 1001178-87-5 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Patent: WO2008/6032,2008,A1
  • 13
  • [ 1001180-21-7 ]
  • [ 1001270-26-3 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[3]Patent: WO2008/6040,2008,A1
  • 14
  • [ 1001180-21-7 ]
  • [ 1001270-64-9 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135779,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Patent: WO2015/73739,2015,A1
[5]Organic Letters,2017,vol. 19,p. 4806 - 4809
[6]Organic Letters,2017,vol. 19,p. 4806 - 4809
[7]Patent: WO2008/6040,2008,A1
  • 15
  • [ 1001180-21-7 ]
  • (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride [ No CAS ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135779,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Organic Letters,2017,vol. 19,p. 4806 - 4809
[5]Patent: WO2008/6040,2008,A1
  • 16
  • [ 1001180-21-7 ]
  • (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride [ No CAS ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[3]Patent: WO2008/6040,2008,A1
  • 17
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-l-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride [ No CAS ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135779,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Organic Letters,2017,vol. 19,p. 4806 - 4809
[5]Organic Letters,2017,vol. 19,p. 4806 - 4809
  • 18
  • [ 1001180-35-3 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Patent: WO2008/6032,2008,A1
  • 19
  • [ 953045-35-7 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[4]Patent: WO2008/6032,2008,A1
  • 20
  • [ 1001178-90-0 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[3]Patent: WO2008/6032,2008,A1
  • 21
  • [ 863725-39-7 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
[2]Patent: WO2012/135750,2012,A1
[3]Patent: WO2012/135750,2012,A1
[4]Patent: WO2012/135750,2012,A1
[5]Patent: WO2008/6032,2008,A1
[6]Patent: WO2008/6032,2008,A1
  • 22
  • [ 1001269-75-5 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
  • 23
  • [ 1001269-77-7 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2012/135750,2012,A1
  • 24
  • [ 1001180-21-7 ]
  • [ 1001382-27-9 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 25
  • [ 1001180-21-7 ]
  • [ 1001180-70-6 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 26
  • [ 1001180-21-7 ]
  • [ 1001227-85-5 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 27
  • [ 1001180-21-7 ]
  • [ 1001227-81-1 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 28
  • [ 1001180-21-7 ]
  • [ 1001201-61-1 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 29
  • [ 1001180-21-7 ]
  • [ 1396257-79-6 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 30
  • [ 1001180-21-7 ]
  • [ 1396257-81-0 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 31
  • [ 1001180-21-7 ]
  • [ 1001180-51-3 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[2]Patent: WO2008/6032,2008,A1
  • 32
  • [ 1001180-21-7 ]
  • [ 1396257-83-2 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 33
  • [ 1001180-21-7 ]
  • [ 1396257-86-5 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 34
  • [ 1001180-21-7 ]
  • C33H46ClN5O5 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 35
  • [ 1001180-21-7 ]
  • C29H40ClN5O4 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 36
  • [ 1001180-21-7 ]
  • C29H39ClFN5O3 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 37
  • [ 1001180-21-7 ]
  • C29H39ClFN5O3 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 38
  • [ 1001180-21-7 ]
  • [ 1097870-30-8 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 39
  • [ 1001180-21-7 ]
  • [ 1097870-39-7 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 40
  • [ 1001180-21-7 ]
  • C29H38ClN5O5 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 41
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylmethylamino)propan-1-one [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 42
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((tetrahydro-2H-pyran-4-yl)amino)propan-1-one [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 43
  • [ 1001180-21-7 ]
  • C26H32ClN5O3 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 44
  • [ 1001180-21-7 ]
  • C27H34ClN5O3 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 45
  • [ 1001180-21-7 ]
  • C27H34F3N5O4 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 46
  • [ 1001180-21-7 ]
  • C31H41F4N5O5 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 47
  • [ 1001180-21-7 ]
  • C24H32ClN5O2*2ClH [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 48
  • [ 1001180-21-7 ]
  • C24H31ClFN5O*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 49
  • [ 1001180-21-7 ]
  • C24H31ClFN5O*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 50
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-3-((cyclopropylmethyl)amino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride salt [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 51
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-3-(2-fluoroethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 52
  • [ 1001180-21-7 ]
  • C24H32ClN5O3*2ClH [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 53
  • [ 1001180-21-7 ]
  • C27H36ClN5O2*2ClH [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 54
  • [ 1001180-21-7 ]
  • C25H34ClN5O2*2ClH [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 55
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride salt [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 56
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one dihydrochloride [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 57
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(((1R,4S)-4-methoxycyclohexyl)amino)propan-1-one [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 58
  • [ 1001180-21-7 ]
  • [ 1396256-36-2 ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 59
  • [ 1001180-21-7 ]
  • C25H32ClN5O2*2ClH [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 60
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-morpholin-3-yl)ethanone hydrochloride salt [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 61
  • [ 1001180-21-7 ]
  • (S)-2-(4-chlorophenyl)-3-(4-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 62
  • [ 1001180-21-7 ]
  • C25H34ClN5O3*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 63
  • [ 1001180-21-7 ]
  • C22H26F3N5O2*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 64
  • [ 1001180-21-7 ]
  • C24H31ClFN5O2*2ClH [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 65
  • [ 1001180-21-7 ]
  • C26H33F4N5O2*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 66
  • [ 1001180-21-7 ]
  • C26H33F4N5O3*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 67
  • [ 1001180-21-7 ]
  • C26H31F4N5O2*2C2HF3O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 68
  • [ 1001180-21-7 ]
  • 2ClH*C23H27ClF3N5O2 [ No CAS ]
Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8110 - 8127
  • 69
  • (R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173768,2013,A1
[2]Patent: WO2013/173768,2013,A1
[3]Patent: WO2013/173768,2013,A1
[4]Patent: WO2015/73739,2015,A1
  • 70
  • (R)-tert-butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
67%Chromat. With isopropylmagnesium chloride; In tetrahydrofuran; at -10℃; for 1h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
[2]Patent: WO2013/173768,2013,A1
[3]Patent: WO2013/173768,2013,A1
[4]Patent: WO2015/73739,2015,A1
  • 71
  • (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodo-pyrimidin-5-yl)butanoic acid [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
33% With isopropylmagnesium chloride; In tetrahydrofuran; at -10℃; for 1h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
[2]Patent: WO2015/73739,2015,A1
  • 72
  • (R)-tert-butyl 4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
88% With isopropylmagnesium chloride; In tetrahydrofuran; at -20℃; for 1h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
52.3 g With isopropylmagnesium chloride; In tetrahydrofuran; at -15 - -10℃; for 1h;Inert atmosphere; (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[dpyrimidin-4-yl)piperazine--carboxylateA solution of (R)-tert-butyl 4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mE) was purged withnitrogen for 30 mm. Isopropyl magnesium chloride solution (159 mE, 2i0 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 hand slowly transferred into a cold 20 wt% aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed withsaturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mE) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). ?H NMR (300 MHz, CDC13) 8.73 (s, IH), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J = 16.5, 1.8 Hz, IH), 1.50 (s, 9H), 1.32 (a, J 6.9 Hz, 3H). HRMS calcd. For C,7H25N403 [M+Hj: 333.1921, found 333.1924.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
[2]Patent: WO2015/73739,2015,A1 .Location in patent: Page/Page column 54; 55
  • 73
  • C21H32IN5O4 [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
88%Chromat. With isopropylmagnesium chloride; In tetrahydrofuran; at -10℃; for 1h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
  • 74
  • C24H32IN5O3 [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
83% With isopropylmagnesium chloride; In tetrahydrofuran; at -10℃; for 1h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
  • 75
  • C24H32BrN5O3 [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
26%Chromat. With TurboGrignard; isopropylmagnesium chloride; In tetrahydrofuran; at 20℃; for 42h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
  • 76
  • C18H27BrN4O4 [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
15%Chromat. With TurboGrignard; isopropylmagnesium chloride; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
  • 77
  • C17H25BrN4O4 [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
78%Chromat. With n-butyllithium; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere; Method A: [0088] A solution of (R)-tert-buty 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2- yl)pyrimidin-4-yl)piperazine-l -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15 C. The mixture was stirred at -10 C for 1 h and slowly transferred into a cold 20 wt % aqueous ammonium chloride (600 mL) with stirring while maintaining the internal temperature below 10 C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was distilled off at reduced pressure below 40 C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35 C and 40 C, followed by heptane (350 mL). The mixture was slowly cooled down to 20 C and product gradually precipitated out during the process. The slurry was filtered and the cake was dried at 40 C under vacuum to give a gray solid (52.3 g, 75% yield over two steps). NMR (300 MHz, CDC13) delta 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J= 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J= 6.9 Hz, 3H). HRMS calcd. For C17H25N403 [M+H]+: 333.1921, found 333.1924. Method B: [0089] Table 1, shows example substrates that were used for preparing (i?)-tert-butyl 4-(5- methyl-7-oxo-6,7-dihydro-5H-cyclopenta[ ]pyrimidin-4-yl)piperazine- 1 -carboxylate, according to the above procedure. The compound in the Substrate column was used in place of (R)-tert- butyl 4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine- 1 - carboxylate in the above procedure, the conditions of the reaction are shown in the Scale and Conditions column, with all other conditions being substantially the same. The amount shown in the Yield column represents the area percentage of the peak of cyclized product in the crude reaction mixture as measured by HPLC-MS. The amount shown in the parenthesis represents the isolated yield. The final product, (R)-tert-bvtiyl 4-(5-methyl-7-oxo-6,7-dihydro-5H- cyclopenta[ ]pyrimidin-4-yl)piperazine-l-carboxylate, was not isolated from the below reactions.
Reference： [1]Patent: WO2013/173768,2013,A1 .Location in patent: Paragraph 0088-0089
  • 78
  • (R)-methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173768,2013,A1
[2]Patent: WO2013/173768,2013,A1
[3]Patent: WO2013/173768,2013,A1
[4]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
[5]Patent: WO2015/73739,2015,A1
  • 79
  • (R)-methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173768,2013,A1
[2]Patent: WO2013/173768,2013,A1
[3]Patent: WO2013/173768,2013,A1
[4]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
[5]Patent: WO2015/73739,2015,A1
  • 80
  • [ 57260-71-6 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173736,2013,A1
  • 81
  • [ 1295516-49-2 ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173736,2013,A1
  • 82
  • (R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173736,2013,A1
[2]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
  • 83
  • (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloropyrimidin-5-yl)butanoic acid [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173736,2013,A1
[2]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
  • 84
  • (R)-tert-butyl 4-(5-(4-(benzyloxy)-4-oxobutan-2-yl)-6-chloropyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173736,2013,A1
[2]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
  • 85
  • (R)-isopropyl 5-(4-(benzyloxy)-4-oxobutan-2-yl)-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-4-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Patent: WO2013/173736,2013,A1
[2]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
  • 86
  • (5R)-benzyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
YieldReaction ConditionsOperation in experiment
With formic acid; palladium 10% on activated carbon; In 2-methyltetrahydrofuran; at 18 - 19℃;Inert atmosphere; A separate vessel was charged with 10 wt% Pd/C [50% wet] (16.5g) and 5% formic acid in 2-methyltetrahydrofuran (250 mL) under nitrogen. The reaction mixture was cooled to an internal temperature of -5 to 0C. The Pd/C slurry was transferred to the reaction flask, and 2- methyltetrahydrofuran (250 mL) was used to rinse the container to transfer all of the Pd/C solids. The reaction mixture was slowly warmed to 17 -19C, stirred at 18-19C for 0.5 to 1 hour, and monitored by TLC. The reaction was cooled to 15C and agitation was stopped and monitored by TLC. Aqueous saturated sodium bicarbonate solution (800 mL) was added slowly to quench the excess formic acid at a rate to maintain to minimize foaming. The reaction mixture was filtered through a Celite pad on polypropylene (50 g) and the reaction flask was rinsed with 2-methyltetrahydrofuran (600 mL) and transferred as a wash of solids. Ethyl acetate (500 mL) was added to this filtrate and the layers were separated. The organic layer was washed with aqueous saturated sodium bicarbonate.solution (2 x 600 mL). The combined aqueous layers were washed with Ethyl acetate (1.0 L). The combined organic layers were washed with brine solution (1.0 L). Charcoal (50 g, 50wt%) and magnesium sulfate (75g, 75wt%) were added to the organic layer and stirred for 5-10 minutes. The solids were removed via filtration, and the filtrate was concentrated at 40 - 45C under vacuum to yield the crude product as light brown semi-solid. Yield = 50 g (crude), structure confirmed by 1H-NMR (CDC13).
Reference： [1]Patent: WO2013/173736,2013,A1 .Location in patent: Page/Page column 33-34
  • 87
  • (S)-benzyl (4-(tert-butoxycarbonyl)piperazin-1-yl)-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidine-6-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666
  • 88
  • (S)-benzyl (4-(tert-butoxycarbonyl)piperazin-1-yl)-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidine-6-carboxylate [ No CAS ]
  • [ 1001180-21-7 ]
  • C22H34N4O4 [ No CAS ]
  • C22H34N4O4 [ No CAS ]
Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 1652 - 1666

Tags: 1001180-21-7 synthesis path| 1001180-21-7 SDS| 1001180-21-7 COA| 1001180-21-7 purity| 1001180-21-7 application| 1001180-21-7 NMR| 1001180-21-7 COA| 1001180-21-7 structure

Same Skeleton Products
Related Products
Categories
Chemistry
Heterocyclic Building Blocks
Piperazines
Piperazines ∩ Amides
Chemistry
Organic Building Blocks
Amides
Piperazines ∩ Amides
Chemistry
Asymmetric Synthesis
Chiral Building Blocks
Chiral Building Blocks ∩ Piperazines
Chemistry
Heterocyclic Building Blocks
Piperazines
Chiral Building Blocks ∩ Piperazines
Chemistry
Organic Building Blocks
Ketones
Aromatic Heterocycles ∩ Ketones
Chemistry
Heterocyclic Building Blocks
Aromatic Heterocycles
Aromatic Heterocycles ∩ Ketones
Chemistry
Organic Building Blocks
Ketones
Amides ∩ Ketones
Chemistry
Organic Building Blocks
Amides
Amides ∩ Ketones
Chemistry
Asymmetric Synthesis
Chiral Building Blocks
Chiral Building Blocks ∩ Ketones
Chemistry
Organic Building Blocks
Ketones
Chiral Building Blocks ∩ Ketones
Chemistry
Heterocyclic Building Blocks
Aromatic Heterocycles
Aromatic Heterocycles ∩ Amides
Chemistry
Organic Building Blocks
Amides
Aromatic Heterocycles ∩ Amides
Chemistry
Heterocyclic Building Blocks
Other Aromatic Heterocycles
Piperazines ∩ Other Aromatic Heterocycles
Chemistry
Heterocyclic Building Blocks
Piperazines
Piperazines ∩ Other Aromatic Heterocycles
Chemistry
Asymmetric Synthesis
Chiral Building Blocks
Chiral Building Blocks ∩ Amides
Chemistry
Organic Building Blocks
Amides
Chiral Building Blocks ∩ Amides
Chemistry
Heterocyclic Building Blocks
Other Aromatic Heterocycles
Aromatic Heterocycles ∩ Other Aromatic Heterocycles
Chemistry
Heterocyclic Building Blocks
Aromatic Heterocycles
Aromatic Heterocycles ∩ Other Aromatic Heterocycles
Chemistry
Heterocyclic Building Blocks
Other Aromatic Heterocycles
Other Aromatic Heterocycles ∩ Ketones
Chemistry
Organic Building Blocks
Ketones
Other Aromatic Heterocycles ∩ Ketones
Chemistry
Asymmetric Synthesis
Chiral Building Blocks
Chiral Building Blocks ∩ Other Aromatic Heterocycles
Chemistry
Heterocyclic Building Blocks
Other Aromatic Heterocycles
Chiral Building Blocks ∩ Other Aromatic Heterocycles
Chemistry
Heterocyclic Building Blocks
Other Aromatic Heterocycles
Other Aromatic Heterocycles ∩ Amides
Chemistry
Organic Building Blocks
Amides
Other Aromatic Heterocycles ∩ Amides
Chemistry
Organic Building Blocks
Ketones
Piperazines ∩ Ketones
Chemistry
Heterocyclic Building Blocks
Piperazines
Piperazines ∩ Ketones
Chemistry
Organic Building Blocks
Aliphatic Cyclic Hydrocarbons
cyclopentane
Chemistry
Heterocyclic Building Blocks
Piperazines
Piperazines ∩ Aromatic Heterocycles
Chemistry
Heterocyclic Building Blocks
Aromatic Heterocycles
Piperazines ∩ Aromatic Heterocycles
Historical Records

Related Functional Groups of
[ 1001180-21-7 ]

Amides

Chemical Structure| 1072027-36-1

[ 1072027-36-1 ]

4-(4-Boc-1-piperazinyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidine

Similarity: 0.65

Chemical Structure| 869198-95-8

[ 869198-95-8 ]

tert-Butyl 2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

Similarity: 0.64

Chemical Structure| 1142188-60-0

[ 1142188-60-0 ]

tert-Butyl 4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Similarity: 0.64

Chemical Structure| 1105187-42-5

[ 1105187-42-5 ]

tert-Butyl 2-amino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

Similarity: 0.62

Chemical Structure| 1616415-40-7

[ 1616415-40-7 ]

(S)-tert-Butyl 4-(6-amino-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Similarity: 0.62

Ketones

Chemical Structure| 157327-41-8

[ 157327-41-8 ]

1-Boc-3-[(Dimethylamino)methylene]-4-oxopiperidine

Similarity: 0.51

Related Parent Nucleus of
[ 1001180-21-7 ]

Other Aromatic Heterocycles

Chemical Structure| 1072027-36-1

[ 1072027-36-1 ]

4-(4-Boc-1-piperazinyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidine

Similarity: 0.65

Chemical Structure| 869198-95-8

[ 869198-95-8 ]

tert-Butyl 2-amino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

Similarity: 0.64

Chemical Structure| 1142188-60-0

[ 1142188-60-0 ]

tert-Butyl 4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Similarity: 0.64

Chemical Structure| 1105187-42-5

[ 1105187-42-5 ]

tert-Butyl 2-amino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

Similarity: 0.62

Chemical Structure| 1616415-40-7

[ 1616415-40-7 ]

(S)-tert-Butyl 4-(6-amino-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Similarity: 0.62

Piperazines

Chemical Structure| 1072027-36-1

[ 1072027-36-1 ]

4-(4-Boc-1-piperazinyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidine

Similarity: 0.65

Chemical Structure| 1616415-40-7

[ 1616415-40-7 ]

(S)-tert-Butyl 4-(6-amino-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Similarity: 0.62

Chemical Structure| 1209646-17-2

[ 1209646-17-2 ]

5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylic acid

Similarity: 0.61

Chemical Structure| 634468-96-5

[ 634468-96-5 ]

tert-Butyl 4-(pyrimidin-5-yl)piperazine-1-carboxylate

Similarity: 0.61

Chemical Structure| 374930-88-8

[ 374930-88-8 ]

tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

Similarity: 0.58