Home Cart 0 Sign in  
X

[ CAS No. 1211568-27-2 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
3d Animation Molecule Structure of 1211568-27-2
Chemical Structure| 1211568-27-2
Chemical Structure| 1211568-27-2
Structure of 1211568-27-2 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 1211568-27-2 ]

Related Doc. of [ 1211568-27-2 ]

Alternatived Products of [ 1211568-27-2 ]

Product Details of [ 1211568-27-2 ]

CAS No. :1211568-27-2 MDL No. :MFCD21145604
Formula : C15H29N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :RBPAAJAFRFIUEJ-UHFFFAOYSA-N
M.W : 283.41 Pubchem ID :67388475
Synonyms :

Calculated chemistry of [ 1211568-27-2 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.93
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 92.04
TPSA : 44.81 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.51
Log Po/w (XLOGP3) : 1.24
Log Po/w (WLOGP) : 0.4
Log Po/w (MLOGP) : 1.4
Log Po/w (SILICOS-IT) : 1.2
Consensus Log Po/w : 1.55

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.05
Solubility : 2.54 mg/ml ; 0.00895 mol/l
Class : Soluble
Log S (Ali) : -1.78
Solubility : 4.71 mg/ml ; 0.0166 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.17
Solubility : 1.91 mg/ml ; 0.00673 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.68

Safety of [ 1211568-27-2 ]

Signal Word:Danger Class:8
Precautionary Statements:P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P332+P313-P362-P403+P233-P405-P501 UN#:1759
Hazard Statements:H302-H315-H318-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1211568-27-2 ]

* 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 [ 1211568-27-2 ]

[ 1211568-27-2 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 1211568-27-2 ]
  • [ 350-46-9 ]
  • [ 2222114-94-3 ]
YieldReaction ConditionsOperation in experiment
93% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 6h; 618.4 4. 4. Synthesis of tert-butyl 4-[[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazine-1-carboxylate Into a 250-mL round-bottom flask, was placed a solution of 1-fluoro-4-nitrobenzene (3 g, 21.26 mmol, 1.00 equiv) in DMSO (80 mL). This was followed by the addition of DIEA (2.7 g, 20.89 mmol, 1.00 equiv) in several batches in 2 minutes. To this was added tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (6 g, 21.17 mmol, 1.00 equiv). The resulting solution was stirred for 6 hours at 100° C. in an oil bath. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (100 mL*2) and the organic layers combined. The resulting mixture was washed with brine (30 mL*2). The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 8.0 g (93%) of tert-butyl 4-[[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazine-1-carboxylate as a light yellow solid. LC-MS (ES+): m/z 405.10 [MH+], tR=0.65 min (1.9 minute run).
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 12h;
  • 2
  • [ 1211568-27-2 ]
  • [ 369-34-6 ]
  • [ 2222114-51-2 ]
YieldReaction ConditionsOperation in experiment
58% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; Sealed tube; 612.1 Synthesis of tert-butyl 4-[[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl]piperazine-1-carboxylate Synthesis of tert-butyl 4-[[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl]piperazine-1-carboxylate Into a 20-30 mL sealed tube, was placed a solution of 1,2-difluoro-4-nitrobenzene (977.5 mg, 6.1 mmol, 1.0 equiv) in dimethylsulfoxide (10 mL), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (1.5 g, 5.1 mmol, 0.8 equiv), N,N-Diisopropylethylamine (2.0 g, 15.3 mmol, 2.5 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 10 mL of water/ice. The resulting solution was extracted with ethyl acetate (20 mL*2) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:0). This resulted in 1.5 g (58%) of tert-butyl 4-[[1-(2-fluoro-4-nitrophenyl) piperidin-4-yl] methyl]piperazine-1-carboxylate as a yellow solid. LC-MS (ES+): m/z 423.30 [MH+], tR=1.58 min (1.9 minute run).
  • 3
  • [ 1211568-27-2 ]
  • [ 2222114-95-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 6 h / 100 °C 2: hydrogen; palladium on activated charcoal / methanol / 3 h / 20 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 12 h / 100 °C 2: hydrogen; palladium on activated charcoal / methanol / 3 h / 20 °C
  • 4
  • [ 1146951-40-7 ]
  • [ 1211568-27-2 ]
YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In methanol at 50℃; for 4h; 3 Intermediate 19 (7.5g) is dissolved in 150mL methanol, 10% Pd (0.75g) is added, hydrogen is replaced 3 times, the temperature is raised to 50°C, and the reaction is carried out for 4h. TLC monitors the completion of the raw material reaction, suction filtration removes 10% Pd, and the filtrate is concentrated to obtain 4.9 g of white solid with a yield of 100%.
100% With Pearlman’s catalyst In ethanol at 20℃;
87% With palladium hydroxide (10%) on carbon; hydrogen In ethanol at 20℃; for 90h; Intermediate 6b: tert-Butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate tert-Butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (9.5 g, 23 mmol) and 10% palladium hydroxide on activated charcoal (3.20 g, 2.28 mmol) in ethanol (40 mL) were stirred under an atmosphere of hydrogen at 1 atm and 20 °C for 18 hours. The reaction mixture was filtered through celite and the solids washed through with EtOH. The filtrate was evaporated to dryness, dissolved in EtOH (40 mL) and 10% palladium hydroxide on activated charcoal (3.20 g, 2.28 mmol) added. The suspension was stirred under an atmosphere of hydrogen at 1 atm and 20 °C for 3 days. The reaction mixture was filtered through celite and the solids washed with EtOH (100 mL). The filtrate was evaporated to dryness to afford the title compound (5.61 g, 87 %) as a grey solid; 1H NMR (400 MHz, DMSO, 30°C) 1.03- 1.2 (2H, m), 1.40 (9H, s), 1.61- 1.79 (3H, m), 2.11 (2H, d), 2.2- 2.31 (4H, m), 2.63 (2H, td), 3.07 (2H, d), 3.22- 3.36 (4H, m), exchangable proton not observed; m/z: ES+ [M+H]+ 284.2.
1.8 g With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 16h; 2 Step 2: Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-l -carboxylate To a solution of tert-butyl 4-[(l-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-l - carboxylate (910 mg, 2.18 mmol, 1 eq) in methanol (15 mL) was added palladium on activated carbon catalyst (500 mg, 10% purity), The suspension was degassed under vacuum and purged with hydrogen several times. The palladium on activated carbon catalyst (100 mg, 0.07 mmol, 10% purity, 3.27e-2 eq) in methanol (15 mL) was added to the mixture and stirred under hydrogen (4 mg, 2.18 mmol, 1 eq) (50 psi) at 25 °C for 16 hours. The reaction mixture was filtered and the filter was concentrated. Compound tert-butyl 4-(4-piperidylmethyl)piperazine-l- carboxylate (1.8 g) was obtained as a colorless gum. LC/MS (ESI) m/z· 284.1 [M+l] +.
With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 16h; 8 Step 8: Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-([1-[(benzyloxy)carbonyl]piperidin-4-yl]methyl)piperazine-1- carboxylate (7.62 g, 18.25 mmol, 1.00 equiv), ethanol (200 mL), Palladium carbon (500 mg). The flask was then vacuumed and flushed with hydrogen using a hydrogen balloon. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. This resulted in 4.66 g (crude) of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate as colorless oil. LC/MS (ESI) m/z: 284.10 [M+1] +.

  • 5
  • [ 1211568-27-2 ]
  • [ 105-36-2 ]
  • [ 2378261-14-2 ]
YieldReaction ConditionsOperation in experiment
63% With potassium carbonate In acetonitrile at 80℃; for 16h; 3 Step 3: Preparation of tert-butyl 4-((l-(2-ethoxy-2-oxoethyl)piperidin-4- yl)methyl)piperazine- 1 -carboxylate To a solution of tert-butyl 4-(4-piperidylmethyl)piperazine-l -carboxylate (650 mg, 2.29 mmol, 1 eq) and ethyl 2-bromo acetate (460 mg, 2.75 mmol, 0.3 mL, 1.2 eq) in acetonitrile (10 mL) was added potassium carbonate (951 mg, 6.88 mmol, 3 eq), the mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched by water (30 mL), and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=l0:l to 0:1). Compound tert-butyl 4-[[l-(2-ethoxy-2-oxo-ethyl)-4-piperidyl]methyl]piperazine-l-carboxylate (537 mg, 1.45 mmol, 63% yield) was obtained as a yellow oil. 'H-NMR (400MHz, CDCL) d 4.16 (q, 7=7.2 Hz, 2H), 3.38 (d, 7=4.8 Hz, 2H), 3.20 (s, 2H), 2.94 (d, 7=11.6 Hz, 2H), 2.36 - 2.27 (m, 4H), 2.21 - 2.11 (m, 4H), 1.73 (d, 7=12.8 Hz, 2H), 1.43 (s, 9H), 1.26 - 1.22 (m, 8H).
  • 6
  • [ 57260-71-6 ]
  • [ 1211568-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 3.17 h / 25 °C 2: hydrogen; palladium on activated charcoal / ethanol / 16 h / 20 °C
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride; glacial acetic acid / dichloromethane / 2 h / 20 °C 2: palladium hydroxide (10%) on carbon; hydrogen / ethanol / 90 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1.1: glacial acetic acid / 1,2-dichloro-ethane / 0.5 h / 20 °C 1.2: 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 50 °C
Multi-step reaction with 2 steps 1: dichloromethane / 3 h / 20 °C 2: Pearlman’s catalyst / ethanol / 20 °C

  • 7
  • [ 138163-08-3 ]
  • [ 1211568-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 3.17 h / 25 °C 2: hydrogen; palladium on activated charcoal / ethanol / 16 h / 20 °C
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride; glacial acetic acid / dichloromethane / 2 h / 20 °C 2: palladium hydroxide (10%) on carbon; hydrogen / ethanol / 90 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1.1: glacial acetic acid / 1,2-dichloro-ethane / 0.5 h / 20 °C 1.2: 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 50 °C
Multi-step reaction with 2 steps 1: dichloromethane / 3 h / 20 °C 2: Pearlman’s catalyst / ethanol / 20 °C

  • 8
  • [ 1211568-27-2 ]
  • [ 5467-74-3 ]
  • [ 2222114-96-5 ]
YieldReaction ConditionsOperation in experiment
58.59% With copper diacetate; triethylamine In dichloromethane at 20℃; for 20h; Molecular sieve; 9 Step 9: Preparation of tert-butyl 4-((1-(4-bromophenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate Into a 250-mL 3-necked round-bottom flask, was placed tert-butyl 4-[(piperidin-4- yl)methyl]piperazine-1-carboxylate (4.27 g, 15.07 mmol, 1 equiv), (4-bromophenyl)boronic acid (3.63 g, 18.07 mmol, 1.20 equiv), dichloromethane (100 mL), 4A MS (5 g), (acetyloxy)cuprio acetate (4.10 g, 22.57 mmol, 1.50 equiv), TEA (8.4 mL, 60.43 mmol, 4.01 equiv). The resulting mixture was purged with air and stirred for 20 h at room temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 3.87 g (58.59%) of tert-butyl 4- [[1-(4-bromophenyl)piperidin-4-yl]methyl]piperazine-1-carboxylate as a light brown solid. LC/MS (ESI) m/z: 438.00 [M+1] +.
  • 9
  • [ 1211568-27-2 ]
  • [ 2500656-81-3 ]
  • [ 2500656-87-9 ]
YieldReaction ConditionsOperation in experiment
71% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20 - 50℃; for 28h; Intermediate 6c: tert-Butyl 4-((1-(5-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate DIPEA (2.80 ml, 16.1 mmol) was added to (1R,3R)-1-(2-chloropyrimidin-5-yl)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3.0 g, 8.1 mmol) and tert-butyl 4- (piperidin-4-ylmethyl)piperazine-1-carboxylate (2.75 g, 9.70 mmol) in DMSO (25 mL) at 20°C under air. The resulting suspension was stirred at 50 °C for 20 hours. The reaction was incomplete and further DIPEA (2.80 mL, 16.1 mmol) was added and the suspension was stirred at 50 °C for a further 8 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (4 x 50 mL) and saturated brine (20 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in heptane to afford the title compound (3.52 g, 71 %) as a white solid; 1H NMR (400 MHz, DMSO, 30°C) 1.00 (2H, d), 1.08 (3H, d), 1.28 (3H, d), 1.40 (12H, s), 1.75 (3H, d), 2.13 (2H, d), 2.26- 2.32 (4H, m), 2.44 - 2.49 (1H, m), 2.6- 2.9 (4H, m), 3.15 (1H, s), 3.30 (5H, s), 4.61 (2H, d), 4.91 (1H, s), 6.98 (1H, td), 7.06 (1H, td), 7.27 (1H, d), 7.43 (1H, d), 8.10 (2H, s), 10.71 (1H, s); m/z: ES+ [M+H]+ 620.5.
  • 10
  • [ 1211568-27-2 ]
  • [ 2229976-08-1 ]
  • [ 2640389-29-1 ]
YieldReaction ConditionsOperation in experiment
34.24% With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3chloro-pyridyl)palladium(II) dichloride; caesium carbonate In N,N-dimethyl-formamide at 80℃; Sealed tube; Inert atmosphere; Step 1: Synthesis of tert-butyl 4-([1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol- 4-yl]piperidin-4-yl]methyl)piperazine-1-carboxylate Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (407 mg, 1.2 equiv), 3- (7-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (386 mg, 1.00 equiv), Cs2CO3 (782 mg, 2.0 equiv), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline (50 mg, 0.05 equiv), DMF (5 mL). The resulting solution was stirred for overnight at 80oC in an oil bath. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC with the following conditions : Column, C18 silica gel; mobile phase, ACN/water (5mM NH4HCO3)=0/100 increasing to ACN/water (5mM NH4HCO3)=60/40 within 30 min . Product was obtained and concentrated under vacuum. This resulted in 215 mg (34.24%) of tert-butyl 4-([1-[2-(2,6-dioxopiperidin-3- yl)-1-oxo-3H-isoindol-4-yl]piperidin-4-yl]methyl)piperazine-1-carboxylate as a white solid
  • 11
  • [ 206551-41-9 ]
  • [ 1211568-27-2 ]
  • [ 2640388-85-6 ]
YieldReaction ConditionsOperation in experiment
25.7% With chloro(2-dicyclohexylphosphino-2‘,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II); caesium carbonate In tetrahydrofuran at 90℃; Inert atmosphere; Step 1: 1. Synthesis of tert-butyl 4-([1-[2-fluoro-3- (methoxycarbonyl)phenyl]piperidin-4-yl]methyl)piperazine-1-carboxylate Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-bromo-2-fluorobenzoate (1.0 g, 4.3 mmol, 1.0 equiv), tert-butyl 4- (piperidin-4-ylmethyl)piperazine-1-carboxylate (1.22 g, 4.3 mmol, 1.00 equiv), Cs2CO3 (4.2 g, 12.8 mmol, 3.0 equiv), RuPhosPd (0.63 g, 0.86 mmol, 0.2 equiv), tetrahydrofuran (15 mL). The resulting solution was stirred overnight at 90. After work-up, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 480 mg (25.7%) of tert-butyl 4-([1-[2-fluoro-3-(methoxycarbonyl)phenyl]piperidin-4-yl]methyl)piperazine-1- carboxylate as a yellow solid. MS (ES+): m/z 436.30[MH+].
  • 12
  • [ 1211568-27-2 ]
  • [ 835616-61-0 ]
  • [ 2229725-33-9 ]
YieldReaction ConditionsOperation in experiment
62.1% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃;
520 mg With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 4h; Sealed tube; Step 1: Preparation of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate Into a 30 mL sealed tube, was placed tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1- carboxylate (600 mg, 2.117 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3- dione (584.77 mg, 2.117 mmol, 1.0 equiv), DIEA (820.83 mg, 6.351 mmol, 3.0 equiv) in DMSO (20 ml). The resulting mixture was stirred for 4 hours at 100 °C in an oil bath. The crude product was purified by Prep-HPLC. This resulted in 520 mg of tert-butyl 4-([1-[2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl)piperazine-1-carboxylate as a yellow green solid. LC/MS (ESI) m/z: 540.25 [M+1] +.
  • 13
  • [ 1211568-27-2 ]
  • [ 2377645-90-2 ]
  • [ 76-05-1 ]
  • [ 2633635-56-8 ]
YieldReaction ConditionsOperation in experiment
150 mg Stage #1: 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 10℃; for 1h; Stage #2: tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate In N,N-dimethyl-formamide at 10℃; for 11h; Stage #3: trifluoroacetic acid 2.1 Step 1: tert-butyl 4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (E48-2) To a solution of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (Intermediate 24, 400 mg, 1.49 mmol) in DMF (5 ml) were added DIEA (385.13 mg, 2.98 mmol) and HATU (680.61 mg, 1.79 mmol) and the RM was stirred at 10 °C for 1 h. Tert- butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (E48-1, 506.37 mg, 1.79 mmol) was added and the RM was stirred at 10 °C for 11 h. The mixture was added into water (20 ml) and the aq. phase was extracted with EtOAc (4 x 20 ml). The combined organic phases were washed with brine (2 x 15 ml), dried over Na2SO4 and concentrated. The residue was triturated with a mixture of MeOH (15 ml) and DMSO (1 ml). The mixture was filtered and the solids were collected, yielding the title compound tert-butyl 4-((1-(4-chloro-3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazine-1-carboxylate, E48-2, as a solid (300 mg). The filtrate was concentrated and purified by preparative HPLC on a Phenomenex Synergi C18 column (150 x 25 mm, 10 m) eluting with ACN (from 10 % to 40 %) in an aq. solution of TFA (0.1 %), yielding the title compound tert-butyl 4-((1-(4- chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazine- 1-carboxylate, E48-2, as a solid TFA salt (150 mg). Method LCMS WX2: Rt = 0.96 min; [M+H]+ = 534.
  • 14
  • [ 1211568-27-2 ]
  • [ 2748834-11-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2.1: water; potassium hydroxide / ethanol / Reflux 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere; Heating 2.1: water; lithium hydroxide / tetrahydrofuran / 35 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h
  • 15
  • [ 1211568-27-2 ]
  • [ 2748834-12-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2.1: water; potassium hydroxide / ethanol / Reflux 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere; Heating 2.1: water; lithium hydroxide / tetrahydrofuran / 35 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C
  • 16
  • [ 1211568-27-2 ]
  • [ 2748833-71-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2.1: water; potassium hydroxide / ethanol / Reflux 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 90 °C / Inert atmosphere
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere; Heating 2.1: water; lithium hydroxide / tetrahydrofuran / 35 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 90 °C / Inert atmosphere
  • 17
  • [ 1211568-27-2 ]
  • [ 2748833-72-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2.1: water; potassium hydroxide / ethanol / Reflux 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 90 °C / Inert atmosphere
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere; Heating 2.1: water; lithium hydroxide / tetrahydrofuran / 35 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 3.2: 6 h 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 90 °C / Inert atmosphere
  • 18
  • [ 1211568-27-2 ]
  • [ 2748834-16-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2: hydrogenchloride / dichloromethane; 1,4-dioxane / 20 °C
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 90 °C 2: sodium hydroxide; lithium hydroxide monohydrate / methanol / 16 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 4: hydrogenchloride; lithium hydroxide monohydrate / 1,4-dioxane / 16 h / 20 °C
  • 19
  • [ 1211568-27-2 ]
  • [ 2748834-10-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2: water; potassium hydroxide / ethanol / Reflux
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere; Heating 2: water; lithium hydroxide / tetrahydrofuran / 35 °C
  • 20
  • [ 1211568-27-2 ]
  • [ 2748834-38-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / lithium hydroxide monohydrate; isopropanol / 6 h / 90 °C 2: lithium hydroxide monohydrate; lithium hydroxide monohydrate / tetrahydrofuran / 35 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 90 °C 2: sodium hydroxide; lithium hydroxide monohydrate / methanol / 16 h / 20 °C
  • 21
  • [ 1211568-27-2 ]
  • [ 1194-02-1 ]
  • [ 2748834-09-3 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In N,N-dimethyl-formamide at 85℃; Inert atmosphere; 7 Example 7 Raw material 35 (150mg, 1.0eq.), intermediate 20 (386mg, 1.1eq.),Potassium carbonate (340mg, 2.0eq.) was dissolved in 12mL of anhydrous N,N-dimethylformamide, protected by argon, heated to 85°C and reacted overnight.TLC detection showed that the reaction of the raw materials was complete. 20 mL of water was added to the reaction solution, extracted with ethyl acetate, the organic phase was added with anhydrous sodium sulfate, dried and concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate = 3/1-1 /1) 429 mg of white solid was obtained, and the yield was 91%.
  • 22
  • [ 1211568-27-2 ]
  • [ 2505498-73-5 ]
  • [ 2748834-15-1 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In N,N-dimethyl-formamide at 85℃; Inert atmosphere; 10 Intermediate 46 (340mg, 1.0eq.), intermediate 20 (295mg, 1.2eq.),Potassium carbonate (240mg, 2.0eq.) was dissolved in 10mL of anhydrous N,N-dimethylformamide, protected by argon, heated to 85°C and reacted overnight.TLC detection showed that the reaction of the raw materials was complete. 20 mL of water was added to the reaction solution, extracted with ethyl acetate, the organic phase was added with anhydrous sodium sulfate, dried and concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate = 3/1-1 /1) 429 mg of white solid was obtained, and the yield was 91%.
  • 23
  • [ 1211568-27-2 ]
  • [ 2748834-23-1 ]
  • [ 2748834-28-6 ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; 17 Example 17 Intermediate 55 (400mg, 1.0eq.), raw material 2 (287mg, 1.0eq.),Potassium carbonate (210mg, 1.5eq.) was dissolved in 10mL of anhydrous N,N-dimethylformamide, protected by argon, heated to 90°C and reacted overnight.TLC detects that the raw material has reacted completely, the reaction solution is concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate=4/1) to obtain 500 mg of white solid with a yield of 75%.
  • 24
  • [ 1211568-27-2 ]
  • [ 403-33-8 ]
  • [ 2748834-34-4 ]
YieldReaction ConditionsOperation in experiment
39% With potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; Heating; 21 Intermediate 68 (1.0g, 1.0eq.), intermediate 20 (1.8g, 1.0eq.),Potassium carbonate (1.3g, 1.5eq) was dissolved in 10mL of anhydrous N,N-dimethylformamide, protected by argon, heated to 90°C and reacted overnight.TLC detects that the raw material has reacted completely, the reaction solution is concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate=4/1) to obtain 1.1 g of white solid with a yield of 39%.
  • 25
  • [ 1211568-27-2 ]
  • [ 65202-50-8 ]
  • [ 2748834-37-7 ]
YieldReaction ConditionsOperation in experiment
80% With hydrogenchloride In lithium hydroxide monohydrate; isopropanol at 90℃; for 6h; 22 YMA327 experiment summary Dissolve raw material 73 (600mg, 1.0eq.) and intermediate 20 (1.2g, 1.2eq.) in 40mL of isopropanol, add 1 drop of concentrated hydrochloric acid, and increase the temperature to 90°C for 6h.TLC detects that the raw material has reacted completely, the reaction solution is concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate=3/1) to obtain 1.2 g of white solid with a yield of 80%.
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 2h;
  • 26
  • [ 89793-12-4 ]
  • [ 1211568-27-2 ]
  • [ 2748834-00-4 ]
YieldReaction ConditionsOperation in experiment
89% With hydrogenchloride In water; isopropyl alcohol at 90℃; for 6h; 3 Intermediate 20 (1.3g, 1.2eq.) and raw material 21 (0.7g, 1.0eq.) were dissolved in 40mL of isopropanol, 1 drop of concentrated hydrochloric acid was added, and the temperature was raised to 90°C for 6h.TLC detects that the raw material has reacted completely, the reaction solution is concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate=3/1) to obtain 1.5 g of white solid with a yield of 89%.
  • 27
  • [ 1211568-27-2 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
62.8% 8 8. 8. Compound t-butyl 4-((1-(5-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy) octahydropenten-2-carbamoyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate 5-Chloro-N-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy)octahydropenten-2-yl) pyrazine-2-carboxamide (30.0 mg, 0.07mmol), t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (40.1 mg, 0.14 mmol), and DIEA (27.8 mg, 0.21 mmol) were added in dioxane (2 mL). The reaction solution was heated to 100 °C and stirred for 6 h, and then cooled to room temperature. The reaction solution was added with ethyl acetate and water for extraction. The organic layer was washed with saturated brine, dried, rotatory evaporated to dry, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(5-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy)octahydropenten-2-carbamoyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (30.0 mg, 0.45 mmol), with a yield of 62.8%.
  • 28
  • [ 1211568-27-2 ]
  • [ 2505503-79-5 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
80% With N-ethyl-N,N-diisopropylamine 2 2. 2. Synthesis of compound t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1054-2) 2-Chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylsulfinyl)-5-oxo-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl) cyclobutyloxy)benzonitrile (0.68 mmol, the crude product from the previous reaction) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (193 mg, 0.68 mmol) were dissolved in dichloromethane (20 mL), to which was then added N,N-diisopropylethylamine (310 mg, 2.38 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1), to provide t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate as a yellow solid (1054-2) (365 mg, 0.54 mmol), with a two-step yield of 80%. MS: calcd. for C36H49ClO7N4 [M+H]+: 678.4; found: 678.3.
  • 29
  • [ 1211568-27-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine 2 2. 2. Synthesis of t-butyl-4-((1-(5-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy) octahydrocyclopenta[c]pyrrol-2-carbonyl)pyrazine-2-yl)piperidine-4-yl)methyl) piperazine- 1 -carboxylate 2-Chloro-4-(((3aR,5r,6aS)-2-(5-chloropyrazine-22-carbonyl)octahydrocyclopenta[c] pyrrol-5-yl)oxy)benzonitrile (185 mg, 0.46 mmol), t-butyl-4-(piperidin-4-ylmethyl) piperazine-1-carboxylate (260 mg, 0.92 mmol) and diisopropylethylamine (297 mg, 2.30 mmol) were added in 8 mL of dioxane. The reaction solution was heated to 115 °C, stirred and reacted overnight under reflux. After cooling to room temperature, the reaction solution was added with ethyl acetate and water for extraction. The organic phase was successively washed with 0.05 N HCl and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain the crude product, which was separated and purified by Pre-TLC, to provide compound butyl-4-((1-(5-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)octahydrocyclopenta[c] pyrrol-2-carbonyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (109 mg), with a yield of 37%. LC/MS (ESI+) calcd for C34H44ClN7O4 [M + H]+ m/z, 650.2; found, 650.2.
  • 30
  • [ 1211568-27-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
58.3% 4 4. 4. Synthesis of compound t-butyl 4-((1-(6-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)hexahydrocyclopenta[c]pyrrole-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate Compounds 2-chloro-4-((((3Ar,5R,6aS)-2-(6-chloropyridazine-3-carbonyl)hexahydrocyclopenta[c]pyrrole-5-yl)oxy)benzonitrile (220 mg, 0.50 mmol) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (186 mg, 0.60 mmol) were sequentially added, followed by addition of 3 mL of NMP and DIEA (211.5 mg, 1.6 mmol). Under nitrogen protection, the mixture was allowed to react overnight under stirring at 110 °C. The reaction solution was added with water and ethyl acetate for extraction. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, rotatory evaporated to dry, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(6-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)hexahydrocyclopenta[c]pyrrole-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate as pale yellow oil (207.0 mg, 0.3 mmol), with a yield of 58.3%. LC/MS (ESI+) calcd for C34H44ClN7O4 (M-56 + H+) m/z, 594.3; found, 594.3.
  • 31
  • [ 1211568-27-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate 4 4) 4) t-Butyl 4-((1-(6-((1-(3-Chloro-4-cyanobenzene)piperidine-4-yl)carbamoyl) pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate t-Butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (71 mg, 0.25 mmol) was dissolved in 5 mL of DMF, to which were successively added potassium carbonate (102 mg, 0.75 mmol) and 6-chloro-N-(1-(3-chloro-4-cyanobenzene)piperidin-4-yl)pyridazine-3-formamide (100 mg, 0.25 mmol), and the mixture was allowed to react 3 h at 80 °C. The reaction solution was cooled to room temperature, to which was added 20 mL of ethyl acetate. The resultant solution was successively washed with water and saturated bine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by thin layer chromatography, to provide the product t-butyl 4-((1-(6-((1-(3-chloro-4-cyanobenzene)piperidine-4-yl)carbamoyl) pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (140 mg), with a yield of 87.9%, LC/MS (ESI+) calcd for C33H45ClN8O3 ([M+H]+) m/z 637.3.
  • 32
  • [ 1211568-27-2 ]
  • [ 448-19-1 ]
  • [ 2764744-89-8 ]
YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In N,N-dimethyl-formamide at 60℃; 23.1 Step 2: Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (1-2) General procedure: 4-fluoro-2-methoxy-1-nitrobenzene (5.0 g, 29.22 mmol),A mixture of Boc-piperazine (6.5 g, 35.06 mmol) and potassium carbonate (6.0 g, 43.24 mmol) in N,N-dimethylformamide (43 mL) was stirred at room temperature. After stirring overnight, potassium carbonate (3.0 g) was added and the mixture was stirred for 2 days. Water was added to the reaction mixture, stirred, filtered, washed with water, and dried under vacuum to obtain the title compound (9.5 g, 96%).
  • 33
  • [ 1211568-27-2 ]
  • [ 2505501-88-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
37% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 115℃; 2. Synthesis of t-butyl-4-((1-(5-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy) octahydrocyclopenta[c]pyrrol-2-carbonyl)pyrazine-2-yl)piperidine-4-yl)methyl) piperazine- 1 -carboxylate 2-Chloro-4-(((3aR,5r,6aS)-2-(5-chloropyrazine-22-carbonyl)octahydrocyclopenta[c] pyrrol-5-yl)oxy)benzonitrile (185 mg, 0.46 mmol), t-butyl-4-(piperidin-4-ylmethyl) piperazine-1-carboxylate (260 mg, 0.92 mmol) and diisopropylethylamine (297 mg, 2.30 mmol) were added in 8 mL of dioxane. The reaction solution was heated to 115 °C, stirred and reacted overnight under reflux. After cooling to room temperature, the reaction solution was added with ethyl acetate and water for extraction. The organic phase was successively washed with 0.05 N HCl and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain the crude product, which was separated and purified by Pre-TLC, to provide compound butyl-4-((1-(5-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)octahydrocyclopenta[c] pyrrol-2-carbonyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (109 mg), with a yield of 37%. LC/MS (ESI+) calcd for C34H44ClN7O4 [M + H]+ m/z, 650.2; found, 650.2.
37% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 115℃; 2. Synthesis of t-butyl-4-((1-(5-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy) octahydrocyclopenta[c]pyrrol-2-carbonyl)pyrazine-2-yl)piperidine-4-yl)methyl) piperazine- 1 -carboxylate 2-Chloro-4-(((3aR,5r,6aS)-2-(5-chloropyrazine-22-carbonyl)octahydrocyclopenta[c] pyrrol-5-yl)oxy)benzonitrile (185 mg, 0.46 mmol), t-butyl-4-(piperidin-4-ylmethyl) piperazine-1-carboxylate (260 mg, 0.92 mmol) and diisopropylethylamine (297 mg, 2.30 mmol) were added in 8 mL of dioxane. The reaction solution was heated to 115 °C, stirred and reacted overnight under reflux. After cooling to room temperature, the reaction solution was added with ethyl acetate and water for extraction. The organic phase was successively washed with 0.05 N HCl and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain the crude product, which was separated and purified by Pre-TLC, to provide compound butyl-4-((1-(5-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)octahydrocyclopenta[c] pyrrol-2-carbonyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (109 mg), with a yield of 37%. LC/MS (ESI+) calcd for C34H44ClN7O4 [M + H]+ m/z, 650.2; found, 650.2.
  • 34
  • [ 1211568-27-2 ]
  • [ 2505502-23-6 ]
  • [ 2505502-24-7 ]
YieldReaction ConditionsOperation in experiment
58.3% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; Inert atmosphere; 4. Synthesis of compound t-butyl 4-((1-(6-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)hexahydrocyclopenta[c]pyrrole-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate Compounds 2-chloro-4-((((3Ar,5R,6aS)-2-(6-chloropyridazine-3-carbonyl)hexahydrocyclopenta[c]pyrrole-5-yl)oxy)benzonitrile (220 mg, 0.50 mmol) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (186 mg, 0.60 mmol) were sequentially added, followed by addition of 3 mL of NMP and DIEA (211.5 mg, 1.6 mmol). Under nitrogen protection, the mixture was allowed to react overnight under stirring at 110 °C. The reaction solution was added with water and ethyl acetate for extraction. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, rotatory evaporated to dry, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(6-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)hexahydrocyclopenta[c]pyrrole-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate as pale yellow oil (207.0 mg, 0.3 mmol), with a yield of 58.3%. LC/MS (ESI+) calcd for C34H44ClN7O4 (M-56 + H+) m/z, 594.3; found, 594.3.
58.3% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; Inert atmosphere; 4. Synthesis of compound t-butyl 4-((1-(6-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)hexahydrocyclopenta[c]pyrrole-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate Compounds 2-chloro-4-((((3Ar,5R,6aS)-2-(6-chloropyridazine-3-carbonyl)hexahydrocyclopenta[c]pyrrole-5-yl)oxy)benzonitrile (220 mg, 0.50 mmol) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (186 mg, 0.60 mmol) were sequentially added, followed by addition of 3 mL of NMP and DIEA (211.5 mg, 1.6 mmol). Under nitrogen protection, the mixture was allowed to react overnight under stirring at 110 °C. The reaction solution was added with water and ethyl acetate for extraction. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, rotatory evaporated to dry, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(6-((3aR,5r,6aS)-5-(3-chloro-4-cyanophenoxy)hexahydrocyclopenta[c]pyrrole-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate as pale yellow oil (207.0 mg, 0.3 mmol), with a yield of 58.3%. LC/MS (ESI+) calcd for C34H44ClN7O4 (M-56 + H+) m/z, 594.3; found, 594.3.
  • 35
  • [ 1211568-27-2 ]
  • [ 2505502-92-9 ]
  • [ 2505502-93-0 ]
YieldReaction ConditionsOperation in experiment
62.8% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 6h; 8. Compound t-butyl 4-((1-(5-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy) octahydropenten-2-carbamoyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate 5-Chloro-N-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy)octahydropenten-2-yl) pyrazine-2-carboxamide (30.0 mg, 0.07mmol), t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (40.1 mg, 0.14 mmol), and DIEA (27.8 mg, 0.21 mmol) were added in dioxane (2 mL). The reaction solution was heated to 100 °C and stirred for 6 h, and then cooled to room temperature. The reaction solution was added with ethyl acetate and water for extraction. The organic layer was washed with saturated brine, dried, rotatory evaporated to dry, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(5-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy)octahydropenten-2-carbamoyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (30.0 mg, 0.45 mmol), with a yield of 62.8%.
62.8% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 6h; 8. Compound t-butyl 4-((1-(5-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy) octahydropenten-2-carbamoyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate 5-Chloro-N-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy)octahydropenten-2-yl) pyrazine-2-carboxamide (30.0 mg, 0.07mmol), t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (40.1 mg, 0.14 mmol), and DIEA (27.8 mg, 0.21 mmol) were added in dioxane (2 mL). The reaction solution was heated to 100 °C and stirred for 6 h, and then cooled to room temperature. The reaction solution was added with ethyl acetate and water for extraction. The organic layer was washed with saturated brine, dried, rotatory evaporated to dry, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(5-((2s,3aR,5R,6aS)-5-(3-chloro-4-cyanophenoxy)octahydropenten-2-carbamoyl)pyrazine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (30.0 mg, 0.45 mmol), with a yield of 62.8%.
  • 36
  • [ 1211568-27-2 ]
  • [ 2505503-79-5 ]
  • [ 2505503-80-8 ]
YieldReaction ConditionsOperation in experiment
365 mg With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; 2. Synthesis of compound t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1054-2) 2-Chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylsulfinyl)-5-oxo-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl) cyclobutyloxy)benzonitrile (0.68 mmol, the crude product from the previous reaction) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (193 mg, 0.68 mmol) were dissolved in dichloromethane (20 mL), to which was then added N,N-diisopropylethylamine (310 mg, 2.38 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1), to provide t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate as a yellow solid (1054-2) (365 mg, 0.54 mmol), with a two-step yield of 80%. MS: calcd. for C36H49ClO7N4 [M+H]+: 678.4; found: 678.3.
365 mg With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; 2. Synthesis of compound t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate (1054-2) 2-Chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylsulfinyl)-5-oxo-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl) cyclobutyloxy)benzonitrile (0.68 mmol, the crude product from the previous reaction) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (193 mg, 0.68 mmol) were dissolved in dichloromethane (20 mL), to which was then added N,N-diisopropylethylamine (310 mg, 2.38 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1), to provide t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate as a yellow solid (1054-2) (365 mg, 0.54 mmol), with a two-step yield of 80%. MS: calcd. for C36H49ClO7N4 [M+H]+: 678.4; found: 678.3.
  • 37
  • [ 1211568-27-2 ]
  • [ 2505504-63-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
61% With potassium carbonate In N,N-dimethyl-formamide at 80℃; 1. Compound t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-22-yl) piperidine-4-yl)methyl)piperazine-1-carboxylic acid 2-Chloro-4-((1r,3r)-3-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyrazine-26(7H)-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (200 mg, 0.46 mmol) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (328 mg, 1.16 mmol) were dissolved in N,N-dimethylformamide (5 mL), to which was then added potassium carbonate (190 mg, 1.38 mmol). The reaction solution was heated to 80 °C and allowed to react overnight under stirring. The reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL * 3). The organic phase was combined and washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane: methanol = 100:1 to 20:1) to obtain a yellow solid t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-22-yl) piperidine-4-yl)methyl)piperazine-1-carboxylate (1056-1) (190 mg, 0.28 mmol), with a yield of 61%. MS: calcd. for C36H49ClO7N4 [M+H]+: 678.4; found: 678.3.
61% With potassium carbonate In N,N-dimethyl-formamide at 80℃; 1. Compound t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-22-yl) piperidine-4-yl)methyl)piperazine-1-carboxylic acid 2-Chloro-4-((1r,3r)-3-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyrazine-26(7H)-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (200 mg, 0.46 mmol) and t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (328 mg, 1.16 mmol) were dissolved in N,N-dimethylformamide (5 mL), to which was then added potassium carbonate (190 mg, 1.38 mmol). The reaction solution was heated to 80 °C and allowed to react overnight under stirring. The reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL * 3). The organic phase was combined and washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane: methanol = 100:1 to 20:1) to obtain a yellow solid t-butyl 4-((1-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-22-yl) piperidine-4-yl)methyl)piperazine-1-carboxylate (1056-1) (190 mg, 0.28 mmol), with a yield of 61%. MS: calcd. for C36H49ClO7N4 [M+H]+: 678.4; found: 678.3.
  • 38
  • [ 1211568-27-2 ]
  • [ 2505500-97-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
87.9% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; 4) t-Butyl 4-((1-(6-((1-(3-Chloro-4-cyanobenzene)piperidine-4-yl)carbamoyl) pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate t-Butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (71 mg, 0.25 mmol) was dissolved in 5 mL of DMF, to which were successively added potassium carbonate (102 mg, 0.75 mmol) and 6-chloro-N-(1-(3-chloro-4-cyanobenzene)piperidin-4-yl)pyridazine-3-formamide (100 mg, 0.25 mmol), and the mixture was allowed to react 3 h at 80 °C. The reaction solution was cooled to room temperature, to which was added 20 mL of ethyl acetate. The resultant solution was successively washed with water and saturated bine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by thin layer chromatography, to provide the product t-butyl 4-((1-(6-((1-(3-chloro-4-cyanobenzene)piperidine-4-yl)carbamoyl) pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (140 mg), with a yield of 87.9%, LC/MS (ESI+) calcd for C33H45ClN8O3 ([M+H]+) m/z 637.3.
87.9% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; 4) t-Butyl 4-((1-(6-((1-(3-Chloro-4-cyanobenzene)piperidine-4-yl)carbamoyl) pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate t-Butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (71 mg, 0.25 mmol) was dissolved in 5 mL of DMF, to which were successively added potassium carbonate (102 mg, 0.75 mmol) and 6-chloro-N-(1-(3-chloro-4-cyanobenzene)piperidin-4-yl)pyridazine-3-formamide (100 mg, 0.25 mmol), and the mixture was allowed to react 3 h at 80 °C. The reaction solution was cooled to room temperature, to which was added 20 mL of ethyl acetate. The resultant solution was successively washed with water and saturated bine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by thin layer chromatography, to provide the product t-butyl 4-((1-(6-((1-(3-chloro-4-cyanobenzene)piperidine-4-yl)carbamoyl) pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (140 mg), with a yield of 87.9%, LC/MS (ESI+) calcd for C33H45ClN8O3 ([M+H]+) m/z 637.3.
  • 39
  • [ 1211568-27-2 ]
  • [ 2505501-27-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
40% With N-ethyl-N,N-diisopropylamine at 110℃; 4. Synthesis of compound t-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptan-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methylpiperazine-1-amide Compounds 2-chloro-4-((2-(6-chloropyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)benzonitrile (222 mg, 0.57 mmol), t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (323 mg, 1.14 mmol), and DIPEA (221 mg, 1.71 mmol) were dissolved in 2 mL of DOX, and the reaction solution was stirred overnight at 110 °C. The reaction solution was added with water, and then extracted with ethyl acetate. The organic phase was washed three times with the saturated solution of ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptan-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methylpiperazine-1-amide(150 mg, 0.23 mmol), with a yield of 40%. LC/MS (ESI+) calcd for C33H42ClN7O4+ [M + H]+ m/z, 636.3; found 636.3.
40% With N-ethyl-N,N-diisopropylamine at 110℃; 4. Synthesis of compound t-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptan-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methylpiperazine-1-amide Compounds 2-chloro-4-((2-(6-chloropyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)benzonitrile (222 mg, 0.57 mmol), t-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (323 mg, 1.14 mmol), and DIPEA (221 mg, 1.71 mmol) were dissolved in 2 mL of DOX, and the reaction solution was stirred overnight at 110 °C. The reaction solution was added with water, and then extracted with ethyl acetate. The organic phase was washed three times with the saturated solution of ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography, to provide compound t-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptan-2-carbonyl)pyridazine-3-yl)piperidine-4-yl)methylpiperazine-1-amide(150 mg, 0.23 mmol), with a yield of 40%. LC/MS (ESI+) calcd for C33H42ClN7O4+ [M + H]+ m/z, 636.3; found 636.3.
  • 40
  • [ 1211568-27-2 ]
  • [ 177363-10-9 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 12h;
  • 41
  • [ 1211568-27-2 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃;
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃;
  • 42
  • [ 1211568-27-2 ]
  • [ 2108096-60-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With Cs2CO3 In toluene at 100℃; for 16h;
With Cs2CO3 In toluene at 100℃; for 16h;
  • 43
  • [ 19099-93-5 ]
  • [ 1211568-27-2 ]
  • [ 2776895-42-0 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: benzyl 4-oxopiperidine-1-carboxylate; tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate In dichloromethane at 20℃; for 2h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 12h; 40.1 The first step: benzyl 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate (40b)benzyl 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-[1,4'-bipiperidine]-1'-carboxylate 4-(Piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (see WO2020201080 for the synthesis method) (300 mg, 1.06 mmol) andBenzyl 4-oxopiperidine-1-carboxylate (40a) (350 mg, 1.5 mmol) was added to 20 mL of dichloromethane, respectively, and reacted at room temperature for 2 h, then sodium triacetoxyborohydride (317 mg, 1.5 mmol) was added, and the room temperature The reaction was carried out for 12h. 50mL of dichloromethane and 50mL of 1mol/L sodium hydroxide aqueous solution were added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v /v)=10:1-1:1) to give 40b (400 mg, yield: 75%).
  • 44
  • [ 1211568-27-2 ]
  • [ 2376679-20-6 ]
  • [ 2776894-35-8 ]
YieldReaction ConditionsOperation in experiment
0.1 g Stage #1: tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate With N,N`-sulfuryldiimidazole; methyl trifluoromethanesulfonate In dichloromethane; acetonitrile at 20℃; for 18h; Inert atmosphere; Stage #2: 2-amino-5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)benzamide In dichloromethane at 90℃; for 18h; Inert atmosphere; 1.1 The first step: 4-[(1-[(4-chloro-2-[(2-chloro-4-(trifluoromethyl)phenyl)carbamoyl]phenyl)aminosulfonyl]piperidine-4 -yl)methyl]piperazine-1-carboxylate tert-butyl ester (1b)tert-butyl 4-[(1-[(4-chloro-2-[(2-chloro-4-(trifluoromethyl)phenyl)carbamoyl]phenyl)sulfamoyl]piperidin-4-yl)methyl]piperazine-1-carboxylate 1,1'-sulfonyldiimidazole (4.0 g, 20.2 mmol) was dissolved in 50 mL of dichloromethane, cooled to 0 °C under nitrogen protection, and methyl trifluoromethanesulfonate (3.65 g, 22.2 mmol) was slowly added After the addition, the temperature was raised to room temperature for 3h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 mL of acetonitrile, and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (4.0 g, 14.1 mmol) was added (see WO2019195609 for the synthesis method), The reaction was carried out at room temperature for 18h. The reaction solution was concentrated under reduced pressure, 200 mL of dichloromethane and 50 mL of water were added to the residue, and the layers were separated. The organic layer was washed with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product obtained after concentration under reduced pressure was separated by silica gel column chromatography. Purification (petroleum ether/ethyl acetate (v/v)=4:1-1:4) yielded 2.4 g of intermediate. The intermediate (0.6 g) was dissolved in 10 mL of dichloromethane, cooled to 0° C. under nitrogen protection, methyl trifluoromethanesulfonate (0.26 g, 1.58 mmol) was added, and the temperature was raised to room temperature for 3 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of acetonitrile, 2-amino-5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)benzamide (1a) (0.350 g was added) , 1.00 mmol) (see WO2019179436 for the synthesis method), the reaction was heated to 90° C. and stirred for 18 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:2) to obtain 1b (0.1 g, yield calculated from compound 1a: 14%).
  • 45
  • [ 1211568-27-2 ]
  • [ 105258-93-3 ]
  • [ 2776895-63-5 ]
YieldReaction ConditionsOperation in experiment
70% Stage #1: tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate; benzyl 3-oxoazetidine-1-carboxylate In dichloromethane at 20℃; for 2h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 12h; 47.1 The first step: tert-butyl 4-((1-(1-((benzyloxy)carbonyl)azetidin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate ( 47b)tert-butyl 4-((1-(1-((benzyloxy)carbonyl)azetidin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate The tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (see WO2020201080 for the synthesis method) (300 mg, 1.06 mmol) and benzyl 3-oxazetidine-1-carboxylate ( 307 mg, 1.5 mmol) were respectively added to 20 mL of dichloromethane, and after stirring at room temperature for 2 h, sodium triacetoxyborohydride (317 mg, 1.5 mmol) was added, and the reaction was carried out at room temperature for 12 h. 50mL of dichloromethane and 50mL of 1mol/L sodium hydroxide aqueous solution were added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v )=10:1) to give 47b (350 mg, yield: 70%).
  • 46
  • [ 1211568-27-2 ]
  • [ 2776894-62-1 ]
  • [ 2776895-38-4 ]
YieldReaction ConditionsOperation in experiment
78% With Potassium bicarbonate In N,N-dimethyl-formamide at 70℃; for 2h; 39.1 The first step: 4-((1-(4-((4-(2-(3-(3-chloro-5-cyanophenyl)prop-2-yl)phenoxy)methyl)pyrimidine- 2-yl)piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (39a)tert-butyl 4-((1-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)piperidin-4-yl) methyl)piperazine-1-carboxylate 9d (200 mg, 0.5 mmol) was dissolved in 5 mL DMF,4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (see WO2020201080 for the synthesis method) (200 mg, 0.7 mmol) and solid potassium bicarbonate (138 mg, 1.38 mmol) were added successively, and the temperature was raised to 70 reaction 2h. Cooled to room temperature, added 30 mL of water, extracted twice with 30 mL of ethyl acetate, the organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v)=1:1) to give 39a (250 mg, yield: 78%).
  • 47
  • [ 1211568-27-2 ]
  • [ 1627093-41-7 ]
  • [ 2839669-54-2 ]
YieldReaction ConditionsOperation in experiment
68.02 % With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; 1; 4 Step 4 To a solution of tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (98.63 mg, 348.03 umol, 1.5 eq) and 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2- yl]methoxy]ethyl-trimethyl-silane (100 mg, 232.02 umol, 1 eq) in DMSO (3 mL) was added DIEA (89.96 mg, 696.05 umol, 121.24 uL, 3 eq). The mixture was stirred at 100 °C for 1 hr. LC- MS (EB2049-126-P1B) showed Reactant 1 was consumed completely and desired mass was detected. The mixture was cooled to room temperature and concentrated, and then the residue was quenched with sat.NaHCO3 (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (30 mL x 2), brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ether gradient 45 mL/min) to afford tert-butyl 4-[[1-[6-[5-(1-methylcyclopropoxy)-2-(2- trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]-4-piperidyl]methyl]piperazine-1- carboxylate (107 mg, 157.83 umol, 68.02% yield) as a light yellow oil.
68.02 % With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; 1; 4 Step 4 To a solution of tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (98.63 mg, 348.03 umol, 1.5 eq) and 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2- yl]methoxy]ethyl-trimethyl-silane (100 mg, 232.02 umol, 1 eq) in DMSO (3 mL) was added DIEA (89.96 mg, 696.05 umol, 121.24 uL, 3 eq). The mixture was stirred at 100 °C for 1 hr. LC- MS (EB2049-126-P1B) showed Reactant 1 was consumed completely and desired mass was detected. The mixture was cooled to room temperature and concentrated, and then the residue was quenched with sat.NaHCO3 (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (30 mL x 2), brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ether gradient 45 mL/min) to afford tert-butyl 4-[[1-[6-[5-(1-methylcyclopropoxy)-2-(2- trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]-4-piperidyl]methyl]piperazine-1- carboxylate (107 mg, 157.83 umol, 68.02% yield) as a light yellow oil.
  • 48
  • [ 1211568-27-2 ]
  • [ 2409005-96-3 ]
  • [ 2839670-85-6 ]
YieldReaction ConditionsOperation in experiment
With Pd-PEPPSI-IPent; caesium carbonate In dimethyl sulfoxide at 100℃; Inert atmosphere; 8 Step 8 To a solution of 3-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (300 mg, 0.88 mmol, 1 eq), tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (299 mg, 1.06 mmol, 1.2 eq) in dimethylsulfoxide (6 mL) was added cesium carbonate (573 mg, 1.76 mmol, 2 eq) and Pd- PEPPSI-pent C1-O-picoline, (85 mg, 0.09 mmol, 0.1 eq) under nitrogen. The reaction was stirred at 100°C for 12 hours. LCMS showed desired MS was detected. dichloromethane (20 mL) and water (20 mL) was added to the mixture, the aqueous phase was extracted with dichloromethane (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The resdiue was purified by prep-TLC (dichloromethane: methanol = 10:1). tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1-oxo- isoindolin-5-yl]-4-piperidyl]methyl]piperazine-1-carboxylate (120 mg, 0.20 mmol, 23% yield, 93% purity) was obtained as a gray solid.
With Pd-PEPPSI-IPent; caesium carbonate In dimethyl sulfoxide at 100℃; Inert atmosphere; 8 Step 8 To a solution of 3-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (300 mg, 0.88 mmol, 1 eq), tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (299 mg, 1.06 mmol, 1.2 eq) in dimethylsulfoxide (6 mL) was added cesium carbonate (573 mg, 1.76 mmol, 2 eq) and Pd- PEPPSI-pent C1-O-picoline, (85 mg, 0.09 mmol, 0.1 eq) under nitrogen. The reaction was stirred at 100°C for 12 hours. LCMS showed desired MS was detected. dichloromethane (20 mL) and water (20 mL) was added to the mixture, the aqueous phase was extracted with dichloromethane (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The resdiue was purified by prep-TLC (dichloromethane: methanol = 10:1). tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-6-fluoro-1-oxo- isoindolin-5-yl]-4-piperidyl]methyl]piperazine-1-carboxylate (120 mg, 0.20 mmol, 23% yield, 93% purity) was obtained as a gray solid.
  • 49
  • [ 1211568-27-2 ]
  • [ 2241583-38-8 ]
  • [ 2839671-54-2 ]
YieldReaction ConditionsOperation in experiment
61.67 % With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 95℃; 2 Step 2 To a solution of 2-(2,6-dioxo-3-piperidyl)-4,7-difluoro-isoindoline-1,3-dione (2.18 g, 7.41 mmol, 1 eq) and tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (2.10 g, 7.41 mmol, 1 eq) in DMSO (10 mL) was added DIEA (2.87 g, 22.23 mmol, 3.87 mL, 3 eq), then stirred at 95 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was acidified by formic acid until pH 5~6, then poured into water (10mL). The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (5 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=0/1) to afford tert-butyl 4-[[1-[2-(2,6-dioxo-3- piperidyl)-7-fluoro-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]piperazine-1-carboxylate (2.6 g, 4.57 mmol, 61.67% yield, 98% purity) as yellow solid.
61.67 % With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 95℃; 2 Step 2 To a solution of 2-(2,6-dioxo-3-piperidyl)-4,7-difluoro-isoindoline-1,3-dione (2.18 g, 7.41 mmol, 1 eq) and tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (2.10 g, 7.41 mmol, 1 eq) in DMSO (10 mL) was added DIEA (2.87 g, 22.23 mmol, 3.87 mL, 3 eq), then stirred at 95 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was acidified by formic acid until pH 5~6, then poured into water (10mL). The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (5 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=0/1) to afford tert-butyl 4-[[1-[2-(2,6-dioxo-3- piperidyl)-7-fluoro-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl]piperazine-1-carboxylate (2.6 g, 4.57 mmol, 61.67% yield, 98% purity) as yellow solid.
  • 50
  • [ 1211568-27-2 ]
  • [ 2222115-19-5 ]
  • [ 2839671-68-8 ]
YieldReaction ConditionsOperation in experiment
780 mg With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 60℃; 3 Step 3 To a solution of 2-(2,6-dioxo-3-piperidyl)-4,5-difluoro-isoindoline-1,3-dione (1 g, 3.40 mmol, 1 eq) and tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (1.00 g, 3.53 mmol, 1.04 eq) in DMSO (20 mL) was added DIEA (1.32 g, 10.20 mmol, 1.78 mL, 3 eq). After addition, the reaction mixture was stirred at 60°C for 1h. LCMS showed the reaction completed. After cooling, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine (30 mL *3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate in petroleum ether) to afford tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-5-fluoro-1,3-dioxo-isoindolin-4-yl]-4- piperidyl]methyl]piperazine-1-carboxylate (780 mg, 1.40 mmol, 41.15% yield) as a yellow solid.
780 mg With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 60℃; 3 Step 3 To a solution of 2-(2,6-dioxo-3-piperidyl)-4,5-difluoro-isoindoline-1,3-dione (1 g, 3.40 mmol, 1 eq) and tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (1.00 g, 3.53 mmol, 1.04 eq) in DMSO (20 mL) was added DIEA (1.32 g, 10.20 mmol, 1.78 mL, 3 eq). After addition, the reaction mixture was stirred at 60°C for 1h. LCMS showed the reaction completed. After cooling, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine (30 mL *3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate in petroleum ether) to afford tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidyl)-5-fluoro-1,3-dioxo-isoindolin-4-yl]-4- piperidyl]methyl]piperazine-1-carboxylate (780 mg, 1.40 mmol, 41.15% yield) as a yellow solid.
Same Skeleton Products
Historical Records