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Chemical Structure| 305329-97-9 Chemical Structure| 305329-97-9
Chemical Structure| 305329-97-9

1-Boc-3-(bromomethyl)pyrrolidine

CAS No.: 305329-97-9

4.5 *For Research Use Only !

Cat. No.: A117494 Purity: 97%

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Product Details of [ 305329-97-9 ]

CAS No. :305329-97-9
Formula : C10H18BrNO2
M.W : 264.16
SMILES Code : BrCC1CN(C(OC(C)(C)C)=O)CC1
MDL No. :MFCD06410515
InChI Key :NQNGQGISAMHLST-UHFFFAOYSA-N
Pubchem ID :24730280

Safety of [ 305329-97-9 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302+H312-H314
Precautionary Statements:P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P362+P364-P405-P501
Class:8
UN#:1760
Packing Group:

Calculated chemistry of [ 305329-97-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 0
Fraction Csp3 0.9
Num. rotatable bonds 4
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 64.46
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

29.54 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

3.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.26
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.26
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.15
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.8
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.29

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.64
Solubility 0.609 mg/ml ; 0.0023 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.52
Solubility 0.804 mg/ml ; 0.00304 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.25
Solubility 1.47 mg/ml ; 0.00557 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.31 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.13

Application In Synthesis of [ 305329-97-9 ]

* 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 [ 305329-97-9 ]

[ 305329-97-9 ] Synthesis Path-Downstream   1~30

  • 1
  • [ 305329-96-8 ]
  • [ 305329-97-9 ]
  • 2
  • [ 305329-97-9 ]
  • [ 105-53-3 ]
  • [ 305329-98-0 ]
  • 3
  • [ 305329-97-9 ]
  • [ 305329-99-1 ]
  • 4
  • [ 85310-69-6 ]
  • [ 305329-97-9 ]
  • 5
  • [ 5731-17-9 ]
  • [ 305329-97-9 ]
  • 6
  • [ 5733-86-8 ]
  • [ 305329-97-9 ]
  • 7
  • [ 114214-69-6 ]
  • [ 305329-97-9 ]
YieldReaction ConditionsOperation in experiment
55% With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 18h; To a solution of 1 ,1 -dimethylethyl 3-(hydroxymethyl)-1 - pyrrolidinecarboxylate (0.56 g, 2.8 mmol) with carbon tetrabromide (1.39 g, 4.2 mmol) in methylene chloride (10 ml_) was added drop wise a solution of triphenyl phosphine (0.73 g, 2.8 mmol in 5 mL of methylene chloride). Upon completion the mixture was stirred 18 h at room temperature. The solvent was removed at reduced pressure and the residue stirred in 10% ethyl acetate 90% hexane. The <n="54"/>mixture was filtered and the resulting solution chromatographed on silica eluting with a gradient of 0 - 25% EtOAc in hexane to afford the desired compound (0.41 g, 55%). MS (ES+) m/z 264 (M+H)+.
55% With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 18h; To a solution of 1 ,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.56 g, 2.8 mmol) with carbon tetrabromide (1.39 g, 4.2 mmol) in methylene chloride (10 ml.) was added drop wise a solution of triphenyl phosphine (0.73 g, 2.8 mmol in 5 ml. of methylene chloride). Upon completion the mixture was stirred 18 h at room temperature. The solvent was removed at reduced pressure and the residue stirred in 10% ethyl acetate 90% hexane. The mixture was filtered and the resulting solution chromatographed on silica eluting with a gradient of 0 - 25% EtOAc in hexane to afford the desired compound (0.41 g, 55%). MS (ES+) m/z 264 (M+H)+.
  • 8
  • [ 305329-97-9 ]
  • [ 842149-46-6 ]
  • [ 937174-89-5 ]
YieldReaction ConditionsOperation in experiment
69% A mixture consisting of intermediate VII (100 mg, 0.35mmol) in DMF (2 mL) with cesium carbonate (290 mg, 0.9 mmol) and the compound of Example 5(a) (290 mg, 1.1 mmol) was stirred at room temperature for 24 h. The mixture was poured into rapidly stirring ice water (7 mL) and stirring continued for 10 min. To this was added cyclohexane (7 mL) and stirring continued for an additional 20 min. The solid was collected by filtration then washed with cyclohexane and dried in vacuo to afford the desired compound (111 mg, 69%). MS (ES+) m/z 464 (M+H)+.
69% With caesium carbonate; In cyclohexane; N,N-dimethyl-formamide; at 0 - 20℃; for 44.5h; A mixture consisting of intermediate VII (100 mg, 0.35mmol) in DMF (2 ml.) with cesium carbonate (290 mg, 0.9 mmol) and the compound of Example 5(a) (290 mg, 1.1 mmol) was stirred at room temperature for 44 h. The mixture was poured into rapidly stirring ice water (7 ml.) and stirring continued for 10 min. To this was added cyclohexane (7 ml.) and stirring continued for an additional 20 min. The solid was <n="48"/>collected by filtration then washed with cyclohexane and dried in vacuo to afford the desired compound (11 1 mg, 69%). MS (ES+) m/z 464 (M+H)+.
  • 9
  • [ 305329-97-9 ]
  • [ 1174717-99-7 ]
  • 2-(4-chlorophenyl)-4-(N-Boc-3-tetrahydropyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Step 1 DMPU (225ml), FeCl3(0.75 g) and CuCl (0.3 g) are added to N-Boc-3-bromomethylpyrrole (24.75g, 0.138mol), and then Et2Zn (106.8ml) is slowly dropped at 40~45 C for 45 minutes to obtain a zinc-reagent. THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl) -thieno [2,3-d] pyridazinyl-7-ethyl formate (30g), and then the zinc-reagent is added to the THF solution at 45C for 4h. The reaction mixture is poured into a saturated brine, filtrated after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined together, washed with a saturated brine (500ml, 3 times) and dried with anhydrous Na2SO4, ands evaporated under reduced pressure to remove solvent to obtain 2-(4-chlorophenyl)-4-(N-Boc-3-tetrahydropyrrolemethyl)-thieno[2,3-d] pyridazinyl -7-ethyl formate (25g). MS (ESI): 502(M+1)
  • 10
  • [ 305329-97-9 ]
  • [ 1384875-67-5 ]
  • [ 1384875-83-5 ]
YieldReaction ConditionsOperation in experiment
Intermediate 25 :N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamide4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7- carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 ml.) and added Cs2C03 (1.42 mmol) and tert-butyl 3-(bromomethyl)pyrrolidine-l- carboxylate (0.85 mmol). Stirred at 45C for 16h and then added H20 (2 ml_). Extracted with EtOAc (3 x 2 ml.) and the combined organic phases were concentrated in vacuo. The residual oil was treated with a mixture of l,l,l,3,3,3-hexafluoro-2- propanol : 2,2,2-trifluoroethanol (3 : 1, 4 ml.) at 150C for 2h. The crude reaction mixture was concentrated on celite in vacuo and purified by standard column chromatography using methanol in DCM as eluent. The obtained compound was recrystallized in methanol : EtOAc affording the title compound as solid.LC-MS: 1.59 min, ES (+), m/z: 406.202
  • 11
  • [ 305329-97-9 ]
  • [ 151266-23-8 ]
  • tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine-1-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; In N,N-dimethyl acetamide; water; at 85℃; for 3h; [00316] A suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (4.5 g, 17.24 mmol, 1.0 equiv), tert-butyl 3 -(bromomethyl)pyrrolidine-l -carboxylate (4.78 g, 18.10 mmol, 1.05 equiv) and K2CO3 (7.15 g, 51.72 mmol, 3.0 equiv) in DMA (40 mL) was heated to 85 C. The reaction was stirred at 85 C for 3 h, at which point the solution was cooled to room temperature. Then, H2O (80 mL) was added to the reaction, and a solid precipitated out. The mixture was filtered, and the solid cake was washed with H2O (2 x 40 mL), and then dried under reduced pressure to give tert-butyl 3-((4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l- yl) methyl)pyrrolidine-l -carboxylate (6 g, 78% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C15H21IN6O2: 445.08; found: 445.1.
78% With potassium carbonate; In N,N-dimethyl acetamide; at 85℃; for 3h; A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.5 g, 17.24 mmol, 1.0 equiv), <strong>[305329-97-9]tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate</strong> (4.78 g, 18.10 mmol, 1.05 equiv) and K2CO3 (7.15 g, 51.72 mmol, 3.0 equiv) in DMA (40 mL) was heated to 85 C. The reaction was stirred at 85 C for 3 h, at which point the solution was cooled to room temperature. Then, H2O (80 mL) was added to the reaction, and a solid precipitated out. The mixture was filtered, and the solid cake was washed with H2O (2 x 40 mL), and then dried under reduced pressure to give tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- yl) methyl)pyrrolidine-1-carboxylate (6 g, 78% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C15H21IN6O2: 445.08; found 445.1.
With potassium carbonate; In N,N-dimethyl acetamide; at 85℃; for 3h; A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.5 g, 17.24 mmol, 1.0 equiv), <strong>[305329-97-9]tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate</strong> (4.78 g, 18.10 mmol, 1.05 equiv) and K2CO3 (7.15 g, 51.72 mmol, 3.0 equiv) in DMA (40 mL) was heated to 85 C. The reaction was stirred at 85 C for 3 h, at which point the solution was cooled to room temperature. Then, H2O (80 mL) was added to the reaction, and a solid precipitated out. The mixture was filtered, and the solid cake was washed with H2O (2 x 40 mL), and then dried under reduced pressure to give tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- yl) methyl)pyrrolidine-1-carboxylate (6 g, 78% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C15H21IN6O2: 445.08; found 445.1.
  • 12
  • [ 305329-97-9 ]
  • 5-(5-methylfuran-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one [ No CAS ]
  • tert-butyl 3-((5-(5-methylfuran-2-yl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
16% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h; General procedure: Potassium carbonate (0.145 mmol) was added to a solution of the appropriate amide (0.048 mmol) and an alkyl halide (0.058 mmol), in DMF (300 muL) and stirred at 80C for 4 h. The reaction mixture was added to water (5mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography to give the desired product.
  • 13
  • [ 305329-97-9 ]
  • C17H22N6O4 [ No CAS ]
  • [ 814-68-6 ]
  • C20H25N7O3 [ No CAS ]
  • 14
  • [ 305329-97-9 ]
  • C17H22N6O4 [ No CAS ]
  • [ 814-68-6 ]
  • C20H25N7O3 [ No CAS ]
  • 15
  • [ 305329-97-9 ]
  • 9-chloro-2-methoxyacridin-3-ol [ No CAS ]
  • tert-butyl 3-[[(9-chloro-2-methoxyacridin-3-yl)oxy]methyl]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 16h; into a 50mL roundbottom flask, was placed a mixture of tertbuty1 3-(bromomethyi)pyrrolidine-i--carboxyiate (230 mg, 0.87 mmol, 1.00 eq.), DMF (10 mL), 9-chloro-2--methoxyacridin-3-ol (226 mg, 0.87 mmoi, I.0() eq.), potassium carbonate (240 mg, 174 mmol, 200eq.) and KI (290 mg, 1.74 mmol, 2.00 eq.). The resulting mixture was stirred at 100 C for 16 h . Themixture was diluted with water (50 mL) and extracted with ethyl acetate thirce. The combinedorganic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/2) to provide tert.-butyi 3 -[[(9chioro2-.methoxyacdin.-3 yl)oxyimethyi1pyrrolidine- 1- carhoxylate as a yellow solid. LCMS ES) [M±ij m/z 4432.
  • 16
  • [ 305329-97-9 ]
  • [ 1151650-79-1 ]
  • 3-(3-chlorophenoxy)-1-(pyrrolidin-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
  • 17
  • [ 305329-97-9 ]
  • [ 937174-90-8 ]
  • 18
  • [ 305329-97-9 ]
  • 4-{2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3-pyrrolinylmethyl)oxy]-1H-imidazo[4,5-c]pyridin-4-yl}-2-methyl-3-butyn-2-ol bistrifluoroacetate [ No CAS ]
  • 19
  • [ 305329-97-9 ]
  • [ 856250-60-7 ]
  • 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • tert-butyl 3-((4-(1-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]
  • tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step.
  • 20
  • [ 305329-97-9 ]
  • [ 856250-60-7 ]
  • 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • 1-(5-fluoro-6-methoxypyridin-3-yl)-3-(1-(pyrrolidin-3-ylmethyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(1-(pyrrolidin-3-ylmethyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification.
  • 21
  • [ 558-30-5 ]
  • [ 305329-97-9 ]
  • [ 856250-60-7 ]
  • 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • 1-(3-((4-(1-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)-2-methylpropan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 37. l-(3-((4-(l-(5-Fluoro-6-methoxypyridin-3-yl)-4.5.7.8-tetrahydro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)-2-methylpropan-2- ol A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lW-pyrazol- 4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l- (pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (100 mg), 2,2- dimethyloxirane (0.065 mL, 0.727 mmol), DIPEA (0.085 ml_, 0.485 mmol) in EtOH (2 mL) was heated using a microwave at 70 C for 1 h. The reaction mixture was treated with MeOH (1 m), co...
  • 22
  • [ 305329-97-9 ]
  • [ 856250-60-7 ]
  • 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • [ 15448-47-2 ]
  • (2R)-1-(3-((4-(1-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
36 mg A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 44. (2R)-l-C3-((4-(l-C5-Fluoro-6-methoxypyridin-3-Yl)-4,5,7,8-tetrahYdro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)propan-2-ol A mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3- ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (100 mg), (R)-2- methyloxirane (42.2 mg, 0.727 mmol), DIPEA (0.085 mL, 0.485 mmol) in EtOH (2 mL) was heated at 70 C for 1 h using a microwave. The reaction mixture was treated with MeOH (1 mL), concentrated under red...
  • 23
  • [ 305329-97-9 ]
  • [ 856250-60-7 ]
  • 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • [ 16088-62-3 ]
  • (2S)-1-(3-((4-(1-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
36 mg A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 44. (2R)-l-C3-((4-(l-C5-Fluoro-6-methoxypyridin-3-Yl)-4,5,7,8-tetrahYdro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)propan-2-ol A mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3- ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (100 mg), (R)-2- methyloxirane (42.2 mg, 0.727 mmol), DIPEA (0.085 mL, 0.485 mmol) in EtOH (2 mL) was heated at 70 C for 1 h using a microwave. The reaction mixture was treated with MeOH (1 mL), concentrated under red...
  • 24
  • [ 305329-97-9 ]
  • [ 856250-60-7 ]
  • 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole [ No CAS ]
  • [ 802294-64-0 ]
  • 1-(3-((4-(1-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazol-3-yl)-1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)propan-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
34 mg A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 50. l-(3-((4-(l-(5-Fluoro-6-methoxypyridin-3-yl)-4.5.7.8-tetrahydro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)propan-l-one A solution of propionic acid (19.76 mg, 0.267 mmol) in DMF (1.25ml_) was treated with HATU (101 mg, 0.267 mmol) and DIPEA (0.085 mL, 0.485 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 30 min. The reaction mixture was treated with a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3- ylmethyl)-lH...
  • 25
  • [ 305329-97-9 ]
  • 5-(4-amino-1-(pyrrolidin-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine trifluoroacetic acid salt [ No CAS ]
  • 26
  • [ 305329-97-9 ]
  • tert-butyl 3-[[4-amino-3-(2-amino-1,3-benzoxazol-5-yl)pyrazolo[3,4-d] pyrimidin-1-yl]methyl]pyrrolidine-1-carboxylate [ No CAS ]
  • 27
  • [ 305329-97-9 ]
  • (4-methylthieno[3,2-b]pyrrol-5-yl)-[1-[2-[2-(pyrrolidin-3-ylmethoxy)phenoxy]ethyl]indol-3-yl]methanone hydrochloride [ No CAS ]
  • 28
  • [ 305329-97-9 ]
  • tert-butyl 3-[[2-(2-bromoethoxy)phenoxy]methyl]pyrrolidine-1-carboxylate [ No CAS ]
  • 29
  • [ 305329-97-9 ]
  • tert-butyl 3-[[2-[2-[3-(4-methylthieno[3,2-b]pyrrole-5-carbonyl)indol-1-yl]ethoxy]phenoxy]methyl]pyrrolidine-1-carboxylate [ No CAS ]
  • 30
  • [ 305329-97-9 ]
  • [ 120-80-9 ]
  • tert-butyl 3-[(2-hydroxyphenoxy)methyl]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere; 0.414 g (1.57 mmol) of te/t-butyl 3-(bromomethyl)pyrrolidine-1 -carboxylate in 1 mL of DMF were added under nitrogen atmosphere to a solution of 0.219 g (1.99 mmol) of catechol (Sigma-Aldrich, Cat. No. 135011 ) and 0.649 g (1.99 mmol) of Cs2C03 in 3 mL of dry DMF. The reaction mixture was stirred overnight at 80C. The reaction solution was then diluted with brine and the product was extracted with EtOAc. The combined organic phases were dried over Na2S04, the solvent was removed and the crude mixture was purified by flash chromatography on silica gel (hexane/acetone, 0% to 10% of acetone (by volume)) to give 0.1 12 g of tert-butyl 3-[(2- hydroxyphenoxy)methyl]pyrrolidine-1-carboxylate (yield: 30%). 1H NMR (CDCb) delta (ppm): 6.98-6.83 (m, 4 H), 5.55 (s, 1 H), 4.07-3.98 (m, 2 H), 3.66-3.58 (m, 1 H), 3.55-3.47 (m, 1 H), 3.45-3.35 (m, 1 H), 3.27-3.18 (m, 1 H), 2.78-2.67 (m, 1 H), 2.17-2.05 (m, 1 H), 1.88-1.74 (m, 1 H), 1.48 (s, 9 H); MS (ESI): m/z: 238 [M-56+H]+.
 

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