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Chemical Structure| 25850-22-0 Chemical Structure| 25850-22-0

Structure of 25850-22-0

Chemical Structure| 25850-22-0

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Product Details of [ 25850-22-0 ]

CAS No. :25850-22-0
Formula : C7H15NO
M.W : 129.20
SMILES Code : CC1(C)CC(N)CCO1
MDL No. :MFCD00778609
InChI Key :VXCNRARJXVLHLI-UHFFFAOYSA-N
Pubchem ID :3809203

Safety of [ 25850-22-0 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H302-H318
Precautionary Statements:P280-P305+P351+P338
Class:3(8)
UN#:2924
Packing Group:

Computational Chemistry of [ 25850-22-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 37.48
TPSA ?

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

35.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.81
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

0.31
Log Po/w (WLOGP)?

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

0.9
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.

0.57
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

1.14
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.94

Water Solubility

Log S (ESOL):?

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

-0.84
Solubility 18.8 mg/ml ; 0.146 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-0.61
Solubility 31.5 mg/ml ; 0.244 mol/l
Class?

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

Very 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

-1.14
Solubility 9.27 mg/ml ; 0.0718 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.

-6.87 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

1.0
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

0.0 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<1.0
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)

2.14

Application In Synthesis of [ 25850-22-0 ]

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

  • Downstream synthetic route of [ 25850-22-0 ]

[ 25850-22-0 ] Synthesis Path-Downstream   1~23

  • 2
  • [ 25850-22-0 ]
  • [ 1102-88-1 ]
  • 4-{(5R,8R,9S,10S,13R,14S,17R)-3-[(E)-2,2-Dimethyl-tetrahydro-pyran-4-ylimino]-14-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl}-5H-furan-2-one [ No CAS ]
  • 3
  • [ 25850-22-0 ]
  • [ 66-28-4 ]
  • 4-{10-[(2,2-dimethyl-tetrahydro-pyran-4-ylimino)-methyl]-3,5,14-trihydroxy-13-methyl-hexadecahydro-cyclopenta[<i>a</i>]phenanthren-17-yl}-5<i>H</i>-furan-2-one [ No CAS ]
  • 4
  • [ 630-64-8 ]
  • [ 25850-22-0 ]
  • C36H55NO9 [ No CAS ]
  • 5
  • [ 508211-79-8 ]
  • [ 25850-22-0 ]
  • [ 508213-21-6 ]
YieldReaction ConditionsOperation in experiment
87.7% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 13h; A mixture of 5-([(3,4-dimethoxyphenyl)amino]carbonyl}amino)-2-{phenyl[4-(trifluoromethyl)phenyl]methoxy}benzoic acid (300 mg, 0.530 mmol), 1-hydroxy-1H-benzotriazole (122 mg, 0.798 mmol), <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-yl amine</strong> (137 mg, 1.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 mg, 0.660 mmol) and DMF (3 ML) was stirred under ice-cooling for 1 hour and at room temperature for 12 hours, was poured into water, and was extracted with ethyl acetate.. The extracted solution was washed with water, was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 1:2), to obtain the titled compound as a solid.. This was recrystallized from hexane and ethyl acetate. 315 mg (87.7%) 1H-NMR (CDCl3) delta; 0.66 to 1.07 (8H, m), 1.27 to 1.86 (2H, m), 3.32 to 3.60 (2H, m), 3.84 (6H, s), 4.02 to 4.19 (1H, m), 6.32 (1H, s), 6.66 to 7.98 (18H, m)
  • 6
  • [ 25850-22-0 ]
  • (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide [ No CAS ]
  • (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
19.8%; 22.1% (4) (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide(2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (861 mg, 2.32 mmol) in THF (8 ml) were added DMF (0.10ml) and oxalylchloride (0.243 ml, 2.79 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (600 mg, 4.64 mmol), triethylamine (1.08 ml, 7.71 mmol) and THF (6 ml), the mixture was stirred under ice-cooling for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 2 : 1 to 1 : 1) to separate two kinds of diastereomers. Firstly eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide yield 247 mg, yield (rate) 22.1%1H-NMR (CDCl3) delta: 1.24-1.40 (8H, m), 1.80-2.30 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.23 (2H, m), 3.65-3.80 (2H, m), 4.19-4.24 (1H, m), 5.51 (1H, d, J = 8.0 Hz), 6.49 (1H, d, J = 7.5 Hz), 6.68-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1622, 1588, 1553, 1507, 1427, 1331, 1262, 1198, 735, 748. Later eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide Yield (amount) 222 mg, yield (rate) 19.8%1H-NMR (CDCl3) delta: 1.20-1.36 (8H, m), 1.76-2.29 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.16 (2H, m), 3.65-3.80 (2H, m), 4.19-4.23 (1H, m), 5.48 (1H, d, J = 7.8 Hz), 6.50 (1H, d, J = 8.1 Hz), 6.71-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1620, 1588, 1549, 1507, 1449, 1427, 1368, 1331, 1262, 1198, 750, 733.
  • 7
  • [ 25850-22-0 ]
  • (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide [ No CAS ]
  • (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
12.9%; 17.4% (4) (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide(2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (861 mg, 2.32 mmol) in THF (8 ml) were added DMF (0.10 ml) and oxalylchloride (0.243 ml, 2.79 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (600 mg, 4.64 mmol), triethylamine (1.08 ml, 7.71 mmol) and THF (6 ml), the mixture was stirred under ice-cooling for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 2 : 1 to 1 : 1) to separate two kinds of diastereomers. Firstly eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide Yield (amount) 195 mg, yield (rate) 17.4%1H-NMR (CDCl3) delta: 1.24-1.40 (8H, m), 1.80-2.30 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.23 (2H, m), 3.65-3.80 (2H, m), 4.19-4.24 (1H, m), 5.51 (1H, d, J = 8.0 Hz), 6.49 (1H, d, J = 7.5 Hz), 6.68-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1622, 1588, 1553, 1507, 1427, 1331, 1262, 1198, 735, 748. Later eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide Yield (amount) 145 mg, yield (rate) 12.9%1H-NMR (CDCl3) delta: 1.20-1.36 (8H, m), 1.76-2.29 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.16 (2H, m), 3.65-3.80 (2H, m), 4.19-4.23 (1H, m), 5.48 (1H, d, J = 7.8 Hz), 6.50 (1H, d, J = 8.1 Hz), 6.71-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1620, 1588, 1549, 1507, 1449, 1427, 1368, 1331, 1262, 1198, 750, 733.
  • 8
  • [ 25850-22-0 ]
  • (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)prop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82.5% (4) (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)prop-2-enamide To a solution of (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (1.00 g, 2.35 mmol) in THF (10 ml) were added DMF (0.10 ml) and oxalylchloride (0.246 ml, 2.82 mmol), which was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (455 mg, 3.53 mmol), triethylamine (1.09 ml, 7.81 mmol) and THF (10 ml), the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to yield the objective product as a solid material. Yield (amount) 1.04 g, yield (rate) 82.5% 1H-NMR (CDCl3) delta: 1.17-1.42 (8H, m), 1.81-1.91 (2H, m), 2.56 (3H, s), 2.75 (3H, s), 3.62-3.74 (2H, m), 4.14-4.22 (1H, m), 5.48 (1H, d, J = 7.6 Hz), 6.73-7.46 (12H, m), 7.99 (1H, s). IR (KBr) cm-1; 3285, 2215, 1661, 1622, 1591, 1547, 1510, 1333, 1231, 1195, 735.
  • 9
  • [ 25850-22-0 ]
  • (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)prop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
47.1% (4) (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)prop-2-enamide To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.677 mmol) in THF (3 ml) were added DMF (0.03ml) and oxalylchloride (0.071 ml, 0.813 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (175 mg, 1.35 mmol), triethylamine (0.313 ml, 2.25 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the objective product as a solid material. Yield (amount) 177 mg, yield (rate) 47.1% 1H-NMR (CDCl3) delta: 1.18-1.40 (8H, m), 1.80-1.90 (2H, m), 2.56 (3H, s), 2.75 (3H, s), 3.69-3.77 (2H, m), 4.16-4.21 (1H, m), 5.49 (1H, d, J = 7.6 Hz), 6.78 (1H, d, J = 15.8 Hz), 6.92-7.26 (9H, m), 7.44 (1H, d, J = 15.8 Hz), 7.94 (1H, s). IR (KBr) cm-1; 3289, 2216, 1661, 1607, 1510, 1333, 1231, 1159, 733.
  • 10
  • [ 25850-22-0 ]
  • [ 1154870-34-4 ]
  • [ 1154870-31-1 ]
YieldReaction ConditionsOperation in experiment
Step 3 : 6-(3- [4-(2,2-Dimethyltetrahvdro-2h-pwan-4-yl)-3-oxopiperazm- 1 -yllcarbonvU -4-fluoro benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate (JJ3).To a 0.4 M solution containing the intermediate JJ2 (leq) and 2,2-dimethyltetrahydro-2H-pyran- 4-amine (1.5 eq) in MeOH, were added NaBH3(CN) (1.5 eq) and catalytic AcOH. The reaction was heated in a MW apparatus (100 0C , 7 min). After evaporation of the solvent the crude intermediate was dissolved in DMF, then HATU (2 eq) and DIPEA (2 eq) were added and the mixture heated in MW apparatus (120 0C, 10 min). The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents and the combined fractions were evaporated under reduced pressure to afford the title compound (JJ3). 1H-NMR (300 MHz, DMSO-d6, 300K) delta: 12.65 (IH, bs), 7.36-7.14 (3H, m), 4.79-4.54 (IH, m), 4.20-4.10 (lH,m), 3.95 (2H, s), 3.86-3.50 (4H, m), 3.46-3.14 (3H, m), 1.99 (6H, s), 1.69-1.35 (4H, m) 1.22-1.10 (6H, m). MS (ES). C25H3iFN4O4 required: 470, found 471 (M+H) +.
  • 11
  • [ 1943-83-5 ]
  • [ 25850-22-0 ]
  • 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% In tetrahydrofuran; at 0 - 20℃; Example 13 A 0 C. suspension of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-amine</strong> (0.806 g, 6.24 mmol) in THF (30 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.585 mL, 6.86 mmol), allowed to warm to RT as the cooling bath expired and stirred overnight. The mixture was treated with additional 2-chloroethyl isocyanate (160 muL) and stirred at RT for an additional 24 hours, then concentrated to dryness, the residue dissolved in EtOAc and washed with saturated NH4Cl (1*), NaHCO3 (1*) and brine (1*), dried over MgSO4 and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (700 mg, 48%) as a yellow oil. MS (ESI) m/z: 235.1 (M+H+).
  • 12
  • [ 25850-22-0 ]
  • 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one [ No CAS ]
  • 13
  • [ 25850-22-0 ]
  • 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonyl chloride [ No CAS ]
  • 14
  • [ 25850-22-0 ]
  • 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide [ No CAS ]
  • 15
  • [ 25850-22-0 ]
  • 5-{(benzyloxy)methyl}isoxazol-3-carboxylic acid [ No CAS ]
  • N-(2,2-dimethyltetrahydropyran-4-yl)-5-benzyloxymethylisoxa zole-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.29 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; Production Example 321 (0641) 5-Benzyloxymethylisoxazole-3-carboxylic acid (0.24 g, 1.0 mmol), <strong>[25850-22-0]4-amino-2,2-dimethyltetrahydropyran</strong> (0.18 ml, 1.2 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) were added to chloroform (amylene addition product) (2.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1.2 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was passed through a short column to remove impurities, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.29 g of N-(2,2-dimethyltetrahydropyran-4-yl)-5-benzyloxymethylisoxa zole-3-carboxamidc: (hereinafter, referred to as Compound of Present Invention (335)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.26(3H, s), 1.29(3H, s), 1.33-1.40(1H, m), 1.41-1.52(1H, m), 1.89-2.00(2H, m), 3.72-3.84(2H, m), 4.27-4.38(1H, m), 4.61(2H, s), 4.65(2H, s), 6.62(1H, br s), 6.72(1H, s), 7.30-7.40(5H, m)
0.29 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; 5-Benzyloxymethyl isoxazole-3-carboxylic acid (0.24 g, 1.0 mmol), <strong>[25850-22-0]4-amino-2,2-dimethyltetrahydropyran</strong> (0.18 ml, 1.2 mmol) And 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) Was added to chloroform (amylene added product) (2.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1.2 mmol) was added at room temperature, After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was passed through a short column of silica gel to remove impurities, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (2,2-dimethyltetrahydropyran-4-yl) -5-benzyloxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (335)) 0.29 g was obtained.
  • 16
  • [ 1194-16-7 ]
  • [ 25850-22-0 ]
YieldReaction ConditionsOperation in experiment
85% With palladium on activated charcoal; hydrogen; ammonium formate; In methanol; water; for 5h; To a stirred solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (2 g, 20 mmol) in MeOH (40 mL) and H2O (5 mL) was added ammonium formate (10.33 g, 160 mmol) and pallidum on carbon (0.5 g). The reaction was stirred under atmospheric hydrogen atmosphere for 5 h. The reaction mixture was filtered through bed of celite and washed with methanol. The resulting filtrate was concentrated under reduced pressure to afford 2,2-dimethyltetrahydro-2H-pyran-4-amine (2.5 g, 85%) as a colourless gummy material. (1S,4S)-4-((2-((2,2-Dimethyltetrahydro-2H-pyran-4-ylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide.
  • 17
  • [ 25850-22-0 ]
  • (1s,4s)-4-((5-amino-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide [ No CAS ]
  • 18
  • [ 25850-22-0 ]
  • (1s,4s)-4-(8-((3-chlorophenyl)amino)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide [ No CAS ]
  • 19
  • [ 25850-22-0 ]
  • 9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine [ No CAS ]
  • 20
  • [ 25850-22-0 ]
  • (1s,4s)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide [ No CAS ]
  • (1s,4s)-4-((2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; To a stirred solution of 4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5 g, 2.2 mmol) in DMF (10 mL) was added <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-amine</strong> (0.24 g, 1.8 mmol) and sodium carbonate (0.53 g, 5.0 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. Completion of the reaction was confirmed by UPLC. The product was isolated and triturated with petroleum ether to afford (1S,4S)-4-((2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.4 g, 61%) as an yellow solid. MS (ESI) m/z 393.2 [M+1]+.
  • 21
  • [ 25850-22-0 ]
  • (2,2-dimethyl-4-propyltetrahydro-2H-pyran-4-yl)acetic acid chloride [ No CAS ]
  • 2-(2,2-dimethyl-4-propyltetrahydro-2H-pyran-4-yl)-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With triethylamine; In benzene; for 4h;Heating; General procedure: To a mixture of 40 mL of a solution of 0.02 mol of amine in anhydrous benzene and 2.6 g (0.026 mol) of triethylamine was gradually added the equimolar amount of chloride B. The mixture was boiled for 4 h. On the next day 10 mL of water was added. The benzene layer was separated and washed with water. Benzene was distilled off, and the residue was distilled in a vacuum.
  • 22
  • [ 25850-22-0 ]
  • C19H17N5O2*ClH [ No CAS ]
  • N-(2,2-dimethyltetrahydropyran-4-yl)-1-methyl-4-[[6-(1-methylpyrazol-3-yl)-3-pyridyl]methyl]pyrrolo[2,3-b]pyridine-6-carboxamide [ No CAS ]
  • 23
  • [ 25850-22-0 ]
  • 4-chloro-3-nitroquinoline-6-carbonitrile [ No CAS ]
  • 4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h; The 4-chloro-3-nitroquinoline-6-carbonitrile (4.74 g, 17.55 mmol) was suspended in MeCN (50 mL) then <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-amine</strong> (2.49 g, 19.3 mmol) was added, after the DIEA (4.54 g, 35.1 mmol) was added the mixture was stirred at 20C for 2h, turning brown to tan. LCMS indicated complete conversion to the desired product. The mixture was concentrated under vacuum, the residue was purified by silica gel column chromatography (PE/EtOAc = 1/1) to give the desired product (4.88 g, 85% yield) as yellow solid. The purity and structure of the product were confirmed by LCMS and 1HNMR. LCMS: RT 0.73 mm, MS 327.0) 1H NMR (400 MHz, DMSO-d6) O 9.09 (5,1H), 9.02 (5, 1H), 8.42 (d, J= 8.4 Hz, 1H), 8.15(dd, J= 8.6, 1.6 Hz, 1H), 8.01 (d, J= 8.6Hz, 1H), 3.98 (m, 1H), 3.76-3.66 (m, 1H), 3.60 (td, J = 12.2, 2.3 Hz, 1H), 2.01 (ddd, J =12.6, 4.6, 2.6 Hz, 1H), 1.93-1.82 (m, 1H), 1.67 (m, 1H), 1.56 (t, J = 12.3 Hz, 1H), 1.19(d, J = 7.7 Hz, 6H).
 

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