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Chemical Structure| 25625-57-4 Chemical Structure| 25625-57-4

Structure of 25625-57-4

Chemical Structure| 25625-57-4

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Product Details of [ 25625-57-4 ]

CAS No. :25625-57-4
Formula : C9H7BrF3NO
M.W : 282.06
SMILES Code : O=C(NC1=CC=CC(C(F)(F)F)=C1)CBr
MDL No. :MFCD00859566
Boiling Point : No data available
InChI Key :OSKNAKFZYROIOL-UHFFFAOYSA-N
Pubchem ID :2317152

Safety of [ 25625-57-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H314
Precautionary Statements:P264-P270-P280-P301+P312+P330-P305+P351+P338+P310-P501
Class:8
UN#:3261
Packing Group:

Computational Chemistry of [ 25625-57-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 53.63
TPSA ?

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

29.1 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.75
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

3.35
Log Po/w (WLOGP)?

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

4.0
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.

2.99
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

2.99
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.02

Water Solubility

Log S (ESOL):?

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

-3.73
Solubility 0.0524 mg/ml ; 0.000186 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.

-3.64
Solubility 0.0648 mg/ml ; 0.00023 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

-4.54
Solubility 0.00817 mg/ml ; 0.000029 mol/l
Class?

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

Moderately 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

Yes
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.

-5.64 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)

1.71

Application In Synthesis of [ 25625-57-4 ]

* 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 [ 25625-57-4 ]

[ 25625-57-4 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 98-16-8 ]
  • [ 598-21-0 ]
  • [ 25625-57-4 ]
YieldReaction ConditionsOperation in experiment
100% In dichloromethane; at 10 - 20℃; for 1.58333h; Description 13. 2-Bromo-lambda/-[3-(trifluoromethyl)phenyl]acetamide; A stirred solution of 3-(trifluoromethyl)aniline (2.Og, 0.012mol) in dichloromethane (60ml) at 1O0C under argon was treated dropwise over 5 minutes with bromoacetyl bromide (1.2ml, 0.0137mol). A white precipitate formed. This was allowed to warm to room temperature with good stirring over 1.5 hours, then treated with solid sodium hydrogen carbonate (1.65g, 0.0196mol) and stirred well for 40 minutes. The mixture was treated with water (100ml), stirred well for 10 minutes, then the dichloromethane layer was isolated by passage through a phase separation cartridge and concentrated under vacuum to afford the title compound as a colourless oil (3.65g, 100%). Mass Spectrum (Electrospray LC/MS): Found 282 (MH+). C9H779BrF3NO requires 281. Ret. time 2.74 min. 1H NMR delta (CDCI3; 400MHz): 4.05 (2H, s), 7.40-7.53 (2H, m), 7.76 (1 H, d), 7.83 (1 H, s), 8.24 (1 H, br s).
100% Description 16. 2-Bromo-lambda/-[3-(trifluoromethyl)phenyl]acetamide; A stirred solution of 3-(trifluoromethyl)aniline (2.Og, 0.012mol) in dichloromethane (60ml) at 1O0C under argon was treated dropwise over 5 minutes with bromoacetyl bromide (1.2ml, 0.0137mol). A white precipitate formed. This was allowed to warm to room temperature with good stirring over 1.5 hours, then treated with solid sodium hydrogen carbonate (1.65g, 0.0196mol) and stirred well for 40 minutes. The mixture was treated with water (100ml), stirred well for 10 minutes, then the dichloromethane layer was isolated by passage through a phase separation cartridge and concentrated under vacuum to afford the title compound as a colourless oil (3.65g, 100%). Mass Spectrum (Electrospray LC/MS): Found 282 (MH+). C9H779BrF3NO requires 281. Ret. time 2.74 min. 1H NMR delta (CDCI3; 400MHz): 4.05 (2H, s), 7.40-7.53 (2H, m), 7.76 (1 H, d), 7.83 (1 H, s), 8.24 (1 H, br s).
100% Description 24. 2-Bromo-lambda/-[3-(trifluoromethyl)phenyl]acetamide; A stirred solution of 3-(trifluoromethyl)aniline (2.Og, 0.012mol) in dichloromethane (60ml) at 1O0C under argon was treated dropwise over 5 minutes with bromoacetyl bromide (1.2ml, 0.0137mol). A white precipitate formed. This was allowed to warm to room temperature with good stirring over 1.5 hours, then treated with solid sodium hydrogen carbonate (1.65g, 0.0196mol) and stirred well for 40 minutes. The mixture was treated with water (100ml), stirred well for 10 minutes, then the dichloromethane layer was isolated by passage through a phase separation cartridge and concentrated under reduced pressure to afford the title compound as a colourless oil (3.65g, 100%). Mass Spectrum (Electrospray LC/MS): Found 282 (MH+). C9H779BrF3NO requires 281. Ret. time 2.74 min.1H NMR delta (CDCI3; 400MHz): 4.05 (2H, s), 7.40-7.53 (2H, m), 7.76 (1 H, d), 7.83 (1 H, s), 8.24 (1 H, br s).
100% Description 1. 2-Bromo-lambda/-[3-(trifluoromethyl)phenyl]acetamideA stirred solution of 3-(trifluoromethyl)aniline (2.Og, 0.012mol) in dichloromethane (60ml) at 1O0C under argon was treated dropwise over 5 minutes with bromoacetyl bromide (1.2ml, 0.0137mol). A white precipitate formed. This was allowed to warm to room temperature with good stirring over 1.5 hours, then treated with solid sodium hydrogen carbonate (1.65g, 0.0196mol) and stirred well for 40 minutes. The mixture was treated with water (100ml), stirred well for 10 minutes, then the dichloromethane layer was isolated by passage through a phase separation cartridge and concentrated under vacuum to afford the title compound as a colourless oil (3.65g, 100%). Mass Spectrum (Electrospray LC/MS): Found 282 (MH+). C9H779BrF3NO requires 281. Ret. time 2.74 min. <n="31"/>1H NMR delta (CDCI3; 400MHz): 4.05 (2H, s), 7.40-7.53 (2H, m), 7.76 (1 H, d), 7.83 (1 H, s), 8.24 (1 H, br s).
100% With triethylamine; In dichloromethane; at 0℃; for 1.25h;Inert atmosphere; General procedure: To a solution of substituted aniline 22a-i (0.81 mmol) and triethylamine (0.89 mmol) in DCM (2 mL) at 0 C was added bromoacetyl bromide (0.81 mmol) dropwise over 15 min, and stirring was continued for an additional 1 h at 0 C. The mixture was dilutedwith DCM (10 mL), washed with HCl (2 10 mL), H2O (1 10 mL),sat. aqueous NaHCO3 (1 10 mL), brine (1 10 mL), dried (Na2SO4),and the solvent removed in vacuo to give bromoacetamides 21a-i.
100% In dichloromethane; at 10 - 20℃; for 1.58333h;Inert atmosphere; Description 4: 2-Bromo-Lambda/-[3-(trifluoromethyl)phenyl]acetamide; A stirred solution of 3-(trifluoromethyl)aniline (2.0 g, 0.012 mol) in DCM (60ml) at 1O0C under argon was treated dropwise over 5 minutes with bromoacetyl bromide (1.2ml,0.0137 mol). A white precipitate formed. This was allowed to warm to room temperature with good stirring over 1.5 hours, then treated with solid sodium hydrogen carbonate (1.65 g, 0.0196 mol) and stirred well for 40 minutes. The mixture was treated with water(100ml), stirred well for 10 minutes, then the dichloromethane layer was isolated by passage through a phase separation cartridge and concentrated under vacuum to afford the title compound as a colourless oil (3.65 g, 100%). Mass Spectrum (ElectrosprayLC/MS): Found 282 (MH+). C9H779BrF3NO requires 281. Ret. time 2.74 min.1H NMR delta (CDCI3; 400MHz): 4.05 (2H, s), 7.40-7.53 (2H, m), 7.76 (1 H, d), 7.83 (1 H, s),8.24 (1 H, br s).
86% With triethylamine; at 0℃; for 1h;Inert atmosphere; General procedure: To a solution of substituted aniline 11a-v (1 equiv) and triethylamine (1.1 equiv) in CH2Cl2 at 0 C was added bromoacetyl bromide (1 equiv) dropwise over 15 min and the mixture was stirred for 1 h at 0 C. The mixture was then diluted with CH2Cl2, washed with HCl x 2, water, sat. aqueous NaHCO3, brine, and dried (Na2SO4) before the solvent was removed in vacuo to give bromoacetamides 12a-v.
A stirred solution of 3-(trifluoromethyl)aniline (2.Og, 0.012mol) in DCM (60ml) at 1O0C under argon was treated dropwise over 5 minutes with bromoacetyl bromide (1.2ml, 0.0137mol). A white precipitate formed. This was allowed to warm to room temperature with good stirring over 1.5 hours, then treated with solid sodium hydrogen carbonate (1.65g, 0.0196mol) and stirred well for 40 minutes. The mixture was treated with water (100ml), stirred well for 10 minutes, then the dichloromethane layer was isolated by passage through a phase separation cartridge and concentrated under vacuum to afford the title compound as a colourless oil (3.65g). Mass Spectrum (Electrospray LC/MS): Found 282 (MH+). C9H779BrF3NO requires 281. Ret. time 2.74 min.1H NMR delta (CDCI3; 400MHz): 4.05 (2H, s), 7.40-7.53 (2H, m), 7.76 (1 H, d), 7.83 (1 H, s), 8.24 (1 H, br s).
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h;Inert atmosphere; General procedure: Commercially available amines (20 mmol) were dissolved in dry DMF (40 ml) under nitrogen. To this solution, Et3N (20 mmol) was added and bromoacetyl bromide (20 mmol) via syringe at 0 C under nitrogen. The mixture was stirred at 0 C for 30 min and then at room temperature for another 2 h. Next, solid NaN3 (30 mmol) was added, and the reaction mixture was stirred overnight. The mixture was poured into water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined extracts were washed with water (3 x 50 ml) and brine (50 ml). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. Silica gel flash chromatography (10 % ethyl acetate in hexane) gave the desired azide product in 70-90 % isolated yield.
General procedure: To a solution of substituted anilines (9a-n) (1 mmol) in DCM andtriethyl amine (1 mmol) was used as a base was cooled to 0-5 C in ice bath was magnetically stirred for 5 min. Then to the above cool solution bromo acetyl bromide (1 mmol) was added slowly,then the reaction mixture was stirred for 30 min, the completion ofthe reaction was checked by TLC. The resulting mixturewas dilutedwith ice cold water and was extracted with dichloro methane. The combined organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure to afford required acetamide derivatives (10a-n).

  • 5
  • [ 25625-57-4 ]
  • [ 17175-39-2 ]
  • 3-[(3'-trifluoromethylphenyl)carbamoyl]imidazo[1,2-a]pyridine [ No CAS ]
  • 6
  • [ 279250-33-8 ]
  • [ 25625-57-4 ]
  • 2-(1-oxy-3',4',5',6'-tetrahydro-2'<i>H</i>-[2,4']bipyridinyl-1'-yl)-<i>N</i>-(3-trifluoromethyl-phenyl)-acetamide [ No CAS ]
  • 7
  • [ 22118-09-8 ]
  • [ 98-16-8 ]
  • [ 25625-57-4 ]
YieldReaction ConditionsOperation in experiment
64% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; 3-Trifluoromethylaniline (1.6 g, 10 mmol) was dissolved in dichloromethane with DIEA (3.4 mL, 20 mmol), cooled to 0 C, and to this solution bromoacetyl chloride was added as a neat liquid (exothermic). After 1 hour the reaction mixture was washed with IN HCl, dried and concentrated to a brown oil which was purified by column chromatography (10 to 40 % EtOAc/liexanes) to give a light brown oil, 1.8 g, 6.4 mmol, 64% YIELD. 1H NMR (500 MHz, CDC13) S 8. 19 (S, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.8 HZ,, 3. 96 (s, 2H).
  • 8
  • [ 25625-57-4 ]
  • [ 57260-71-6 ]
  • C18H24F3O3N3 [ No CAS ]
  • 9
  • [ 57260-73-8 ]
  • [ 25625-57-4 ]
  • [ 847150-19-0 ]
YieldReaction ConditionsOperation in experiment
50% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 6h; Tert-butyl 2-AMINOETHYLCARBAMATE (0.32 g, 2 mmol) was dissolved in dichloromethane with DIEA (0.6 mL, 3.4 mmol). To this solution, 2-BROMO-N- (3- (TRIFLUOROMETHYL)- phenyl) acetamide was added and the reaction mixture stirred for 6 hours at room temperature. The reaction mixture was concentrated to an oil and purified by column chromatography (eluent: ETOAC) to give the product 0.37 g, 1.02 mmol, 50% YIELD.1H NMR (500 MHz, CDCl3) 5 9.39 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 4.68 (s, 1H), 3.36 (s, 2H), 3.22 (dd, J = 11. 2,5. 5 Hz, 2H), 2.74 (t, J= 5. 7 HZ, 2H).
  • 10
  • [ 25625-57-4 ]
  • [ 847149-82-0 ]
YieldReaction ConditionsOperation in experiment
With sodium azide; In N,N-dimethyl-formamide; General procedure: Commercially available amines (20 mmol) were dissolved in dry DMF (40 ml) under nitrogen. To this solution, Et3N (20 mmol) was added and bromoacetyl bromide (20 mmol) via syringe at 0 C under nitrogen. The mixture was stirred at 0 C for 30 min and then at room temperature for another 2 h. Next, solid NaN3 (30 mmol) was added, and the reaction mixture was stirred overnight. The mixture was poured into water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined extracts were washed with water (3 x 50 ml) and brine (50 ml). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. Silica gel flash chromatography (10 % ethyl acetate in hexane) gave the desired azide product in 70-90 % isolated yield.
  • 11
  • [ 25625-57-4 ]
  • 2-[3-(4-cyanophenyl)-2-oxo-1,4-diazaspiro[4.4]non-3-en-1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
25 - 34% To a solution of 4-(3-oxo-1 ,4-diazaspiro[4.4]non-1-en-2-yl)benzonitrile D36 (1.0 eq., 100 mg, 0.418 mmol,) in dimethylformamide (2 ml), 60% sodium hydride dispersion in mineral oil (1.1 eq., 18mg) was added at 0 0C. The reaction was stirred for 20 minutes at r.t. 2- Bromo-lambda/-[3-(trifluoromethyl)phenyl]acetamide (1.2 eq., 141 mg, 0.502 mmol) dissolved in dimethylformamide (2 ml) was added by syringe pump over 30 minutes. The reaction was left stirring for 4 hours at r.t. Water (50 ml) was added and the aqueous layer extracted with ethyl acetate (3 x 50ml ); organics were alternatively washed with water (2 x 30ml) and brine (2 x 30ml). The organics were combined and dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product. The crude product was purified by column chromatography (Ethyl acetate in hexane eluant) on silica column to yield the title compound, (56 mg, 25 %). Found 441 (MH+). C23H19F3N4O2 requires 440. Ret. Time 3.20 min . 1H NMR delta (DMSO, 400MHz) 1.70 (2H, m), 1.94 (4H, m), 2.16 (2H, m), 4.38 (2H, s), 7.44 (1 H, d), 7.58 (1 H, t), 7.75 (1 H, d), 8.02 (2H, d), 8.10 (1 H, s), 8.50 (2H, d), 10.48 (1 H, br. S).; Alternative preparation; To a solution of 4-(3-oxo-1 ,4-diazaspiro[4.4]non-1-en-2-yl)benzonitrile D36 (1.0 eq., 700mg, 2.93 mmol) in dimethylformamide (14 ml), 60% sodium hydride dispersion in mineral oil (1.1 eq., 128mg, 5.37mmol) was added at 0 0C. The reaction was stirred for 20 minutes at r.t. 2-Bromo-lambda/-[3-(trifluoromethyl)phenyl]acetamide (1.2 eq., 987 mg, 3.52 mmol) dissolved in dimethylformamide (14 ml) was added by syringe pump over 30 minutes. The reaction was left stirring over the weekend at r.t. Water (50 ml) was added and the aqueous layer extracted with ethyl acetate (2 x 50ml ); organics were combined alternatively, washed with water (2 x 50ml) and brine (2 x 50ml). The organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product. The crude product was purified by column chromatography (Ethyl acetate in hexane eluant) on silica column followed by MDAP to yield the title compound, (437 mg, 34 %). Found 441 (MH+). C23H19F3N4O2 requires 440. Ret. Time 3.16 min . 1H NMR delta (DMSO, 400MHz) 1.71 (2H, m), 1.94 (4H, m), 2.16 (2H, m), 4.38 (2H, s), 7.44 (1 H, d), 7.58 (1 H, t), 7.75 (1 H, d), 8.01 (2H, d), 8.10 (1 H, s), 8.50 (2H, d), 10.47 (1 H, br. S).
  • 12
  • [ 25625-57-4 ]
  • 2-[3-(4-cyanophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% To a solution of 4-(3-oxo-1 ,4-diazaspiro[4.5]dec-1-en-2-yl)benzonitrile D37 (1.0 eq., 0.395 mmol, 100 mg) in dimethylformamide (2 ml), 60% sodium hydride dispersion in mineral oil (1.1 eq., 17 mg) added at 0 0C. The reaction was stirred for 20 minutes at r.t. 2-bromo-lambda/- [3-(trifluoromethyl)phenyl]acetamide (1.2 eq., 0.474 mmol, 133 mg) dissolved in dimethylformamide (2 ml) was added by syringe pump over 30 minutes. The reaction was left stirring for 4 hours at r.t. Water (30 ml) added and the aqueous layer extracted with ethyl acetate (2 x 30ml); organics were alternatively washed with water (2 x 30ml) and brine (2 x 30ml). The organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product. The crude product was purified by column chromatography (Ethyl acetate in hexane) on silica column to yield the title compound (71 mg, 40 %) Mass Spectrum (Electrospray LC/MS): Found 455 (MH+). C24H21 F3N4O2 requires 454. Ret. Time 3.39 min.1H NMR delta (DMSO, 400MHz) 1.38 (3H, m), 1.76 (3H, m), 1.891 (2H, q), 2.034 (2H, m), 4.376 (2H, s), 7.434 (1 H, d), 7.579 (1 H, t), 7.747 (1 H, d), 8.031 (2H, m), 8.095 (1 H, s), 8.521 (2H, m), 10.55 (1 H, br. S).
  • 13
  • [ 1044505-05-6 ]
  • [ 25625-57-4 ]
  • [ 1044504-94-0 ]
YieldReaction ConditionsOperation in experiment
Example 6. 3-{4-[(Methyloxy)methyl]phenyl}-1 -{lambda/-[3-(trifluoromethyl)phenyl]glycyl}- 1,4-diazaspiro[4.5]dec-3-en-2-one; A stirred solution of 3-{4-[(methyloxy)methyl]phenyl}-1 ,4-diazaspiro[4.5]dec-3-en-2-one (170 mg, 0.624 mmol, Description 9, Method A) in dry dimethylformamide (2.75ml) at O0C under argon was treated portionwise with sodium hydride (30mg of 60% oil dispersion) <n="48"/>and maintained for 30 minutes, then a solution of 2-bromo-N-[3- (trifluoromethyl)phenyl]acetamide (200 mg, 0.709 mmol, Description 13) in dry dimethylformamide (2.75ml) was added via syringe pump over a period of 1 hour to the solution at O0C. The reaction mixture was allowed to warm to room temperature with stirring over a period of 2.5 hours, then treated with water (30ml) and extracted with EtOAc (2 x 20ml). The combined extract was washed with water (25ml), dried (Na2SO4) and concentrated under vacuum to leave a yellow oil (327mg), which was purified by chromatography on a Biotage 25+M column eluting with 0-15% EtOAc/dichloromethane. Fractions containing the required material were combined and concentrated under vacuum to give a colourless oil, which was dissolved in ether (10ml) and the title compound crystallised slowly on standing overnight as a white solid (133mg). Mass Spectrum (Electrospray LC/MS): Found 474 (MH+). C25H26F3N3O3 requires 473. Ret. time 3.52 min. 1H NMR delta (CDCI3; 400MHz): 1.30-1.45 (3H, m), 1.80-1.96 (3H, m), 1.96-2.13 (4H, m), 3.42 (3H, s), 4.26 (2H, s), 4.54 (2H, s), 7.35 (1 H, m), 7.40 (1 H, m), 7.47 (2H, d), 7.65 (1 H, d), 7.82 (1 H, s), 8.44 (2H, d), 9.15 (1 H, s).
  • 14
  • [ 1044505-07-8 ]
  • [ 25625-57-4 ]
  • [ 1044504-95-1 ]
YieldReaction ConditionsOperation in experiment
50.2% Example 7. 3-{4-[(Methyloxy)methyl]phenyl}-1 -{lambda/-[3-(trifluoromethyl)phenyl]glycyl}- 1,4-diazaspiro[4.4]non-3-en-2-one; A stirred solution of 3-{4-[(methyloxy)methyl]phenyl}-1 ,4-diazaspiro[4.4]non-3-en-2-one (141 mg, 0.546 mmol, Description 11 ) in dry dimethylformamide (2.5ml) at O0C under argon was treated with sodium hydride (26.2 mg, 0.655 mmol) and stirred well for 20 minutes, then a solution of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (185 mg, 0.655 mmol, Description 13) in dry dimethylformamide (2.5ml) was added by syringe pump over 50 minutes. The reaction mixture was allowed to warm to room temperature over 1 hour, then treated with water (25ml) and extracted with EtOAc (2 x 20ml). The combined extract was washed with water (2 x 25ml), dried (Na2SO4) and concentrated under vacuum to leave a pale brown solid (290mg). This was purified by chromatography on a Biotage 25+M column eluting with 0-20% EtOAc/dichloromethane. Collected fractions containing required material were combined and concentrated under vacuum to afford the title compound as a white solid (140mg, 50.2%). Mass Spectrum (Electrospray LC/MS): Found 460 (MH+). C24H24F3N3O3 requires 459. Ret. time 3.28 min.1H NMR delta (CDCI3; 400MHz): 1.83-1.94 (2H, m), 1.97-2.22 (6H, m), 3.42 (3H, s), 4.27 (2H, s), 4.54 (2H, s), 7.34 (1 H, m), 7.40 (1 H, m), 7.47 (2H, d), 7.64 (1 H, d), 7.84 (1 H, s), 8.41 (2H, d), 9.18 (1 H, s).
  • 15
  • [ 1044507-01-8 ]
  • [ 25625-57-4 ]
  • [ 1044506-88-8 ]
YieldReaction ConditionsOperation in experiment
Example 5: 2-[3-(4-Bromophenyl)-2-oxo-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-1 -yl]-N-[3- (trifluoromethyl)phenyl]acetamide; 3-(4-Bromophenyl)-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D19) (100mg, 0.32mmol) in DMF (4ml) was cooled to ice bath temp and treated with sodium hydride (14.23 mg, 0.356 mmol) under an atmosphere of argon. The mixture was stirred for 30 minutes then 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (D16) (100 mg, 0.356 mmol) in DMF (2ml) was added over 1.5 hour by syringe pump. The mixture was then allowed to warm to room temp overnight. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried using sodium sulphate and the solvent was removed. The residue was chromatographed on a silica column eluted with a gradient of 0-5% methanol in DCM. A mixture was obtained which was purified by low pH MDAP to give the title compound (81 mg).1H NMR (d6DMSO) delta: 1.65-1.80 (2H, m), 2.06-2.28 (2H, m), 3.5 (1 H, m), 3.65 (1 H, m), 3.8-3.95 (2H, m), 4.5 (2H, m), 7.42 (1 H, m), 7.61 (1 H, m), 7.77 (3H, m) 8.08 (1 H, m), 8.32 (2H, s), 10.6 (1 H, s). 19F NMR (DMSO) delta: -61.4 (s), Mass Spectrum (Electrospray LC/MS): Found 510 (MH+). Ret. time 3.33 min.
  • 16
  • [ 1044507-04-1 ]
  • [ 25625-57-4 ]
  • [ 1044506-89-9 ]
YieldReaction ConditionsOperation in experiment
Example 6: 2-[3-(4-Bromophenyl)-2-oxo-7-oxa-1 ,4-diazaspiro[4.4]non-3-en-1 -yl]-N-[3- (trifluoromethyl)phenyl]acetamide; 3-(4-Bromophenyl)-7-oxa-1 ,4-diazaspiro[4.4]non-3-en-2-one (D21 ) (0.6g) in DMF (4ml) was cooled to ice bath temp and treated with sodium hydride (81 mg) under argon. The mixture was stirred for 30 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D16) (631 mg) in DMF (3ml) was added over 2 hours by syringe pump. The mixture was then allowed to warm to room temp overnight. The solvent was partially removed then in vacuo and then poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried with brine and sodium sulphate and the solvent was removed. The mixture was purified by MDAP and then crystallised by stirring with ether to give the title compound. (414mg) 1H NMR (CDCI3) delta: 2.4-2.6 (2H, m), 3.96 (1 H, m), 4.06 (1 H, m), 4.22 (1 H, m), 4.35 (3H, m), 7.4 (2H, m), 7.65 (3H, m), 7.88 (1 H, m), 8.33 (2H, m) 8.75 (1 H, br) 19F NMR (DMSO) delta: -62.8 (s), Mass Spectrum (Electrospray LC/MS): Found 496/8 (MH+). Ret. time 3.08 min.
  • 17
  • [ 1044501-23-6 ]
  • [ 25625-57-4 ]
  • [ 1044501-07-6 ]
YieldReaction ConditionsOperation in experiment
Example 8: 2-[3-(3-Bromophenyl)-2-oxo-1 ,3-diazaspiro[4.5]dec-1 -yl]-lambda/-[3- (trifluoromethyl)phenyl]acetamide; To a solution of 3-(3-bromophenyl)-1 ,3-diazaspiro[4.5]decan-2-one (D23) (44 mg, 0.142 mmol) in 2ml DMF, at 00C was added sodium hydride (5.69 mg, 0.142 mmol). The solution was stirred at 00C for 30 minutes before addition of a solution of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D24) (40.1 mg, 0.142 mmol) in 2ml DMF using a <n="46"/>syringe pump at 3ml/hr. The solution was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched with methanol and the solution evaporated to dryness and the residue purified using mass directed auto-purification chromatography to give the title compound (6mg). 1H NMR (CDCI3) delta: 0.95-1.25 (2H, m), 1.30-1.45 (2H, m), 1.65-1.75 (4H, m), 1.80-1.90 (2H, m), 3.70 (2H, s), 3.98 (2H, s), 7.20- 7.26 (2H, m), 7.30-7.42 (2H, m), 7.55-7.57 (1 H, m), 7.58-7.7 (2H, m), 7.85 (1 H, s). Mass Spectrum (Electrospray LC/MS): Found 512 (MH+). C23H2379BrF3N3O2 requires 510. Ret. time 3.73 min.
  • 18
  • [ 1132817-67-4 ]
  • [ 1132817-68-5 ]
  • [ 25625-57-4 ]
  • [ 1132817-32-3 ]
  • [ 1132817-33-4 ]
YieldReaction ConditionsOperation in experiment
Example 1a. 2-{3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 ,4- diazaspiro[4.4]non-3-en-1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamide hydrochloride(Method A), andExample 2. 2-{3-[4-(5-Methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 ,4-diazaspiro[4.4]non-3-en-1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamideA mixture of 3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.4]non-3-en-2-one (120mg) contaminated with 3-[4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-1 , 4- diazaspiro[4.4]non-3-en-2-one (approx. 4:1 ) ((D4), Method A) in DMF (4ml) was cooled to ice bath temperature and treated with sodium hydride (60% in oil) (19.57mg) under an atmosphere of argon. The mixture was stirred for 30 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (115mg) in DMF (2ml) was added over 1 hour by syringe pump. The mixture was then allowed to warm to room temp overnight. The mixture was purified by multiple MDAPs to give two fractions. These were seperately loaded onto SCX and eluted with 2M-NH3-MeOH.First eluting isomer was 2-{3-[4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 , 4- diazaspiro[4.4]non-3-en-1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide (E2) (15mg).1H NMR (CDCI3) delta: ~1.6 (obs, m), 1.88 (2H, m), 1.9 - 2.2 (4H, m), 2. 23 (3H, s), 4.28 (2H, s), 6.99 (1 H, m), 7.38 (1 H, m), 7.42 (2H, m), 7.52 (1 H, m), 7.7 (1 H, m), 7.82 (1 H, s), 8.59(2H, m) 9.07 (1 H, m).Mass Spectrum (LC/MS): Found 496 (MH+). Ret. time 1.72 min.Second eluting isomer gave 2-{3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 , 4- diazaspiro[4.4]non-3-en-1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamide, which was converted to the HCI salt with DCM/Et2O/HCI to give a white solid (E1 a) (41 mg).1H NMR (D6-DMSO) delta: 1.7 (2H, m), 1.9 - 2.1 (4H, m), 2.2 (2H, m), 2.37 (3H, s), 3.9 (1 H, m), 4.40 (2H, m), 7.45 (1 H, m), 7.58 (2H, m), 7.77 (1 H, m), 7.95 (2H, m), 8.13 (2H, m)8.55 (2H, m), 9.73 (1 H, s), 10.8 (1 H, s).19F NMR (DMSO) delta: -60.4 <n="55"/>Mass Spectrum (LC/MS): Found 496 (MH+). Ret. time 1.86 min.
Example 1 b. 2-{3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 ,4- diazaspiro[4.4]non-3-en-1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamide(Method B)3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.4]non-3-en-2-one ((D4), Method B) (7.6g) contaminated with the 5 isomer in DMF (180ml) was cooled to ice bath temp and treated with sodium hydride (60% in oil) (1.136g) under an atmosphere of argon. The mixture was stirred for 50 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (7.65g) in DMF (50ml) was added over 2 hours by syringe pump. The mixture was stirred at ice bath temperature for 1 hour, then allowed to warm to room temp overnight. The mixture was diluted with methanol then loaded onto 2 x 7Og SCX cartridges, which had previously been eluted with methanol. The cartridges were washed with methanol then the compound was eluted with 2M methanolic ammonia/DCM -2:1. All the ammonia eluent was combined and evaporated to approx. 150ml when a product began to precipitate. The mixture was boiled for a few minutes then cooled to ice bath temperature. The white precipitate was collected by filtration washed with ether (approx. 50ml) and dried to give a white solid which was chromatographed using a Chiralpak IC column eluting with heptane-ethanol (20:80). The first eluting isomer was collected, the solvent was removed, the residue dissolved in refluxing methanol (approx. 750ml) and the mixture was filtered, then reduced to approx. 250ml when hot filtered ethanol (approx. 600ml) was added and the volume reduced to approx. 250ml and then allowed to cool to ice bath temperature. The white crystals were collected by filtration, washed with filtered ice cold ethanol and dried over 18h hours at 5O0C to give the title compound E1 b (6.196g). 1H NMR (DMSO) delta: 1.7 (2H, m), 1.9 - 2.1 (4H, m), 2.2 (2H, m), 2.37 (3H, s), 4.40 (2H, m), 7.45 (1 H, m), 7.58 (2H, m), 7.76 (1 H, m), 7.82 (2H, m), 8.10 (1 H, m) 8.29 (1 H, M), 8.47 (2H, s), 10.6 (1 H, s). 19F NMR (DMSO) delta: -61.4 Mass Spectrum (LC/MS): Found 496 (MH+). Ret. time 1.85 min
  • 19
  • [ 1132817-69-6 ]
  • [ 1132817-70-9 ]
  • [ 25625-57-4 ]
  • [ 1132817-34-5 ]
  • [ 1132817-35-6 ]
YieldReaction ConditionsOperation in experiment
A mixture of 3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one contaminated with 3-[4-(5-Methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2- one (approx. 4:1 ) (D7) (150mg) in DMF (5ml) was cooled to ice bath temp and treated with sodium hydride (60% in oil) (23.35mg) under an atmosphere of argon. The mixture was stirred for 30 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (115mg) in DMF (2.5ml) was added over 45 minutes by syringe pump. The mixture was then allowed to warm to room temp overnight when the solvent was partially removed. The mixture was purified by multiple MDAP's to give two isomers.First eluting isomer was 3-[4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3- en-2-one (E4) (32mg).1H NMR (CDCI3) delta: ~1.6 (obs, m), 1.88 (2H, m), 1.8 - 2.2 (6H, m), 2. 20 (3H, s), 4.28 (2H, s), 6.94 (1 H, m), 7.38 (1 H, m), 7.4 (3H, m), 7.65 (1 H, s), 7.70 (1 H, m), 7.80 (1 H, m), 7.89(1 H, s), 8.62 (2H, m) 9.17 (1 H, m).19F NMR (CDCI3) delta: -62.7Mass Spectrum (LC/MS): Found 510 (MH+). Ret. time 2.34 min.Second eluting isomer gave 3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4- diazaspiro[4.5]dec-3-en-2-one (E3) (100mg).1H NMR (CDCI3) delta: ~1.6 (obs, m), 1.88 (2H, m), 1.8 - 2.2 (6H, m), 2. 28 (3H, s), 4.27 (2H, s), 7.01 (1 H, m), 7.38 (1 H, m), 7.48 (1 H,m), 7.50 (2H, m), 7.68 (1 H, m), 7.7 (1 H, m), 7.82(1 H, s), 7.90 (1 H, s), 8.61 (2H, m) 9.16 (1 H, m).19F NMR (CDCI3) delta: -62.7Mass Spectrum (LC/MS): Found 510 (MH+). Ret. time 2.42 min.
  • 20
  • [ 1132817-71-0 ]
  • [ 25625-57-4 ]
  • [ 1132817-36-7 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride (0.018g of 60% in mineral oil) was added in two portions to a solution of 3-[4-(1 H-imidazol-1-yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D9) (0.1 1g) in DMF (3ml) stirred at ice bath temperature. The mixture was stirred for 30 minutes then 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (D8) (0.119g) in DMF (2.5ml) was added by syringe pump over 45 minutes. The reaction was then allowed to warm to room temperature overnight, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and the solvent was removed. The residue was chromatographed on a silica column eluted with 0-5% 2M NH3/MeOH/DCM and the main fraction was collected. The title compound was obtained as a white crystalline solid on stirring with ether (140mg). 1H NMR (CDCI3) delta: -1.6 (obs, m), 1.8 - 2.15 (8H, m), 4.28 (2H, s), 7.25 (obs, m), 7.4 (3H, m), 7.51 (2H, m), 7.67 (1 H, m), 7.96 (1 H, s), 8.62 (2H, m), 9.14 (1 H, m). 19F NMR (CDCI3) delta: -62.7 Mass Spectrum (LC/MS): Found 496 (MH+). Ret. time 2.38 min.
  • 21
  • [ 1132817-72-1 ]
  • [ 25625-57-4 ]
  • [ 1132817-38-9 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride (12.97mg of 60% in mineral oil) was added in two portions to a solution of 3-[4-(2-methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D10) (1 OOmg) in DMF (3ml) stirred at ice bath temperature. The mixture was stirred for 30 minutes then <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (91 mg) in DMF (2.5ml) was added by syringe pump over 45 minutes. The reaction was then allowed to warm to room temperature overnight then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and solvent removed. The residue was chromatographed on a silica column eluted with 0-5% 2M NH3/MeOH/DCM and the main fraction was collected. A white solid was obtained on stirring with ether. This was purified by MDAP. The main peak was collected, loaded onto SCX which was then washed with methanol followed by 2M methanolic ammonia. The methanolic ammonia fraction was evaporated to give the title compound as a white solid. 1H NMR (CDCI3) delta: -1.4 (2H, m), 1.7 - 2.15 (8H, m), 2.42 (3H, s), 4.28 (2H, s), 7.06 (2H, m), 7.4 (4H, m), 7.67 (1 H, m), 7.81 (1 H, m), 8.61 (2H, m), 9.1 1 (1 H, br). 19F NMR (CDCI3) delta: -62.7 Mass Spectrum (LC/MS): Found 510 (MH+). Ret. time 2.42 min.
  • 22
  • [ 1132817-73-2 ]
  • [ 25625-57-4 ]
  • [ 1132817-39-0 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride (13mg of 60% oil dispersion) was added in two portions to a solution of 3- [4-(2-propyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D11 ) (0.1g) in DMF (3ml) stirred at ice bath temperature. The mixture was stirred for 30 minutes then 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (D8) (86mg) in DMF (2.5ml) was added by syringe pump over 45 minutes. The reaction was then allowed to warm to room temperature overnight then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and solvent removed. The residue was purified by MDAP, the main fraction was collected, solvent removed and the residue was dissolved in DCM, and treated with 1 M HCI in ether to give the the title compound as a white crystalline solid (79mg). <n="59"/>1H NMR (CDCI3) delta: -1.3 (3H, m), 1.8 - 2.1 (obs, m), 3.1 (2H, m), 4.40 (2H, m), 7.1 (2H, m), 7.36 (1 H, m), 7.45 (1 H, m), 7.65 (2H, m), 7.95 (1 H, s), 8.20 (1 H, m), 8.66 (2H, m),10.3 (1 H, br).19F NMR (CDCI3) delta: -65.2Mass Spectrum (LC/MS): Found 538 (MH+). Ret. time 2.01 min.
  • 23
  • [ 1132817-74-3 ]
  • [ 25625-57-4 ]
  • [ 1132817-89-0 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride (18.00mg of 60% in mineral oil, 0.450mmol) was added to a stirring, ice- bath cooled solution of 3-[4-(2-pyridinyl)phenyl]-7-oxa-1 ,4-diazaspiro[4.4]non-3-en-2-one (D17) (110mg) in DMF (4 ml) under argon. After stirring for 30 min. a solution of 2-bromo- N-[3-(trifluoromethyl)phenyl]acetamide (D8) (106 mg, 0.375 mmol) in DMF (2 ml) was added over 1 hour using a syringe pump, maintaining an ice-bath temperature. The resulting reaction mixture was allowed to come to room temperature then stirred for a further 5 hours. The reaction mixture was diluted with MeOH (15 ml) and passed through an SCX column (2 g). After washing with MeOH (30 ml) the partially purified product was eluted with 2M NH3-MeOH (5 ml). Evaporation afforded a yellow solid which was purified by MDAP. Passing the appropriate fractions through an SCX column, washing with MeOH then eluting with 2M NH3-MeOH afforded 2-{2-oxo-3-[4-(2-pyridinyl)phenyl]-7-oxa- 1 ,4-diazaspiro[4.4]non-3-en-1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide (86 mg). The free-base in DCM (2 ml) was treated with an excess of 1 M HCI in diethyl ether (0.870 ml). The volatiles were removed in vacuo and the residue dried at high vacuum at 50 0C to afford the title compound as a cream solid (90 mg).1H NMR (CDCI3) delta: 2.30 (1 H, m), 2.51 (1 H, m obscured by DMSO), 3.80 (1 H, d), 4.00 (1 H, d), 4.16 (2H, m), 4.45 (2H, m), 7.44 (1 H, d), 7.51 (1 H, m), 7.59 (1 H, m), 7.77 (1 H, d), 8.04 (1 H, m), 8.14 (2H, m), 8.28 (2H, m), 8.51 (2H, m), 8.75 (1 H, m), 10.70 (1 H, s). Mass Spectrum (LC/MS): Found 495 (MH+). Ret. time 2.54 min.
  • 24
  • [ 1132817-75-4 ]
  • [ 25625-57-4 ]
  • [ 1132817-90-3 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride (24.71 mg of 60% in mineral oil, 0.618mmol) was added to a, stirring, ice- bath cooled solution of 3-[4-(2-pyridinyl)phenyl]-1 ,4-diazaspiro[4.4]non-3-en-2-one (D18) (150mg, 0.515mmol) in DMF (4ml) under argon. After stirring for 30 min. a solution of 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (D8) (145 mg, 0.515mmol) in DMF (2ml) was added over 1 hour using a syringe pump, maintaining an ice-bath temperature. The resulting reaction mixture was allowed to come to room temperature then stirred for a further 14 hours. The reaction mixture was diluted with MeOH (15ml) and passed through an SCX column (2g). After washing with MeOH (30ml) the partially purified product was eluted with 2M NH3-MeOH (5ml). Evaporation afforded a yellow solid which was contaminated with approx 6% bis-alkylated material (by LCMS ). The solid was triturated with diethyl ether to afford 2-{2-oxo-3-[4-(2-pyridinyl)phenyl]-1 ,4-diazaspiro[4.4]non-3-en- 1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide (155mg, 61.1%). The free-base in DCM (2 ml) was treated with an excess of 1 M HCI in diethyl ether (1.574ml, 1.574mmol). The volatiles were removed in vacuo and the residue dried to afford the title compound as a cream solid (150 mg).1H NMR (CDCI3) delta: 1.70 (2H, m), 2.00 (4H,bm), 2.15 (2H, m), 4.39 (2H, s), 7.43 (1 H, d), 7.52 (1 H, m), 7.59 (1 H, m), 7.77 (1 H, m), 8.06 (1 H, m), 8.15 (2H, m), 8.26 (2H, d), 8.49 (2H, d), 8.75 (1 H, m), 10.70 (1 H, s). Mass Spectrum (LC/MS): Found 493 (MH+). Ret. time 2.81 min.
  • 25
  • [ 1132817-79-8 ]
  • [ 25625-57-4 ]
  • [ 1132817-49-2 ]
YieldReaction ConditionsOperation in experiment
A solution of 3-[3-(2-pyridinyl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D24) (21 mg) in DMF (4ml) was cooled to 00C. Sodium hydride (2.75mg of 60% in mineral oil, 0.069mmol) was added. The solution was stirred at 00C for 45 minutes before the slow addition (1 hr) of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (19.40mg) in DMF (1 ml) using a syringe pump. The resulting solution was allowed to warm to room temperature overnight and stirred for another 18 hours. The solution was then cooled again whilst stirring to 00C and sodium hydride (2.75mg, 0.069mmol) was added. Stirring continued for 45 minutes before the slow addition (1 hr) of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (19.40mg) in DMF (1 ml) using a syringe pump. The resulting solution was allowed to warm to room temperature and stirred over the weekend, then methanol (5ml) was added and the solution was evaporated to dryness, then re-dissolved in DCM (5ml) and water (5ml) was added. The resulting solution was poured through a phase separating cartridge and evaporated to dryness Purification using mass directed auto-purification chromatography gave the title compound as a white solid (22mg). 1H NMR (CD3OD) delta: 1.39-1.51 (3H, m), 1.81-1.91 (3H, m), 1.98-2.10 (assume 4H, m), 4.39 (2H, s), 7.37-7.41 (2H, m), 7.48-7.52 (1 H, t), 7.61-7.65 (1 H, t), 7.56-7.77 (1 H, d), 7.92-7.93 (2H, m), 8.01 (1 H, s), 8.12-8.15 (2H, m), 8.48-8.50 (1 H, m), 8.63-8.97 (1 H, m), 8.98 (1 H, s). Mass Spectrum (Electrospray LC/MS): Found 507 (MH+). C28H25F3N4O2 requires 506. Ret. time 3.14 min.
  • 26
  • [ 1132817-80-1 ]
  • [ 25625-57-4 ]
  • [ 1132817-51-6 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride (60% in mineral oil, 22.33 mg, 0.558 mmol) was added to a, stirring, ice- bath cooled solution of 3-[4-(2-pyridinyl)phenyl]-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D26) (143 mg) in DMF (4 ml) under argon. After stirring for 30 min. a solution of 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (D8) (131 mg) in DMF (2 ml) was added over 1 h using a syringe pump, maintaining an ice-bath temperature. The resulting reaction mixture was allowed to come to room temperature then stirred for a further 5 h. LCMS indicated the reaction had gone to completion. The reaction mixture was diluted with MeOH (15 ml) and passed through an SCX column (2g). After eluting with MeOH (30 ml) the partially purified product was eluted with 2M NH3-MeOH (5 ml). Evaporation afforded a cream solid which was purified by MDAP (extended retention time). Passing <n="67"/>the appropriate fractions through an SCX column, washing with MeOH then eluting with2M NH3-MeOH afforded the free-base of 2-{2-oxo-3-[4-(2-pyridinyl)phenyl]-7-oxa-1 ,4- diazaspiro[4.5]dec-3-en-1-yl}-N-[3-(trifluoromethyl)phenyl]- acetamide as a white foam(160 mg). 1H NMR (CDCI3) delta: 2.00 (2H, m), 2.10-2.35 (2H, m), 3.70-3.90 (3H, m), 4.01 (1 H, m), 4.48(2H, ABq), 7.26-7.40 (3H, m and CHCI3), 7.62 (1 H, m), 7.81 (3H, m), 8.13 (2H, m), 8.59(2H, m), 8.73 (1 H, m), 9.04 (1 H, s).Mass Spectrum (Electrospray LC/MS): Found 509 (MH+). C27H23F3N4O3 requires 508. Ret. time 2.55 min. A solution of the free base (155 mg) in DCM (2 ml) was treated with an excess of 1 M HCI in diethyl ether (1.524 ml, 1.524 mmol). The volatiles were removed in vacuo and the residue dried under high vacuum at 5O0C to give the title compound (hydrochloride salt) as a cream solid.Mass Spectrum (Electrospray LC/MS): Found 509 (MH+). C27H23F3N4O3 requires 508. Ret. time 2.51 min.
  • 27
  • [ 1132817-81-2 ]
  • [ 25625-57-4 ]
  • [ 1132817-58-3 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride in mineral oil (46.4 mg, 1.160 mmol) was added to a stirring, ice-bath cooled solution of 3-[4-(2,4-dimethyl-1 H-imidazol-1 -yl)phenyl]-1 , 4-diazaspiro[4.4]non-3- <n="70"/>en-2-one (D27) (265 mg, 0.773 mmol) in DMF (6 ml) under argon. After stirring for 30 min. a solution of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (218 mg, 0.773 mmol) in DMF (2.5 ml) was added over 1 h using a syringe pump maintaining an ice-bath temperature. The resulting reaction mixture was allowed to come to room temperature then stirred for a further 4 h. LCMS indicated the reaction had gone almost to completion. The reaction mixture was diluted with MeOH (15 ml) and passed through an SCX column (1Og). After eluting with MeOH (70 ml) the partially purified product was eluted with 2M NH3-MeOH (20 ml). Evaporation afforded a brown oil (400 mg). A 100 mg aliquot was purified by MDAP (extended retention time). Passing the appropriate fractions through an SCX column, washing with MeOH then eluting with 2M NH3-MeOH afforded the free- base of the title compound as an off-white foam (40 mg).1H NMR (CDCI3) delta: 1.80 - 2.20 (8H, bm), 2.26 (3H, s), 2.40 (3H, s), 4.30 (2H, s), 6.78 (1 H, d), 7.40 (4H, m), 7.68 (1 H, d), 7.83 (1 H, s), 8.56 (2H, m), 9.18 (1 H, s). Mass Spectrum (Electrospray LC/MS): Found 510 (MH+). C27H26F3N5O3 requires 509. Ret. time 1.68 min.The remaining 300 mg crude was similarly purified by MDAP to afford additional product(110 mg , white powder) and product contaminated with a regioisomeric impurity carried through from D27 (1 10mg foamed white solid). A solution of the free-base (35 mgfrom the first purification) in DCM (2 ml) was treated with an excess of 1 M HCI in diethyl ether (0.206 ml, 0.206 mmol). The volatiles were removed in vacuo and the residue dried under high vacuum at 550C to afford the title compound as a cream solid (37 mg).Mass Spectrum (Electrospray LC/MS): Found 510 (MH+). C27H26F3N5O2 requires 509. Ret. time 1.79 min.
  • 28
  • [ 1132817-82-3 ]
  • [ 25625-57-4 ]
  • [ 1132817-60-7 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride in mineral oil (21.40 mg, 0.535 mmol) was added to a, stirring, ice-bath cooled solution of 3-[4-(4,5-dimethyl-1 H-imidazol-1 -yl)phenyl]-1 , 4-diazaspiro[4.4]non-3- en-2-one (D28) (150 mg, 0.486 mmol) in DMF (5 ml) under argon. After stirring for 30 min. a solution of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (137 mg) in DMF (3 ml) was added over 1 h using a syringe pump maintaining an ice-bath temperature. The resulting reaction mixture was allowed to come to room temperature then stirred for a <n="71"/>further 4 h. The reation mixture was diluted with methanol (20 ml) and applied to an SCX column (1Og). After washing with MeOH (50 ml) the product was eluted with 2M NH3-MeOH. Evaporation of the solvent afforded a brown gum. On dissolving in 1 :1MeOH:DMSO for MDAP purification a small amount of white solid precipitated. This was collected, washed with diethyl ether and dried The material was reapplied to an SCX column (1g) in MeOH (10 ml), washing (30 ml MeOH) and eluting as described above to remove residual DMSO. Drying afforded the free-base of the title compound as a white solid (20 mg).1H NMR (CDCI3) delta: 1.80 - 2.15 (8H, bm), 2.17 (3H, s, overlapping with adjacent bm), 2.25 (3H, s), 4.30 (2H, s), 7.40 (4H, m), 7.58 (1 H, s), 7.68 (1 H, d), 7.84 (1 H, s), 8.57 (2H, d),9.32 (1 H, s).Mass Spectrum (Electrospray LC/MS): Found 510 (MH+). C27H26F3N5O3 requires 509. Ret. time 1.81 min.A solution of the free-base (20 mg) in DCM (2 ml) was treated with an excess of 1 M HCI in diethyl ether (0.12 ml, 0.120 mmol). The volatiles were removed in vacuo and the residue dried under high vacuum at 550C to afford the title hydrochloride as a pale yellow solid (20 mg).Mass Spectrum (Electrospray LC/MS): Found 510 (MH+). C27H26F3N5O3 requires 509. Ret. time 1.77 min.
  • 29
  • [ 1132817-84-5 ]
  • [ 1132817-83-4 ]
  • [ 25625-57-4 ]
  • [ 1132817-63-0 ]
  • [ 1132817-64-1 ]
YieldReaction ConditionsOperation in experiment
Example 20. 2-{3-[3-(4-Methyl-1H-imidazol-1-yl)phenyl]-2-oxo-1 ,4- diazaspiro[4.5]dec-3-en-1 -yl}-lambda/-[3-(trifluoromethyl)phenyl]acetamide hydrochloride andExample 21. 2-{3-[3-(5-Methyl-1H-imidazol-1-yl)phenyl]-2-oxo-1 ,4-diazaspiro[4.5]dec- 3-en-1 -yl}-lambda/-[3-(trifluoromethyl)phenyl]acetamide hydrochlorideA stirred solution of D29 (70mg), a mixture of approx. 65% of 3-[3-(4-methyl-1 H-imidazol- 1-yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one; 15% of 3-[3-(5-methyl-1 H-imidazol-1- yl)phenyl]-1 ,4-diazaspiro[4.5]dec-3-en-2-one and 20% impurities, in DMF (3ml) at O0C under argon was treated with sodium hydride (9.99mg of 60% oil dispersion; 0.250mmol) and maintained for 15 minutes, then allowed to warm to room temperature and stir for 25 minutes. The mixture was re-cooled to O0C and treated dropwise over 1 hour via syringe <n="72"/>pump with a solution of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D8) (77 mg) in DMF (2ml). The reaction mixture was then allowed to warm to room temperature and stir over a weekend, then concentrated under vacuum. The residue was treated with 10% Na2CO3 solution (10ml) and extracted with EtOAc (2 x 15ml). The combined extract was dried (Na2SO4) and concentrated under vacuum to leave an orange oil, which was purified by MDAP to give a good separation of the two methyl imidazole isomers. The first eluting component was the 5-methylimidazole isomer, containing approx. 5% of the 4-isomer, obtained as a colourless oil (8mg). A solution of this material in dichloromethane (2ml) was treated with 1 M HCI in ether (0.031 ml, 0.031 mmol) and the resulting mixture concentrated under a flow of air followed by drying under vacuum at 5O0C overnight to afford the title compound E21 as a white solid (9mg). This contained approx. 5% of the corresponding 4-methylimidazole isomer.Mass Spectrum (Electrospray LC/MS): Found 510.2 (MH+). C27H26F3N5O2 requires 509. Ret. time 1.87 min.1H NMR (d6DMSO) delta: 1.30-1.45 (3H, m), 1.72-1.85 (3H, m), 1.85-1.98 (2H, m), 1.98-2.12 (2H, m), 2.22 (3H, s), 4.41 (2H, s), 7.36 (1 H, d), 7.57 (1 H, t), 7.63 (1 H, s), 7.77 (1 H, d), 7.80-7.93 (2H, m), 8.12 (1 H, s), 8.53 (1 H, s), 8.61 (1 H, d), 9.37 (1 H, s), 10.72 (1 H, s).The second eluting component was the 4-methylimidazole isomer, containing approx. 6% of the 5-isomer, obtained as a white semi-solid. (22mg). A solution of this material in dichloromethane (2ml) was treated with 1 M HCI in ether (0.086 ml, 0.086 mmol) and the resulting mixture concentrated under a flow of air followed by drying under vacuum at5O0C overnight to afford the title compound E20 as a white solid (24mg). This contained approx. 6% of the corresponding 5-methylimidazole isomer.Mass Spectrum (Electrospray LC/MS): Found 510.2 (MH+). C27H26F3N5O3 requires 509.Ret. time 1.91 min.1H NMR (d6DMSO) delta: 1.28-1.48 (3H, m), 1.70-1.83 (3H, m), 1.83-2.12 (4H, m), 2.49 (3H, s), 4.42 (2H, s), 7.38-7.47 (1 H, m), 7.58 (1 H, t), 7.72-7 '.87 (2H, m), 7.97 (1 H, d), 8.04 (1 H, s), 8.14 (1 H, s), 8.50-8.60 (2H, m), 9.58 (1 H, s), 10.75 (1 H, s).
  • 30
  • [ 1132817-85-6 ]
  • [ 25625-57-4 ]
  • [ 1132817-56-1 ]
YieldReaction ConditionsOperation in experiment
3-[4-(2-Methyl-1 H-imidazol-1 -yl)phenyl]-1 ,4-diazaspiro[4.4]non-3-en-2-one (D30) (62mg) in DMF (5ml) was cooled to ice bath temp and treated with sodium hydride 60% in oil (10 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes when 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (D8) (65.4mg) in DMF (1 ml) was added over 1 hour by syringe pump, then allowed to warm to room temperature overnight. The reaction had only gone to approx. 60%, therefore it was re-cooled and the cooled mixture treated with sodium hydride (60% in oil) (7 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes when additional 2-bromo-N-[3- (trifluoromethyl)phenyl]acetamide (50mg) in DMF (1 ml) was added over 1 hour by syringe pump, then mixture was stirred for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layers were dried with hydromatrix and the solvent was removed and the combined residue was purified by multiple high pH MDAP. The main fractions were combined, evaporated and taken up in DCM, then treated with 1 M HCI in ether and the solvent was removed. A white crystalline solid was obtained on stirring with ether which was collected by filtration to give the title compound (155mg). Mass Spectrum (LC/MS): Found 496 (MH+). Ret. time 1.73 min. 1H NMR (d6DMSO) delta: 1.7 (2H, m), 1.85-2.1 (4H, m), 2.2 (2H, m), 2.6 (obs, s), 4.41 (2H, s), 6.95 (1 H, m), 7.7-7.85 (4H, m), 7.96 (1 H, m), 8.13 (1 H, m), 8.56 (2H, m), 10.75 (1 H, s), 14.7 (1 H, br). 19F NMR (CDCI3) delta: 61 ,4
  • 31
  • [ 1132817-87-8 ]
  • [ 25625-57-4 ]
  • [ 1132878-87-5 ]
YieldReaction ConditionsOperation in experiment
Example 10a Chiral isomer 12-{3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamide hydrochloride <n="62"/>3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D31 a), isomer 1 (94mg) in DMF (6ml) was cooled to ice bath temp and treated with sodium hydride 60% in oil (13mg) under an atmosphere of argon. The mixture was stirred for 20 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (85mg) in DMF (2.5ml) was added over 1.5 hours by syringe pump. The mixture was then allowed to warm to room temp overnight. The solvent was partially removed and the residue was purified by low pH MDAP. The fractions were loaded onto SCX and the free base was eluted with 2M methanolic ammonia. The solvent was removed and the residue was dissolved in DCM, treated with HCI-Et2O, solvent removed and a white solid was obtained from ether (78mg).1H NMR (DMSO) delta: 1.75 (2H, m), 2.05-2.35 (obs, m), 2.45 (3H, s), 3.4-3.6 (obs, m), 3.9 (2H, m), 4.98 (2H, m), 7.45 (1 H, m), 7.58 (1 H, m), 7.75 (1 H, m), 7.98 (2H, m), 8.12 (2H, m), 8.58 (2H, m), 9.63 (1 H, s), 10.74 (1 H, s). 19F NMR (DMSO) delta: 61.4 Mass Spectrum (LC/MS): Found 512 (MH+). Ret. time 1.63 min.Example 10b Chiral isomer 2 2-{3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en- 1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide-'J <n="63"/>3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D31 b), isomer 2 (94mg) in DMF (6ml) was cooled to ice bath temp and treated with sodium hydride 60% in oil (12mg) under an atmosphere of argon. The mixture was stirred for 20 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (85mg) in DMF (2.5ml) was added over 1.5 hours by syringe pump. The mixture was then allowed to warm to room temp overnight. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine and then dried with hydromatrix and the solvent was removed to give the title compound (104mg). 1H NMR (CDCI3) delta: 1.7 (obs, m), 2.0 (2H, m), 2.15-2.4 (2H, m), 3.31 (3H, m), 3.71 (1 H, m), 3.85 (2H, m), 4.05 (1 H, m), 4.45 (2H, m), 7.10 (1 H, s), 7.3-7.5 (4H, m), 7.68 (1 H, m), 7.84 (1 H, m), 7.94 (1 H, m), 8.60 (2H, m), 9.09 (1 H, s). 19F NMR (DMSO) delta: 62.7 Mass Spectrum (LC/MS): Found 512 (MH+). Ret. time 1.62 min.
  • 32
  • [ 1132817-93-6 ]
  • [ 25625-57-4 ]
  • [ 1132817-94-7 ]
YieldReaction ConditionsOperation in experiment
Example 10a Chiral isomer 12-{3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamide hydrochloride <n="62"/>3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D31 a), isomer 1 (94mg) in DMF (6ml) was cooled to ice bath temp and treated with sodium hydride 60% in oil (13mg) under an atmosphere of argon. The mixture was stirred for 20 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (85mg) in DMF (2.5ml) was added over 1.5 hours by syringe pump. The mixture was then allowed to warm to room temp overnight. The solvent was partially removed and the residue was purified by low pH MDAP. The fractions were loaded onto SCX and the free base was eluted with 2M methanolic ammonia. The solvent was removed and the residue was dissolved in DCM, treated with HCI-Et2O, solvent removed and a white solid was obtained from ether (78mg).1H NMR (DMSO) delta: 1.75 (2H, m), 2.05-2.35 (obs, m), 2.45 (3H, s), 3.4-3.6 (obs, m), 3.9 (2H, m), 4.98 (2H, m), 7.45 (1 H, m), 7.58 (1 H, m), 7.75 (1 H, m), 7.98 (2H, m), 8.12 (2H, m), 8.58 (2H, m), 9.63 (1 H, s), 10.74 (1 H, s). 19F NMR (DMSO) delta: 61.4 Mass Spectrum (LC/MS): Found 512 (MH+). Ret. time 1.63 min.Example 10b Chiral isomer 2 2-{3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en- 1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide-'J <n="63"/>3-[4-(4-Methyl-1 H-imidazol-1 -yl)phenyl]-7-oxa-1 ,4-diazaspiro[4.5]dec-3-en-2-one (D31 b), isomer 2 (94mg) in DMF (6ml) was cooled to ice bath temp and treated with sodium hydride 60% in oil (12mg) under an atmosphere of argon. The mixture was stirred for 20 minutes when <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (85mg) in DMF (2.5ml) was added over 1.5 hours by syringe pump. The mixture was then allowed to warm to room temp overnight. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine and then dried with hydromatrix and the solvent was removed to give the title compound (104mg). 1H NMR (CDCI3) delta: 1.7 (obs, m), 2.0 (2H, m), 2.15-2.4 (2H, m), 3.31 (3H, m), 3.71 (1 H, m), 3.85 (2H, m), 4.05 (1 H, m), 4.45 (2H, m), 7.10 (1 H, s), 7.3-7.5 (4H, m), 7.68 (1 H, m), 7.84 (1 H, m), 7.94 (1 H, m), 8.60 (2H, m), 9.09 (1 H, s). 19F NMR (DMSO) delta: 62.7 Mass Spectrum (LC/MS): Found 512 (MH+). Ret. time 1.62 min.
  • 33
  • [ 1132817-88-9 ]
  • [ 25625-57-4 ]
  • [ 1132817-66-3 ]
YieldReaction ConditionsOperation in experiment
Sodium hydride in mineral oil (2.283 mg, 0.057 mmol) was added to a, stirring, ice-bath cooled solution of 3-[4-(1-methyl-1 H-imidazol-2-yl)phenyl]-1 ,4-diazaspiro[4.4]non-3-en-2- one (D32) (14 mg) in DMF (2 ml) under argon. After stirring for 30 min. a solution of 2- bromo-N-[3-(trifluoromethyl)phenyl]acetamide (13.42 mg) in DMF (1 ml) was added over 1 h using a syringe pump maintaining an ice-bath temperature. The resulting reaction mixture was allowed to come to room temperature then stirred for a further 1 h. The reaction mixture was diluted with MeOH (5 ml) and passed through an SCX column (2g). After eluting with MeOH (20 ml) the partially purified product was eluted with 2M NH3- MeOH (5 ml). Evaporation afforded a cream solid which was purified by MDAP to afford the free-base of the title compound (70% purity).1H NMR) delta: 1.70-2.25 (8H, bm), 3.81 (3H, s), 4.27 (2H, s), 7.03 (1 H, s), 7.18 (1 H, s), 7.35(1 H, m), 7.40 (1 H, m), 7.64 (1 H, m), 7.80 (2H, m), 7.84 (1 H, m), 8.54 (2H, m), 9.28 (1 H, bs) .Mass Spectrum (Electrospray LC/MS): Found 496 (MH+). C26H24F3N5O2 requires 495. Ret. time 1.70 min.A solution of the free-base (14 mg, 0.028 mmol) in DCM (5 ml) was treated with an excess of 1 M HCI in diethyl ether (0.94 ml, 0.94 mmol). The volatiles were removed in vacuo and the residue dried under high vac at 5O0C to afford the title compound as a pale yellow solid (15 mg). Mass Spectrum (Electrospray LC/MS): Found 496 (MH+). C25H24CIN5O2 requires 495. Ret. time 1.63 min.
  • 34
  • [ 1130098-60-0 ]
  • [ 25625-57-4 ]
  • [ 1130098-74-6 ]
YieldReaction ConditionsOperation in experiment
Example 1. 2-{2-Oxo-3-[4-(2-pyridinyl)phenyl]-1 ,3-diazaspiro[4.5]dec-1 -yl}-N-[3- (trifluoromethyl)phenyl]acetamide formateA solution of 3-[4-(2-pyridinyl)phenyl]-1 ,3-diazaspiro[4.5]decan-2-one (D5) (16mg, 0.052mmol) in 2ml DMF was cooled to 00C before the addition of sodium hydride (2.082mg, 0.052mmol). The solution was stirred at 00C for 45 minutes before the slow addition (1 hr) of <strong>[25625-57-4]2-bromo-N-[3-(trifluoromethyl)phenyl]acetamide</strong> (D1 ) (14.68mg, 0.052mmol) in 2ml DMF using a syringe pump. The resulting solution was allowed to warm to room temperature overnight when 1 ml of methanol was added. The solution was evaporated to dryness and then purified using mass directed auto-purification chromatography to give the title compound (6mg).1H NMR (CDCI3) delta: 1.19-1.28 (1 H, m), 1.39-1.47 (2H, m), 1.72-1.88 (assume 7H, m), 3.79 (2H, s), 4.02 (2H, s), 7.21-7.26 (3H, m), 7.32-7.34 (1 H, m), 7.39-7.43 (1 H, m), 7.68-7.78 (4H, m), 8.01-8.04 (2H, m), 8.68-8.70 (1 H, m), 9.19 (1 H, s). Mass Spectrum (Electrospray LC/MS): Found 509 (MH+). C28H27F3N4O2 requires 508. Ret. time 2.84 min.
  • 35
  • 3-[4-(5-methyl-1H-imidazol-1-yl)phenyl]-1,3-diazaspiro[4.5]decan-2-one [ No CAS ]
  • [ 1130098-64-4 ]
  • [ 25625-57-4 ]
  • 2-{3-[4-(5-methyl-1H-imidazol-1-yl)phenyl]-2-oxo-1,3-diazaspiro[4.5]dec-1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide [ No CAS ]
  • [ 1130098-76-8 ]
YieldReaction ConditionsOperation in experiment
Example 3. 2-{3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 ,3-diazaspiro[4.5]dec- 1 -yl}-N-[3-(trifluoromethyl)phenyl]acetamide formateA solution of 3-[4-(4-methyl-1 H-imidazol-1 -yl)phenyl]-1 ,3-diazaspiro[4.5]decan-2-one containing approx. 10% of 3-[4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-1 , 3- diazaspiro[4.5]decan-2-one (D7) (total mass 87mg, 0.280mmol) in DMF (5ml) was cooled to 00C, then sodium hydride (1 1.21 mg, 0.280mmol) was added. The solution was stirred at 00C for 45 minutes before the slow addition (2hr) of 2-bromo-N-[3- (trifluoromethyl)phenyl]acetamide (D1 ) (79mg, 0.280mmol) in DMF (2ml) using a syringe pump. The resulting solution was allowed to warm to room temperature overnight, then methanol (5ml) was added. The solution was evaporated to dryness then re-dissolved in DCM (5ml) and water (5ml) was added. The resulting mixture was poured through a phase separating cartridge, and the DCM solution evaporated to dryness and purified using mass directed auto-purification chromatography to give the title compound (9mg) in 93% purity (contaminated with 7% of 2-{3-[4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo- 1 ,3-diazaspiro[4.5]dec-1-yl}-N-[3-(trifluoromethyl)phenyl]acetamide). A second fraction was also obtained (32mg) containing the title compound and approximately 18% of 2-{3- [4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 ,3-diazaspiro[4.5]dec-1-yl}-N-[3- (trifluoromethyl)phenyl]acetamide.1H NMR (CDCI3) delta: 1.15-1.30 (1 H, m), 1.35-1.1.50 (2H, m), 1.72-1.76 (5H, m), 1.84-1.89 (2H, m), 2.32 (3H, s), 3.76 (2H, s), 4.03 (2H, s), 6.99 (1 H, s), 7.33-7.43 (4H, m), 7.69-7.71 (3H, m), 7.84 (1 H, s), 8.08 (1 H, s), 8.29 (1 H, s), 9.17 (1 H, s); also 3.25 (unidentified broad peak). Mass Spectrum (Electrospray LC/MS): Found 512 (MH+). C27H28F3N5O2 requires 511. Ret. time 1.83 min.
 

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