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Chemical Structure| 135865-78-0 Chemical Structure| 135865-78-0

Structure of 135865-78-0

Chemical Structure| 135865-78-0

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Product Details of [ 135865-78-0 ]

CAS No. :135865-78-0
Formula : C14H19NO3
M.W : 249.31
SMILES Code : CC(C)(C)OC(=O)N[C@@H](CC=O)C1=CC=CC=C1
MDL No. :MFCD11559103
InChI Key :ZGPCDZZHEWGTEU-LBPRGKRZSA-N
Pubchem ID :11817535

Safety of [ 135865-78-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 135865-78-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.43
Num. rotatable bonds 7
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 69.77
TPSA ?

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

55.4 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.26
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

1.89
Log Po/w (WLOGP)?

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

2.52
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.

1.98
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

2.37
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.2

Water Solubility

Log S (ESOL):?

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

-2.36
Solubility 1.09 mg/ml ; 0.00435 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.

-2.68
Solubility 0.526 mg/ml ; 0.00211 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

-3.76
Solubility 0.0437 mg/ml ; 0.000175 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.

-6.48 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<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)

2.43

Application In Synthesis of [ 135865-78-0 ]

* 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 [ 135865-78-0 ]

[ 135865-78-0 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 135865-77-9 ]
  • [ 103365-47-5 ]
  • [ 135865-78-0 ]
  • 2
  • [ 167834-23-3 ]
  • [ 135865-78-0 ]
YieldReaction ConditionsOperation in experiment
To a dry, cooled (-78° C.) solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate from Step A (1.00 g, 3.41 mmol) was added a solution of DiBAl-H (6.82 mL, 6.82 mmol, 1 M in CH2Cl2) slowly over 30 min. After an additional 30 min of stirring at -78° C., the reaction was quenched by the rapid addition of saturated aqueous Rochelle's salt (32 mL). The cooling bath was then removed and the reaction was allowed to rapidly stir until a noticeable decrease in the amount of emulsion was observed. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2.x.30 mL). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexanes 5:95 to 40:60, to give the title compound. MS: m/z=150 (M-CO2C4H7).
With diisobutylaluminium hydride; Synthesis of compounds 69-71 see tableScheme V (for compounds 69-71 )
  • 3
  • [ 60421-23-0 ]
  • [ 135865-78-0 ]
  • [ 957122-37-1 ]
YieldReaction ConditionsOperation in experiment
To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate from Step B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol). After stirring at ambient temperature for 20 min, NaHB(OAc)3 (1.74 g, 8.22 mmol) was added as a solid. Upon completion of the reaction, saturated aqueous NaHCO3 (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHCO3 (3 mL) was then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, to give the title compound. MS: m/z=377 (M+1).
  • 4
  • 1-isopropyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2-one [ No CAS ]
  • [ 135865-78-0 ]
  • [(S)-3-(1-isopropyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl)-1-phenyl-propyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% Preparation 7; [ (S) -3- (l-Isopropyl-3- (tetrahydropyran-4-ylmethyl) - bicyclo [3.2.1] -2-oxo-lbeta, 3 , 8-triaza-spiro [4.5] dodec-8-yl) -1- phenyl -propyl] - carbamic acid tert-butyl ester; To 500 mg (1.55 mmol) of l-isopropyl-3 - (tetrahydropyran-4- ylmethyl) -bicyclo [3.2.1] -lbeta, 3, 8-triaza-spiro [4.5] dodecan-2-one in anhydrous DCE (40 mL) was added 388 mg (1.55 mmol) of ((S) -3- oxo-1-phenyl-propyl) -carbamic acid tert-butyl ester and 260 muL (1.86 mmol) of triethylamine . The reaction mixture was stirred for 30 minutes and 412 mg (1.94 mmol) of sodium triacetoxyborohydride was added in one portion. Then the reaction mixture was agitated overnight at room temperature, diluted with DCM, washed with saturated solution of sodium bicarbonate and dried over sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with DCM/Methanol (0 to 8percent) to yield 731 mg (85percent) of [(S)-3-(l- isopropyl-3 - (tetrahydropyran-4-ylmethyl) -bicyclo [3.2.1] -2 -oxo- lbeta, 3 , 8-triaza-spiro [4.5] dodec-8-yl) -1 -phenyl -propyl] - carbamic acid tert-butyl ester as a white solid.
  • 5
  • C23H30N2O5 [ No CAS ]
  • [ 135865-78-0 ]
  • 6
  • [ 24424-99-5 ]
  • 1.) NaH; 2.) SOCl2 [ No CAS ]
  • [ 135865-78-0 ]
  • 7
  • [ 37088-66-7 ]
  • [ 135865-78-0 ]
  • 9
  • [ 135865-78-0 ]
  • [ 359644-06-7 ]
  • 10
  • [ 135865-78-0 ]
  • [ 357187-63-4 ]
  • 11
  • [ 135865-78-0 ]
  • ((3Z,5E)-(S)-7-Benzenesulfonyl-1-phenyl-hepta-3,5-dienyl)-carbamic acid tert-butyl ester [ No CAS ]
  • 13
  • [ 56613-80-0 ]
  • [ 135865-78-0 ]
  • 14
  • [ 102089-75-8 ]
  • [ 135865-78-0 ]
  • 15
  • [ 67341-01-9 ]
  • [ 135865-78-0 ]
  • 16
  • [ 374725-04-9 ]
  • [ 135865-78-0 ]
  • (S)-[3-(4-{ethyl-[2-(4-methanesulfonylphenyl)-acetyl]-amino}-piperidin-1-yl)-1-phenyl-propyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
This Example illustrates the preparation of [(S)- [3- (4- F ETHYL- [2- (4-METHANESULFONYL-] [PHENYL)-ACETYL]-AMINO}-PIPERIDIN-1-YL)-1-PHENYL-PROPYL]-CARBAMIC] acid tert-butyl ester (Compound No. [1] of Table [: Q.] To a stirred solution of [(S)-(3-OXO-1-PHENYL-PROPYL)-CARBAMIC] acid tert-butyl ester (Method C, 25g, 100 [MMOL),] N-ethyl-2- (4-methanesulfonyl-phenyl)-N-piperidin-4-yl- acetamide (Method A, 36g, 110 mmol) and glacial acetic acid (6. [0ML)] in a 1 : 1 mixture of DCM and methanol [(500ML)] was added portionwise sodium triacetoxyborohydride (25g, 120 mmol) at ambient temperature. The reaction mixture was stirred for a further 12 hours, then 2N sodium hydroxide solution (500mL) was cautiously added during 30 minutes and the resulting mixture extracted into DCM [(500ML).] The crude product was purified by chromatography on silica eluting with a 9: 1 mixture of ethyl acetate and methanol to give the title compound as a colourless gum, which slowly solidified (40g). A portion was [CRYSTALLISED] from ethyl acetate to give a white solid, m. p. [115-116°C.] 1H NMR : [1.] 0 and 1.1 (t, 3H), [1.] 35 (s, 9H), 1.5 (m, 2H), 1.7 (m, 4H), 1.9 (m, 2H), 2.2 (t, 2H), 2.8 (m, 2H), 3.15 (s, 3H), 3.2 and 3.3 (q, 2H), 3.6 and 4.1 (m, 1H), 3.8 and 3.85 (s, 2H), 4.5 (m, 1H), 7.2 (m, 5H), 7.4 (br d, 1H), 7.5 (d, 2H), 7.8 (d, 2H). LCMS: 558 [(MH+).]
  • 17
  • [ 458529-69-6 ]
  • [ 135865-78-0 ]
YieldReaction ConditionsOperation in experiment
With sodium bis(2-methoxyethoxy)aluminum hydride; In toluene; at -20 - 15℃; for 1h; To a solution of (S)-N-methyl-N-methoxy-3-phenyl-3-Bocaminopropionamide (5.52g, 17. [9MMOL)] in toluene [(180ML)] at-20°C was added sodium bis (2-methoxyethoxy) aluminium hydride (65percent solution [IN TOLUENE,] 35. 8mmol) dropwise. The resulting mixture was stirred at- [15°C] for [LH.] The mixture was washed with saturated aqueous sodium dihydrogen phosphate solution (250mL). The organic phase was dried [(NA2S04).] and concentrated to give the title compound (5g). [1H NMR] : 1.4 (s, 9H), 2.8 (m, 2H), 5.1 (m, 1H), 7. 3 (m, [5H),] 8.6 (m, [IH),] 9.6 (t, [IH).]
  • 18
  • 4-[2-(4-methanesulphonylphenylsulphonyl)ethyl]piperidine hydrochloride [ No CAS ]
  • [ 135865-78-0 ]
  • [ 718611-16-6 ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; In dichloromethane; for 16h; Method U (S) N- (3-Amino-3-phenylpropyl)-4- [2- (4-methanesulphonylphenylsulphonyl) ethyl] piperidine Sodium triacetoxyborohydride (1.6g) was added to a mixture of (S) 3-phenyl-3- (tert- BUTOXYCARBONYLAMINO) propionaldehyde (1.23g) and 4- [2- (4-METHANESULPHONYLPHENYL- sulphonyl) ethyl] piperidine hydrochloride (1.215g) (Method B) in dichloromethane (50ML) and the mixture was stirred for 16 hours. The reaction mixture was washed successively with 2M sodium hydroxide (15ML), water (15ML) and brine (15ML) and dried. The dichloromethane solution was stirred with PS-NCO (isocyanate resin, 1. 5G) for 16 hours and filtered. The filtrate was chromatographed on a 50g silica Bond Elut column eluting with ethyl acetate to give the Boc protected title compound as a white solid, yield 1.595g, MHF 565. The Boc protected compound (1.59g) was dissolved in 4M HCI/DIOXANE (LOML) and allowed to stand at room temperature for 1 hour. The reaction mixture was evaporated to dryness, redissolved in 2M sodium hydroxide (10ML) and extracted with dichloromethane (2X20ML) and dried. Removal of the solvent gave the title compound, yield 0.56g, MH+ 465.
  • 19
  • 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine [ No CAS ]
  • [ 135865-78-0 ]
  • tert-butyl (1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 18h; Preparation 12 tert-Butyl (1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate acetic acid (0.6 ml, 10.4 mmol) was added to a stirred solution of 3-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (Preparation 11) (2.0 g, 6 mmol) and <strong>[135865-78-0]tert-butyl (1S)-3-oxo-1-phenylpropylcarbamate</strong> (WO0039125) (1.7 g, 6.8 mmol) dissolved in dichloromethane (40 ml) under nitrogen at room temperature.sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was then added and the reaction was held at room temperature for 18 hours.The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution (50 ml) and dichloromethane (50 ml).The organic phase was removed and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO4) and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel eluding with a solvent gradient of dichloromethane:methanol:concentrated aqueous ammonia (96:4:0.4, by volume, changing to 94:6:0.6).Product containing fractions were evaporated to afford the title compound as a white foam (2.53 g). 1H NMR (400 MHz, CDCl3): delta: 7.40-7.20 (10H, m), 5.90 (1H, br s), 4.80 (1H, br s), 4.40 (1H, m), 3.70 (2H, s), 3.50 (2H, s), 3.30 (1H, m), 3.20 (1H, m), 2.85 (2H, m), 2.65 (2H, m), 2.45-2.30 (5H, m), 2.20 (2H, m), 2.00-1.70 (4H, m), 1.45-1.20 (13H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 592, [M+H]+ 570.
  • 20
  • 1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine [ No CAS ]
  • [ 135865-78-0 ]
  • tert-butyl (1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 18h; Preparation 33 tert-Butyl (1S)-3-[3-endo-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate acetic acid (0.14 g, 2.37 mmol) was added to a stirred solution of 1-endo-(8-azabicyclo[3.2.1]oct-3-yl)-5-benzyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (Preparation 32) (0.8 g, 2.37 mmol) and <strong>[135865-78-0]tert-butyl (1S)-3-oxo-1-phenylpropylcarbamate</strong> (WO0039125) (0.711 g, 2.85 mmol) dissolved in dichloromethane (12 ml) under nitrogen at room temperature.sodium triacetoxyborohydride (0.60 g, 2.85 mmol) was then added and the reaction was held at room temperature for 18 hours.The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution (50 ml) and dichloromethane (50 ml).The organic phase was removed and the aqueous phase was washed with dichloromethane (50 ml).The combined organic phases were dried (MgSO4) and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel eluding with a solvent gradient of dichloromethane:methanol:concentrated aqueous ammonia (99:1:0.1, by volume, changing to 90:10:1).Product containing fractions were evaporated to afford the title compound as a white foam (1.17 g). 1H NMR (400 MHz, CDCl3): delta: 7.40-7.20 (10H, m), 5.80 (1H, m), 4.80 (1H, m), 4.40 (1H, m), 3.65 (2H, s), 3.50 (2H, m), 3.40-3.20 (2H, m), 2.70-2.60 (4H, m), 2.55-2.35 (5H, m), 2.20 (2H, t), 2.10-1.10 (17H, m) ppm. LRMS (electrospray): m/z [M+H]+ 570.
YieldReaction ConditionsOperation in experiment
Step B tert-Butyl (1S)-3-oxo-1-phenylpropylcarbamate The compound was prepared from the title compound in Example 1, Step A (4 mmol, 1.1 g) as described in WO 00/39125, pp. 57-58. The aldehyde was further purified by flash chromatography on silica gel using a step gradient of hexanes, 4percent EtOAc/hexanes, 8percent EtOAc/hexanes, 12percent EtOAc/hexanes and 16percent EtOAc/hexanes. The aldehyde eluted in 16percent EtOAc/hexanes. Removal of solvent under reduced pressure afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): delta 9.78 (s, 1H), 7.36-7.41 (m, 2H), 7.28-7.35 (m, 3H), 5.23 (br s, 1H), 5.12 (br s, 1H), 2.84-3.04 (m, 2H), 1.45 (s, 9H). MS (ESI): m/z 290 (dihydrate+Na).
  • 22
  • [ 313708-59-7 ]
  • [ 135865-78-0 ]
  • [ 478408-20-7 ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; To a solution of the title compound from Step B (10 mmol, 2.5 g was added the product of Step E (11 mmol, 4.5 g) and N,N-diisopropylethylamine (40 mmol, 7 mL) in 40 mL of DCM was added NaBH(OAc)3 (30 mmol, 6.4 g). The slurry was sonicated briefly and the reaction mixture was allowed to stand at RT for 1 h. The reaction mixture was washed with 20 mL of H2O. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluding with 1:20:79 NH4OH/EtOAc/hexanes and 1:40:59 NH4OH/EtOAc/hexanes, affording the title compound as a white foamy solid. MS (ESI): m/z 503 (M+H). HPLC B: 1.78 min.
  • 23
  • [ 848076-54-0 ]
  • [ 135865-78-0 ]
  • {3-[3-(4-bromobenzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-yl]-1-(S)-phenylpropyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
75.8% Example 2. {3-[3-(4-Bromobenzyl)-2,4-dioxo-1, 3,8-triaza- spiro [4.5] dec-8-yl]-1-(S)-phenylpropyl}-carbamic acid tart-butyl ester (Compound 4); To a solution of 115 mg (0.307 mmol) of 3- (4- bromobenzyl) -1, 3,8-triaza-spiro [4.5] decane-2,4-dione hydrochloride in 5 mL of anhydrous DCE were added successively 76.6 mg (0.307 mmol) of (3-OXO-1- (S)- PHENYLPROPYL)-CARBAMIC acid tert-butyl ester and 50 pL (0.358 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 85 mg (0.382 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate were added. Then the solution was extracted with DCM, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography on bond elute silica gel eluting with 20percent ETHANOL/ETHYL acetate and Compound 4, as a colorless solid, was obtained (133 mg, 75. 8percent). 1H NMR (400 MHz, CDC13) 6 [PPM] 7.44 (D, 2H), 7.36-7. 2 (m, 7H), 6.06 (br S, 1H), 4.85-4. 7 (m, 1H), 4.58 (m, 2H), 3.0-2. 8 (m, 2H), 2.5-1. 5 (m, 10 H), 1. 42 (s, 9H). LC/MS: m/z 572.52 (MH+).
  • 24
  • [ 86732-22-1 ]
  • [ 135865-78-0 ]
  • [ 1056618-49-5 ]
YieldReaction ConditionsOperation in experiment
46% A solution of 4a (6.25g , 31 mmol) in DCM (200 mL) was added to 35 (1.0 g, 4.97 mmol). To the resulting mixture was added NaBH(OAc)3 (9.86 g, 47 mmol) in two portions and the reaction stirred for 18 h at RT. The reaction was washed with a solution 5percent NaHC03 (100 mL). The organic phase was dried (Na2S04) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with DCM/ 3.5percent MeOH (containing 10percent NH40H) to afford 6.8 g (46percent) of 36a as a viscous liquid: MS (ES+) m/z 436 (M + H)+.
  • 25
  • [ 135865-78-0 ]
  • [ 135865-78-0 ]
  • C27H37N5O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% To the mixture of 35 (0.20 g, 0.82 mmol, CAS 135865-78-0) and 44 (0.18 g, 0.75 mmol) in DCM (10 mL) was added sodium triacetoxyborohydride (0.24g, 1.12 mmol) and the resulting solution was stirred at RT for 3 h. The mixture was diluted with DCM and washed with saturated NaHC03. The organic layer was dried (MgS04), filtered and evaporated. The crude product and purified by Si02 column chromatography eluting with DCM:MeOH:NH40H (140:10:1) to afford 0.29 g (80 percent) of 53a: ms (ES+) m/z 480 (M + H).
  • 26
  • 1-isopropyl-3-methyl-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2,4-dione [ No CAS ]
  • [ 135865-78-0 ]
  • [(S)-3-(1-isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl)-1-phenyl-propyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% To 300 mg (1.19 mmol) of l-isopropyl-3-methyl- bicyclo[3.2.1]-lbeta,3, 8-triaza-spiro[4.5]dodecan-2, 4-dione in anhydrous DCE (30 itiL) was added 309 mg (1.24 mmol) of ((S)- 3-oxo-l-phenyl-propyl) -carbamic acid tert-butyl ester. The reaction mixture was stirred for 30 minutes and 380 mg (1.79 mmol) of sodium triacetoxyborohydride was added in one portion. Then the reaction mixture was agitated overnight at room temperature, diluted with DCM, washed with saturated solution of sodium bicarbonate and dried over sodium sulfate. The residue was purified by flash silica gel chromatography eluting with ethyl acetate:hexanes (0 to 100percent) then DCM.-methanol (9:1) to yield 509 mg (85percent) of [(S)- 3- (l-isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-lbeta,3, 8- triaza-spiro [4.5]dodec-8-yl) -1-phenyl-propyl]-carbamic acid tert-butyl ester.
YieldReaction ConditionsOperation in experiment
Preparation 3 tert-Butyl (1S)-3-oxo-1-phenylpropylcarbamate Diisobutylaluminium hydride (1 M in dichloromethane, 60 ml, 60 mmol) was cooled to -78° C. and added dropwise to a solution of the title compound from Preparation 2 (8.39 g, 30 mmol) in dichloromethane (150 ml) at -78° C. The reaction was stirred for 90 minutes then methanol (pre-cooled to -78° C., 40 ml) was added. The mixture was allowed to warm to room temperature and poured into 2 M aqueous hydrochloric acid (200 ml). The layers were separated and the aqueous phase extracted with dichloromethane (2*). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 6.72 g. 1H NMR (400 MHz, CDCl3): delta [ppm] 1.42 (9H, s), 2.86-3.00 (2H, m), 5.06 (1H, bs), 5.20 (1H, bs), 7.22-7.38 (5H, m), 9.75 (1H, s). LRMS: m/z 250.1 (MH30).
YieldReaction ConditionsOperation in experiment
Step F tert-Butyl-(1S)-1-phenyl-3-(4-[3-benzyl-1-ethyl(1H-pyrazol-5-yl)]piperidin-1-yl)propylcarbamate To a solution of the title compound from preparation Example 1, Step B (10 mmol, 2.5 g), 4-[3-benzyl-1-ethyl-pyrazol-5-yl]piperidine, bis HCl salt (Example 1, Step E, 11 mmol, 4.5 g) and N,N-diisopropylethylamine (40 mmol, 7 mL) in 40 mL of DCM was added NaBH(OAc)3 (30 mmol, 6.4 g). The slurry was sonicated briefly and the reaction mixture was allowed to stand at ambient temperature for 1 h. The reaction mixture was washed with 20 mL of H2O. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluding with 1:20:79 NH40OH/EtOAc/hexanes and 1:40:59 NH4OH/EtOAc/hexanes, affording the title compound as a white foamy solid. MS (ESI): m/z 503 (M+H). HPLC B: 1.78 min.
  • 29
  • [ 941691-18-5 ]
  • [ 135865-78-0 ]
  • {(S)-3-[3-(4-methoxy-benzyl)-2-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl]-1-phenyl-propyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
58.7% To a solution of 109 mg (0.35 mmol) of 3- (4-methoxy- benzyl) -1,3, 8-triaza-spiro [4.5] decan-2-one hydrochloride in 10 mL of anhydrous DCE were added successively 87.1 mg (0.35 mmol) of ( (S) -3-oxo-l-phenyl-propyl) -carbamic acid tert-butyl ester and 49 muL (0.35 mmol) of triethylamine . The reaction mixture was agitated at room <n="56"/>temperature for 10 minutes before adding 117 mg (0.525 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 20 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 4percent) giving { (S) -3- [3- (4-methoxy-benzyl) -2-oxo-l, 3 , 8-triaza-spiro [4.5] dec- 8 -yl] -1 -phenyl -propyl } -carbamic acid tert-butyl ester as a white solid (104.6 mg, 58.7percent).1H NMR (400 MHz, DMSO-ds): delta [ppm] 7.38 (d, IH), 7.28- 7.14 (m, 5H), 7.10 (d, 2H), 6.86 (d, 2H), 6.78 (br S, IH), 4.46 (q, IH), 4.12 (s, 2H), 3.70 (s, 3H), 3.28 (m, 2H), 2.90 (s, 2H), 2.14 (m, 4H), 1.72 (m, 2H), 1.51 (m, 4H) , 1.31 (S, 9H) .
  • 30
  • 2-(4-methoxy-benzyl)-1,2,8-triaza-spiro[4.5]decan-3-one dihydrochloride [ No CAS ]
  • [ 135865-78-0 ]
  • {(S)-3-[2-(4-methoxy-benzyl)-3-oxo-1,2,8-triaza-spiro[4.5]dec-8-yl]-1-phenyl-propyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
84.1% To a solution of 220 mg (0.63 mmol) of 2- (4-methoxy- benzyl) -1,2, 8-triaza-spiro [4.5] decan-3-one dihydrochloride in 12 mL of anhydrous DCE were added successively 157.5 mg (0.63 mmol) of ( (S) -3-oxo-l- phenyl -propyl ) -carbamic acid tert-butyl ester and 176 muL (1.26 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 209 mg (0.94 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 20 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 6percent) giving 269.6 mg (84.1percent) of ((S)- 3- [2- (4-methoxy-benzyl) -3-oxo-l, 2 , 8-triaza- spiro [4.5] dec-8-yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester as a pale yellow oil.1H NMR (400 MHz, DMSO-d6) : delta [ppm] 7.41 (d, IH), 7.27- 7.14 (m, 7H), 6.84 (d, 2H), 5.31 (s, IH), 4.46 (q, IH), <n="58"/>4.29 (S, 2H) , 3.69 (s, 3H) , 2.26 (m, 2H) , 2.20 (s, 2H) , 2.12 (m, 4H) , 1.68 (m, 2H) , 1.45 (m, 4H) , 1.31 (s, 9H) .
  • 31
  • [ 941691-23-2 ]
  • [ 135865-78-0 ]
  • {(S)-3-[2-(4-methoxy-benzyl)-1,3-dioxo-2,8-diaza-spiro[4.5]dec-8-yl]-1-phenyl-propyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.4% To a solution of 374 mg (1.29 mmol) of 2- (4-methoxy- benzyl) -2, 8-diaza-spiro [4.5] decane-1, 3-dione in 20 mL of anhydrous DCE was added 322 mg (1.29 mmol) of ((S) -3- oxo-1-phenyl -propyl) -carbamic acid tert-butyl ester. The reaction mixture was agitated at room temperature for 10 minutes before adding 432 mg (1.94 mmol) of sodium triacetoxyborohydride . After an overnight agitation, 40 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 3percent) giving 466.9 mg (69.4percent) of ((S)- 3- [2- (4-methoxy-benzyl) -1, 3-dioxo-2 , 8-diaza- spiro [4.5] dec- 8 -yl] -1 -phenyl -propyl} -carbamic acid tert- butyl ester as a colorless solid.1H NMR (400 MHz, DMSOd6): delta [ppm] 7.43 (d, IH), 7.26 (m, 4H), 7.18 (m, IH), 7.13 (d, 2H), 6.84 (d, 2H), 4.51 (q, IH), 4.44 (S, 2H), 3.69 (s, 3H), 2.70 (m, 2H), 2.60 (s, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.80-1.72 (m, 4H), 1.47 (d, 2H) , 1.33 (S, 9H) .
  • 32
  • [ 135865-78-0 ]
  • 3-(4-methoxy-benzyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one hydrochloride [ No CAS ]
  • {(S)-3-[3-(4-methoxy-benzyl)-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-8-yl]-1-phenyl-propyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
70.4% To a solution of 806 mg (2.58 mmol) of 3- (4-methoxy- benzyl) -l-oxa-3 , 8-diaza-spiro [4.5] decan-2-one hydrochloride in 50 mL of anhydrous DCE were added successively 643 mg (2 58 mmol) of ( (S) -3 -oxo-1 -phenyl - propyl) -carbamic acid tert-butyl ester and 360 muL (2.58 mmol) of triethylamine . The reaction mixture was agitated at room temperature for 10 minutes before adding 860 mg (3.87 mmol) of sodium triacetoxyborohydpide . After an overnight agitation, 40 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2 x 50 mL) , dried over sodium sulfate, filtered and concentrated m vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with methanol/DCM (0percent to 2percent) giving { (S) -3- [3- (4-methoxy- benzyl) -2-oxo- l-oxa-3 , 8-diaza-spiro [4.5] dec-8-yl] -1- phenyl -propyl} -carbamic acid tert-butyl ester as a white solid (922 mg, 70 4percent) . 1H NMR (400 MHz, DMSO-d6) . delta [ppm] 7.39 (d, IH), 7.26 (m, 4H), 7.16 (m, 3H), 6.89 (d, 2H), 4.48 (m, IH), 4.23 (s, 2H), 3.70 (s, 3H), 3.10 (s, 2H), 2.31 (m, 4H), 2 18 (m, 2H) , 1.70 (m, 6H) , 1.31 (s, 9H) .
  • 33
  • [ 172739-04-7 ]
  • [ 135865-78-0 ]
  • [ 872001-34-8 ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 4h; EXAMPLE 3; 2-Cyclohexyl-N-{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-malonamic acid methyl ester (I-20) and 2-cyclohexyl-N-{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-1-phenyl-propyl}-malonamic acid; trifluoroacetate salt (I-14); Step 1-; A mixture of 43 (4.07 g, 16.3 mmol), 11a (3.0 g, 14.8 mmol), NaBH(OAc)3 (4.71 g, 22.2 mmol) and HOAc (2.1 mL, 37.1 mmol) in DCM (100 mL) was stirred at RT for 4 h. The reaction was quenched by addition of 5percent NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried (MgSO2), filtered and concentrated in vacuo. The residue was purified via SiO2 chromatography eluting with DCM/MeOH to afford 44a.
  • 34
  • [ 20980-22-7 ]
  • [ 135865-78-0 ]
  • [ 1114997-31-7 ]
  • 35
  • [ 4774-24-7 ]
  • [ 135865-78-0 ]
  • [ 1114997-40-8 ]
 

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