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Structure of 364794-80-9

Chemical Structure| 364794-80-9

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Product Details of [ 364794-80-9 ]

CAS No. :364794-80-9
Formula : C17H26BNO3
M.W : 303.20
SMILES Code : CC1(C)C(C)(C)OB(C2=CC(CN3CCOCC3)=CC=C2)O1
MDL No. :MFCD06797489
InChI Key :RCGRLLZELIIKDH-UHFFFAOYSA-N
Pubchem ID :2795578

Safety of [ 364794-80-9 ]

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

Computational Chemistry of [ 364794-80-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 22
Num. arom. heavy atoms 6
Fraction Csp3 0.65
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 92.89
TPSA ?

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

30.93 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
Log Po/w (XLOGP3)?

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

2.37
Log Po/w (WLOGP)?

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

1.29
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.

1.3
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

2.19
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.43

Water Solubility

Log S (ESOL):?

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

-3.22
Solubility 0.184 mg/ml ; 0.000607 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.

-2.66
Solubility 0.663 mg/ml ; 0.00219 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

-4.58
Solubility 0.00807 mg/ml ; 0.0000266 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

Yes
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

Yes
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

Yes
Log Kp (skin permeation)?

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

-6.47 cm/s

Druglikeness

Lipinski?

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

0.0
Ghose?

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

None
Veber?

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

0.0
Egan?

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

0.0
Muegge?

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

0.0
Bioavailability Score?

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

0.55

Medicinal Chemistry

PAINS?

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

0.0 alert
Brenk?

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

1.0 alert: heavy_metal
Leadlikeness?

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

No; 1 violation:MW<0.0
Synthetic accessibility?

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

3.17

Application In Synthesis of [ 364794-80-9 ]

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

  • Downstream synthetic route of [ 364794-80-9 ]

[ 364794-80-9 ] Synthesis Path-Downstream   1~35

  • 2
  • [ 364794-80-9 ]
  • [ 364793-60-2 ]
  • 4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morpholinylmethyl)-phenyl]-3-quinolinecarbonitrile [ No CAS ]
  • 3
  • [ 364794-80-9 ]
  • [ 364793-73-7 ]
  • 4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinylmethyl]phenyl }-3-quinolinecarbonitrile [ No CAS ]
  • 4
  • [ 956034-15-4 ]
  • [ 364794-80-9 ]
  • C21H23ClN4O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 100℃; for 0.166667 - 0.666667h;Microwave irradiation; Example 223 2-(lH-indazol-4-yl)-4-morpholino-6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidine 299[00823] 2-Chloro-6-iodo-4-morpholinothieno[3,2-£/lpyrimidine 19 (50 mg) was <n="215"/>coupled to 4-[3-(4,4,5,5-tetramethyl-l,332-dioxaborolan-2-yl)]benzylmorpholine, and then reacted with 4-(4,4,5,5-tetramemyl-l,3,2-dioxaborolan-2-yl)-17Wndazole 7 via GeneralProcedure F. The product was purified by reverse phase HPLC to yield 2.6 mg of 299. MS.(Ql) 513.2 (M)+; General Procedure F Suzuki coupling reactions in one pot[00245] 2-CMoro-64odo-4rmorpholmothieno[3,2-£?]pyrimidine 19 (leq), phenylboronic acid or heterocycleboronic acid (R1 -B(OH)2, 1.1 eq) and bis(triphenylphosphine)palladium(II) dichloride (O.leq) in lMNa2CC>3 aqueous solution (3 eq) and acetonitrile (3eq) was heated to 100 0C in a sealed microwave reactor for 10 to 40 min to give 20. Upon completion, 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazole 7 (1.3 eq) and bis(triphenylphosphine)palladium(II) dichloride (O.leq) were added in the same pot. The reaction mixture was heated to 150 0C in a sealed microwave reactor for 10 to 15min. The mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were concentrated to yield crude 21.
  • 6
  • [ 73183-34-3 ]
  • [ 364793-82-8 ]
  • 4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morholinylmethyl) phenyll-3-quinolinecarbonitrile [ No CAS ]
  • [ 364794-80-9 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; In water; dimethyl sulfoxide; ethyl acetate; toluene; EXAMPLE 26 4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morholinylmethyl) phenyll-3-quinolinecarbonitrile To a dry flask under a nitrogen atmosphere was added 200 mg (0.78 mmol) of 4-(3-bromobenzyl) morpholine, 0.218 g (0.86 mmol) of bis(pinacolato) diboron, 230 mg (2.34 mmol) of potassium acetate, 5 mL of dimethylsulfoxide and 32 mg (0.04 mmol) of [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane. The reaction mixture was heated at 80 C. for 2 hours. After cooling, the mixture was partitioned between 20 mL of toluene, 40 mL of ethyl acetate and 40 mL of water. The layers were separated and the aqueous layer was further extracted with 30 mL of ethyl acetate. The organic layers were combined and washed with 4*40 mL water. After drying over magnesium sulfate, removal of the solvents gave crude 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl]morpholine as a dark oil.
  • 7
  • [ 73183-34-3 ]
  • [ 364793-86-2 ]
  • [ 364794-79-6 ]
  • [ 364794-80-9 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; In dichloromethane; dimethyl sulfoxide; EXAMPLE 28 4-(2,4-Dichloro-5-methoxyanilino)-7-3-[2-(4-morpholinvl) ethvllphenyl }-3-quinolinecarbonitrile By the procedure used to prepare 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl]morpholine, in Example 26, 1.0 g (3.70 mmol) of <strong>[364793-86-2]4-(3-bromophenethyl) morpholine</strong>, was reacted with 1.03 g (4.07 mmol) of bis(pinacolato) diboron, 1.1 g (11.0 mmol) of potassium acetate and 0.3 g (0.37 mmol) of [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane in 25 mL of anhydrous dimethylsulfoxide to provide crude 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenethyllmorpholine. This material was purified by flash silica gel chromatography, eluding with a gradient of 99:1 methylene chloride/methanol to 97.5:2.5 methylene chloride/methanol, to provide 0.52 g of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl]morpholine as a light brown liquid; MS (ES) m/z 318.3 (M+1).
  • 8
  • [ 747413-06-5 ]
  • [ 364794-80-9 ]
  • C37H36ClN3O5 [ No CAS ]
  • 9
  • [ 1161498-11-8 ]
  • [ 364794-80-9 ]
  • [ 1161500-58-8 ]
YieldReaction ConditionsOperation in experiment
Example 109: (S)-N-((S)-l-Cyano-2-(3'-(morpholinomethyl)biphenyl-4- yl)ethyl)piperidine-2-carboxamide ditrifluoroacetate(S)-tert-Buty{ 2-((S)- 1 -cyano-2-(4-iodophenyl)ethylcarbamoyl)piperidine- 1 -carboxylate (200 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.70 mg) in dioxane (5 mL) were treated with 4-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)morpholine (188 mg) and the mixture was stirred at room temperature for 15 min under nitrogen. An aqueous solution of potassium carbonate (2M, 0.414 mL) was added and the mixture was stirred for 18 h at 75 0C. After 4 further additions of 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride the mixture was heated for a total of 48 h. The mixture was evaporated and ethyl acetate was added. The resulting dark brown mixture was purified by flash silica chromatography, eluting with 20% ethyl acetate in isohexane and then with 40% ethyl acetate in isohexane containing 0.5% triethylamine to give a colourless oil. Formic acid (2 mL) was added and the mixture was heated at 50 0C for 12 min. The cooled mixture was basified with 0.880 aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated. The resulting oil was purified by preparative HPLC on a Waters X-Bridge column using a 95-5% gradient of aqueous 0.1% TFA in acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford the title compound (0.054g) as a yellow oil.1H NMR (399.825 MHz, D2O) delta 7.82 (d, J = 7.9 Hz, IH), 7.77 (s, IH), 7.73 - 7.68 (m, 2H), 7.62 (t, J = 7.8 Hz, IH), 7.52 (d, J = 7.7 Hz, IH), 7.49 - 7.43 (m, 2H), 5.08 (t, J = 7.8 Hz, <n="156"/>IH), 4.45 (s, 2H), 4.11 (d, J = 12.3 Hz, 2H), 3.90 - 3.83 (m, IH), 3.79 (t, J = 12.3 Hz, 2H), 3.48 (d, J = 12.3 Hz, 3H), 3.43 - 3.18 (m, 4H), 3.02 (t, J = 21.7 Hz, IH), 2.16 - 2.04 (m, IH), 1.99 - 1.82 (m, 2H), 1.80 - 1.44 (m, 3H) m/z 433 [M+H]+
  • 10
  • [ 1062295-41-3 ]
  • [ 364794-80-9 ]
  • N-{(2S)-5-[3-(4-morpholinylmethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; Reflux; Example 7: N-{(2S)-5-[3-(4-morpholinylmethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2- propanesulfonamideA mixture of N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.31 mmol, Description 1 ), 4-[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}morpholine (114 mg, 0.38 mmol), Pd(PPh3)4 (3.6 mg, 3.1 umol), and Na2CO3 (67 mg, 0.63 mmol) in a 3:1 mixture of dioxane:water (2 ml) was stirred and refluxed at 90 0C under argon for 16 hours. The mixture was allowed to cool and was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude product as a yellow oil, which was purified using MDAP. The resulting material was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the desired product as a white foam (81 mg, 62%). LC/MS (ES): Found 415 (ES+), retention time 0.74 mins (2 minute run). C23H30N2O3S requires 414.1H NMR (400MHz, CDCI3): delta 7.51-7.53 (1 H, m), 7.41-7.47 (3H, m), 7.38 (1 H, t, J = 7 Hz), 7.27-7.32 (2H, m), 4.28-4.39 (2H, m), 3.70-3.74 (4H, m), 3.56 (2H, s), 3.33-3.42 (2H, m), 3.21 (1 H, septet, J = 7 Hz), 2.92-3.01 (2H, m), 2.46-2.50 (4H, m), 1.41 (6H, d, J = 7 Hz).
  • 11
  • [ 110-91-8 ]
  • [ 214360-74-4 ]
  • [ 364794-80-9 ]
  • 12
  • [ 99-90-1 ]
  • [ 364794-80-9 ]
  • [ 1177195-80-0 ]
  • 13
  • [ 1049093-75-5 ]
  • [ 364794-80-9 ]
  • [ 1382722-81-7 ]
  • 14
  • [ 851684-46-3 ]
  • [ 364794-80-9 ]
  • [ 1432450-84-4 ]
  • 15
  • [ 1338796-33-0 ]
  • [ 364794-80-9 ]
  • [ 1430464-38-2 ]
YieldReaction ConditionsOperation in experiment
27% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 125℃; for 0.5h;Inert atmosphere; Microwave irradiation; To a mixture of N-(3-iodo-lH-indazol-5-yl)-2-(pyrrolidin-l-yl)-2- (thiophen-3-yl)acetamide (56.6 mg, 0.125 mmol) and 4-(3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)morpholine (33.3 mg, 0.11 mmol) in PhCH3/EtOH (1.5 mL/3 mL) was added 1 M aq Na2C03 (0.3 mL, 0.3 mmol), followed by Pd(PPh3)4 (5.8 mg, 0.005 mmol). The resulting mixture was purged with Ar and microwaved 30 min at 125 C. After removal of solvents, it was purified by flash chromatography (EtO Ac/hex 0 to 100 %, then MeOH/DCM 5-15 %) and then triturated with Et20 to give the title compound as beige solid (15 mg, 27 %). ? NMR (400 MHz, CD3OD) delta 8.37 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.55-7.47 (m, 4H), 7.45-7.39 (m, 2H), 7.35 (d, J = 4.8 Hz, 1H), 4.15 (s, 1H), 3.72 (t, J = 4.6 Hz, 4H), 3.65 (s, 2H), 2.75-2.65 (m, 2H), 2.60-2.50 (m, 6H), 1.90-1.85 (m, 4H); MS ESI 502.2 [M + H]+, calcd for [C28H31N502S + H]+ 502.2.
  • 16
  • [ 1443284-06-7 ]
  • [ 364794-80-9 ]
  • [ 1443283-80-4 ]
YieldReaction ConditionsOperation in experiment
0.106 g With tetrakis(triphenylphosphine) palladium(0); tripotassium phosphate dihydrate; In 1,2-dimethoxyethane; water; at 150℃; for 0.25h;Inert atmosphere; Microwave irradiation; To 149 mg (0.48 mmol) of 6-chloro-1 -methyl-3-(3-pyridyl)-4-(trifluoromethyl)-1 H- pyrazolo[3,4-b]pyridine in 4.8 ml of a 1/1 DME/H20 mixture under an inert atmosphere of argon are added 0.173 g (0.57 mmol) of 4-[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl]morpholine, 0.355 g (1.43 mmol) of potassium phosphate dihydrate and 1 1 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium. The reaction medium is heated at 150C for 15 minutes by microwave. The reaction medium is hydrolysed with water and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel, eluting with a dichloromethane/methanol mixture. After recrystallization from diisopropyl ether, 0.106 g of a white solid is obtained. MH+: 454 Melting point: 155C 1H NMR (400 MHz, DMSO-d6) delta 8.68 - 8.74 (m, 2 H), 8.22 - 8.29 (m, 2 H), 8.19 (s, 1 H), 7.96 (dt, J=7.9 Hz, 1 .7 Hz, 1 H), 7.50 - 7.61 (m, 3 H), 4.28 (s, 3 H), 3.55 - 3.69 (m, 6 H), 2.43 (m, 4 H)
  • 17
  • [ 110-91-8 ]
  • [ 443776-76-9 ]
  • [ 364794-80-9 ]
  • 18
  • [ 76-09-5 ]
  • [ 364794-80-9 ]
  • 19
  • [ 87199-15-3 ]
  • [ 364794-80-9 ]
  • 20
  • tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate [ No CAS ]
  • [ 364794-80-9 ]
  • tert-butyl cyclopropyl(3-formyl-6-(3-(morpholinomethyl)phenyl)imidazo[1,2-a]pyrazin-8-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 2h;Reflux; Example 182 Synthesis of tert-butyl cyclopropyl(3-formyl-6-(3-(morpholinomethyl)phenyl)imidazo[1,2-a]pyrazin-8-yl)carbamate Tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate (100 mg, 0.26 mmol), <strong>[364794-80-9]4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine</strong> (118 mg, 0.39 mmol), 3M Na2CO3 (1.3 mL, 2.60 mmol) and DME (3.5 mL) were combined. The solution was degassed with a stream of N2 for 10 min. Pd(PPh3)4 was added and the solution was refluxed for 2 h. The solution was partitioned between dichloromethane (25 mL) and water (25 mL). The aqueous layer was further extracted with dichloromethane (2*25 mL). The organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via preparative TLC (5% MeOH/dichloromethane) to afford tert-butyl cyclopropyl(3-formyl-6-(3-(morpholinomethyl)phenyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (60 mg, 48%). LCMS (ES): >95% pure, m/z 478 [M+1]+.
48% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 2h;Inert atmosphere; Reflux; Tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate (100 mg, 0.26 mmol), <strong>[364794-80-9]4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine</strong> (118 mg, 0.39 mmol), 3M Na 2CO 3 (1.3 mL, 2.60 mmol) and DME (3.5 mL) were combined. The solution was degassed with a stream of N 2 for 10 min. Pd(PPh 3) 4 was added and the solution was refluxed for 2 h. The solution was partitioned between dichloromethane (25 mL) and water (25 mL). The aqueous layer was further extracted with dichloromethane (2×25 mL). The organics were washed with brine (50 mL), dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified via preparative TLC (5% MeOH/dichloromethane) to afford tert-butyl cyclopropyl(3-formyl-6-(3-(morpholinomethyl)phenyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (60 mg, 48%).
  • 21
  • 7-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
  • [ 364794-80-9 ]
  • 7-(3-(morpholinomethyl)phenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
  • 22
  • 7-bromo-5-(1-cyclohexyl-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
  • [ 364794-80-9 ]
  • 5-(1-cyclohexyl-1H-pyrazol-5-yl)-7-(3-(morpholinomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
  • 23
  • 1-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine [ No CAS ]
  • [ 364794-80-9 ]
  • 4-((2'-fluoro-4‘-(4-methylpiperazin-1-yl)-5‘-nitro-[1,1'-biphenyl]-3-yl)methyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
54.7% With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 90℃;Inert atmosphere; Sealed tube; A vial was charged with the mixture obtained in l-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine,<strong>[364794-80-9]3-(4-morpholinomethyl)phenylboronic acid pinacol ester</strong> (0.498 g, 1.642 mmol), XPhos Pd G2 (0.017 g, 0.022 mmol), and XPhos (10.44 mg, 0.022 mmol). The vial was sealed with a cap and septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (volume: 10 ml) and a 2M aq. solution of sodium carbonate monohydrate (ACS) (2.74 ml, 5.47 mmol) were added via syringe and the vial was evacuated and backfilled with nitrogen an additional time. The reaction was heated at 90C in an aluminum block overnight. LCMS indicated complete consumption of the starting material(s). The peak at 1.56 minutes ionized for the mass of the target product. The reaction was cooled to room temperature and concentrated onto celite. Purification by silica gel flash chromatography [1 -10% MeOH/DCM + l% NH4OH;] afforded the desired4-((2'-fluoro-4'-(4-methylpiperazin- l-yl)-5'-nitro-[l,Gamma-biphenyl]-3-yl)methyl)mo holine (0.248 g, 0.598 mmol, 54.7% yield) as a yellow oil. LCMS [M+H]+ 415 g/mol.
  • 24
  • 1-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine [ No CAS ]
  • [ 364794-80-9 ]
  • 1-(2-fluoro-3‘-(morpholinomethyl)-5-nitro-[1,1‘-biphenyl]-4-yl)-N,N-dimethylpyrrolidin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 95℃;Inert atmosphere; Sealed tube; A vial was charged with a mixture of l-(4-bromo-5-fluoro-2- nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.092 g, 0.28 mmol, prepared as described in Example 21 above), <strong>[364794-80-9]3-(4-morpholinomethyl)phenylboronic acid pinacol ester</strong> (0.12 g, 0.39 mmol), XPhos Pd G2 (0.0044 g, 0.005 mmol) and XPhos (0.0026 g, 0.005 mmol). The vial was sealed with a septum cap and evacuated and backfilled with nitrogen. 1,4-Dioxane (4 mL) and 2M Aq sodium carbonate (0.70 mL, 1.4 mmol) were added via syringe. The vial was evacuated and backfilled an additional time before being heated at 95 C overnight. The reaction was cooled to room temperature and concentrated directly onto celite. Flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] afforded 1 -(2-fluoro-3'-(morpholinomethyl)-5 -nitro-[1 , 1 '-biphenyl] -4-yl)-N,N- dimethylpyrrolidin-3-amine (0.110 g, 86 %). LCMS [M+H]+: 429.5.
  • 25
  • 4-(4-chloro-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine [ No CAS ]
  • [ 364794-80-9 ]
  • 4-((4‘-(3,4-dimethylpiperazin-1-yl)-2‘-fluoro-5‘-nitro-[1,1‘-biphenyl]-3-yl)methyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 100℃;Inert atmosphere; A vial was charged with the mixture obtained in Step 1 (0.22 g), 3-(4- mo holinomethyl) henylboronic acid pinacol ester (0.16 g, 0.52 mmol), XPhos Pd G2 (0.006 g, 0.007 mmol) and XPhos (0.004 g, 0.007 mmol). The vial was sealed with a septum cap and evacuated and backfilled with nitrogen. 1,4-Dioxane (4 mL) and a 2M aq. solution of sodium carbonate (0.90 mL, 1.7 mmol) were added via syringe. The vial was evacuated and backfilled an additional time before being heated at 100 C in an aluminum block overnight. The reaction was cooled to room temperature and concentrated directly onto celite. Flash chromatography [0.5-5% MeOH/DCM + 1% NH4OH] afforded the desired 4-((4'-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-5'-nitro- [1,Gamma-MurhoEtabetaetagamma1]-3-gamma1^betaiotagamma1)piiotaomicronphiEtaomicron1etabeta (0.18 g, 62%). LCMS [M+H]+: 429.7.
  • 26
  • (R)-4-(4-chloro-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine [ No CAS ]
  • [ 364794-80-9 ]
  • (R)-4-((4‘-(3,4-dimethylpiperazin-1-yl)-2‘-fluoro-5‘-nitro-[1,1'-biphenyl]-3-yl)methyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 100℃;Inert atmosphere; A 30 mL vial was charged with a mixture of (R)-4-(4-chloro-5-fluoro-2- nitrophenyl)-l,2-dimethylpiperazine (0.050 g, 0.174 mmol), 3-(4- mophiholinomethyl)phenylboronic acid pinacol ester (0.074 g, 0.243 mmol), XPhos Pd G2 (2.73 mg, 3.48 muetaiotaomicron) and XPhos (1.657 mg, 3.48 muetaiotaomicron). The vial was sealed with a cap/septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (2 ml) and 2M Aq sodium carbonate (0.434 ml, 0.869 mmol) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated in an aluminum block overnight at 100 C. LCMS indicated very clean conversion to the desired product. The reaction mixture was loaded onto celite and purified by flash chromatography [0.1-5% MeOH/DCM + 1% NH4OH] to afford the product (0.152 mmol, 87 % yield) as a yellow film.
  • 27
  • [ 364794-80-9 ]
  • 6-chloro-N-[4-(4-methylpiperazin-1-yl)-3'-morpholin-4-ylmethyl-biphenyl-3-yl]-4-trifluoromethylnicotinamide [ No CAS ]
  • 28
  • [ 364794-80-9 ]
  • 6-oxo-4-trifluoromethyl-1,6-dihydro-pyridine-3-carboxylic acid [4-(4-methyl-piperazin-1-yl)-3'-morpholin-4-ylmethyl-biphenyl-3-yl]-amide [ No CAS ]
  • 29
  • 5-bromo-2-(4-methyl-piperazin-1-yl)-phenylamine [ No CAS ]
  • [ 364794-80-9 ]
  • 4-(4-methyl-piperazin-1-yl)-3'-morpholin-4-ylmethyl-biphenyl-3-ylamine trihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% A stirring solution of <strong>[364794-80-9]4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine</strong> 22 (5.37 g,17.7 mmol), 5-bromo-2-(4-methyl-piperazin-1-yl)-phenylamine 24 (3.97 g, 14.7 mmol), potassiumphosphate (9.43 g, 44.4 mmol), water (4.12 mL) and 1-butanol (68.0 mL) in a 250 mL round bottomsealed tube pressure vessel was purged with nitrogen, then SPhos Pd G2 (0.750 g, 1.04 mmol) wasadded in one portion, the mixture was purged for an additional 5 min, then the mixture was sealedand heated at 70 C in an oil bath overnight. The crude reaction mixture was allowed to cool to roomtemperature, was filtered through celite with warm 95% EtOH:H2O (3 x 50 mL) and concentrated toafford a brown solid. The crude solid was diluted with EtOH (200 mL), cooled to 0 C in an ice bathand concentrated HCl (20 mL) was added in one portion. The mixture was removed from the ice bathand stirred for 1h at room temperature. The resulting suspension was filtered, washed with cold EtOH(2 x 50 mL) and dried under vacuum to afford 6.85 g (98%) of 4-(4-methyl-piperazin-1-yl)-3'-morpholin-4-ylmethyl-biphenyl-3-ylamine hydrochloride 26. 1H NMR (400 MHz, DMSO-d6) delta 7.97 (s,1H), 7.72 - 7.60 (m, 4H), 7.59 - 7.51 (m, 1H), 7.38 (d, J = 8.3 Hz, 1H), 4.44 (s, 2H), 3.95 - 3.79 (m,4H), 3.49 (d, J = 11.5 Hz, 2H), 3.42 - 3.08 (m, 11H), 2.82 (s, 3H). 13C NMR (400 MHz, DMSO-d6) delta143.12, 139.45, 136.94, 131.22, 130.83, 130.11, 130.01, 129.53, 127.55, 125.13, 122.75, 120.57,63.05, 58.78, 52.64, 50.63, 48.37, 42.15. LRMS m/z calcd. for C22H30N4O ([M+H]+) 367.25, found367.46.
  • 30
  • (R)-3-bromo-6-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one [ No CAS ]
  • [ 364794-80-9 ]
  • (R)-6-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-2-methyl-3-(3-(morpholinomethyl)phenyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one [ No CAS ]
  • 31
  • [ 956034-15-4 ]
  • [ 364794-80-9 ]
  • 2-(1H-indazol-4-yl)-4-morpholino-6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidine [ No CAS ]
  • 32
  • [ 1403993-19-0 ]
  • [ 364794-80-9 ]
  • (R)-4-(3-(5-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)thiophen-2-yl)benzyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 150℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; General procedure: To a mixture of derivative of type IV (50 mg, 0.147 mmol) intoluene (1.5 mL) and EtOH (0.75 mL) were successively added thedesired boronic ester or acid of type V (0.176 mmol, 1.2 eq.), K2CO3(0.294 mmol, 2.0 eq.) and Pd(PPh3)4 (0.0147 mmol, 10 mol %). Thereaction mixture was degassed with Ar and irradiated under microwavefor 20 min at 150 C. Alternatively PdCl2(dppf) 10 mol %,could be used as catalyst. In this case the base was switched toNa2CO3 (2.0 eq.) and the irradiation performed for 40 min at 100 C.In both cases, after cooling, the volatiles were removed underreduced pressure and the crude material purified by flash chromatography(CH2Cl2/MeOH 80/20 NH4OH 0.1 mL).
  • 33
  • [ 823-78-9 ]
  • [ 364794-80-9 ]
  • 34
  • [ 1404051-38-2 ]
  • [ 364794-80-9 ]
  • (R)-4-((3'-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)[1,1′-biphenyl]-3-yl)methyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 150℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; General procedure: To a mixture of derivative of type IV (50 mg, 0.147 mmol) intoluene (1.5 mL) and EtOH (0.75 mL) were successively added thedesired boronic ester or acid of type V (0.176 mmol, 1.2 eq.), K2CO3(0.294 mmol, 2.0 eq.) and Pd(PPh3)4 (0.0147 mmol, 10 mol %). Thereaction mixture was degassed with Ar and irradiated under microwavefor 20 min at 150 C. Alternatively PdCl2(dppf) 10 mol %,could be used as catalyst. In this case the base was switched toNa2CO3 (2.0 eq.) and the irradiation performed for 40 min at 100 C.In both cases, after cooling, the volatiles were removed underreduced pressure and the crude material purified by flash chromatography(CH2Cl2/MeOH 80/20 NH4OH 0.1 mL).
  • 35
  • [ 364794-80-9 ]
  • [ 87476-73-1 ]
 

Historical Records

Technical Information

Categories

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[ 364794-80-9 ]

Morpholines

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