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Chemical Structure| 51421-99-9 Chemical Structure| 51421-99-9

Structure of 51421-99-9

Chemical Structure| 51421-99-9

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Product Details of [ 51421-99-9 ]

CAS No. :51421-99-9
Formula : C5H5ClN2O
M.W : 144.56
SMILES Code : ClC1=NC(=NC=C1)OC
MDL No. :MFCD09025734
InChI Key :XCAMEGPUILTZSU-UHFFFAOYSA-N
Pubchem ID :575230

Safety of [ 51421-99-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 51421-99-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 33.53
TPSA ?

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

35.01 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.79
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

1.47
Log Po/w (WLOGP)?

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

1.14
Log Po/w (MLOGP)?

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

0.33
Log Po/w (SILICOS-IT)?

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

1.56
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.26

Water Solubility

Log S (ESOL):?

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

-2.09
Solubility 1.18 mg/ml ; 0.00813 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.

-1.81
Solubility 2.23 mg/ml ; 0.0154 mol/l
Class?

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

Very soluble
Log S (SILICOS-IT)?

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

-2.37
Solubility 0.612 mg/ml ; 0.00424 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.

-6.14 cm/s

Druglikeness

Lipinski?

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

0.0
Ghose?

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

None
Veber?

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

0.0
Egan?

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

0.0
Muegge?

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

1.0
Bioavailability Score?

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

0.55

Medicinal Chemistry

PAINS?

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

0.0 alert
Brenk?

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

0.0 alert: heavy_metal
Leadlikeness?

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

No; 1 violation:MW<1.0
Synthetic accessibility?

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

1.8

Application In Synthesis of [ 51421-99-9 ]

* 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 [ 51421-99-9 ]

[ 51421-99-9 ] Synthesis Path-Downstream   1~21

  • 3
  • [ 128796-39-4 ]
  • [ 51421-99-9 ]
  • [ 1159816-20-2 ]
YieldReaction ConditionsOperation in experiment
22% a) 4-(4-(Trifluoromethyl)phenyl)pyrimidin-2(1H)-one (CAS Registry Number 1159816-20-2) A suspension of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (500 mg, 3.47 mmol), 4-(trifluoromethyl)phenylboronic acid (788 mg, 4.17 mmol), PdCl2(dppf) (283 mg, 0.347 mmol) and K2CO3 (958 mg, 6.94 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 95 C. for 20 h. The suspension was cooled, H2O was added and the suspension was filtered to afford a light colored solid. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. The white solid was diluted with concentrated HCl solution (10 mL) and stirred at reflux for 4 h. The reaction was cooled, and the solution was neutralized with saturated NaHCO3 solution. The resulting suspension was filtered to afford 185 mg (22%) of the title compound as a white solid: ESI MS m/z 241 [M+H]+.
  • 4
  • [ 6783-05-7 ]
  • [ 51421-99-9 ]
  • [ 1260494-66-3 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 95℃; for 16h; a) (E)-2-Methoxy-4-styrylpyrimidine A solution of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (0.36 g, 2.5 mmol), trans-2-phenylvinylboronic acid (0.56 g, 3.8 mmol) and potassium carbonate (0.69 g, 5.0 mmol) in DMSO (8.0 mL) was purged with argon for 5 min. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.18 g, 0.25 mmol) was added to the above solution. The reaction mixture was purged with argon for 5 min and then heated at 95 C. for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water (2*) and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel hexanes/ethyl acetate 95:5 to 60:40) to afford the title compound (0.51 g, 96%) as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 8.47 (d, J=5.0 Hz, 1H), 7.92 (d, J=16.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.42-7.35 (m, 3H), 7.01 (d, J=16.0 Hz, 1H), 6.94 (d, J=5.0 Hz, 1H), 4.07 (s, 3H).
  • 5
  • 6-(trifluoromethyl)-3-pyridinylboronic acid [ No CAS ]
  • [ 51421-99-9 ]
  • [ 1260494-33-4 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 100℃; for 4h;Inert atmosphere; a) 2-Methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine A solution of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (0.50 g, 3.5 mmol), 2-trifluoromethyl)pyridine-5-boronic acid (1.0 g, 5.2 mmol) and potassium carbonate (0.95 g, 6.9 mmol) in DMSO was degassed with argon for 10 min. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.26 g, 0.35 mmol) was then added to the above solution. The reaction mixture was degassed with argon for 5 min and then heated at 100 C. for 4 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water (2*) and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel hexanes/ethyl acetate 95:5 to 50:50) to afford the title compound (0.80 g, 90%) as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 9.37 (d, J=2.0 Hz, 1H), 8.69 (d, J=5.5 Hz, 1H), 8.61 (dd, J=8.0, 2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.44 (d, J=5.0 Hz, 1H), 4.12 (s 3H).
  • 6
  • [ 6783-05-7 ]
  • [ 51421-99-9 ]
  • [ 1260494-67-4 ]
  • 7
  • [ 3289-47-2 ]
  • [ 51421-99-9 ]
  • 8
  • [ 3289-47-2 ]
  • [ 51421-99-9 ]
  • [ 25902-86-7 ]
  • 9
  • [ 199679-23-7 ]
  • [ 51421-99-9 ]
  • [ 1394349-95-1 ]
YieldReaction ConditionsOperation in experiment
With dimethylimidazolium iodide; sodium hydride; In 1,4-dioxane; mineral oil; at 20℃;Reflux; 159.2 2-Chloro-5-(2-methoxyDyrimidine-4-carbonyl)benzoic acid methyl esterA 60% suspension of NaH in mineral oil (51 mg) was added to a solution of 4-chloro-2- methoxypyrimidine (123 mg), intermediate 159.1 (170 mg) and dimethylimidazolium iodide (96 mg) in dioxane (35 mL). The reaction mixture was heated to reflux for 4h30 and ON at RT. It was diluted with water and extracted with EtOAc. The organic phase was dried over MgS04 and concentrated in vacuo. The crude was purified by CC (Hept/EtOAc 1/0 to 7/3) to give 49 mg of the titled compound as a light yellow solid.LC-MS (B): tR = 0.77 min; [M+H]+: 307.19
49 mg With sodium hydride; 1,3-dimethylimidazolim iodide; In 1,4-dioxane; mineral oil; at 20 - 30℃; 159.2 2-Chloro-5-(2-methoxypyrimidine-4-carbonyl)benzoic acid methyl ester A 60% suspension of NaH in mineral oil (51 mg) was added to a solution of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (123 mg), intermediate 159.1 (170 mg) and dimethylimidazolium iodide (96 mg) in dioxane (35 mL). The reaction mixture was heated to reflux for 4 h30 and ON at RT. It was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC (Hept/EtOAc 1/0 to 7/3) to give 49 mg of the titled compound as a light yellow solid. LC-MS (B): tR=0.77 min; [M+H]+: 307.19
  • 10
  • [ 1400633-46-6 ]
  • [ 51421-99-9 ]
  • [ 1400633-70-6 ]
YieldReaction ConditionsOperation in experiment
20% With caesium carbonate;palladium diacetate; XPhos; In 1,4-dioxane; at 100 - 140℃; for 72h;Inert atmosphere; Sealed tube; Microwave irradiation; Palladium(II) acetate (4.2 mg, 0.019 mmol) was added to a stirred suspension of 2- phenoxymethyl-6H-imidazo[l,2-c]pyrimidin-5-one (150 mg, 0.62 mmol), 4-chloro-2- methoxy-pyrimidine (107.9 mg, 0.75 mmol), Cs2C03 (283.6 mg, 0.87 mmol) and 2- dicyclohexylphosphino-2',4',6'-triiso-propyl-l,l'-biphenyl (26.7 mg, 0.056 mmol) in 1,4- dioxane (2 mL) under nitrogen and in a sealed tube. The mixture was stirred at 100 C for 3 days and at 140 C for 15 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether to yield 6-(2- methoxy-pyrimidin-4-yl)-2-phenoxymethyl-6H-imidazo[l,2-c]pyrimidin-5-one (43 mg, 20% yield) as a white solid. 1H NMR (400 MHz,CDCl3) delta ppm 4.09 (s, 3 H), 5.18 (d, J=0.9 Hz, 2 H), 6.77 (dd, J=8.2, 0.6 Hz, 1 H), 6.95 - 7.06 (m, 3 H), 7.27 - 7.36 (m, 2 H), 7.85 (d, J=0.7 Hz, 1 H), 7.91 (d, J=5.5 Hz, 1 H), 8.24 (d, J=8.1 Hz, 1 H), 8.65 (d, J=5.5 Hz, 1 H).
20% With palladium diacetate; caesium carbonate; XPhos; In 1,4-dioxane; at 100 - 140℃; for 72.25h;Inert atmosphere; Microwave irradiation; Palladium(II)acetate (4.2 mg, 0.019 mmol) was added to a stirred suspension of 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (150 mg, 0.62 mmol), <strong>[51421-99-9]4-chloro-2-methoxy-pyrimidine</strong> (107.9 mg, 0.75 mmol), Cs2CO3 (283.6 mg, 0.87 mmol) and 2-dicyclohexylphosphino-2',4',6'-triiso-propyl-1,1'-biphenyl (26.7 mg, 0.056 mmol) in 1,4-dioxane (2 mL) under nitrogen and in a sealed tube. The mixture was stirred at 100 C. for 3 days and at 140 C. for 15 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether to yield 6-(2-methoxy-pyrimidin-4-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (43 mg, 20% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 4.09 (s, 3H), 5.18 (d, J=0.9 Hz, 2H), 6.77 (dd, J=8.2, 0.6 Hz, 1H), 6.95-7.06 (m, 3H), 7.27-7.36 (m, 2H), 7.85 (d, J=0.7 Hz, 1H), 7.91 (d, J=5.5 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.65 (d, J=5.5 Hz, 1H).
  • 11
  • [ 51421-99-9 ]
  • [ 57260-71-6 ]
  • [ 1447727-11-8 ]
YieldReaction ConditionsOperation in experiment
1.6 g With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; 6.01.12.01 4- 2-methoxy-pyrimidin-4-yl)-piperazine-l-carboxylic acid tert-butyl ester 1.3 g piperazine-l-carboxylic acid tert-butyl ester and 1.42 mL DIPEA were added to 1 g 2,4- dichlor-pyrimidine in 10 mL dichlormethane. The reaction was stirred over night at RT. The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ ethylacetate) to yield 1.6 g of the desired compound. Rt: 2.10 min (method I), (M+H)+: 299
  • 12
  • 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ No CAS ]
  • [ 51421-99-9 ]
  • 2-(benzyloxy)-5-(2-methoxypyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% With palladium diacetate; caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 24h; [00587] Palladium (II) acetate (2.8 mg, 0.012 mmol) was added to a stirred suspension of 2-(benzyloxy)-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (0.1 g, 0.41 mmol), 4-chloro-2- methoxy-pyrimidine (0.120 g, 0.82 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (17.7 mg, 0.037 mmol) and CS2CO3 (0.19 g, 0.58 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 100 C for 24 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 95/5). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with diethyl ether to yield 2-(benzyloxy)-5-(2- methoxypyrimidin-4-yl)-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (51 mg, 35% yield) as a white solid. dsHnNsOs. 1H NMR (500 MHz, CDC13) delta ppm 4.03 (s, 3 H), 4.33 (dd, J=6.6, 5.2 Hz, 2 H), 4.64 (dd, J=6.6, 5.2 Hz, 2 H), 5.23 (s, 2 H), 6.40 (s, 1 H), 7.31 - 7.36 (m, 1 H), 7.39 (t, J=7.4 Hz, 2 H), 7.42 - 7.48 (m, 2 H), 7.89 (d, J=5.8 Hz, 1 H), 8.44 (d, J=5.8 Hz, 1 H).
  • 13
  • [ 56961-30-9 ]
  • [ 51421-99-9 ]
  • [ 1394348-84-5 ]
YieldReaction ConditionsOperation in experiment
General procedure: This compound was prepared using a method analogousto that of Example 102 (intermediate 102.1 ), <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> replacing 2,6-difluoropyridine exceptthat the reaction mixture was stirred for 1 hat 80 C. then for18 hat RT and that the product precipitated out off the aqueousphase after acidification and was isolated by filtration LC-MS (B): tR=0.60 min; [M+H]+: 281.07
  • 14
  • [ 17642-17-0 ]
  • [ 51421-99-9 ]
  • [ 1394349-19-9 ]
YieldReaction ConditionsOperation in experiment
General procedure: This compound was prepared using a method analogousto that of Example 102 (intermediate 102.1 ), <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> replacing 2,6-difluoropyridine andintermediate 132.4 replacing 2-chloro-5-hydroxybenzoicacid except that the reaction mixture was stirred for 30 min at80 C. LC-MS (B): tR=0.65 min; [M+H]+: 297.04
  • 15
  • [ 1621526-49-5 ]
  • [ 51421-99-9 ]
  • [ 1621525-53-8 ]
YieldReaction ConditionsOperation in experiment
INTERMEDIATE 62 4-("3-Bromo-4-fluoro-lH"-pyrazol-l-vn-2-methoxypyrimidine To a solution of 3-bromo-4-fluoro-lH-pyrazole (500 mg, 3.03 mmol) in anhydrous DMSO (6 mL) was added NaH (133 mg, 3.13 mmol) at 0C. The mixture was stirred for 30 min at 0 C, followed by the addition of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (438 mg, 3.03 mmol) in DMSO (2 mL). The resulting mixture was stirred at 90 C overnight. The mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (40 mL x 3). The organic layer was collected and dried over Na2S04. The solvent was removed in vacuo to give the crude product. This was purified by flash chromatography (ISCO Combiflash, 24g, Biotage Si column, ~60 mL/min, 100% hexanes 5 min, gradient to 100% EtOAc in hexanes 15 min) to afford 4-(3-bromo-4-fluoro-lH-pyrazol-l-yl)-2-methoxypyrimidine. LCMS calc. = 274.98; found = 274.90 (M+H)+.
  • 16
  • [ 51421-99-9 ]
  • 4-hydrazinyl-2-methoxypyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With hydrazine hydrate; In ethanol; at 85℃; for 1h;Inert atmosphere; Step 59.1: 4-hydrazinyl-2-methoxypyrimidine To a stirred solution of 526 <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (5.7 g, 39.4 mmol) in EtOH (100 mL) under Ar was added hydrazine hydrate (3.83 mL, 79 mmol) and the reaction mixture was heated up and stirred at 85 C. for 1 hr. Volatiles were removed under reduced pressure and the resulting crude material was purified by silica gel column chromatography (CH2Cl2/MeOH/1-5%/NH3 1%) to afford the title product (4.40 g, 31.4 mmol, 80% yield) as white solid. ESI-MS: 141 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
80% With hydrazine hydrate; In ethanol; at 58℃; for 1h;Inert atmosphere; To a stirred solution of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (5.7 g, 39.4 mmol) in EtOH (100 mL)under Ar was added hydrazine hydrate (3.83 mL, 79 mmol) and the reaction mixture washeated up and stirred at 85C for 1 hr. Volatiles were removed under reduced pressure and the resulting crude material was purified by silica gel column chromatography (CH2CI2/MeOH/1- 5%/NH3 1%) to afford the title product (4.40 g, 31.4 mmol, 80% yield) as white solid. ESl-MS:141 [M+H] (LC-MS 2); R = 0.47 (CH2CI2/MeOH 9:1).
  • 17
  • C11H18BF3NO2(1-)*K(1+) [ No CAS ]
  • [ 51421-99-9 ]
  • C16H23N3O3 [ No CAS ]
  • 18
  • tert-butyl methyl(3-phenyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)carbamate [ No CAS ]
  • [ 51421-99-9 ]
  • tert-butyl (3-(3-(2-methoxypyrimidin-4-yl)phenoxy)-3-phenylpropyl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In ethanol; toluene; at 90℃; for 16h;Inert atmosphere; Step 1 : tert-Butyl (3-(3-(2-methoxypyrimidin-4-yl)phenoxy)-3- phenylpropyl)(methyl)carbamate. (0379) A Radley tube was charged with tert-butyl methyl(3-phenyl-3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)propyl)carbamate (Intermediate 1 , 200 mg, 0.163 mmol), <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (250 mg, 1 .73 mmol), PdCI2(dppf)-CH2Cl2 (13.3 mg, 0.016 mmol) and purged with argon. Degassed Na2CC>3 solution (0.4 M, 0.41 mL, 0.163 mmol) was added followed by toluene/EtOH (9/1 , 7 mL) and the reaction mixture heated at 90 C for 16 h under argon atmosphere. The layers were separated and the organic phase was washed with water and concentrated to dryness under reduced pressure. The residue was purified by combiflash chromatography (neutral alumina, CH/EtOAc up to 100%) to give the title compound (28 mg, 38% yield).
  • 19
  • tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate [ No CAS ]
  • [ 51421-99-9 ]
  • (S)-tert-butyl 4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With [(2-di-tert-butylphosphino-2?,4?,6?-triisopropyl-1, 1?-biphenyl)-2-(2?-amino-1,1?-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate; In tetrahydrofuran; To a mixture of tert-butyl (S)-2-amino-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoate (101 mg, 232 mumol) and <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (28 mg, 194 mol) in t-AmOH (2 mL) was added 2.0M t-BuONa in THF (194 muL, 388 muL) and tBuXPhos-Pd-G3 (15 mg, 19 mumol) and the resulting mixture was heated to 100 C. for 15 h, cooled to rt, and then concentrated in vacuo to give a ((S)-tert-butyl 4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino)-2-((2-methoxypyrimidin-4-yl) amino) butanoate intermediate, LCMS (ESI+): m/z=543.4 (M+H)+, which was used without further purification. Of the butanoate intermediate, 100 mg, 184 mumol, was taken up in DCM (2 mL) was added TFA (333 muL) and the resulting mixture was stirred at rt for 3 h and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to give the title compound. LCMS (ESI+): m/z=487.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.81 (br s, 1H) 7.47-7.62 (m, 1H) 7.01 (br d, J=7.21 Hz, 1H) 6.35 (br d, J=13.57 Hz, 1H) 6.18-6.28 (m, 2H) 4.31 (br s, 1H) 3.73 (s, 3H) 3.23 (br s, 2H) 3.19 (s, 4H) 2.67 (br s, 1H) 2.59 (brt, J=6.11 Hz, 4H) 2.31-2.43 (m, 5H) 1.86-1.97 (m, 1H) 1.71-1.78 (m, 3H) 1.54 (br dd, J=14.73, 7.40 Hz, 2H) 1.41 (br d, J=7.21 Hz, 2H) 1.03 (t, J=5.50 Hz, 3H).
  • 20
  • (S)-tert-butyl 2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate [ No CAS ]
  • [ 51421-99-9 ]
  • (S)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoic acid [ No CAS ]
  • 21
  • (S)-tert-butyl 2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoate [ No CAS ]
  • [ 51421-99-9 ]
  • (S)-tert-butyl 4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methoxypyrimidin-4-yl)amino)butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With [(2-di-tert-butylphosphino-2?,4?,6?-triisopropyl-1, 1?-biphenyl)-2-(2?-amino-1,1?-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate; In tetrahydrofuran; at 100℃; for 15h; To a mixture of (S)-tert-butyl 2-amino-4-(((S)-2-fluoro-3-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoate (150 mg, 331 mumol) and <strong>[51421-99-9]4-chloro-2-methoxy-pyrimidine</strong> (40 mg, 276 mol) in t-AmOH (3 mL) then was added 2.0M t-BuONa in THF (276 muL, 552 mumol) and t-BuXPhos-Pd-G3 (22 mg, 28 mumol) and the resulting mixture was heated to 100 C. for 15 h, cooled to rt, and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=561.5 (M+H)+
 

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