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Chemical Structure| 37554-70-4

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2-Chloro-5-fluoro-4-methoxypyrimidine

CAS No.: 37554-70-4

4.5 *For Research Use Only !

Cat. No.: A801906 Purity: 98%

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Product Details of [ 37554-70-4 ]

CAS No. :37554-70-4
Formula : C5H4ClFN2O
M.W : 162.55
SMILES Code : COC1=NC(Cl)=NC=C1F
MDL No. :MFCD07440062
Boiling Point : No data available
InChI Key :HLVJKADQILYNGE-UHFFFAOYSA-N
Pubchem ID :13530704

Safety of [ 37554-70-4 ]

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

Calculated chemistry of [ 37554-70-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 33.49
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.

2.02
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

1.57
Log Po/w (WLOGP)?

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

1.7
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.

0.78
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

2.0
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.61

Water Solubility

Log S (ESOL):?

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

-2.21
Solubility 0.991 mg/ml ; 0.0061 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.

-1.92
Solubility 1.97 mg/ml ; 0.0121 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

-2.67
Solubility 0.352 mg/ml ; 0.00216 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

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.

-6.18 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)

1.84

Application In Synthesis [ 37554-70-4 ]

* 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 [ 37554-70-4 ]

[ 37554-70-4 ] Synthesis Path-Downstream   1~25

  • 1
  • [ 124-41-4 ]
  • [ 2927-71-1 ]
  • [ 37554-70-4 ]
YieldReaction ConditionsOperation in experiment
75% In methanol; at 0 - 20℃; for 12.0h; 2-Chloro-5-fluoro-4-methoxypyrimidine; To a stirred solution of 2,4-dichloro-5-fluoropyrimidine (30.0 g, 180.7 mmol) in MeOH (200 ml) cooled to 0 C was slowly added NaOMe (19.5 g, 361.4 mmol). The mixture was stirred at room temperature for 12 h. At the end of the reaction, the solvent was removed by evaporation. The residue was partitioned between CH2Cl2 (200 ml) and H2O (200 ml). The CH2Cl2 layer was washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuo to give 22.0 g (75% yield) of the product as a white solid.
7.38% In tetrahydrofuran; at -10 - 20℃; Preparation of compound 55a: 2-chloro-5-fluoro-4-methoxypyrimidine2,4-Dichloro-5-fluoropyrimidine (515 mg, 3.08 mmol) was weighed into a 150 mL RBF, and was suspended in THF (5.0 mL). The stirring suspension was cooled to -10 C. NaOMe (250 mg, 4.63 mmol) was added in one portion at -10 C. An additional 0.5 eq of NaOMe were added and the suspension was stirred at RT for 21 h. The suspension was diluted with MeOH, and the the solvents were removed in vacuo. The crude material was purified by flash chromatography (eluting with 100%o DCM) to give 2-chloro-5- fluoro-4-methoxypyrimidine (37 mg, 0.228 mmol, 7.38 %> ) as an amorphous white solid. MS (ESI, pos. ion) m/z: 162.9 (M+l). .H NMR (400 MHz, DMSO-d6) delta ppm 8.60 (d, J=2.7 Hz, 1 H), 4.04 (s, 3 H).
  • 4
  • [ 67-56-1 ]
  • [ 2927-71-1 ]
  • [ 37554-70-4 ]
YieldReaction ConditionsOperation in experiment
81% With sodium; at 20℃; Sodium (0.45 g, 19.6 mmol) was added in portions to methanol (20 mL). Once all the sodium had reacted, a solution of 2,4-dichloro-5-fluoropyrimidine (Preparation 15a, 3.25 g, 19.5 mmol) in methanol (10 mL) was added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine, dried (MgS04), filtered and the solvent was removed under reduced pressure to give the title compound (81%) as an orange solid, which was used without further purification.LRMS (m/z): 163 (M+1)+.H-NMR 5 (CDCI3): 4.11 (s, 3H), 8.20 (d, 1 H)
81% title compound (81%) as an orange solid, which was used without further purification.LRMS (m/z): 163 (M+1)+.1H-NMR delta (CDCl3): 4.11 (s, 3H), 8.20 (d, 1 H)
80% With sodium; at 20℃; To a mixture of sodium (450 mg, 19 mmol) in methanol (20 mL) was added a solution of 2,4-dichloro-5-fluoropyrimidine (3.25 g, 19 mmol) in methanol (10ml_). The reaction mixture was stirred at room temperature overnight before being partitioned between water and diethyl ether. The organic phase was separated, washed with brine and evaporated to dryness to give the title compound as an orange oil (80%), which was used in the next step without further purification.1H-NMR delta (400 MHz, CDCI3): 4.1 (s, 3H), 8.2 (s, 1 H).
80% With sodium; at 20℃; sodium (450 mg, 19 mmol) in methanol (20 mL) was added a solution of 2,4-dichloro-5-fluoropyrimidine (3.25 g, 19 mmol) in methanol (10mL). The reaction mixture was stirred at room temperature overnight before being partitioned between water and diethyl ether. The organic phase was separated, washed with brine and evaporated to dryness to give the title compound as an orange oil (80%), which was used in the next step without further purification.1H-NMR delta (400 MHz, CDCl3): 4.11 (s, 3H), 8.20 (s, 1 H).

  • 5
  • [ 110-91-8 ]
  • [ 37554-70-4 ]
  • C9H12FN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 12.0h; General procedure: (5-Fluoro-4-methoxypyrimidin-2-yl)isobutylamine; To a stirred solution of <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (10.0 g, 61.7 mmol) and isobutylamine (6.8 g, 92.6 mmol) in MeCN (200 ml) was added DIEA (11.9 g, 92.6 mmol). The mixture was stirred at 80 C for 12 h. At the end of the reaction, the resulting mixture was cooled and partitioned between EtOAc (200 ml) and H2O (200 ml). The EtOAc layer was washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2-5% EtOAc/PE to afford 5.2 g (42% yield) of the product as a yellow solid.
  • 6
  • [ 78-81-9 ]
  • [ 37554-70-4 ]
  • [ 1365748-95-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 12.0h; General procedure: (5-Fluoro-4-methoxypyrimidin-2-yl)isobutylamine; To a stirred solution of <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (10.0 g, 61.7 mmol) and isobutylamine (6.8 g, 92.6 mmol) in MeCN (200 ml) was added DIEA (11.9 g, 92.6 mmol). The mixture was stirred at 80 C for 12 h. At the end of the reaction, the resulting mixture was cooled and partitioned between EtOAc (200 ml) and H2O (200 ml). The EtOAc layer was washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2-5% EtOAc/PE to afford 5.2 g (42% yield) of the product as a yellow solid.1H NMR (400 MHz, CDCl3) delta 7.92 (d, J = 2.8 Hz, 1H), 5.03 (br s, 1H), 3.99 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H), 1.91 (m, 1H), 0.99 (d, J = 6.4 Hz, 6H).
  • 7
  • [ 62-53-3 ]
  • [ 37554-70-4 ]
  • [ 1365748-94-2 ]
YieldReaction ConditionsOperation in experiment
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 12.0h;Inert atmosphere; Reflux; (5-Fluoro-4-methoxypyrimidin-2-yl)phenylamine; To a stirred solution of <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (16.0 g, 98.8 mmol) and phenylamine (13.8 g, 141.8 mmol) in 1,4-dioxane (500 ml) was added Cs2CO3 (97.8 g, 296.3 mmol) followed by Pd2(dba)3 (2.7 g, 2.9 mmol) and BINAP (3.1 g, 4.9 mmol) under N2. The mixture was heated at reflux for 12 h. On completion, the mixture was filtered to remove the inorganic salts and the filtrate was partitioned between CH2Cl2 (500 ml) and H2O (500 ml). The CH2Cl2 layer was washed with brine (500 ml), dried over NaSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 5% EtOAc/PE, to afford 13.0 g (63% yield) of the product as a yellow solid.1H NMR (400 MHz, CDCl3) delta 8.07 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.34 (m, 2H), 7.16 (br s, 1H), 7.07 (m, 1H), 4.06 (s, 3H).
  • 8
  • [ 1382782-07-1 ]
  • [ 37554-70-4 ]
  • [ 1382782-95-7 ]
YieldReaction ConditionsOperation in experiment
33% With caesium carbonate; XPhos;palladium diacetate; at 120℃; for 16.0h;Sealed tube; Inert atmosphere; Palladium (II) acetate (2.79 mg, 0.012 mmol) was added to a stirred suspension of 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-4-one (100 mg, 0.41 mmol), cesium carbonate (0.18 g, 0.57 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (17 mg, 0.037 mmol) and <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (0.2 g, 1.23 mmol) in a sealed tube and under nitrogen. The reaction mixture was stirred at 120 C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(5-fluoro-4-methoxy- pyrimidin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[ 1 ,5-a]pyrazin-4-one (50 mg, 33% yield) as a white solid. 1H NMR (500 MHz, CDC13) delta ppm 4.10 (s, 3 H), 4.41 - 4.57 (m, 4 H), 5.12 (s, 2 H), 6.93 - 7.04 (m, 3 H), 7.09 (s, 1 H), 7.27 - 7.34 (m, 2 H), 8.28 (d, J=2.3 Hz, 1 H).
  • 9
  • [ 1401349-55-0 ]
  • [ 37554-70-4 ]
  • N-tert-butyl-5-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine 2,2,2-trifluoroacetate [ No CAS ]
  • 10
  • [ 1401349-55-0 ]
  • [ 37554-70-4 ]
  • [ 1401349-57-2 ]
YieldReaction ConditionsOperation in experiment
60.7% With potassium phosphate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 130℃; for 0.333333h;microwave irradiation; Inert atmosphere; Sealed tube; Preparation of compound 55b: N-tert-butyl-5-(3-(5-fluoro-4-methoxypyrimidin-2- yl)-l-tosyl-lH-indol-5-yl)-l,3,4-oxadiazol-2-amine N-tert-Butyl-5-(3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-y^^l,3,4-oxadiazol-2-amine (166 mg, 0.309 mmol), dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (6.63 mg, 0.014 mmol) (Strem), Pd2(dba)3 (6.37 mg, 6.96 muiotaetaomicron) (Strem), potassium phosphate (148 mg, 0.696 mmol) (Sigma-Aldrich) and 2- chloro-5-fluoro-4-methoxypyrimidine (37.7 mg, 0.232 mmol) were weighed into a 5 mL glass microwave tube. The tube was purged with argon and the solids were treated with dioxane (2 mL) and water (0.200 mL). The tube was sealed, and the contents were heated an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130 C for 20 min. The mixture was treated with H20 and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 5-60% EtOAc in Hex) to give N-tert-butyl-5-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-l-tosyl-lH-indol-5-yl)- l,3,4-oxadiazol-2-amine (75.5 mg, 0.141 mmol, 60.7 % ) as an off white solid. MS (ESI, pos. ion) m/z: 537.0 (M+l). .H NMR (400 MHz, DMSO-d6) delta ppm 8.98 - 9.03 (m, 1 H), 8.72 (d, J=3.1 Hz, 1 H), 8.56 (s, 1 H), 8.16 (d, J=8.8 Hz, 1 H), 8.02 - 8.07 (m, 2 H), 7.86 - 7.92 (m, 1 H), 7.64 (s, 1 H), 7.40 - 7.48 (m, 2 H), 4.22 (s, 3 H), 2.33 (s, 3 H), 1.35 - 1.41 (m, 9 H).
  • 11
  • [ 1401349-55-0 ]
  • [ 37554-70-4 ]
  • [ 1401349-58-3 ]
YieldReaction ConditionsOperation in experiment
76% With potassium phosphate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 130℃; for 0.5h;microwave irradiation; Inert atmosphere; Sealed tube; Preparation of compound 56b: N-tert-butyl-5-(3-(4-cyclopropyl-5-fluoropyrimidin- 2-yl)-l-tosyl-lH-indol-5-yl)-l,3,4-oxadiazol-2-amineTo a 5 mL glass microwave tube containing N-tert-butyl-5-(3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-tosyl-lH-indol-5-yl)-l,3,4-oxadiazol-2-amine (166 mg, 0.309 mmol) was added 2-chloro-4-cyclopropyl-5-fluoropyrimidine (69.4 mg, 0.402 mmol), potassium phosphate (197 mg, 0.928 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2- yl)phosphine (8.9 mg, 0.019 mmol), and Pd2(dba)3 (8.5 mg, 9.28 muiotaetaomicron). The tube was purged with argon, the solids were treated with dioxane (3 mL) and Water (0.3 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130 C for 30 min. The mixture was treated with H20 and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 5-60% EtOAc in Hex) affording N-tert-butyl-5-(3-(4- cyclopropyl-5-fluoropyrimidin-2-yl)-l osyl-lH-indol-5-yl)-l,3,4-oxadiazol-2-amine (129 mg, 76 % ) as a light yellow viscous oil. MS (ESI, pos. ion) m/z: 547.1 (M+l).
  • 12
  • [ 1312535-18-4 ]
  • [ 37554-70-4 ]
  • [ 1312535-38-8 ]
YieldReaction ConditionsOperation in experiment
With methanesulfonic acid; In 1,4-dioxane; at 100℃; INTERMEDIATE 9: 5-fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrimidin-2-amineTo a flask containing <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (0.32 g, 1.97 mmol) and 3-methyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.40 g, 1.72 mmol) were added dioxane (17 mL) and methanesulfonic acid (0.13 mL, 1.97 mmol). The reaction was heated at 100C overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 5-fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrimidin-2-amine. MS ESI calc'd for Ci8H2 BFN303 [M + H]+ 360, found 360. H NMR (500 MHz, DMSO-d6) delta 9.51 (s, 1H), 8.27 (d, J= 3.2, 1H), 8.00 (s, 1H),7.57 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 2.25 (s, 3H), 1.26 (s, 12H).
With methanesulfonic acid; In 1,4-dioxane; at 100℃; Preparative Example 1.3 - 5-Fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl]pyrimidin-2-amine PrepEx. 1.3 [00217] A solution of <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (0.32 g, 1.97 mmol) and 3- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.40 g, 1.72 mmol) in dioxane (17 mL) and methanesulfonic acid (0.13 mL, 1.97 mmol) was heated to 100C overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated in reduced pressure. The residue was purified by chromatography on silica gel to afford 5-fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine. MS ESI calc'd for Ci8H24BFN303 [M + H]+ 360, found 360. 'H NMR (500 MHz, DMSO-d6) delta 9.51 (s, 1H), 8.27 (d, J= 3.2, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 2.25 (s, 3H), 1.26 (s, 12H).
With methanesulfonic acid; In 1,4-dioxane; at 100℃; Preparative Example 1.11 5-Fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]pyrimidin-2-amine Methanesulfonic acid (0.13 mL, 1.97 mmol) was added to a solution of 2-chloro- 5-fluoro-4-methoxypyrimidine (0.32 g, 1.97 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (0.40 g, 1.72 mmol) in dioxane (17 mL). The reaction mixture was heated at 100C overnight. The reaction was then cooled to room temperature, diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 5- fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]- pyrimidin-2-amine. MS ESI calc'd for CisH^BF sOs [M + H]+ 360, found 360. lH NMR (500 MHz, DMSO-d6) delta 9.51 (s, IH), 8.27 (d, J= 3.2, IH), 8.00 (s, IH), 7.57 (s, IH), 7.07 (s, IH), 4.01 (s, 3H), 2.25 (s, 3H), 1.26 (s, 12H).
  • 13
  • [ 1454303-09-3 ]
  • [ 37554-70-4 ]
  • [ 1454303-02-6 ]
YieldReaction ConditionsOperation in experiment
72% With palladium diacetate; caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 18.0h;Sealed tube; Inert atmosphere; 22. PREPARATION OF 5-(5-FLUORO-4-METHOXY-PYRIMIDIN-2-YL)-2- PHENOXYMETHYL-6,7-DIHYDRO-5H-OXAZOLO[5,4-C] PYRIDIN-4-ONE (EXAMPLE B22). [00522] Palladium (II) acetate (2.78 mg, 0.012 mmol) was added to a stirred suspension of 2-phenoxymethyl-6,7-dihydro-5H-oxazolo[5,4-c]pyridin-4-one (0.1 g, 0.41 mmol), 2-chloro- 5-fluoro-4-methoxy-pyrimidine (0.13 g, 0.82 mmol), cesium carbonate (0.187 g, 0.57 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.018 g, 0.037 mmol) in 1,4- dioxane (2 mL) in a sealed tube and under nitrogen. The mixture was stirred at 100 C for 18 h. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 80/20). The desired fractions were collected, the solvents evaporated in vacuo and triturated with diethyl ether to yield the title compound (0.109 g, 72% yield ) as a white solid. d8Hi5FN404. 1H NMR (400 MHz, CDC13) delta ppm 3.07 (t, J= 6.7 Hz, 2 H), 4.08 (s, 3 H), 4.36 (t, J= 6.7 Hz, 2 H), 5.23 (s, 2 H), 6.98 - 7.06 (m, 3 H), 7.28 - 7.36 (m, 2 H), 8.26 (d, J= 2.5 Hz, 1 H).
  • 14
  • [ 37554-70-4 ]
  • C23H20FN7O2S [ No CAS ]
  • 15
  • tert-butyl ((4aR,7aR,E)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-ylidene)carbamate [ No CAS ]
  • [ 37554-70-4 ]
  • C28H28FN7O4S [ No CAS ]
  • 16
  • [ 1192479-49-4 ]
  • [ 37554-70-4 ]
  • 5-((4aR,7aR)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-2-imino-3-methyl-4-oxooctahydro-1H-pyrrolo[3,4-d]pyrimidin-7a-yl)-thiophene-2-carbonitrile [ No CAS ]
  • 17
  • [ 1192479-49-4 ]
  • [ 37554-70-4 ]
  • C22H24FN7O4S [ No CAS ]
  • 18
  • [ 557-21-1 ]
  • [ 37554-70-4 ]
  • C6H4FN3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 48.0h;Inert atmosphere; A mixture of zinc(II) cyanide (10.8 g, 92 mmol) and <strong>[37554-70-4]2-chloro-5-fluoro-4-methoxypyrimidine</strong> (15.0 g, 92 mmol) in dimethylformamide (200 mL) was degassed at room temperature by bubbling nitrogen through the solution for 10 min. Tetrakis(triphenylphosphine)palladium(0) (10.0 g, 8.65 mmol) was added, degassing was continued another 10 min and the reaction was heated 2 days at 90C. The mixture was cooled to room temperature and diluted with ethyl acetate (150 mL), brine (50 mL) and concentrated aqueous ammonium hydroxide (10 mL). After mixing, the layers were separated and the aqueous phase was extracted with another portion of ethyl acetate (150 mL). The combined organic phases were washed with 2 x 20 mL brine then dried over sodium sulfate, filtered and concentrated by rotary evaporation at 60C. Purification over Si02 with a hexane/ethyl acetate gradient gave recovered chloropyrimidine starting material and 5.5 g of the desired cyano pyrimidine as a colorless oil. The recovered starting material was reprocessed as above to give another 3.0 g of the depicted intermediate (total yield 8.5 g, 60% yield). -NuMuRho (500 MHz, CDC13) delta 8.41 (s, 1H), 4.17 (s, 3H) ppm.
  • 19
  • [ 37554-70-4 ]
  • C7H7FN2O3 [ No CAS ]
  • 20
  • [ 37554-70-4 ]
  • C6H5FN2O3 [ No CAS ]
  • 21
  • [ 37554-70-4 ]
  • C11H8FN3O4 [ No CAS ]
  • 22
  • [ 37554-70-4 ]
  • 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1H-pyrazol-5-yl)isoxazole [ No CAS ]
  • 23
  • [ 37554-70-4 ]
  • C19H16FN5O2 [ No CAS ]
  • 24
  • [ 37554-70-4 ]
  • C17H13FN6O2 [ No CAS ]
  • 25
  • [ 37554-70-4 ]
  • C17H13FN6O2 [ No CAS ]
 

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