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[ CAS No. 4983-28-2 ] {[proInfo.proName]}

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Chemical Structure| 4983-28-2
Chemical Structure| 4983-28-2
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Product Details of [ 4983-28-2 ]

CAS No. :4983-28-2 MDL No. :MFCD09743796
Formula : C4H3ClN2O Boiling Point : -
Linear Structure Formula :- InChI Key :BOGPIHXNWPTGNH-UHFFFAOYSA-N
M.W : 130.53 Pubchem ID :14595700
Synonyms :

Calculated chemistry of [ 4983-28-2 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 29.06
TPSA : 46.01 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.08
Log Po/w (XLOGP3) : 0.81
Log Po/w (WLOGP) : 0.84
Log Po/w (MLOGP) : -0.45
Log Po/w (SILICOS-IT) : 1.22
Consensus Log Po/w : 0.7

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.71
Solubility : 2.52 mg/ml ; 0.0193 mol/l
Class : Very soluble
Log S (Ali) : -1.36
Solubility : 5.72 mg/ml ; 0.0439 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.66
Solubility : 2.88 mg/ml ; 0.0221 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.43

Safety of [ 4983-28-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4983-28-2 ]

* 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.

  • Upstream synthesis route of [ 4983-28-2 ]
  • Downstream synthetic route of [ 4983-28-2 ]

[ 4983-28-2 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 22536-65-8 ]
  • [ 4983-28-2 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With boron tribromide In dichloromethane at 20℃;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
2-Chloro-5-methoxypyrimidine (0.46 g, 3.18 mmol) in methylene chloride (10 mL) was treated with 1.0 N boron tribromide (16 mL, 16 mmol) at room temperature. The solution was stirred overnight. After this time the reaction was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extraxted with additional DCM. The combined organic layers were dried (MgSO4), filtered, and concnetrated. The residue was purified by flash column chromatography on silica gel to give 0.26 g of compound 112A (62percent): 1H NMR (DMSO-D6): δ 10.03 (s, IH), 8.30 (s, 2H), ESI (-)/MS: 129 (M-H)-.
61% With boron tribromide In dichloromethane at 20℃; for 20 h; Intermediate 4: 2-Chloro-5-hydroxypyrimidineTo a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.7g, 61percent).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s).
55%
Stage #1: With boron tribromide In dichloromethane at -78 - 20℃; for 20 h;
Stage #2: With methanol In dichloromethane at -78℃;
Stage #3: With sodium hydroxide In methanol; water
Intermediate 4: 2-Chloro-5-hydroxypyrimidine To a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.0g, 55percent).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s).
27% With boron tribromide In dichloromethane at 0 - 20℃; for 16 h; Boron tribromide (30mL) was slowly added to a solution of 2-chloro-5-methoxypyrimidine (2g, 13.83mmol) in DCM (lOmL) at 0 °C. Allowed the reaction mass to stir at room temperature for 16h. Then the reaction mixture was slowly quenched with ice cold water, warmed to room temperature and diluted with DCM (lOOmL). The aqueous layer was separated and extracted with DCM (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford desired title compound (0.5g, 27percent) as a solid. LCMS: m/z = 129.0 (M-H)+ (Negative mode).

Reference: [1] Patent: WO2010/80503, 2010, A1, . Location in patent: Page/Page column 225
[2] Patent: WO2011/144578, 2011, A1, . Location in patent: Page/Page column 27
[3] Patent: WO2011/144577, 2011, A1, . Location in patent: Page/Page column 24-25
[4] Patent: WO2016/164703, 2016, A1, . Location in patent: Page/Page column 50
[5] Patent: US5589478, 1996, A,
[6] Patent: US2011/82165, 2011, A1, . Location in patent: Page/Page column 61-62
  • 2
  • [ 56621-90-0 ]
  • [ 4983-28-2 ]
YieldReaction ConditionsOperation in experiment
25% With sulfuric acid In water for 2 h; Reflux Example 8
Synthesis of 2-chloropyrimidine-5-ol
Compound 41
Referring to the reaction scheme of , Compound 40 (40 g, 0.31 mol) in 2N sulfuric acid was refluxed for 2 hrs.
After cooling to r.t., the reaction mixture was extracted with EtOAc using continuous overnight liquid-liquid extraction.
The combined EtOAc layers were washed with brine, dried over magnesium sulfate, and filtered.
After solvent removal in vacuo and recrystallization with EtOH, 10 g (25percent) yellow solid 41 was obtained. 1H NMR (DMSO-d6) δ 10.93 (brs, 1H), 6.45 (t, J=4.88 Hz, 1H), 3.57 (t, J=4.4 Hz, 4H), 2.01-1.98 (m, 4H).
Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1117 - 1127
[2] Patent: US2014/235858, 2014, A1, . Location in patent: Paragraph 0094
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 22, p. 8796 - 8805
  • 3
  • [ 1003845-06-4 ]
  • [ 4983-28-2 ]
Reference: [1] Patent: WO2011/84402, 2011, A1, . Location in patent: Page/Page column 153-154
  • 4
  • [ 56622-03-8 ]
  • [ 4983-28-2 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1990, vol. 26, # 6, p. 668 - 670[2] Khimiya Geterotsiklicheskikh Soedinenii, 1990, # 6, p. 801 - 803
  • 5
  • [ 100-39-0 ]
  • [ 4983-28-2 ]
  • [ 138274-14-3 ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate In methanol at 20℃; for 14 h; Example 9
Synthesis of 2-chloro-5-benzyloxy-pyrimidine
Compound 31
Referring to the reaction scheme of , potassium carbonate (11.6 g, 84.3 mmol) was added to 10 g of the alcohol 40 (76.6 mmol) in 500 mL of MeOH, followed by benzyl bromide (10.1 mL, 84.3 mmol).
After 14 hrs stirring at r.t., the reaction was stopped by addition of water (300 mL).
MeOH was evaporated and the remaining aqueous layer was extracted with CHCl3.
The combined CHCl3 layers were washed with brine, dried over magnesium sulfate, and filtered.
Removal of the solvent followed by silica gel chromatography using 100:1 CHCl3:MeOH as eluent gave 15 g (89percent) of 2-amino-5-benzyloxy-pyrimidine (31) as a white solid. 1H NMR (CDCl3) δ 8.27 (s, 2H), 7.37-7.30 (m, 5H), 5.09 (s, 2H).
Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2288 - 2300
[2] Patent: US2014/235858, 2014, A1, . Location in patent: Paragraph 0095
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 22, p. 8796 - 8805
[4] Patent: WO2011/147951, 2011, A1, . Location in patent: Page/Page column 63
  • 6
  • [ 100-44-7 ]
  • [ 4983-28-2 ]
  • [ 138274-14-3 ]
Reference: [1] Patent: WO2011/144577, 2011, A1, . Location in patent: Page/Page column 27-28
[2] Patent: WO2011/144578, 2011, A1, . Location in patent: Page/Page column 40; 41
  • 7
  • [ 667-27-6 ]
  • [ 4983-28-2 ]
  • [ 1192813-64-1 ]
YieldReaction ConditionsOperation in experiment
38% With caesium carbonate In N,N-dimethyl-formamide at 80℃; To a solution of 2-chloro-5-hydroxypyrimidine (4.13 g) in DMF (40 mL) were added ethyl 2-bromo-2,2-difluoroacetate (12.83 g) and cesium carbonate (20.59 g), and the mixture was reacted at 80°C overnight. The reaction solution was cooled to room temperature, and then poured into water. The mixture was extracted with ethyl acetate thrice. The organic layer was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 80:20 to 60:40) to give the titled compound (2.16 g) as a colorless liquid (yield 38percent). MS(APCI)m/z; Not detected.
Reference: [1] Patent: EP2390254, 2011, A1, . Location in patent: Page/Page column 88
  • 8
  • [ 1514-87-0 ]
  • [ 4983-28-2 ]
  • [ 1192813-64-1 ]
YieldReaction ConditionsOperation in experiment
43% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h; To a solution of 93 mg (0.71 mmol) of 4-hydroxy-1-methyl piperidine in 1.0 ml of N,N-dimethylformamide, 0.28 g (0.86 mmol) of cesium carbonate and 0.32 mg (2.2 mmol) of methyl chlorodifluoroacetate were added, and the reaction solution was stirred at 100° C. for 1 hour.
After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate.
The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to provide 55 mg of the title compound as a colorless oil (yield: 43percent).
1H-NMR spectrum (500 MHz, CDCl3) δ ppm: 8.53 (2H, s), 6.62 (1H, t, J=71 Hz).
Reference: [1] Patent: US2013/109653, 2013, A1, . Location in patent: Paragraph 0817-0819
  • 9
  • [ 1895-39-2 ]
  • [ 4983-28-2 ]
  • [ 1192813-64-1 ]
YieldReaction ConditionsOperation in experiment
39.7% at 90℃; for 24 h; Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine 2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C. for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30percent ethyl acetate/hexanes) to afford 2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7percent yield) as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]+=181.14.
39.7% at 90℃; for 24 h; Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2- difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90 °C for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30 percent ethyl acetate/hexanes) to afford 2- chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7 percent yield) as a pale yellow oil. MS (LC/MS) R.T. = 1.32; [M+H]+ = 181.14.
Reference: [1] Patent: US2009/270405, 2009, A1, . Location in patent: Page/Page column 90
[2] Patent: WO2011/53292, 2011, A1, . Location in patent: Page/Page column 149-150
  • 10
  • [ 2516-33-8 ]
  • [ 4983-28-2 ]
  • [ 169677-66-1 ]
YieldReaction ConditionsOperation in experiment
659 mg With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 20℃; A) 2-chloro-5-(cyclopropylmethoxy)pyrimidine To a solution of cyclopropylmethanol (276 mg), 2-chloropyrimidin-5-ol (500 mg) and triphenylphosphine (1.51 g) in toluene (20 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (659 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.49 (2H, m), 0.49-0.69 (2H, m), 1.07-1.46 (1H, m), 4.00 (2H, d, J=7.2 Hz), 8.53 (2H, s).
Reference: [1] Patent: US2014/243310, 2014, A1, . Location in patent: Paragraph 1698
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