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[ CAS No. 3993-78-0 ] {[proInfo.proName]}

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Chemical Structure| 3993-78-0
Chemical Structure| 3993-78-0
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Product Details of [ 3993-78-0 ]

CAS No. :3993-78-0 MDL No. :MFCD00038021
Formula : C4H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :DBGFGNCFYUNXLD-UHFFFAOYSA-N
M.W :129.55 Pubchem ID :223332
Synonyms :

Calculated chemistry of [ 3993-78-0 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.45
TPSA : 51.8 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) : -6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.29
Log Po/w (XLOGP3) : 0.82
Log Po/w (WLOGP) : 0.72
Log Po/w (MLOGP) : -0.05
Log Po/w (SILICOS-IT) : 0.98
Consensus Log Po/w : 0.75

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 : 2.5 mg/ml ; 0.0193 mol/l
Class : Very soluble
Log S (Ali) : -1.49
Solubility : 4.19 mg/ml ; 0.0324 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.87
Solubility : 1.74 mg/ml ; 0.0135 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.48

Safety of [ 3993-78-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3993-78-0 ]

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

  • Upstream synthesis route of [ 3993-78-0 ]
  • Downstream synthetic route of [ 3993-78-0 ]

[ 3993-78-0 ] Synthesis Path-Upstream   1~17

  • 1
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YieldReaction ConditionsOperation in experiment
69% With ammonium hydroxide In water at 20℃; To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 percent w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 percent EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 percent; 2-chloro-4-aminopyrimidine 600 mg, 69 percent.
23% With ammonia In water at 20℃; for 5 h; Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25percent, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23percent) of 2 and 1.73 g (26percent) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
Reference: [1] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 62
[2] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[3] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
[4] Patent: WO2006/114409, 2006, A1, . Location in patent: Page/Page column 18
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1973 - 1978
[6] Chemische Berichte, 1905, vol. 38, p. 1690
[7] Chemische Berichte, 1905, vol. 38, p. 1690
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[9] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
[10] Patent: US2007/238737, 2007, A1, . Location in patent: Page/Page column 11
[11] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
[12] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
[13] Patent: CN106317147, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067
[14] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 10
  • 2
  • [ 108-53-2 ]
  • [ 3993-78-0 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 20 - 95℃; Inert atmosphere
Stage #2: With ammonium hydroxide In water at 20℃; Cooling wit ice
In a three neck IL round bottom flask equipped with reflux condenser was added 2-amino- 4(3H)-pyrimidinone A.ll (10Og, 0.9 mol) (available from Toronto Research Chemicals) followed by POCl3 (168 ml, 1.800mol) at room temperature and under an atmosphere of N2. To this was cautiously added ClSO3H (4.8ml, 72.01 mmol). The solution was heated to 950C for 4 hrs, before it was cooled to room temperature. The solution was then cooled in an ice bath before it was poured into 700ml of ice water with vigorous stirring. Adjusted the pH to ~7 with NH4OH (30percent by weight) (temperature was held below 2O0C). A tan colored solid was collected by filtration. The solid was dried under vacuum at 7O0C overnight to afford 4-chloro- 2-pyrimidinamine A.12 (108g, 92percent) as an off white solid.1H NMR (400 MHz, (CD)3SO) δ 8.17 (d, J = 5.2 Hz, IH), 7.07 (br s, 2H), 6.64 (d, J = 5.2 Hz, IH); ESI MS: M + H+ 130.0 m/z.
Reference: [1] Patent: WO2009/158011, 2009, A1, . Location in patent: Page/Page column 31
[2] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
  • 3
  • [ 97229-11-3 ]
  • [ 3993-78-0 ]
YieldReaction ConditionsOperation in experiment
100% With aq. NH3 In isopropyl alcohol Example 48
2-Amino-4-Chloropyrimidine
To a solution of 4-chloro-2-methanesulfonylpyrimidine (5 g, 26 mmol) in i-PrOH (20 ml) 20percent aq. NH3 (20 ml) was added and the mixture stirred for 20 min. at room temperature.
The mixture was extracted with CH2Cl2 four times and the organic solvent removed under vacuum. 2-Amino-4-chloropyrimidine (3.3 g, 100percent) was obtained as a white solid.
1H-NMR (CDCl3, 200 MHz) δ5.26 (br, 2H, NH2), 6.67 (d, J5.2, 1H, H5), 8.17 (d, J5.2, 1H, H6).
MS (CI, CH4) m/z 132 (37ClM+1, 33),131 (37ClM+, 2), 130 (35ClM+1, 87), 129 (35ClM, 8), 97 (100), 94 (M-Cl, 53).
Reference: [1] Patent: US2004/58939, 2004, A1,
  • 4
  • [ 108-53-2 ]
  • [ 3993-78-0 ]
YieldReaction ConditionsOperation in experiment
73% at -5 - 90℃; for 5 h; Inert atmosphere In a three neck 250 mL round bottom flask equipped with reflux condenser was added isocytosine (20 g, 0.18 mol) followed by phosphorus oxychloride (40 mL, 0.43 mol) at -5 °C and under an atmosphere of nitrogen. To this was cautiously added chlorosulfonic acid (4 mL, 0.06 mol). The solution was permitted to heat spontaneously to room temperature and then heated at 45 °C for 1 h. It was then heated cautiously at 90 °C for 4 h, before it was cooled to room temperature. The mixture was then cooled in an ice bath before it was pour onto 400 mL of ice water with vigorous stirring. Adjusted the pH to 7 with ammonia water (28percent by weight) (temperature was held below 20 °C). A tan colored solid was collected by filtration. The solid was dried to afford 4-chloro-2-pyrimidinamine (17 g, 73percent yield) as an off white solid. m.p. 166-167 °C.
Reference: [1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 18 - 26
  • 5
  • [ 3934-20-1 ]
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Reference: [1] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[2] Patent: WO2008/70740, 2008, A1, . Location in patent: Page/Page column 201
  • 6
  • [ 108-53-2 ]
  • [ 3993-78-0 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 10, p. 4149 - 4153
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4409 - 4424
  • 7
  • [ 3934-20-1 ]
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Reference: [1] Chemische Berichte, 1905, vol. 38, p. 1690
  • 8
  • [ 3934-20-1 ]
  • [ 7461-50-9 ]
  • [ 3993-78-0 ]
YieldReaction ConditionsOperation in experiment
69% With ammonium hydroxide In water at 20℃; To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 percent w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 percent EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 percent; 2-chloro-4-aminopyrimidine 600 mg, 69 percent.
23% With ammonia In water at 20℃; for 5 h; Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25percent, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23percent) of 2 and 1.73 g (26percent) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
Reference: [1] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 62
[2] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[3] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
[4] Patent: WO2006/114409, 2006, A1, . Location in patent: Page/Page column 18
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1973 - 1978
[6] Chemische Berichte, 1905, vol. 38, p. 1690
[7] Chemische Berichte, 1905, vol. 38, p. 1690
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[9] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
[10] Patent: US2007/238737, 2007, A1, . Location in patent: Page/Page column 11
[11] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
[12] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
[13] Patent: CN106317147, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067
[14] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 10
  • 9
  • [ 3934-20-1 ]
  • [ 7664-41-7 ]
  • [ 7461-50-9 ]
  • [ 3993-78-0 ]
Reference: [1] Chemische Berichte, 1905, vol. 38, p. 1690
  • 10
  • [ 3993-78-0 ]
  • [ 156-81-0 ]
Reference: [1] Patent: US2416617, 1944, ,
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 3758,3760
  • 11
  • [ 67-56-1 ]
  • [ 3993-78-0 ]
  • [ 155-90-8 ]
YieldReaction ConditionsOperation in experiment
84% at 5℃; for 4 h; Reflux Na (2.2 g, 92.6 mmol) was dissolved in 30 mL of methanol. To this solution was added 7 (6.0 g, 46.3 mmol) in small portions at 5 °C. When the addition was complete, this mixture was heated to reflux for 4 h. After cooling, then the solvent was evaporated. The residue was dissolved in 30 mL of hydrochloric acid solution (20percent by weight) and filtered. The filtrate was alkalified with 10 mol/L sodium hydroxide solution to pH 9. After seeding and stirring for 1 h, the crystalline precipitate of the pyrimidinamine 8a which formed was filtered off and dried at about 60 °C. The yield was 84percent, m.p. 117-119 °C.
73% at 110℃; for 1 h; Microwave irradiation 4-Chloropyrimidin-2-amine (200 mg, 1.54 mmol) was dissolved in methanol (2 mL), and the mixture was stirred with heating at 110°C for 1 hr in a microwave synthesizer. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentration under reduced pressure to give 4-methoxypyrimidin-2-amine (140 mg, 73percent). ESIMS m/z: 126 (M + H)+; 1H NMR (270 MHz, CDCl3, δ): 3.88 (s, 3H), 4.96 (br s, 2H), 6.04-6.17 (m, 1H), 7.93-8.10 (m, 1H)
Reference: [1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 18 - 26
[2] Patent: EP2740730, 2014, A1, . Location in patent: Paragraph 0372
  • 12
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  • [ 124-41-4 ]
  • [ 155-90-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 21, p. 7705 - 7712
[2] Journal of the American Chemical Society, 1945, vol. 67, p. 735,737
[3] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[4] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[5] Patent: WO2008/70740, 2008, A1, . Location in patent: Page/Page column 201
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 2011, vol. 186, # 3, p. 552 - 557
[7] Patent: EP3235816, 2017, A1, . Location in patent: Paragraph 0108
  • 13
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Reference: [1] Patent: WO2012/7345, 2012, A2, . Location in patent: Page/Page column 90; 91
  • 14
  • [ 557-21-1 ]
  • [ 3993-78-0 ]
  • [ 36314-98-4 ]
Reference: [1] Patent: WO2012/40137, 2012, A1, . Location in patent: Page/Page column 98-99
  • 15
  • [ 3993-78-0 ]
  • [ 1692-25-7 ]
  • [ 66521-66-2 ]
YieldReaction ConditionsOperation in experiment
72% With 1-(2,6-diisopropylphenyl)-3-(2-oxo-2-(2,4,6-tri-tert-butylphenylamino)ethyl)-1H-imidazol-3-ium bromide; palladium diacetate; sodium hydroxide In water; dimethyl sulfoxide at 100℃; for 10 h;          Pd(OAc)(35.00 mg, 0.15 mmol) and 1-(2,6-diisopropylphenyl)-3-(2-oxo-2-(2,4,6-tri-tert-butylphenylamino)ethyl)-1H-imidazol-3-iumbromide (96.00 mg, 0.15 mmol) was dissolved in 10 ml of DMSO : H2O,and 4-chloropyrimidin-2-amine (2.00 g, 15.43 mmol), NaOH (0.93 g, 23.15 mmol),pyridin-3-ylboronic acid (2.28 g, 18.5 mmol)  were added. The mixture was heated to 100 oCand stirred for 10h. After cooling, the mixturewas poured into EtOAc (40.0 mL and washed with water (2 ×10.0 mL), brine (2 × 25.0 mL), then dried over MgSO4, evaporation ofthe solvent under reduced pressure provided the crude product, which waspurified by column chromatography (hexane : EtOAc = 1:1) afford product as off white solid 1.92 g, 11.15 mmol) in 72percent yield. 1HNMR (300 MHz, DMSO): δ 9.23(dd, J =1.5 Hz, 1H), 8.68 (dd, J1= 3.0 Hz, J2 = 1.8 Hz,1H), 8.41-8.35 (m, 2H), 7.55-7.50 (m, 1H), 7.20 (d, J1 = 5.1 Hz, 1H), 6.78 (bs, 2H);   13C NMR (75 MHz, CDCl3): δ 163.8, 161.6, 159.4, 151.1, 148.0, 134.1,123.7, 106.0. HRMS(ESI) calcd. for C9H9N4 [M+H]+173.0827, found 173.0825.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 49, p. 6657 - 6661
  • 16
  • [ 3993-78-0 ]
  • [ 815610-16-3 ]
YieldReaction ConditionsOperation in experiment
95% With hydrogen iodide In water at 0 - 20℃; for 3 h; 2-Amino-4-chloropyrimidine (55) (13.0g, 100mmol) was added to a 57wt.percent aqueous solution of hydriodic acid (115ml, 1.00mol) at 0°C and the mixture was stirred at room temperature for 3h. The mixture was cooled to 0°C and the resulting precipitate was removed by filtration and taken up in cold 5N aqueous Na2CO3 (200ml). The mixture was extracted with EtOAc (3×500ml) and the combined organic layers were concentrated under reduced pressure to deliver 2-amino-4-iodopyrimidine (21.1g, 95.0mmol, 95percent yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 7.78 (d, J=5.0Hz, 1H), 7.02 (br. s, 2H), 7.00 (d, J=5.0Hz, 1H). MS (ESI, pos. ion) m/z: 222.1 (M+1).
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 80, p. 364 - 382
[2] Organic Letters, 2014, vol. 16, # 3, p. 708 - 711
  • 17
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  • [ 1044767-99-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5467 - 5482
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6766 - 6783
[3] Patent: US2013/53362, 2013, A1, . Location in patent: Paragraph 0878; 0879
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