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[ CAS No. 5305-59-9 ]

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Chemical Structure| 5305-59-9
Chemical Structure| 5305-59-9
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CAS No. :5305-59-9 MDL No. :MFCD00053576
Formula : C4H4ClN3 Boiling Point : 289°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :129.55 g/mol Pubchem ID :238012
Synonyms :

Safety of [ 5305-59-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5305-59-9 ]

  • Upstream synthesis route of [ 5305-59-9 ]
  • Downstream synthetic route of [ 5305-59-9 ]

[ 5305-59-9 ] Synthesis Path-Upstream   1~10

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YieldReaction ConditionsOperation in experiment
88% With ammonia In isopropyl alcohol at 25℃; for 1 h; General procedure: To a suspension of 4,6-dichloropyrimidine 53 (3.0 g, 20 mmol) in isopropanol (40 mL) was added appropriate amine at such a rate that the internal temperature did not rise above 40 °C. After completion of the addition, the reaction mixture was stirred for 1 h at 25 °C. Water (30 mL) was added, and the resulting suspensio nwas cooled in an ice bath to 0 °C. The precipitated product was filtered off and washed with cold isopropanol/water (2:1, 50 mL) and water. The collected material was dried in vacuo to afford the title compounds.
81% at 30℃; for 15 h; A mixture of 4, 6-dichloropyrimidine (20 g, 0.14 mol) and NH4OH (200 mL) was heated at 30 °C for 15 hours with stirring. The resulting precipitate was collected via filtration, and the filter cake was washed with water (100 mL). The resultant solid was purified by silica gel column chromatography, eluting with EtOAc to give the desired product as a white solid ( 14 g, 81 percent yield) . LCMS (ESI) m/z : 130.1 [M+H+] .
80% at 100℃; Sealed tube Step 1:
6-chloropyrimidin-4-amine Intermediate 14
4,6-Dichloropyrimidine (7.5 g, 50 mmol) was suspended in ammonium hydroxide (64 mL) in a sealed tube.
The tube was sealed and heated at 100° C. in an oil bath overnight.
The reaction mixture was cooled to rt.
The solid was removed by filtration, washed with water and dried under high vacuum to afford 6-chloropyrimidin-4-amine (5.23 g, 80percent) LC-MS (AA) ES+ 130.
77% With ammonia In ethanol at 80℃; for 1.5 h; Compound 1-1-1 (10 g, 67.1 mmol) was disposed into a stainless steel vessel, and EtOH saturated with NH3 (g) in advance (40 mL) was added. The reaction mixture was heated to 80° C., reacted for 1.5 h, and then cooled down to r.t., concentrated in vacuo and stripped to give a crude product which was triturated with water and filtered to afford compound 8-6 (6.7 g, Yield 77percent). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.20 (s, 1H), 7.22 (s, 2H), 6.45 (s, 1H)
71% With ammonia In ethanol at 100℃; for 1.5 h; In a stainless pressure vessel 4, 6-Dichloropyrimidine (10.0 g, 67. 1 mmol) in ammonia saturated ethanol (40 mL) was heated to 100°C in a stainless steel pressure vessel for 1.5 h. Removal of the solvent in vacuo gave a solid which was triturated with water (270 mL) then filtered to give 6-amino-4-chloropyrimidine (1) (6. 18 g, 71percent) as white crystals. APCI-MS Found [M + H] + = 130, 132.
67% With ammonia In methanol at 85℃; for 16 h; 4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67percent yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +.
67% With ammonia In methanol at 85℃; for 16 h; 4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67percent yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +.

Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[2] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 11 - 20
[3] Patent: WO2012/35039, 2012, A1, . Location in patent: Page/Page column 84
[4] Patent: US2012/15943, 2012, A1, . Location in patent: Page/Page column 54
[5] ChemMedChem, 2017, vol. 12, # 16, p. 1390 - 1398
[6] Patent: US2017/313683, 2017, A1, . Location in patent: Paragraph 0346-0347
[7] Patent: WO2005/89763, 2005, A1, . Location in patent: Page/Page column 35
[8] Patent: WO2005/34840, 2005, A2, . Location in patent: Page/Page column 67-70
[9] Patent: WO2005/34840, 2005, A2, . Location in patent: Page/Page column 67-70
[10] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 5, p. 1146 - 1150
[11] Patent: US2004/23977, 2004, A1, . Location in patent: Page/Page column 7
[12] Journal of Physical Organic Chemistry, 2013, vol. 26, # 12, p. 1038 - 1043
[13] Patent: WO2007/104538, 2007, A1, . Location in patent: Page/Page column 52
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Reference: [1] Patent: US2005/227933, 2005, A1, . Location in patent: Page/Page column 29
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Reference: [1] Patent: EP1420021, 2004, A1, . Location in patent: Page 23-24
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  • [ 1193-21-1 ]
  • [ 71-36-3 ]
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Reference: [1] Patent: US2002/137755, 2002, A1,
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  • [ 1193-22-2 ]
  • [ 91-66-7 ]
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Reference: [1] Journal of the American Chemical Society, 1958, vol. 80, p. 2182,2184
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  • [ 1004-40-6 ]
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Reference: [1] Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1 - 8
  • 7
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  • [ 53557-69-0 ]
YieldReaction ConditionsOperation in experiment
70% With hydrogen iodide; sodium iodide In water at 70℃; for 0.5 h; Description 93; 6-IodoPvrimidin-4-amine-",; A mixture of 4-amino-6-chloropyrimidine [WO-A-0245652] (1. 00 g, 7.72 mmol), sodium iodide (5.79 g, 38.6 mmol) and 40percent HI (20 ml) were heated at 70°C for 30 min, then allowed to cool to room temperature. The precipitate was removed by filtration, and partitioned between dichloromethane and sat. NaHCO3. The organic layer was separated, and dried over Na2SO4, filtered, and evaporated to give the title compound (1.2 g, 70percent). 1H NMR (400 MHz, DMSO-d6) 6.89 (1 H, s), 7.04 (2 H, br s), 8.04 (1 H, s).
65% With hydrogen iodide In water at 0 - 20℃; for 18.5 h; 6-Chloropyrimidin-4-ylamine (450 mg) was added in portions to HI (57percent wt. aq. , 20 mL) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C and then at ambient temperature for 18 hours. The reaction mixture was treated with NaHC03 (sat. aq. ) until pH8 was achieved and then the product extracted with EtOAc (2 x 30 mL). The combined organics were washed with NaOH (2M, aq. ), dried (MgS04), filtered and then concentrated. The crude product was used directly without further purification (500 mg, 65percent); lH NMR (CDCl3) ; 6.90 (s, 1H), 7.03 (s, 2H), 8.05 (s, 1H); MS m/e MHs 221.
47% With hydrogen iodide In water at 0 - 20℃; for 3 h; General procedure: 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.
Reference: [1] Patent: WO2005/47279, 2005, A1, . Location in patent: Page/Page column 50
[2] Patent: WO2005/60970, 2005, A1, . Location in patent: Page/Page column 124
[3] European Journal of Medicinal Chemistry, 2014, vol. 80, p. 364 - 382
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YieldReaction ConditionsOperation in experiment
44% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h; The 400mg4-amino-6-chloro-pyrimidine, 1.51g (1.5equiv) adding cesium carbonate flask, 10mLN, N '-dimethyl formamide as a solvent, adding 405 μ L (1.5equiv) morpholine, heating to 100 °C, reaction 12h. Adding proper amount of water, extraction with ethyl acetate, saturated salt water washing, drying by anhydrous sodium sulfate, filter, evaporate solvents under reduced pressure, the residue is purified by silica gel column chromatography separation, methanol/dichloromethane = 1/50 elution, to get the yellow solid 245 mg, yield 44percent.
Reference: [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 18, p. 8326 - 8344
[2] Patent: CN105418592, 2016, A, . Location in patent: Paragraph 0097; 0098; 0099; 0100; 0101
[3] Journal of the American Chemical Society, 1958, vol. 80, p. 2182,2184
[4] Patent: US4503050, 1985, A,
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YieldReaction ConditionsOperation in experiment
40% at 125℃; for 0.333333 h; Microwave irradiation Step A: 6-(pyridin-3-yl)pyrimidin-4-amine
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3- ylboronic acid (0.384 g, 3.13 mmol), Na2C03 (0.795 g, 7.50 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/water. The mixture was heated in the microwave synthesizer at 125 °C for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60 percent ethyl acetate in hexanes, then 5-25 percent 9: 1methanol: ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4- amine (0.17 g, 0.987 mmol, 40 percent yield) as an off-white solid. LCMS R.T. = 0.31; [M+H]+ = 173.11.
40% With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 125℃; for 0.333333 h; Microwave irradiation A mixture of 6-chloropyrimidin-4-amine (0.324 g,2.5 mmol), pyridin-3-ylboronic acid (0.384 g, 3.13 mmol),Na2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspendedin a mixture ofDME/EtOH/water. The mixture was heated inthe microwave synthesizer at 125° C. for 20 min and concentrated.The residue was purified by silica gel chromatography(10-60percent ethyl acetate in hexanes, then 5-25percent 9: I methanol:ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3yl)pyrimidin-4-amine (0.17 g, 0.987 mmol, 40percent yield) as an off-white solid.
Reference: [1] Patent: WO2011/53292, 2011, A1, . Location in patent: Page/Page column 249
[2] Patent: JP5714745, 2015, B2, . Location in patent: Paragraph 0445; 0446
[3] Patent: WO2011/56503, 2011, A1, . Location in patent: Page/Page column 49
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YieldReaction ConditionsOperation in experiment
72% With Iodine monochloride In N,N-dimethyl-formamide at 45℃; To a solution of 3.03 g (23.39 mmol) of 6-chloropyrimidin-4-amine in 60 mL of dimethylformamide was added dropwise a solution of iodine monochloride (2.34 mL, 46.70 mmol) in 40 mL of dimethylformamide. Then the mixture was stirred at 45 °C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a 4percent aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0percent to 20percent, methanol-dichloromethane) to obtain 4.28 g (72percent yield) of the title compound. LRMS (m/z): 256 (M+1 )+.
47% With N-iodo-succinimide In N,N-dimethyl-formamide at 100℃; for 8 h; To a solution of 6-chloropyri.midin-4-amme (1 ,29 g, 10 mmol) in DMF (8 mL) was added N-iodosuccinimide (2.25 g, 10 mmol) in one portion to give an orange mixture. The reaction mixture was stirred at 100 °C for 8 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL), and the resulted mixture was washed successively with a mixture of saturated \a --S;O; aqueous solution and saturated NaHC03 aqueous solution (1/2 (v/v), 100 mL x 3), water (150 mL x 3) and brine (100 mL). Then the organic phase was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (1.20 g, yield 47.0percent). MS (ESI, pos. ion) m/z: 255.8 [M+H]+; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-Λ) δ (ppm): 8.12 (s, 1H).
46.97% With N-iodo-succinimide In N,N-dimethyl-formamide at 100℃; for 8 h; The compound 6-chloropyrimidine-4-amino (1.29 g, 10 mmol) was dissolved in DMF (8 mL), and thenNIS (2.25 g, 10 mmol) was added and the reaction mixture was stirred at 100 ° C for 8 hours, then cooled to room temperature and concentrated under reduced pressureShrink The residue was dissolved in EtOAc (300 mL) and the resulting mixture was washed with a mixture of saturated aqueous Na2S204 / saturated aqueous NaHCO3 (v / v, 1/2, 100 mL x 3) followed by water (150 mL x 3) and brine (100 mL)The resulting organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE /EtOAc (v / v) = 5/1) to give the title compound as a white solid (1.20 g, 46.97percent).
Reference: [1] Patent: WO2014/60432, 2014, A1, . Location in patent: Page/Page column 128; 129
[2] Journal of Heterocyclic Chemistry, 2014, vol. 51, # SUPPL. 1, p. E380-E383
[3] Tetrahedron Letters, 2010, vol. 51, # 27, p. 3597 - 3598
[4] Patent: WO2015/175579, 2015, A1, . Location in patent: Paragraph 346
[5] Patent: CN104513235, 2017, B, . Location in patent: Paragraph 0765; 0766; 0767
[6] Patent: US2011/245257, 2011, A1, . Location in patent: Page/Page column 36
[7] Patent: US2014/275004, 2014, A1, . Location in patent: Paragraph 0621
[8] Patent: WO2014/160028, 2014, A1, . Location in patent: Page/Page column 67
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