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[ CAS No. 5305-40-8 ]

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Chemical Structure| 5305-40-8
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CAS No. :5305-40-8 MDL No. :MFCD02257701
Formula : C5H2Cl2N2O Boiling Point : 286.1°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :176.99 g/mol Pubchem ID :819691
Synonyms :

Safety of [ 5305-40-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H317-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5305-40-8 ]

  • Upstream synthesis route of [ 5305-40-8 ]
  • Downstream synthetic route of [ 5305-40-8 ]

[ 5305-40-8 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 5305-40-8 ]
  • [ 5399-92-8 ]
YieldReaction ConditionsOperation in experiment
83% With triethylamine; hydrazine In 1,4-dioxane at 20℃; for 1 h; Synthesis of Compound 4.1. Hydrazine hydrate (11.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol), and triethylamine (30 mL, 22 mmol) in 1,4-dioxane (600 mL), while cooling to maintain an internal temperature below 20° C. After the addition was complete, the reaction was warmed to RT. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford compound 4.1 (29 g, 83percent) as a light yellow solid. 1H NMR (400.13 MHz, DMSO-d6) δ14.52 (br. s, 1H), 8.83 (s, 1H), 8.45 (s, 1H). MS m/z 155 [M+1]+.
71% With triethylamine; hydrazine In methanol at -60 - 20℃; Hydrazine hydrate (2.0 ml, 41 mmol) was slowly added to a solution of 4,6- dichloropyrimidine-5-carbaldehyde (7.2 g, 41 mmol) in MeOH (150 ml) -60 0C (nitromethane-dry ice bath) followed by triethylamine (6.8 mL, 49 mmol). The mixture was allowed to warm to rt and stirred for 2 h. MeOH was removed in vacuo and water <n="65"/>(150 mL) was added. The mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered through a glass funnel. Removal of solvent gave 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (4.45 g, 71percent). MS (ESI, pos. ion) m/z: 155 [M+H]+
68.9% With hydrazine hydrate; triethylamine In methanol at -65 - 20℃; To the solution of 4,6-dichloropyrimidine-5-carbaldehyde(1.0 g, 0.006 mol) in methanol (20 mL) at -65 °C, triethylamine (0.97 mL,1.2 equivalents (eq.)) wasadded. A solution of hydrazine monohydrate (0.274 mL 1.0 eq.) in methanol (10 mL) was slowlydripped into above stirred solution by using a constant-pressure dropping funnel. The mixture wasallowed to warm to room temperature and stirred for 2–3 h. The reaction mixture was concentratedin vacuo and crude product was diluted with water (20 mL), and extracted with EtOAc (60 mL x 3).The combined organic layer was washed with saturated solution of NaCl (60 mL x 3), dried overMgSO4 and concentrated to give compound 2. Yield: 68.9percent. 1H-NMR (400 MHz, deuteriated dimethylsulfoxide (DMSO-d6)) δ 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M - H]-.
68.9% With hydrazine hydrate; triethylamine In methanol at -65 - 20℃; In a 100 mL three-necked flask, 1.0 g of 4,6-dichloro-5-pyrimidinecarboxaldehyde and 20 mL of methanol were added and dissolved with stirring. The temperature was lowered to -65 ° C and 0.97 mL (1.2 eq) of triethylamine was added dropwise. 0.274 mL (1.0 eq) of hydrazine monohydrate was diluted with 10 mL of methanol and dropped slowly using a dropping funnel. Recovery was completed to room temperature, the reaction 2 ~ 3h, TLC monitoring. After the reaction was completed, the solvent was evaporated to dryness. The solid was dissolved with ethyl acetate (30 mL x 3), filtered, and combined, washed with saturated NaCl solution (60 mL x 3). Dried over anhydrous MgSO4, the solvent was removed by rotary evaporation and dried to give a pale yellow solid in a yield of 68.9percent.
68.9% With hydrazine hydrate; triethylamine In methanol at -65 - 20℃; In a 100 mL three-necked flask, 4,6-dichloro-5-pyrimidine formaldehyde (1.0 g, 5.68 mmol) was added.Methanol (20 mL) was dissolved by stirring, cooled to -65[deg.] C., and triethylamine (0.97 mL, 6.81 mmol) was added dropwise. Hydrazine monohydrate (0.274 mL, 5.68 mmol) was diluted with methanol (10 mL) and slowly dropped using a dropping funnel. After the completion of the addition, the reaction was allowed to return to room temperature for 2 to 3 h and monitored by TLC. The reaction is over,The solvent was evaporated and dried. The solid was dissolved in ethyl acetate (30 mL x 3), filtered and combined and washed with saturated NaCl solution (60 mL)×3). Dry over anhydrous MgSO4, evaporate the solvent, and dry to give a pale yellow solid (0.60 g, 68.9percent yield)
68.9% With triethylamine; hydrazine In methanol at -65 - 20℃; for 4 h; General procedure: To the solution of 4,6-dichloropyrimidine-5-carbaldehyde 2 (1.0g, 5.6mmol) in methanol (20mL) at−65°C, triethylamine (0.97mL) was added. A solution of hydrazine monohydrate (0.274mL 1.0 eq.) in methanol (10mL) was slowly dripped into above stirred solution by using a constant-pressure dropping funnel. The mixture was allowed to warm to room temperature and stirred for 2–3h. The reaction mixture was concentrated in vacuo and crude product was diluted with water (20mL), and extracted with EtOAc (60mL×3). The combined organic layer was washed with saturated solution of NaCl (60mL×3), dried over MgSO4 and concentrated to give compound 3 (0.602g, yield: 68.9percent.) 1H NMR (400MHz, deuteriated dimethyl sulfoxide (DMSO-d6)) δ 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M− H].
27% With triethylamine; hydrazine In tetrahydrofuran at 160℃; for 0.333333 h; Molecular sieve; microwave irradiation A suspension of 4,6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (lOmL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 μ, 5.650 mmol). The reaction was allowed to stir at RT for 10 minutes before being heated to 160°C for 20 minutes in the microwave. The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSC ), and concentrated in vacuo. This was purified by column chromatography (ISCO Companion.(TM)., 40g column, MeOH / DCM) to give the required product (117mg, 27percent Yield).JH NMR (DMSO, 400 MHz) δ 8.45 (IH, s), 8.84 (IH, s), 14.54 (IH, br s) ppm; MS (ES*) 154.96
27% With triethylamine; hydrazine In tetrahydrofuran at 20 - 160℃; for 0.5 h; Molecular sieve; Microwave irradiation A suspension of 4,6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (10 mL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 μL, 5.650 mmol).
The reaction was allowed to stir at RT for 10 minutes before being heated to 160° C. for 20 minutes in the microwave.
The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSO4), and concentrated in vacuo.
This was purified by column chromatography (ISCO Companion.(TM)., 40 g column, MeOH/DCM) to give the required product (117 mg, 27percent Yield).
1H NMR (DMSO, 400 MHz) δ 8.45 (1H, s), 8.84 (1H, s), 14.54 (1H, br s) ppm; MS (ES+) 154.96

Reference: [1] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 18
[2] Patent: WO2008/153947, 2008, A2, . Location in patent: Page/Page column 42; 63-64
[3] Molecules, 2017, vol. 22, # 4,
[4] Patent: CN106496232, 2017, A, . Location in patent: Paragraph 0049; 0050; 0051; 0052
[5] Patent: CN107383014, 2017, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078
[6] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 210 - 228
[7] Patent: WO2011/139273, 2011, A1, . Location in patent: Page/Page column 48; 49
[8] Patent: US2012/172379, 2012, A1, . Location in patent: Page/Page column 23
[9] Patent: US2007/10523, 2007, A1, . Location in patent: Page/Page column 9
[10] Patent: WO2011/29043, 2011, A1, . Location in patent: Page/Page column 126
  • 2
  • [ 7803-57-8 ]
  • [ 5305-40-8 ]
  • [ 5399-92-8 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With triethylamine In tetrahydrofuran at 0℃; for 0.166667 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere
General procedure: To a 20 mL vial was added 1 (97percent, 88 mg, 0.5 mmol), Et3N (0.070mL, 0.5 mmol), and THF (1 mL). The reaction mixture was allowed to stir at 0 °C for 10 min under a N2 atmosphere. To the solution was added hydrazine monohydrate (2p; 0.026 mL, 0.525 mmol) in THF (1 mL) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 1 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 (6 mL) and H2O (10 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 6 mL). The combined organic layers were dried(MgSO4) and concentrated in vacuo to obtain 4p; yield: 56 mg(74percent);
Reference: [1] Synthesis (Germany), 2013, vol. 45, # 13, p. 1791 - 1806
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  • [ 2644-70-4 ]
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Reference: [1] Organic Letters, 2013, vol. 15, # 8, p. 1882 - 1885
  • 4
  • [ 5305-40-8 ]
  • [ 60-34-4 ]
  • [ 23000-43-3 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.166667 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere
General procedure: To a 20 mL vial was added 1 (97percent, 88 mg, 0.5 mmol), Et3N (0.070mL, 0.5 mmol), and THF (1 mL). The reaction mixture was allowed to stir at 0 °C for 10 min under a N2 atmosphere. To the solution was added hydrazine monohydrate (2p; 0.026 mL, 0.525 mmol) in THF (1 mL) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 1 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 (6 mL) and H2O (10 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 6 mL). The combined organic layers were dried(MgSO4) and concentrated in vacuo to obtain 4p; yield: 56 mg(74percent);
53% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 3.16667 h; Example 2-Synthesis of 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 2
To 4,6-dichloro-pyrimidine-5-carbaldehyde (2.90 g, 16.39 g) and diisopropylethylamine (2.12 g, 2.85 mL, 16.39 mmol) in THF (100 mL) cooled at 0° C. was added dropwise methylhydrazine (0.83 g, 0.95 mL, 18.03 mmol) in 10 mL THF.
The reaction mixture was stirred at 0° C. for 10 min, and warmed to room temperature and stirred for 3 h.
Then, the solvent was removed at reduced pressure and the crude was chromatographed by Biotage (DCM: EtOAc) to afford 1.47 g, 53percent of the desired compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 8.17 (s, 1H), 4.17 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 154.83, 154.53, 153.23, 131.90, 113.65, 34.47.
Reference: [1] Synthesis (Germany), 2013, vol. 45, # 13, p. 1791 - 1806
[2] Patent: US2017/355700, 2017, A1, . Location in patent: Paragraph 0100
[3] Tetrahedron Letters, 2008, vol. 49, # 52, p. 7395 - 7397
[4] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 19
  • 5
  • [ 7339-53-9 ]
  • [ 5305-40-8 ]
  • [ 23000-43-3 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 8, p. 1882 - 1885
  • 6
  • [ 5305-40-8 ]
  • [ 23000-43-3 ]
Reference: [1] Molecules, 2017, vol. 22, # 4,
[2] Patent: CN107383014, 2017, A,
[3] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 210 - 228
  • 7
  • [ 5305-40-8 ]
  • [ 5305-45-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 5, p. 1516 - 1522
[2] Patent: US2011/152296, 2011, A1,
[3] Patent: US2011/245257, 2011, A1,
[4] Patent: WO2012/68343, 2012, A1,
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7223 - 7226,4
[6] Patent: WO2006/118749, 2006, A1,
  • 8
  • [ 1193-24-4 ]
  • [ 5305-40-8 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: at 0℃; for 1 h;
Stage #2: at 20℃; for 0.5 h;
EXAMPLE 1; 4-[6-Amino-5-(methoxyimino-methyl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid (4-isopropoxy-phenyl)-amidea. 4,6-Dichloro-pyrimidine-5-carbaldehyde; A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0 0C was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient EPO <DP n="48"/>temperature. The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure. The residue was poured into ice water and extracted six times with ethyl ether. The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent). 1H NMR (CDCl3) δ 10.46 (s, IH), 8.90 (s, IH).
Reference: [1] Patent: WO2006/135719, 2006, A1, . Location in patent: Page/Page column 46-47
[2] Patent: WO2005/7647, 2005, A1, . Location in patent: Page/Page column 164
[3] Patent: EP1333029, 2003, A1,
[4] Patent: WO2005/56524, 2005, A2, . Location in patent: Page/Page column 108
[5] Patent: WO2006/118749, 2006, A1, . Location in patent: Page/Page column 87
  • 9
  • [ 68-12-2 ]
  • [ 1193-24-4 ]
  • [ 5305-40-8 ]
YieldReaction ConditionsOperation in experiment
95% at 0 - 20℃; for 4.5 h; Heating / reflux A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient temperature.
The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure.
The residue was poured into ice water and extracted six times with ethyl ether.
The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent).
1H NMR (CDCl3) δ 10.46 (s, 1H), 8.90 (s, 1H).
95% at 0 - 20℃; for 4.5 h; Heating / reflux A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient temperature.
The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure.
The residue was poured into ice water and extracted six times with ethyl ether.
The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent).
1H NMR (CDCl3) δ 10.46 (s, 1H), 8.90 (s, 1H).
95% at 0 - 20℃; for 4.5 h; b.
4,6-Dichloro-pyrimidine-5-carbaldehyde
A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient temperature.
The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure.
The residue was poured into ice water and extracted six times with ethyl ether.
The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent).
1H NMR (CDCl3) δ 10.46 (s, 1H), 8.90 (s, 1H).
95%
Stage #1: at 0℃; for 1 h;
Stage #2: at 20℃; for 3.5 h; Reflux
Amixture of DMF (3.2 mL, 41.34mmol) and POCl3 (10 mL,109,24mmol) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine(2.5 g, 22.3mmol), and stirred for 0.5 h at ambient temperature. Theheterogeneous mixture was heated at reflux for 3 h and the volatiles wereremoved at reduced pressure. The residue was poured into ice water andextracted six times with ethyl ether. The organic phase was washed with aqueousNaHCO3, dried over anhydrous Na2SOandconcentrated to afford a yellow solid (3.7 g, 95percent).
94% at 70℃; for 24 h; A 250mL three-necked flask was added POCl3 (91.4 mL, 1.12 mol) and cooledto -10 °C. With stirring, DMF (30.1 mL, 0.446 mol) was added in 30 min. then 3 (25 g, 0.223 mol) was added. Thereactor was heated to maintain at 70°C for 24 h. After being cooled to room temperature,the reaction mixture was poured into 500 mL of cold water (0-5 °C) withstirring. The resulting mixture was extracted with ethyl acetate (3×600 ml)., which was washed with brine (600 mL)and dried over Na2SO4. The organic phase was evaporatedto give the crude product, which was isolated by column chromatography onsilica gel (EtOAc-petroleum = 1:10, v/v) to give the title compound (37.1 g, 94.0percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm: 10.48(s, 1H), 8.91 (s, 1H).
85%
Stage #1: at 0℃; for 1 h;
Stage #2: at 0 - 20℃; for 3.5 h; Reflux
30 mL of phosphorylchloride (POCl3) was cooled down to 0° C., to which 9.6 mL of anhydrous dimethylformamide (DMF) was slowly added. 1 hour later, 7.85 g (70.0 mmol) of 4,6-dihydroxypyrimidine was added thereto.
The reaction mixture was heated at room temperature, followed by stirring at room temperature for 30 minutes.
The reaction mixture was refluxed for 3 hours.
The mixture was cooled down to room temperature.
The reaction mixture was slowly added to ice water, followed by extraction with ethylacetate.
The extracted organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure.
The obtained solid was washed with hexane/diethyl ether (5/1, v/v) to give 10.5 g of 4,6-dichloropyrimidine-5-carbaldehyde as a white solid (5.95 mmol, yield: 85percent).
1H NMR(300 MHz, CDCl3) δ 10.47 (s, 1H), 8.90 (s, 1H).
75% at 0 - 110℃; for 5 h; To DMF (64 niL) at O0C was added POCl3 (200 niL) dropwise. After 1 hour, 2,4-dihydroxypyrimidine (50 g, 446 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then at HO0C for 3 hours. After cooling to room temperature the solution was poured into ice water portion wise, being careful to keep the mixture from becoming excessively exothermic. The mixture was extracted with ether (8X); the combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated in vacuo to provide compound 1.1 (58.6 g, 75percent) as a pale yellow solid.
75.4% for 3 h; Cooling with ice; Reflux DMF (5.50 mL, 71.34 mmol) was slowly added dropwise under ice-coolingPOCl3 (17.00 mL, 185.71 mmol),Stirring reaction 1h,Remove the ice bath,4,6-dihydroxypyrimidine (4.00 g, 35.68 mmol) was added,Temperature reflux 3h,Cooled to room temperature,Poured into ice water,Dichloromethane extraction,Concentrated under reduced pressure,Petroleum ether-ethyl acetate (P: E = 4: 1 (V: V)),4.74 g of a yellow solid,Yield 75.4percent
74%
Stage #1: at 0℃; for 1 h;
Stage #2: for 3.5 h; Reflux
Example 1-Synthesis of 4, 6-dichloropyrimidine-5-carbaldehyde 1
This compound was synthesized similar to a patent.
To POCl3 (107.3 mmol, 10 mL) cooled at 0° C. was added DMF (41.3 mmol, 3.2 mL) dropwise, and the mixture was stirred for 1 h.
Then, 4, 6-dihydroxylpyrimidine (22.3 mmol, 2.50 g) was added, stirred for 30 minutes and refluxed for 3 h.
After removing the volatiles at reduced pressure, it was poured into ice and extracted with ethyl acetate three times (3*200 mL).
The combined ethyl acetate extracts were washed with 200 mL saturated NaHCO3, dried with Na2SO4, and concentrated under reduced pressure to afford 2.91 g, 74percent of the desired compound as an orange solid. 1H NMR (500 MHz, CDCl3): δ 10.48 (s, 1H), 9.92 (s, 1H).
13C NMR (125 MHz, CDCl3): δ 185.61, 162.69, 159.58, 124.89.
72.7%
Stage #1: at 0℃; for 0.5 h;
Stage #2: at 120℃; for 5 h;
The DMF 30ml of dimethylformamide and 80ml of phosphorus oxychloride were mixed and stirred at 0 30 minutes,Was added 4,6-dihydroxypyrimidine and 20.0g (0.18mol). Heated to 120 , refluxed for 5 hours. Concentrated under reduced pressureTo dryness, the residue was poured into ice water, extracted three times with ethyl acetate, the combined organic phases, the organic phase was driedAnd concentrated to give a yellow solid 23.1g, yield 72.7percent.
70%
Stage #1: at 0 - 10℃; for 1 h; Inert atmosphere
Stage #2: Inert atmosphere
(1) Weigh POCl3 (4 eq) into the reaction flask, and under nitrogen protection, cool to about 0°C. Add DMF (1.85 eq) to the feed solution. When adding, control the temperature at 08°C, add it. Feed solution 0 ~ 10 °C, stirring 1h,To the solution was added 4,6-dihydroxypyrimidine. After the addition was completed, the mixture was naturally warmed to room temperature and stirred for 1 hour. Then, the mixture was warmed to reflux and stirred for 2 hours. The mixture was cooled and stirred overnight.The feed solution was evaporated under reduced pressure to remove excess POCl3, the residue was slowly added to ice water, the product was extracted with ethyl acetate (2 volumes *3), the organic phases were combined, washed with water (2 volumes) and washed with saturated sodium bicarbonate solution (2 The volume of) was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4,6-dichloropyrimidine-5-carboxaldehyde (yield: 70percent), which was used directly in the next reaction.
68%
Stage #1: at 0℃; Inert atmosphere
Stage #2: at 20 - 135℃; for 5 h; Reflux
Intermediate 16: 4,6-Dichloro-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (249 mL, 671 mmol) was added slowly to dimethylformamide (75 mL) with continuous stirring at 0° C. under nitrogen. After the addition was complete, was added 4,6-dihydroxypyrimidine (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 50.0 g, 446 mmol) and stirred at room temperature for 2 hours followed by refluxing (135° C.) for 3 hours. The reaction mixture was cooled to room temperature, poured into chilled water with stirring and extracted with diethyl ether (3.x.200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 4,6-dichloro-pyrimidine-5-carbaldehyde (54.0 g, 68percent) as a white solid, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 10.45 (s, 1H).
68.4%
Stage #1: at 0 - 10℃; for 3.5 h; Inert atmosphere
Stage #2: at 3 - 155℃; Inert atmosphere
Stage #3: at 20℃;
4,6-Dichloropyrimidine-5-carbaldehyde (26) [0168] In a 5 L 4-neck flask equipped with a mechanical stirrer, an addition funnel, a condenser, a thermocouple, and a N2 sweep into an aqueous NaOH scrubbing solution, phosphorous oxychloride (POCl3, 1 L, 10.572 mol, 4.82 equiv) was charged and cooled in an ice/salt bath. N,N-Dimethylformamide (DMF, 320 mL, 4.138 mol, 1.85 equiv) was then added dropwise to the flask at 0±2° C. After addition of approximately 100 mL of DMF over approximately 0.5 h, crystallization occurred and the reaction temperature was increased from 0 to 10° C. Addition was stopped and the mixture was allowed to re-cool to approximately 2° C. The remaining DMF was added over 2.5 h at below 8° C. The suspension became very thick making stirring difficult. When addition of DMF was complete, the mixture was stirred at 3-5° C. for 0.5 h. 4,6-Dihydroxypyrimidine (250 g, 2.232 mol) was added portion wise as a solid. After about one third of 4,6-dihydroxypyrimidine was added, the reaction mixture became more mobile, and a slow exothermic phenomena occurred with the reaction temperature increasing to approximately 12° C. over 0.5 h. The remaining 4,6-dihydroxypyrimidine was added portion wise over 0.25 h with the reaction temperature increasing from 12 to 27° C. The reaction temperature was maintained at 25-27° C. with intermittent cooling during which time the yellow suspension became thinner, then thicker once again. After the exothermic phenomenon subsided in about 1 h, the reaction mixture was heated slowly. At about 55° C. the reaction mixture became extremely thick and the second mild exothermic phenomenon was occurred. The heating mantle was removed while the reaction temperature continued to increase to about 63° C. and remained at this temperature for several minutes before dropping. Heating of the mixture was resumed until gentle reflux (about 100° C.) was attained. At about 95° C. a steady, fairly rapid evolution of HCl gas began and the reaction mixture gradually thinned and darkened. After about 0.5 h, a clear brown solution developed with the reflux temperature slowly increasing to 115° C. over 1.25 h. After a total of 2.5 h at reflux, the reaction mixture was cooled to ambient temperature and stirred overnight at ambient temperature. Excess amount of POCl3 (as much as possible) was removed under reduced pressure (bath temperature 45-50° C.). The thick residual brown oil was poured very slowly into cold H2O (5 L) in a 20 L separation funnel, adding ice as needed to maintain the aqueous mixture near room temperature. The aqueous mixture was extracted with EtOAc (2×3 L followed by 1×2 L). The combined EtOAc extracts were washed with H2O (2×2.5 L), saturated NaHCO3 aqueous solution (1 L), brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure (bath temperature at 35° C.) to afford the crude 4,6-dichloropyrimidine-5-carbaldehyde (270 g, 395 g theoretical, 68.4percent) as yellow-orange solids. A 20 g portion of this crude material was purified by Kugelrohr distillation (oven temperature at 90-100° C., 225 mTorr) to give 15.3 g of pure 4,6-dichloropyrimidine-5-carbaldehyde as a white solid that turned yellow on standing at room temperature. 1H NMR (300 MHz, CDCl3) δ 10.46 (s, 1H), 8.89 (s, 1H) ppm.
58% at 0 - 20℃; for 3 h; Heating / reflux Dimethylformamide (31.82 mL, 413 mmol) was added dropwise to phosphorus oxychloride (100 mL, 1.07 mol) at O0C. To this mixture at O0C was added 4, 6- dihydroxypyrimidine (25 g, 223 mmol). The mixture was stirred at rt for 30 min and then at reflux for 2.5 h. The volatiles were removed in vacuo and the mixture was poured over ice water and extracted 6X with ether. The combined organics were washed with aqueous saturated sodium bicarbonate and dried over sodium sulfate to give 22.78 g (58percent) of 4,6- dichloro-5-formylpyrimidine (J. Med. Chem. 2002, 45, 3639).
57%
Stage #1: at 0℃; for 0.3 h;
Stage #2: at 130℃; for 3.5 h;
To cooled (0° C.) phosphorus oxychloride (20.0 mL, 215 mmol, 4.8 equiv.) was added DMF (6.4 mL, 83 mmol, 1.9 equiv) dropwise over 3 min. The reaction mixture was stirred for fifteen min and the ice bath was removed. 4,6-Dihydroxypyrimidine (5.0 g, 44.6 mmol, 1.0 equiv.) was added and the reaction mixture was heated to 130° C. and stirred for 3.5 hr. The mixture was cooled to RT and concentrated. Ice was slowly added to the dark brown residue, followed by 600 mL of ice water. The aqueous mixture was extracted with diethyl ether (5.x.100 mL), and the organic extracts were washed with aqueous saturated NaHCO3 (2.x.100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate and concentrated in vacuo to provide Compound 15 (4.42 g, 57percent) as a crude orange solid, which was used without further purification.
57%
Stage #1: at 0℃; for 1 h;
Stage #2: at 20℃; for 3.5 h; Heating / reflux
(Ref: A. Gomtsyan, S. Didomenico, C-H. Lee, M. A. Matulenko, K. Kim, E. A. Kowaluk, C. T. Wismer, J. Mikusa, H. Yu, K. Kohlhass, M. F. Jarvis, S. S. Bhagwat; J. Med. Chem., 2002, 45, 3639-3648.) A mixture of DMF (32 mL) and POCl3 (100 mL) at 0° C. was stirred for 1 hour, treated with 4,6-dihydroxypyrimidine (25.0 g, 223 mmol), and stirred for 0.5 hour at room temperature. The heterogeneous mixture was then heated to refluxed and stirred for 3 hours. The reaction was cooled to room temperature and the resulting viscous, black liquid was poured onto ice water and extracted with diethyl ether (6.x.100 mL). The organic phase was subsequently washed with NaHCO3, and water, dried over MgSO4, and concentrated to give 25 as a yellow solid (20.0 g, 57percent yield). 1H NMR (CDCl3) δ 10.41 (s, 1H), 8.85 (s, 1H).
56% at 30℃; for 4.33333 h; Heating / reflux DMF (7 mL) was added dropwise to POC13 (22 mL) keeping the internal temperature below 30 °C. 4, [6-DIHYDROXYPYRIMIDINE] [(5. 0] g) was added maintaining the temperature below [30 °C.] The reaction mixture was stirred for 20 minutes and then heated to reflux for 4 hours. Excess POC13 was removed by evaporation and the resulting viscous mixture was poured into a stirred ice solution. The product was extracted with diethyl ether (6 x 50 mL). The combined organics were concentrated in vacuo and then purified by flash chromatography on silica eluting with hexane: EtOAc (7: 1 to 2: 1) to afford the title compound as [A] white crystalline solid (4.42 g, 56percent); [1H] NMR [(CDC13)] 8 8. 89 (s, 1H), 10.46 (s, 1H).
55% at 0 - 20℃; for 4.5 h; Reflux 4,6-Dichloro-5-pyrimidinecarbaldehyde; A mixture of DMF (64 mL) and POCl3 (200 mL) at 0° C. was stirred for 1 h and then treated with 4,6-pyrimidinediol (50.0 g, 446 mmol), and further stirred for 0.5 h at rt. Then the heterogeneous mixture was heated under reflux for 3 h. The volatiles were removed under reduced pressure, and the residue was poured into ice water and extracted six times with diethyl ether. The organic phase was washed with aqueous NaHCO3 and water, dried over Na2SO4, concentrated under reduced pressure, and crystallized (EtOAc-petroleum ether) to give 4,6-dichloro-5-pyrimidinecarbaldehyde (43.5 g, 55percent); LC-MS (ESI) m/z 177 [M+H]+.
40%
Stage #1: at 0℃; for 1 h;
Stage #2: at 0℃; for 4 h; Heating / reflux
Preparation 95-A; 4.6-Dichloropyrimidine-5-carbaldehvde; Charge DMF (8.9 mL, 1.3eq) in a round bottom flask and cool to 00C. Add POCl3 (32.6 mL, 4.0eq) to the reaction drop wise at 00C. Stir the reaction mass at 00C for Ih. Charge 4,6-dihydroxy pyrimidine (10.Og, l.Oeq) to the reaction mass and allowed it to come to room temperature slowly. Reflux the reaction mass for 4h and monitor the reaction by TLC (10percent acetone in DCM). Concentrate the reaction mass under vacuum and pour the concentrated reaction mass over crushed ice. Extract the product with diethyl ether and wash with saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate it under vacuum to get pale yellow solid as product (6.2g, 40 percent).

Reference: [1] Patent: US2006/281700, 2006, A1, . Location in patent: Page/Page column 34
[2] Patent: US2006/281755, 2006, A1, . Location in patent: Page/Page column 40
[3] Patent: US2006/281764, 2006, A1, . Location in patent: Page/Page column 25
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3353 - 3358
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 12, p. 2936 - 2941
[6] Patent: US2018/105527, 2018, A1, . Location in patent: Paragraph 0797-0799
[7] Patent: WO2006/65703, 2006, A1, . Location in patent: Page/Page column 94
[8] Patent: CN107043366, 2017, A, . Location in patent: Paragraph 0085; 0086
[9] Patent: US2017/355700, 2017, A1, . Location in patent: Paragraph 0099
[10] Patent: CN105622613, 2016, A, . Location in patent: Paragraph 0109; 0148; 0149; 0150; 0151; 0152; 0153
[11] Patent: CN107759601, 2018, A, . Location in patent: Paragraph 0105-0109
[12] Patent: US2009/286812, 2009, A1, . Location in patent: Page/Page column 23
[13] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0168
[14] Journal of Medicinal Chemistry, 2010, vol. 53, # 13, p. 5012 - 5024
[15] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1132 - 1135
[16] Patent: WO2006/90261, 2006, A1, . Location in patent: Page/Page column 78
[17] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 39
[18] Patent: US2007/72864, 2007, A1, . Location in patent: Page/Page column 33; 21
[19] Patent: WO2004/13141, 2004, A1, . Location in patent: Page 88
[20] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3639 - 3648
[21] Patent: US2011/152296, 2011, A1, . Location in patent: Page/Page column 14-15
[22] European Journal of Organic Chemistry, 2009, # 34, p. 5920 - 5926
[23] Patent: WO2008/140947, 2008, A1, . Location in patent: Page/Page column 37
[24] Synthesis, 2008, # 6, p. 891 - 896
[25] Patent: WO2004/65380, 2004, A1, . Location in patent: Page 167
[26] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 101-102
[27] Patent: WO2007/84815, 2007, A2, . Location in patent: Page/Page column 41
[28] Patent: WO2010/151735, 2010, A2, . Location in patent: Page/Page column 56
[29] Patent: WO2011/29043, 2011, A1, . Location in patent: Page/Page column 126
[30] Patent: US2011/245257, 2011, A1, . Location in patent: Page/Page column 14
[31] Patent: WO2012/68343, 2012, A1, . Location in patent: Page/Page column 28
[32] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7223 - 7226,4
[33] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3052 - 3059
[34] Patent: CN107759623, 2018, A, . Location in patent: Paragraph 0110
  • 10
  • [ 14256-99-6 ]
  • [ 5305-40-8 ]
YieldReaction ConditionsOperation in experiment
50% With trichlorophosphate In DMF (N,N-dimethyl-formamide) at 0 - 90℃; for 6.5 h; 4, 6-Dichloro-pyrimidine-5-carbaldehyde : DMF (7 mL, 0.09 mol) was added to POC13 (21 mL, 0.23 mol) at 0°C. The reaction mixture was stirred at room temperature for 0.5 h. 4,6-Dihydroxy-pyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was heated to 90°C for 6 h and cooled to room temperature. A large excess of crushed ice was added to the reaction mixture very slowly under ice-bath. The mixture was extracted with CH2C12. The combined organic layers were washed with water, brine, and dried over NA2S04. After concentration, the residue was purified by column chromatography (20percent EtOAc/ hexane) to yield the title compound (4 g, 50percent). 1H NMR (400 MHz, CDC13) 8 8.91 (1H, s), 7.87 (1H, s). LRMS (M+H) + M/Z 177.
50% With trichlorophosphate In DMF (N,N-dimethyl-formamide) at 90℃; for 6 h; DMF (7 mL, 0.09 mol) was added to POCl3 (21 mL, 0.23 mol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. 4,6-Dihydroxy-pyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was heated to 90° C. for 6 h and cooled to room temperature. A large excess of crushed ice was added to the reaction mixture very slowly under ice-bath. The mixture was extracted with CH2Cl2. The combined organic layers were washed with water, brine, and dried over Na2SO4. After concentration, the residue was purified by column chromatography (20percent EtOAc/hexane) to yield the title compound (4 g, 50percent). 1H NMR (400 MHz, CDCl3) δ 8.91 (1H, s), 7.87 (1H, s). LRMS (M+H)+ m/z 177.
Reference: [1] Patent: WO2004/63151, 2004, A2, . Location in patent: Page 38
[2] Patent: US2004/44203, 2004, A1, . Location in patent: Page 30
  • 11
  • [ 1193-21-1 ]
  • [ 68-12-2 ]
  • [ 5305-40-8 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: at 0℃; for 1 h;
Stage #2: at 120℃; for 3 h;
A mixture of phosphorus oxychloride (20ML, 0. 22 mol) and N,-DIMETHYLFORMAMIDE (6.4 mL) was stirred at 0°C for 1 hour. 4,6-Dichloropyrimidine (5.00 g, 44.6 mmol) was added to the reaction mixture, which was then stirred for 3 hours at 120°C. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ice-water and extracted with ether. The separated organic phase was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual solid was triturated with hexane to give 4,6-dichloro- pyrimidine-5-carbaldehyde (4.73 g, 60percent).
Reference: [1] Patent: WO2004/43926, 2004, A1, . Location in patent: Page 140
  • 12
  • [ 68-12-2 ]
  • [ 1193-24-4 ]
  • [ 5305-40-8 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 3, p. 531 - 544
  • 13
  • [ 5305-40-8 ]
  • [ 60025-09-4 ]
Reference: [1] Patent: US2011/152296, 2011, A1,
[2] Patent: US2011/245257, 2011, A1,
[3] Patent: WO2012/68343, 2012, A1,
  • 14
  • [ 5305-40-8 ]
  • [ 60025-06-1 ]
Reference: [1] Patent: US2018/105527, 2018, A1,
  • 15
  • [ 67-56-1 ]
  • [ 5305-40-8 ]
  • [ 4558-59-2 ]
YieldReaction ConditionsOperation in experiment
46.3% at 90℃; for 1 h; The compound 4,6-dichloropyrimidine-5-carbaldehyde (5 g, 28.25 mmol) was suspended in dry MeOH (100 mL)After K2CO3 (7.8 g, 56.5 mmol) was added thereto, the reaction mixture was stirred at 90 ° C for 1 hour and then concentrated under reduced pressure to giveThe residue was dissolved in a mixed solvent of water (100 mL) and DCM (100 mL), separated on a liquid phase, the aqueous phase was extracted with DCM (50 mL × 3)The combined organic phases were concentrated under reduced pressure, the residue was diluted in DCM / PE (1 mL / 20 mL) and the resulting mixture stirred at room temperatureThe mixture was stirred for 3 hours and then filtered off with suction to give a yellow solid which was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1)Purification gave the title compound as a white solid (2.2 g, 46.3percent).
Reference: [1] Patent: CN104513235, 2017, B, . Location in patent: Paragraph 1355; 1356; 1357; 1384; 1385; 1386
  • 16
  • [ 5305-40-8 ]
  • [ 77-92-9 ]
  • [ 4558-59-2 ]
YieldReaction ConditionsOperation in experiment
20% With sodium methylate In methanol REFERENCE EXAMPLE 15
Preparation of 4,6-dimethoxypyrimidine-5-carboaldehyde
43.6g (246 mmol) of 4,6-dichloropyrimidine-5-carboaldehyde was dissolved in 200 m of methanol, and 120g (622 mmol) of 28percent sodium methoxide was added under cooling with ice and then reacted for 2 hours at room temperature.
After completion of the reaction, the solvent was distilled off, and an aqueous citric acid solution was added, followed by extraction with ethyl acetate.
The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained crude crystals were washed with isopropyl ether to obtain 8.3g (yield: 20percent) of 4,6-dimethoxypyrimidine-5-carboaldehyde.
Reference: [1] Patent: EP1211246, 2002, A1,
  • 17
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 5305-40-8 ]
  • [ 4558-59-2 ]
YieldReaction ConditionsOperation in experiment
44% at 0 - 70℃; for 2 h; The compound 4,6-dichloropyrimidine-5-carbaldehyde (20 g, 113.0 mmol) was suspended in dry methanol (100 mL)To the reaction was slowly added a solution of sodium methoxide (27.47 g, 508.5 mmol) in dry methanol (100 mL) at 0 ° C. The reaction was warmed to 70 ° C and stirred for 2 hours, then cooled to 0 ° C and quenched by the addition of aqueous hydrochloric acid (1M, 300 mL). The resulting mixture was neutralized to pH = 7 by the addition of saturated aqueous NaHCO 3 and the mixture was washed with The residue was purified by silica gel column chromatography (diethyl ether / ethyl acetate = 4/1) The title compound was obtained as a white solid (8.37 g, 44percent).
Reference: [1] Patent: CN104513235, 2017, B, . Location in patent: Paragraph 0781; 0782; 0783
  • 18
  • [ 3315-60-4 ]
  • [ 5305-40-8 ]
  • [ 4558-59-2 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 42, p. 7545 - 7548
  • 19
  • [ 5305-40-8 ]
  • [ 911461-47-7 ]
Reference: [1] Russian Chemical Bulletin, 2005, vol. 54, # 8, p. 1907 - 1914
[2] Patent: US2015/87658, 2015, A1,
[3] Patent: CN104513235, 2017, B,
  • 20
  • [ 5305-40-8 ]
  • [ 1022150-11-3 ]
Reference: [1] Patent: CN105622613, 2016, A,
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