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Chemical Structure| 31230-17-8
Chemical Structure| 31230-17-8
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Product Details of [ 31230-17-8 ]

CAS No. :31230-17-8 MDL No. :MFCD00075180
Formula : C4H7N3 Boiling Point : -
Linear Structure Formula :- InChI Key :FYTLHYRDGXRYEY-UHFFFAOYSA-N
M.W :97.12 Pubchem ID :93146
Synonyms :

Calculated chemistry of [ 31230-17-8 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.25
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 2.0
Molar Refractivity : 27.96
TPSA : 54.7 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.53
Log Po/w (XLOGP3) : 0.27
Log Po/w (WLOGP) : 0.31
Log Po/w (MLOGP) : -0.27
Log Po/w (SILICOS-IT) : 0.79
Consensus Log Po/w : 0.32

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.14
Solubility : 7.02 mg/ml ; 0.0723 mol/l
Class : Very soluble
Log S (Ali) : -0.98
Solubility : 10.2 mg/ml ; 0.105 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.18
Solubility : 6.43 mg/ml ; 0.0662 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.32

Safety of [ 31230-17-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 31230-17-8 ]

* 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 [ 31230-17-8 ]
  • Downstream synthetic route of [ 31230-17-8 ]

[ 31230-17-8 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 1118-61-2 ]
  • [ 31230-17-8 ]
YieldReaction ConditionsOperation in experiment
94.2% With hydrazine hydrate In ethanol at 85 - 95℃; Large scale Add 10 g of 3-aminobutenenitrile and 5 L of ethanol to a 10 L reaction flask, stir to stir, stir until dissolved, and add 2500 g of 80percent hydrazine hydrate.Stir at room temperature for 10-20 min., slowly heat to reflux, the reaction temperature is 85-95 ° C;Note the large amount of gas generated;When the heat preservation reaction is 1.5-2.5, TLC monitoring, the raw material reaction is completed; the reaction liquid is concentrated under reduced pressure at 50-60 ° C to 20percent-30percent of the original reaction liquid volume;The oil pump is rectified to obtain a pale yellow liquid (light yellow solid after cooling), 2230 g, yield 94.2percent. The purity of 3-amino-5-methylpyrazole is above 98percent by GC and HPLC, and the single impurity is less than 0.5. percent.
75% at 80℃; for 8 h; S1. 2.46g 3-amino crotonitril (1) and 20mL mass fraction of 25percent hydrazine hydrate dissolved in 50mL three-necked flask;80 heated to reflux for 8h;After the reaction, excess hydrazine hydrate was drained under vacuum; the residue was distilled to give 3-amino-5-methylpyrazole (2) in 75percent yield;
Reference: [1] Patent: CN108341782, 2018, A, . Location in patent: Paragraph 0018; 0019; 0021; 0022
[2] Patent: CN104844567, 2017, B, . Location in patent: Paragraph 0031; 0034; 0039; 0044
  • 2
  • [ 2469-99-0 ]
  • [ 31230-17-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4672 - 4684
[2] Bioorganic and Medicinal Chemistry Letters, 2018,
  • 3
  • [ 763-33-7 ]
  • [ 31230-17-8 ]
YieldReaction ConditionsOperation in experiment
65% Reflux 2.46 g of 3-aminocrotononitrile (18) and 20 mL of a 25percent hydrazine hydrate mixture were placed in a 50 mL three-necked flask.Heat to reflux reaction.After the reaction, the excess hydration was drained under vacuum.After the residue was distilled, 1.9 g of 3-amino-5-methylpyrazole (19) was obtained in a yield of 65percent.
Reference: [1] Patent: CN108191822, 2018, A, . Location in patent: Paragraph 0056; 0057; 0058
  • 4
  • [ 1780-72-9 ]
  • [ 5720-05-8 ]
  • [ 31230-17-8 ]
  • [ 1159187-59-3 ]
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 157 - 169
  • 5
  • [ 110580-44-4 ]
  • [ 5720-05-8 ]
  • [ 31230-17-8 ]
  • [ 1159187-59-3 ]
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 157 - 169
  • 6
  • [ 13752-78-8 ]
  • [ 31230-17-8 ]
Reference: [1] Patent: US5597941, 1997, A,
  • 7
  • [ 34362-22-6 ]
  • [ 31230-17-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 1267 - 1273
  • 8
  • [ 5720-05-8 ]
  • [ 31230-17-8 ]
  • [ 1159187-59-3 ]
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 157 - 169
  • 9
  • [ 1780-72-9 ]
  • [ 108-98-5 ]
  • [ 31230-17-8 ]
  • [ 882-33-7 ]
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 157 - 169
  • 10
  • [ 1001-56-5 ]
  • [ 31230-17-8 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1959, vol. 624, p. 1,19
  • 11
  • [ 31230-17-8 ]
  • [ 108-24-7 ]
  • [ 83725-05-7 ]
YieldReaction ConditionsOperation in experiment
43% With sodium hydrogencarbonate In water for 16 h; Reflux 4.1.1
N-(3-methyl-1H-pyrazol-5-yl)acetamide (2)
5-methyl-1H-pyrazol-3-amine (1) (10g, 103 mmol) was dissolved in 100 mL of distilled water, NaHCO3 (26g, 309 mmol) was slowly added.
Acetic anhydride (19.5 mL, 206 mmol) was then added dropwise and the resulting suspension was heated at reflux for 16 h (monitored by TLC).
Then, the mixture was allowed to cool down to RT, white crystals precipitated slowly.
The precipitate was collected, washed with water and dried to provide the desired product 2 (6.2g, 44 mmol, 43percent yield) without further purification. Mp: 210-211 °C; 1H NMR (400 MHz, DMSO‑d6) δ 11.92 (s, 1H), 10.19 (s, 1H), 6.24 (s, 1H), 2.17 (s, 3H), 1.96 (s, 3H).
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 428 - 441
  • 12
  • [ 31230-17-8 ]
  • [ 83725-05-7 ]
Reference: [1] Patent: US6118008, 2000, A,
  • 13
  • [ 31230-17-8 ]
  • [ 57097-81-1 ]
YieldReaction ConditionsOperation in experiment
62% With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 70℃; for 0.5 h; S2. 1.9 g of 3-amino-5-methylpyrazole (2),15mL concentrated hydrobromic acid,2.8g cuprous bromide mixed into 100mL three-necked flask,Heated to 70 ;Take about 1.5g sodium nitrite dissolved in 5mL water,Using a constant pressure funnel slowly dropping into a three-necked flask;After the addition is completed,The reaction solution was stirred at 70 for 30min,After cooling to room temperature, 20 mL THF was added,20mL water;The mixture was extracted three times with 30 mL of ether, the organic layer was washed with sodium thiosulfate solution, dried over magnesium sulfate, filtered through silica gel,The solvent was distilled off under reduced pressure to give 3-methyl-5-bromopyrazole (3) in a yield of 62percent;
52% at 70℃; for 0.5 h; 1.9 g of 3-amino-5-methylpyrazole (19), 15 mL of concentrated hydrobromic acid, and 2.8 g of cuprous bromide were placed in a 100 mL three-necked flask and heated to 70 °C.Approximately 1.5 g of sodium nitrite was dissolved in 5 mL of water and slowly added dropwise to a three-necked flask using a constant pressure funnel.After the completion of the addition, the reaction solution was stirred at 70 ° C for 30 min, then cooled to room temperature, and 20 mL of THF (tetrahydrofuran) and 20 mL of water were added.It was extracted three times with 30 mL of diethyl ether. The organic layer was washed with sodium thiosulfate solution and dried over magnesium sulfate.After filtration with silica gel, the solvent was evaporated under reduced pressure to give 1.7 g of 3-methyl-5-bromopyrazole (20) in a yield of 52percent.
Reference: [1] Patent: CN104844567, 2017, B, . Location in patent: Paragraph 0031; 0035; 0040; 0045
[2] Patent: CN108191822, 2018, A, . Location in patent: Paragraph 0059; 0060; 0061
  • 14
  • [ 31230-17-8 ]
  • [ 116834-96-9 ]
Reference: [1] Patent: US5859007, 1999, A,
  • 15
  • [ 102-52-3 ]
  • [ 31230-17-8 ]
  • [ 116834-96-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2706 - 2725
  • 16
  • [ 31230-17-8 ]
  • [ 24424-99-5 ]
  • [ 1065204-79-6 ]
  • [ 578008-32-9 ]
YieldReaction ConditionsOperation in experiment
59% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.5 h; S-Ammo-S-methyl-pyrazole-l-carboxylic acid tert-butγl esterNaH (95percent, 0.57g, 22.7mmol) was added slowly to a 00C solution of 3-Amino-5- methylpyrazole (2.Og, 20.6mmol) in THF (40ml). BoC2O (4.94g, 22.7mmol) was added after 30 min and the mixture was allowed to warm to room temperature. After stirring for 2 h at room temperature, the mixture was poured into a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with CHCI3. The combined organic phases were dried over Na2SO4. Removal of the solvent in vacuum gave a crude mixture of the title compound and its 2-carboxylic acid tert.- butyl ester isomer, which were separated by chromatography on silica in ethyl acetate / heptane 2:1. Yield 2.4g, 59percent.1H-NMR: (400 MHz, D6-DMSO) 5.60 (IH, s), 5.27 (2H, s), 2.34 (3H, s), 1.51 (9H, s); MS (ESI+) = 198.26 (MH-H)+.
48% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.5 h; Step E: Preparation of tert-butyl 3 -amino-5 -methyl- lH-pyrazole-1- carboxylate.To a stirred solution of 3 -amino-5 -methyl-pyrazole (1.94 g, 20 mmol) in N, N- dimethylformamide (20 mL) at 0 °C was added 60percent sodium hydride/mineral oil (880 mg, 22 mmol) and the resulting mixture was stirred at rt for 30 min. Di-tert-butyl dicarbonate (4.8 g, 22 mmol) was slowly added and the resulting mixture was stirred at rt for 2 h. The mixture was then poured into saturated aq sodium hydrogen carbonate and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to afford tert-butyl 3 -amino-5 -methyl- 1H- pyrazole-l-carboxylate (1.9 g, 48percent) and tert-butyl 5 -amino-3 -methyl- lH-pyrazole-1- carboxylate (1.1 g, 28percent). For tert-butyl 3 -amino-5 -methyl- lH-pyrazole-l-carboxylate 1H NMR (400 MHz, DMSO-d6) δ 5.60 (s, 1H), 5.28 (s, 2H), 2.34 (s, 3H), 1.51 (s, 3H). For tert-butyl 5 -amino-3 -methyl- lH-pyrazole-l-carboxylate 1H NMR (400 MHz, DMSO-de) δ 6.22 (s, 2H), 5.15 (s, 1H), 2.00 (s, 3H), 1.54 (s, 3H); LC-MS (ESI) m/z 198 (M+H)+
38%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 5.5 h; Inert atmosphere
To a suspension of NaH (220 mg, 5.50 mmol) in anhydrous THF (3.5 mL) was added a solutionof 3-amino-5-methyl-1H-pyrazole (500 mg, 5.00 mmol) in anhydrous THF (6.5 mL) at 0 °C under argon atmosphere. After stirring for 30 min, Boc2O (1.31 mL, 5.50 mmol) was added and stirred at rt for 5.5 h. After the completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (4 × 75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. Purification by column chromatography (1:1 → 1:2 hexanes/EtOAc) yielded S1r(377 mg, 38percent) as a light brown solid and S1r' (472 mg, 48percent) as a white solid.
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[2] Patent: WO2006/32518, 2006, A1, . Location in patent: Page/Page column 200
[3] Patent: WO2012/30944, 2012, A2, . Location in patent: Page/Page column 81-82
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2114 - 2124
[5] Nucleosides, Nucleotides and Nucleic Acids, 2014, vol. 33, # 8, p. 552 - 582
  • 17
  • [ 31230-17-8 ]
  • [ 24424-99-5 ]
  • [ 578008-32-9 ]
YieldReaction ConditionsOperation in experiment
40%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 2 h;
PREPARATION 19; feri-Butyl 3-amino- -methyl-1 H-pyrazole-1 -car boxy late; Sodium hydride (60percent dispersion in mineral oil, 0.81 g, 33.96 mmol) was added slowly to a stirred suspension of 5-methyl-1 H-pyrazol-3-amine (3.00 g, 30.90 mmol) in tetrahydrofuran (150 mL) at 0 °C. The mixture was stirred for 30 minutes, then di-tert- butyl dicarbonate (7.40 g, 33.96 mmol) was added to the reaction. The mixture was stirred and warmed to room temperature. After 2 hours, saturated aqueous sodium hydrogencarbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (Na2S04) and evaporated. Followed by purification of the crude product by flash chromatography (2.44 g, 40percent).LRMS (m/z): 198 (M+1 )+.1 H NMR (400 MHz, METHANOL-^) δ ppm 1.61 (s, 9 H) 2.10 (s, 3 H) 4.85 (s, 2 H) 5.24 (s, 1 H)
40%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h;
Stage #2: at 20℃; for 2 h;
Sodium hydride (60percent dispersion in   mineral oil, 0.81 g, 33.96 mmol) was added slowly to a stirred suspension of   5-methyl-1H-pyrazol-3-amine (3.00 g, 30.90 mmol) in   tetrahydrofuran (150 mL) at 0 °C. The mixture was stirred for 30 minutes, then   di-tert-butyl dicarbonate (7.40 g, 33.96 mmol) was added to the reaction. The mixture was stirred and warmed to room temperature. After 2 hours, saturated   aqueous sodium hydrogencarbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (Na2SO4) and evaporated. Followed by purification of the crude product by flash chromatography (2.44 g, 40percent).LRMS (m/z): 198 (M+1)+.1 H NMR (400 MHz, METHANOL-d4) δ ppm 1.61 (s, 9 H) 2.10 (s, 3 H) 4.85 (s, 2 H) 5.24 (s, 1 H)
Reference: [1] Patent: WO2012/41476, 2012, A1, . Location in patent: Page/Page column 56
[2] Patent: EP2441755, 2012, A1, . Location in patent: Paragraph 0171
[3] Patent: WO2003/105853, 2003, A1, . Location in patent: Page 69
[4] Patent: WO2007/17649, 2007, A1, . Location in patent: Page/Page column 64
[5] Patent: WO2016/193939, 2016, A1, . Location in patent: Page/Page column 81; 82
[6] Bioorganic and Medicinal Chemistry Letters, 2018,
  • 18
  • [ 31230-17-8 ]
  • [ 5750-76-5 ]
  • [ 543712-81-8 ]
YieldReaction ConditionsOperation in experiment
89.5% With triethylamine In ethanol at 20℃; for 16 h; To a solution of 5-methyl-l /-pyrazol-3-amine (4.00 g, 41.2 mmol) in absolute EtOH (100 mL) were added Et3 (12.51 g, 123.6 mmol) and 2,4,5-trichloropyrimidine (7.56 g, 41.2 mmol). The reaction was stirred at room temperature for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a pale yellow solid (9.00 g, 89.5percent). MS (ESI, pos. ion) m/z: 244.1 [M+H]+; NM (600 MHz, DMSO-i: δ (ppm) 12.32 (br. s, 1H), 9.70 (s, 1H), 8.33 (s, 1H), 6.28 (s, 1H), 2.25 (s, 3H).
89.5% With triethylamine In ethanol at 20℃; for 16 h; 5-methyl-1H-pyrazol-3-amine (4.00 g, 41.2 mmol) was dissolved in absolute ethanol (100 mL). Et3N (12.51 g, 123.6 mmol) and 2,4,5-trichloropyrimidine (7.56 g, 41.2 mmol) were added thereto. After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 1/1) to give the title compound as a pale yellow solid (9.00 g, 89.5percent).
76% With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 48 h; Inert atmosphere Step 1: Compound 1a (3.64 g, 20 mmol), 3-amino-5-methyl-pyrazole (1.94 g, 20 mmol) and diisopropylethylamine (5.17 g, 40 mmol) were added to 20 mL of ethanol solution and then stirred at room temperature for 2 days. The insoluble substance was collected to obtain Compound 1b (3.7 g, Yield 76percent), MS [M + 1]+ 244.0.
76% With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 48 h; Inert atmosphere Compound la (3.64 g. 20 mmol), 3-amino-5-me- thyl-pyrazole (1.94 g, 20 mmol) and diisopropylethylamine (5.17 g, 40 mmol) were added to 20 mE of ethanol solution and then stirred at room temperature for 2 days. The insoluble substance was collected to obtain Compound lb (3.7 g, Yield76percent), MS [M+l] 244.0.

Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 262 - 276
[2] Organic Process Research and Development, 2013, vol. 17, # 9, p. 1123 - 1130
[3] Patent: WO2015/94803, 2015, A1, . Location in patent: Paragraph 323
[4] Patent: CN104672250, 2017, B, . Location in patent: Paragraph 0762; 0763; 0764; 0765
[5] Patent: EP2754659, 2014, A1, . Location in patent: Paragraph 0061-0063
[6] Patent: US2014/378488, 2014, A1, . Location in patent: Paragraph 0093; 0094; 0095
[7] Patent: WO2009/7753, 2009, A2, . Location in patent: Page/Page column 56-57
[8] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4672 - 4684
[9] Patent: WO2007/49041, 2007, A1, . Location in patent: Page/Page column 58
[10] Patent: WO2009/158431, 2009, A2, . Location in patent: Page/Page column 29-30
  • 19
  • [ 639090-53-2 ]
  • [ 31230-17-8 ]
  • [ 639090-55-4 ]
YieldReaction ConditionsOperation in experiment
91% With N-ethyl-N,N-diisopropylamine; potassium iodide In N,N-dimethyl-formamide at 50℃; for 6 h; A mixtrue of compound 0105 (3.0 g, 8.85 mmol) and 5-Methyl-2H-pyrazol-3- ylamine (0.94 g, 9.7 mmol)in DMF (16 mL) was treated with diisopropylethylamine <n="58"/>(1.25 g, 9.7 mmol ) and potassium iodide (1.76 g, 10.6 mmol). The mixture was stirred at 50 0C for 6 hours. The solvent was evaporated under reduce pressure and the residue was recrystallized in ethyl acetate. The title compound 0106 was obtained as a white solid (2.0 g, 91percent): LCMS: 401 [M+l] +; 1U NMR (DMSO- d6) δ 0.82 (d, J= 6.6 Hz , 4H), 1.85 (m, IH), 1.99 (s, IH), 5.24 (bs, IH), 6.47 (bs, IH), 7.55 (m, 2H), 7.71 (m, 2H), 10.22 (s,lH ), 11.95 (s,lH).
78% With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 85℃; for 4 h; A mixture of compound C (1.0 g, 2.94 mmol)and 3-amino-5-methylpyrazole (314 mg, 3.23 mmol) in dimethylformamide (6 ml) was treated with diisopropylethylamine(0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3.53 mmol). The mixture was stirred under nitrogen at 85 ° for 4 hours, cooled to room temperature and diluted with ethyl acetate. The solution was washed with water (x 4), dried over magnesium sulphate and concentrated to 5 ml to afford, upon crystallization and harvesting of colourless crystals, the title compound D (920 mg, 78percent). 1H-NMR DMSO-d6, δ 0.80-0.87 (4H, m), 1.77- 1.85 (IH5 m), 1.92 (IH, s), 5.24 (IH, br s), 6.47 (IH, br s), 7.55 (2H, d), 7.70-7.80 (2H, m), 10.24 (IH5 s), 10.47 (IH, s), 11.92 (IH, s).
78% With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 85℃; for 4 h; A mixture of compound C (1.0 g, 2.94 mmol)and 3-amino-5- methylpyrazole (314 mg, 3.23 mmol) in dimethylformamide (6 ml) was treated with diisopropylethylamine (0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3.53 mmol). The mixture was stirred under nitrogen at 85 ° for 4 hours, cooled to room temperature and diluted with ethyl acetate. The solution was washed with water (x 4), dried over magnesium sulphate and concentrated to 5 ml to afford, upon crystallization and harvesting of colourless crystals, the title compound D (920 mg, 78percent). 1H-NMR DMSO-d6, δ 0.80-0.87 (4H, m), 1.77-1.85 (IH, m), 1.92 (IH, s), 5.24 (IH, br s), 6.47 (IH, br s), 7.55 (2H, d), 7.70-7.80 (2H, m), 10.24 (IH, s), 10.47 (IH, s), 11.92 (IH, s).
78% With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 85℃; for 4 h; A mixture of compound C (1.0 g, 2.94 mmol)and 3-amino-5-methylpyrazole (314 mg, 3.23 mmol) in dimethylforrnamide (6 ml) was treated with diisopropylethylamine (0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3.53 mmol). The mixture was stirred under nitrogen at 85 ° for 4 hours, cooled to room temperature and diluted with ethyl acetate. The solution was washed with water (x 4), dried over magnesium sulphate and concentrated to 5 ml to afford, upon crystallization and harvesting of colourless crystals, the title compound D (920 mg, 78percent). 1H-NMR DMSO-d6, δ 0.80-0.87 (4H, m), 1.77-1.85 (IH, m), 1.92 (IH, s), 5.24 (IH, br s), 6.47 (IH, br s), 7.55 (2H, d), 7.70-7.80 (2H, m), 10.24 (IH, s), 10.47 (IH, s), 11.92 (IH, s).

Reference: [1] Patent: WO2009/86012, 2009, A1, . Location in patent: Page/Page column 56; 57
[2] Patent: WO2007/14250, 2007, A2, . Location in patent: Page/Page column 18
[3] Patent: WO2008/13807, 2008, A2, . Location in patent: Page/Page column 7
[4] Patent: WO2007/136615, 2007, A2, . Location in patent: Page/Page column 33-34
[5] Patent: US2009/105270, 2009, A1,
  • 20
  • [ 639090-53-2 ]
  • [ 31230-17-8 ]
  • [ 639090-55-4 ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide); water; ethyl acetate at 20 - 85℃; for 4 h; mixture of compound C (1.0 g, 2.94 mmol) and 3-amino-5-methylpyrazole (314 mg, 3.23 mmol) in [DIMETHYLFORMAMIDE] (6 ml) was treated with diisopropylethylamine (0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3.53 mmol). The mixture was stirred under nitrogen at 85 [] for 4 hours, cooled to room temperature and diluted with ethyl acetate. The solution was washed with water (x 4), dried over magnesium sulphate and concentrated to 5 ml to afford, upon crystallization and harvesting of colourless crystals, the title compound D (920 mg, 78percent). 1H-NMR DMSO-d6, 8 0. 80-0.87 (4H, m), 1.77-1. 85 [(1H,] m), 1.92 [(1H,] s), 5.24 [(1H,] br s), 6.47 [(1 H,] br s), 7.55 [(2H,] d), 7.70-7. 80 (2H, m), 10.24 [(1 H,] s), 10.47 [(1 H,] s), 11.92 (1H, [S).]
19% With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 90℃; for 11 h; Inert atmosphere [4- (4,6-dichloro-pyrimidin-2-yl-sulfonyl) phenyl] carboxamide cyclopropylmethyl (2. 5g, 7. 35mmol) and 3-methyl-5-aminopyrazole (0 . 79g, 8. 08mmol) was dissolved DMF (15mL) in, followed by the addition of diisopropylethylamine (1.54mL, 8. 83mmol) and sodium iodide (1.33g, 8. 83mmol), and the reaction under nitrogen heating the reaction to 90 ° C for 11 hours.After the solvent was purified by column chromatography (CH2C12 / CH30H (V / V) = 10/1) was removed, to give a white solid (554mg, 19percent).
Reference: [1] Patent: WO2004/833, 2003, A1, . Location in patent: Page 45-46
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[3] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[4] Patent: CN104024246, 2016, B, . Location in patent: Paragraph 0333; 0334
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  • [ 31230-17-8 ]
  • [ 1229236-86-5 ]
YieldReaction ConditionsOperation in experiment
22%
Stage #1: With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 1 h;
Stage #2: With hydrogenchloride In 2-methyltetrahydrofuran; water
Stage #3: With sodium hydroxide In butan-1-ol
Prepare active catalyst by combining palladium chloride (160 mg, 0.90 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.10 g, 1.84 mmol) in DMF (25 mL) and warming to form a solution. Add the preformed catalyst to a solution of 3-methyl-1H-pyrazol-5-amine (3.0 g, 29.65 mmol), 4-((6-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholine hydrochloride (9.0 g, 20.19 mmol), potassium bicarbonate (6.0 g, 59.93 mmol) in DMF (65 mL) and heat to 150° C. for 1 h. Cool the reaction to 60° C. and add mercaptopropyl functionalized silica (500 mg) and stir for 1 h then filter to remove the silica. Cool to ambient temperature, add 2-methyltetrahydrofuran (125 mL) and extract with water to remove DMF. Add HCl to the organic solution to form the 3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine hydrochloride salt. Add the HCl salt (1.1 g) to sodium hydroxide (10 mL, 1N) in n-butanol (10 mL) and stir. Filter the resulting mixture to obtain 0.22 g of the free base, imidazo[1,2-b]pyridazin-6-amine, 3-[(4-chloro-2-fluorophenyl)methyl]-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(4-morpholinylmethyl), (22percent yield, M+1.=470).
Reference: [1] Patent: US2010/152181, 2010, A1, . Location in patent: Page/Page column 5
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