Home Cart 0 Sign in  

[ CAS No. 2380-63-4 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
Chemical Structure| 2380-63-4
Chemical Structure| 2380-63-4
Structure of 2380-63-4 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 2380-63-4 ]

Related Doc. of [ 2380-63-4 ]

Alternatived Products of [ 2380-63-4 ]

Product Details of [ 2380-63-4 ]

CAS No. :2380-63-4 MDL No. :MFCD00005688
Formula : C5H5N5 Boiling Point : -
Linear Structure Formula :- InChI Key :LHCPRYRLDOSKHK-UHFFFAOYSA-N
M.W : 135.13 Pubchem ID :75420
Synonyms :
4-Aminopyrazolo[3,4-d]pyrimidine

Calculated chemistry of [ 2380-63-4 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 36.09
TPSA : 80.48 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) : -7.25 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.31
Log Po/w (XLOGP3) : -0.18
Log Po/w (WLOGP) : -0.06
Log Po/w (MLOGP) : -0.42
Log Po/w (SILICOS-IT) : 0.47
Consensus Log Po/w : 0.02

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.23
Solubility : 7.95 mg/ml ; 0.0588 mol/l
Class : Very soluble
Log S (Ali) : -1.05
Solubility : 11.9 mg/ml ; 0.0882 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.77
Solubility : 2.27 mg/ml ; 0.0168 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.75

Safety of [ 2380-63-4 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P301+P310-P305+P351+P338 UN#:2811
Hazard Statements:H301-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 2380-63-4 ]

* 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 [ 2380-63-4 ]
  • Downstream synthetic route of [ 2380-63-4 ]

[ 2380-63-4 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 5399-92-8 ]
  • [ 2380-63-4 ]
YieldReaction ConditionsOperation in experiment
57% With ammonium hydroxide In tetrahydrofuran at 20 - 30℃; for 2 h; To a solution of 36 (200 rng, 1.29 mmoi) in THF (2.0 mL) is added ammonium hydroxide (2,0 mL). After stirring at 20---30 °C for 2 hours, the mixture is concentrated. triturated with MeCN (0.5 niL), and collected by fiheration to give 37 as a red solid (100 mg, 57percent yield)
Reference: [1] Patent: WO2017/161349, 2017, A1, . Location in patent: Paragraph 0250
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 784,787[3] Journal of the American Chemical Society, 1957, vol. 79, p. 6407,6413
[4] Patent: WO2016/187723, 2016, A1, . Location in patent: Page/Page column 51
  • 2
  • [ 16617-46-2 ]
  • [ 77287-34-4 ]
  • [ 2380-63-4 ]
YieldReaction ConditionsOperation in experiment
100% at 180℃; A. Selected Reaction Procedures; Synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA18); A solution of 250 mL of formamide and 3-amino-4-pyrazolecarbonitrile (25 g, 0.231 mol) was heated to 180° C. overnight under an argon atmosphere. Reaction was cooled and 400 mL of dH2O were added. The resulting solid was filtered and rinsed with cold dH2O. White solid precipitate was collected and dried in vacuo overnight to yield BA18 (39 g, 100percent yield). ESI-MS (M+H)+ m/z calcd 136.1, found 136.1.
94% at 170℃; for 5 h; Inert atmosphere 3-amino-4-pyrazolyl methyl cyanide (2g) was suspended formamide (10 mL) at, and heated at 170 5h under nitrogen. The reaction mixtureIt was cooled to room temperature and add water (15mL). The solid was collected and washed with water, washed thoroughly with methanol, and air dried to give a white solidDonor compound 2 (2.337g, 94percent yield)
93% for 1 h; Reflux A solution of 200 mL of formamide and 3-amino-4-pyrazolecarbonitrile (101) (55 g, 0.509 mol) was stirred at reflux for 1 h. The reaction mixture was cooled to room temperature and 800 mL of water was added. The resulting solid was collected by filtration, rinsed with water and dried in vacuo to yield the desired product, 1H-pyrazolo[3,4-d]pyrimidin-4-amine (102) (64 g, 93percent yield) as an off-white solid. ESI-MS (M+H)+m/z: 135.95
79% at 180℃; Inert atmosphere 87B: Compound 87A (800 mg, 7.4 mmol) was dissolved in 8 mL of formamide and the resulting solution was heated at 180°C overnight under nitrogen atmosphere. The reaction was cooled and water was added. The resulting solid was filtered and rinsed with cold water. The solid was dried in vacuo to give compound 87B as a pale yellow powder (790 mg, 79percent yield). NMR (ppm, DMSO): "58.13 (s, 1 H), 8.07 (s, 1H) 7.57 (s, 2H).

Reference: [1] Patent: US2007/293516, 2007, A1, . Location in patent: Page/Page column 12; 16
[2] Patent: CN105315283, 2016, A, . Location in patent: Paragraph 0105; 0106; 0107; 0108
[3] Patent: US2015/225407, 2015, A1, . Location in patent: Paragraph 0405
[4] Patent: WO2012/3544, 2012, A1, . Location in patent: Page/Page column 102
[5] Journal of the American Chemical Society, 1956, vol. 78, p. 784,787[6] Journal of the American Chemical Society, 1957, vol. 79, p. 6407,6413
  • 3
  • [ 77287-34-4 ]
  • [ 16617-46-2 ]
  • [ 2380-63-4 ]
YieldReaction ConditionsOperation in experiment
95% at 180℃; Inert atmosphere Commercially available 5-amino-lH-pyrazole-4-carbonitrile (2.0 g, 18.5 mmol) was mixed with formamide (10 mL) and heated to 180°C overnight under nitrogen. The solution was cooled to rt, 60 mL of water was added, and the resulting precipitate was collected by vacuum filtration to yield C (2.367 g, 95percent). 3/4 NMR (DMSO-d6, 300 MHz) δ 8.13 (s, 1H), 8.06 (s, 1H)
93% at 180℃; for 2 h; Microwave irradiation 5-amino-i H-pyrazole-4-carbonitrile (3 g, 27.77 mmol) and formamide (15 ml) were added to a 20 ml microwave vial and the mixture heated at 180°C for 2 hours using microwave radiation. The precipitate formed on cooling was filtered off and washed with water (50 ml) and allowed to dry giving the product as a cream solid (3.5 g, 25.92 mmol,93 percent). 111 NMR (500 MH DM80) 6 13.34 (a, IH), 8.13 (s, IH), 8,07 (a, IH), 7.69 (br.m 2H) laC NMR (12 MHz, DM50) 6 158 19 (CH), 15603 (C) 154 98 CC), 132 /9(CH)199.83 MS (ES +ve) [M+H]t: 136.0, 157.9 (+Nab (ES veflMLHfl 133.9
91% at 180℃; for 4 h; A mixture of commercially available S-amino-lH-pyrazole^-carbonitrile (16.22 g, 0.15 mol) and formamide (84.6 ml) was heated at 180° C for 4 hr under a nitrogen atmosphere. The solution was cooled to ambient temperature and the crystals were separated, washed with water and dried to afford the product (18.6 g, 91 percent).
90% at 160℃; for 5 h; Scheme 1 depicts the synthesis of 2-( 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl) iodide (Cpd. 1-3), an intermediate in the synthesis of the compounds of the invention and its further reactions to obtain final inhibitor analogs. Cyano substituted aminopyrazole 1-1 is heated with formamide at 1600C for 5 hours to yield 2-( 4- amino-lH-pyrazolo[3,4-d]pyrimidine (compound 1-2) in 90percent yield. This intermediate is reacted with N- iodosuccinimide in dimethylformamide at 800C for 16 hours, to produce 2-( 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3- yl iodide (Cpd. 1-3) in 90percent yield.
90% at 160℃; for 5 h; Scheme 1 depicts the synthesis of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl) iodide. Cyano substituted aminopyrazole 1-1 is heated with formamide at 160° C. for 5 hours to yield 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidine (compound 1-2) in 90percent yield. This intermediate is reacted with N-iodosuccinimide in dimethylformamide at 80° C. for 16 hours, to produce 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl) iodide (Cpd. 1-3) in 90percent yield.
88% at 200℃; for 0.5 h; Microwave irradiation 5-Amino-1H-pyrrazole-4-carbonitrile (0.10 g, 0.93 mmol) and formamide (1 ml) were heated in a microwave at 200 °C for 30 min. The resulting precipitate was filtered and washed with water to afford 4 as brown solid in 88percent yield (0.109 g, 0.81 mmol). 1H NMR (200 MHz, DMSO-d6): δ 13.22 (s, 1 H), 8.13 (s, 1 H), 8.07 (s, 1 H), 7.52 (b, 2 H); 13C NMR (50 MHz, DMSO-d6): δ 158.0, 155.9, 154.8, 132.6, 99.6; HRMS (CI) calcd for C5H5N5 (M) 135.0545, found 135.0546.
82% at 210℃; for 2 h; A solution of 3-amino-4-cyanopyrazole (9.8 g, 0.09 mol) and formamide (100 mL, 2.5 mol) was stirred at 210 °C for 2 h. After cooling to room temperature, water (200 mL) was added and the obtained solid was filtered. The crude product was suspended in hot water (100 mL) and conc HCl (5 mL), then charcoal (10 g) was added and the mixture was boiled for 15 min. After charcoal filtration, sodium hydroxide (2 N) was added (pH = 8) and the precipitated solid was filtered, giving S1 as a white solid (10 g, 82percent);1H NMR (300 MHz, DMSO d6) d 13.35 (s, 1H), 8.13 (s, 1H), 8.07 (s,1H), 7.62 (s, 2H)
76% at 165℃; for 5 h; Inert atmosphere Step 1A solution of 5-amino-lH-pyrazole-4-carbo trile (10 g, 92.51 mmo., 1.00 equiv) in formamide (80 niL) was stirred under nitrogen at 165°C for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration. The filter cake was washed first with 20 niL of water then 20 mL of methanol and dried to yield 9.5 g (76percent) of lH-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
76% at 165℃; for 5 h; Inert atmosphere A solution of 5-amino-lH-pyrazole-4-carbonitrile (10 g, 92.51 mmol, 1.00 equiv) in formamide (80 mL) was stirred under nitrogen at 165°C for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration. The filter cake was washed first with 20 mL of water then 20 mL of methanol and dried to yield 9.5 g (76percent) of lH-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
76% at 165℃; for 5 h; Inert atmosphere A solution of 5-amino-4H-pyrazolecarbonitrile (10g, 92.51 mmol, 1.00 equiv) in formamide (80 mL) was stirred under nitrogen at 165°C for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration. The filter cake was washed first with 20 mL of water then 20 mL of methanol and dried to yield 9.5 g (76percent) of 1H..pyrazolo[3,4-d]pyrimidin4-amine as a white solid.
76% at 165℃; for 5 h; Inert atmosphere Step 1. A solution of 5-amino-1H-pyrazole-4-carbonitrile (10 g, 92.51 mmol, 1.00 equiv) in formamide (80 mL) was stirred under nitrogen at 165 °C for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration. The filter cake was washed first with 20 mL of water then 20 mL of methanol and dried to yield 9.5 g (76percent) of 1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
76% at 165℃; for 5 h; Inert atmosphere Step 1.
A solution of 5-amino-1H-pyrazole-4-carbonitrile (10 g, 92.51 mmol, 1.00 equiv) in formamide (80 mL) was stirred under nitrogen at 165° C. for 5 h.
The reaction mixture was cooled to room temperature and the solid was collected by filtration.
The filter cake was washed first with 20 mL of water then 20 mL of methanol and dried to yield 9.5 g (76percent) of 1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
13.1 g at 180℃; Inert atmosphere To 5-amino-1H-pyrazole-4-carbonitrile (15 g, 138.76 m mol) was added formamide (75 mL) under nitrogen atmosphere and the reaction mixture was heated at 180 °C overnight. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 0 °C and water (50 mL) was added, and a precipitate formed. The precipitate was collected by filtration and dried to obtain 13.1 g of 1H-pyrazolo[3, 4-d]pyrimidin-4-amine as a yellow solid.
13.1 g at 180℃; Inert atmosphere To 5-amino-1H-pyrazole-4-carbonitrile (15 g, 138.76 m mol) was added formamide (75 mL) under nitrogen atmosphere and the reaction mixture was heated at 180 °C overnight. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 0 °C and water (50 mL) was added, whereupon a precipitate formed. The precipitate was collected by filtration and dried to obtain 13.1 g of 1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid.
19.7 g at 130℃; for 24 h; Inert atmosphere 5-Amino-1H-pyrazole-4-carbonitrile (20 g) was added to formamide (130 mL),and the reaction mixture was heated under nitrogen at 13 0°C for 24 hours. Water (200 mL) was added to the reaction mixture, and the mixture was stirred at 0°C to 5°C for 2 hours. The solid obtained was filtered followed by washing with water (30 x 2 mL), and was kept in an oven at 50°C for 16 hours to obtain the title compound.Yield: 19.7g

Reference: [1] Patent: WO2011/94628, 2011, A1, . Location in patent: Page/Page column 98
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4697 - 4710
[3] Patent: WO2016/185160, 2016, A1, . Location in patent: Page/Page column 47; 48
[4] Patent: WO2007/126841, 2007, A2, . Location in patent: Page/Page column 68-69
[5] Patent: WO2010/6086, 2010, A2, . Location in patent: Page/Page column 78
[6] Patent: WO2010/51042, 2010, A1, . Location in patent: Page/Page column 128
[7] Patent: US2014/357651, 2014, A1, . Location in patent: Paragraph 0460
[8] Patent: US2016/789, 2016, A1, . Location in patent: Paragraph 0320; 0321
[9] Tetrahedron Letters, 2011, vol. 52, # 44, p. 5761 - 5763
[10] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 17, p. 4774 - 4786
[11] Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4590 - 4609
[12] Patent: WO2012/158795, 2012, A1, . Location in patent: Page/Page column 76
[13] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 165
[14] Patent: WO2013/191965, 2013, A1, . Location in patent: Page/Page column 156
[15] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 49
[16] Patent: US2014/323464, 2014, A1, . Location in patent: Paragraph 0427-0429
[17] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1161 - 1166
[18] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 12, p. 1687 - 1690
[19] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5162 - 5174
[20] Patent: WO2009/62118, 2009, A2, . Location in patent: Page/Page column 165-166
[21] Patent: WO2015/58084, 2015, A1, . Location in patent: Paragraph 0205; 0241; 0273
[22] Patent: WO2015/69441, 2015, A1, . Location in patent: Paragraph 0190; 0208; 0216
[23] Patent: WO2016/79693, 2016, A1, . Location in patent: Page/Page column 24
[24] Patent: WO2016/132383, 2016, A1, . Location in patent: Page/Page column 21; 22
[25] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9976 - 9989
  • 4
  • [ 16617-46-2 ]
  • [ 2380-63-4 ]
Reference: [1] Patent: US6921763, 2005, B2,
  • 5
  • [ 16617-46-2 ]
  • [ 2380-63-4 ]
Reference: [1] Patent: US2002/156081, 2002, A1,
  • 6
  • [ 3473-63-0 ]
  • [ 16617-46-2 ]
  • [ 2380-63-4 ]
YieldReaction ConditionsOperation in experiment
84.1% at 120℃; for 45 h; Inert atmosphere 1L the reaction bottle 54.05g (0.5mol) 3-amino-4-cyano pyrazole, 540 ml in glycol monomethyl ether, under the protection of nitrogen at room temperature by adding 67.68g (0.65mol) carboximidamide acetate, system protection of nitrogen, 120 °C reaction 45h. After the reaction is complete cooling to room temperature, the system there is a large amount of solid precipitated, filtering, ponders the cake to use 100 ml methyl alcohol minute 2 run washes, and get crude intermediate 62.2g, crude product by 250 ml of toluene and 250 ml acetic acid re-crystallization, filtration, ≥ 99percent purity by white solid 56.82g, yield: 84.1percent, HPLC: 99.91percent.
Reference: [1] Patent: CN105859728, 2016, A, . Location in patent: Paragraph 0070; 0071; 0072
[2] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1132 - 1135
  • 7
  • [ 50-00-0 ]
  • [ 16617-46-2 ]
  • [ 2380-63-4 ]
YieldReaction ConditionsOperation in experiment
76% at 165℃; for 5 h; Inert atmosphere Step 1
A solution of 5-amino-1H-pyrazole-4-carbonitrile (10 g, 92.51 mmol, 1.00 equiv) in formamide (80 mL) was stirred under nitrogen at 165° C. for 5 h.
The reaction mixture was cooled to room temperature and the solid was collected by filtration.
The filter cake was washed first with 20 mL of water then 20 mL of methanol and dried to yield 9.5 g (76percent) of 1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reference: [1] Patent: US8673925, 2014, B1, . Location in patent: Page/Page column 200
  • 8
  • [ 78972-81-3 ]
  • [ 2380-63-4 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1984, vol. 20, # 2, p. 215 - 221[2] Khimiya Geterotsiklicheskikh Soedinenii, 1984, vol. 20, # 2, p. 259 - 264
  • 9
  • [ 315-30-0 ]
  • [ 2380-63-4 ]
Reference: [1] Journal of the American Chemical Society, 1956, vol. 78, p. 784,787[2] Journal of the American Chemical Society, 1957, vol. 79, p. 6407,6413
  • 10
  • [ 3258-05-7 ]
  • [ 2380-63-4 ]
  • [ 18646-11-2 ]
Reference: [1] Nucleosides and Nucleotides, 1999, vol. 18, # 4-5, p. 745 - 757
  • 11
  • [ 2380-63-4 ]
  • [ 83255-86-1 ]
YieldReaction ConditionsOperation in experiment
72% With N-Bromosuccinimide In N,N-dimethyl-formamide at 80℃; for 2.5 h; lH-pyrazolo[3,4-d]pyrimidin-4-amine (20.0 g, 148.0 mmol) and N- bromosuccinimide (27.7 g, 155.4 mmol) are suspended in DMF (400 ml) and heated to 80°C for 2.5 hrs. After cooling to room temperature, the reaction is quenched with water (dropwise, 800 ml). The precipitate is filtered and suspended in a saturated solution of Na2S03 (100 ml). The solid was filtered and washed with water (3 x 100 ml) and cold ethanol (2 x 50 ml). After drying under vacuum, the 3-bromo-lH- pyrazolo[3,4-d]pyrimidin-4-amine is obtained as beige solid (22.7 g, 105.9 mmol, 72percent).
64.4% With N-Bromosuccinimide In N,N-dimethyl-formamide at 80℃; for 8 h; The mixture of S1 (10 g, 74 mmol) and N-bromosuccinimide(15.8 g, 89 mmol) in DMF (100 mL) was stirred at 80 °C for 8 h. The resulting mixture was allowed to cool to room temperature and then diluted with 300 mL of water. The precipitate was filtered and washed with 2 60 mL of saturated aqueous sodium sulfite, 2 100 mL of water, respectively, and dried under vacuum to yield S2 as a light-yellow solid (10.2 g, 64.4percent), which was used directly without further purification. 1H NMR (300 MHz, DMSO d6) d13.78 (s, 1H), 8.19 (s, 1H), 6.89 (s, 2H)
27.9 g With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃; for 4 h; A mixture of 1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula II, 25 g), Nbromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60°C for 4 hours. The reaction mixture was gradually cooled to 25°C to 30°C, and then filtered. Deionized water (750 mL) was added to the filtrate, and the mixture was stirred at 25°C to30°C for 30 minutes. The solid obtained was filtered, then washed with deionized water (50 mL), and then dried under vacuum at 60°C for 10 hours to 12 hours to obtain the title compound.Yield: 27.9 g
27.9 g With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃; for 4 h; Example 2: Preparation of 3-bromo-lH-pyrazolor3.4-dlpyrimidin-4-amine (Formula III, when X is bromine) A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II, 25 g), N- bromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60°C for 4 hours. The reaction mixture was gradually cooled to room temperature, and then filtered. The filtrate was poured into deionized water (750 mL), and then the mixture was stirred at room temperature for 30 minutes. The solid obtained was filtered, then washed with water (50 mL). The resulting solid was dried at 60°C under vacuum for 10 hours to 12 hours to obtain the title compound. Yield: 27.9 g
2.5 g With bromine In water at 20℃; for 2 h; Reflux To a solution of 4-aminopyrazolo[3,4-d]pyrimidine (2g) and H2O 25 mL, bromine (2 g) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 h.Then, it was reacted under reflux for 1 h, dried under reduced pressure, and dissolved in water.The title compound (2.5 g) was obtained.

Reference: [1] Patent: WO2017/17619, 2017, A1, . Location in patent: Page/Page column 8-9
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 17, p. 4774 - 4786
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 7, p. 753 - 755[4] Khimiya Geterotsiklicheskikh Soedinenii, 1982, # 7, p. 982 - 984
[5] Patent: EP2548877, 2013, A1, . Location in patent: Paragraph 0416
[6] ChemMedChem, 2013, vol. 8, # 10, p. 1673 - 1680
[7] Patent: WO2016/79693, 2016, A1, . Location in patent: Page/Page column 25
[8] Patent: WO2016/151438, 2016, A1, . Location in patent: Page/Page column 10-11
[9] Patent: WO2017/161344, 2017, A1, . Location in patent: Paragraph 0813; 0818
[10] Patent: WO2017/134685, 2017, A2, . Location in patent: Page/Page column 31
[11] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9976 - 9989
[12] Patent: WO2018/2958, 2018, A1, . Location in patent: Page/Page column 35; 36
[13] Patent: CN105198887, 2017, B, . Location in patent: Paragraph 0027-0069; 0075-0117; 0123-0141; 0147-0165
[14] Patent: CN108329321, 2018, A, . Location in patent: Paragraph 0499; 0502; 0503
  • 12
  • [ 2380-63-4 ]
  • [ 151266-23-8 ]
YieldReaction ConditionsOperation in experiment
100% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; Synthesis of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA19); A solution of 3H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 0.074 mol) and n-iodo-succinamide (25 g, 0.111 mol) in DMF (80 mL) was heated to 80° C. overnight under an argon atmosphere. The resulting solid was filtered and rinsed with cold EtOH. Product was dried in vacuo overnight to yield BA19 (24 g, 100percent yield). ESI-MS (M+H)+ m/z calcd 262.0, found 262.0
96% With N-iodo-succinimide In N,N-dimethyl-formamide at 70℃; Darkness Step 1: 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine A mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (5.0 g, 37 mmol) and NIS (10.7 g, 45 mmol) in DMF (100 mL) was stirred at 70° C. overnight. Then the mixture was cooled to room temperature and filtered to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (4.1 g) as a white solid. The filtrate was concentrated and the residue was treated with 10percent Na2SO3 and filtered to give another batch. (5.1 g, 96percent of total yield)
96% With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 2 h; NIS(1.1eq, 4.95 g, 22 mmol) was slowly added into the mixture of 9(1eq, 2.70 g, 20 mmol) and DMF (50 mL) at r.t. The reaction mixturewas continued stirred at r.t. overnight. The solvent was removed invacuo and water was added. The mixture was subjected to sonicationfor 10 min. The precipitate was collected by filtration, rinsedwith water, and dried. The solid 10 was used for the next stepwithout further purification (5.01 g, 96percent yield).
95% With N-iodo-succinimide In N,N-dimethyl-formamide for 16 h; Inert atmosphere NIS (250 g, 1.11 mol, 1.5 eq.) was added to a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 g, 0.74 mol, 1.0 eq.) in DMF (800 mL).
The reaction was stirred at 80˜85° C. for 16 hours under nitrogen atmosphere.
The reaction mixture was filtered, and the filter cake was washed with ethanol (1000 mL*3) to give the title compound (184 g, yield: 95percent).
93.7% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 12 h; Inert atmosphere To a mixture of lff-pyrazole[3,4-r/]pyrfniidite-4-ani.iie (5 g, 37.03 nimol) in N.N dimethylformamide (40 ml.) was added ;V-iodo nccinimide (12.5 g, 55.6 tnmol) and the reaction mixture was heated at SO i:'C for 12 hours under argon atmosphere. The resultant solid was filtered, rinsed with cold ethanol and dried in vacuuni overnight to gi e the product as a pale brown solid (9 g, yield 93.7 percent). -NMR (DMSO~i 400 MHz): δ 1 .80 (s, I H), 8.17 (s, 1 H ), 7.00 (s, 2H); MS (ES) m/e 262 ΓΜ + I f .
92% With N-iodo-succinimide In N,N-dimethyl-formamide at 90℃; for 0.166667 h; Microwave irradiation 1H-Pyrazolo[3,4-d]pyrimidin-4-amine (4, 0.10 g, 0.74 mmol) and N-iodosuccinimide (0.25 g, 1.1 mmol) in DMF (2 ml) were heated in a microwave at 90 °C for 10 min. The resulting precipitate was filtered and washed with water to afford 5 as a brown solid in 92percent yield (0.17 g, 0.65 mmol). 1H NMR (200 MHz, DMSO-d6): δ 13.82 (s, 1H), 8.18 (s, 1 H), 7.10 (b, 2 H); 13C NMR (50 MHz, DMSO-d6): δ 157.6, 156.0, 155.0, 102.5, 89.8; HRMS (CI) calcd for C5H5IN5 (M) 261.9511, found 261.9510.
90% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 16 h; Scheme 1 depicts the synthesis of 2-( 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl) iodide (Cpd. 1-3), an intermediate in the synthesis of the compounds of the invention and its further reactions to obtain final inhibitor analogs. Cyano substituted aminopyrazole 1-1 is heated with formamide at 1600C for 5 hours to yield 2-( 4- amino-lH-pyrazolo[3,4-d]pyrimidine (compound 1-2) in 90percent yield. This intermediate is reacted with N- iodosuccinimide in dimethylformamide at 800C for 16 hours, to produce 2-( 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3- yl iodide (Cpd. 1-3) in 90percent yield.
90% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 16 h; Scheme 1 depicts the synthesis of 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl) iodide. Cyano substituted aminopyrazole 1-1 is heated with formamide at 160° C. for 5 hours to yield 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidine (compound 1-2) in 90percent yield. This intermediate is reacted with N-iodosuccinimide in dimethylformamide at 80° C. for 16 hours, to produce 2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl) iodide (Cpd. 1-3) in 90percent yield.
90% With N-iodo-succinimide In N,N-dimethyl-formamide at 50℃; To a solution of 4-aminopyrazolo[3,4-d]pyrimidine (5.00 g, 37.0 mmol) in DMF (130 mL) was added N-iodosuccinimide (10.83 g, 48.14 mmol). The reaction mixture was heated overnight at 50 °C. Additional N-iodosuccinimide (1.67 g, 7.41 mmol) was added and heating was continued at 50 °C for a second night. The mixture was then allowed to cool to rt and concentrated to one half volume under reduced pressure. Water was added and the resulting precipitate was collected by suction filtration. The solids were washed with water and ethanol, then dried in vacuo at 40 °C to afford the product, 4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidine (Intermediate 14, 8.66 g, 90percent). LCMS (AA): m/z 262 (M+H); 1H MR (400 MHz, -DMSO) δ 13.80 (s, 1H), 8.16 (s, 1H).
90.6% With N-iodo-succinimide In N,N-dimethyl-formamide at 50℃; for 48 h; A mixture of lH-Pyrazolo[3,4-d]pyrimidin-4-ylamine (11.75 g, 0.09 mol) (Step A) and N-iodosuccinimide (25.45 g, 0.11 mol) in dimethylformamide (300 ml) was stirred at 50° C for 24 hr. A second batch of N-iodosuccinimide (3.92 g, 0.02 mol) was added and the solution stirred for additional 24 hr. Upon standing at room temperature, a precipitate was formed which was separated by filtration and washed with dimethylformamide and ethanol to afford 10.05 g of the title compound. The filtrate was concentrated in vacuo to about one half of the original volume and 500 ml of water was added. The precipitated product was separated by filtration and washed with ethanol to afford a second batch of the product (10.53 g, combined yield 20.58 g, 90.6 percent); LC/MS, API-ES, Pos, (M+H)+, 262.1.
89% With N-iodo-succinimide In N,N-dimethyl-formamide at 50℃; for 48 h; Compound C (2.367 g, 17.5 mmol) and N-iodosuccinimide (4.810 g, 21.4 mmol) were added to dimethylformamide (60 mL) and stirred at 50°C for 24 hours. Another batch of N-iodosuccinimide (0.871 g, 3.8 mmol) was added to the reaction mixture and was allowed to stir for an additional 24 hours. The reaction mixture was cooled to room temperature and water (100 mL) was added, forming a precipitate that was collected by filtration to yield D (4.1 g, 89percent). lR NMR (DMSO- d6, 300 MHz) δ 8.18 (s, 1H).
89% With N-chloro-succinimide; sodium iodide In N,N-dimethyl-formamide at 80℃; To a four-port adding DMF flask (800 ml), by adding N-chloro succinimide (197.62g, 1 . 48mol), by a hot water bath or ice water bath temperature control, temperature control in the 30 °C, add NaI (221.84g, 1 . 48mol), stirring after adding 7.0h, then batch by adding 4-amino-pyrazolo [3,4-d] pyrimidine (100g, 0.74mol), suck, raising the temperature to 80 °C. HPLC central control, reaction is ended. After treatment, the reaction liquid by adding water, cooling to 0-5°C, filtering, drying, to obtain the product. Yield: 89percent, purity: 99.3percent (HPLC).
87.8% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 22 h; Inert atmosphere 1H-pyrazolo [3,4-d] pyrmidin-4-amine (20 g, 148.0 mmol, 1.0 eq) was placed in a three-necked flask. To the flask was added 150 mL of DMF (N, N-dimethylformamide), and the mixture was stirred and replaced with nitrogen 3 times. NIS (N-iodosuccinimide) (50 g, 222.0 mmol, 1.5 eq) was added and the solution was heated at 80° C. The reaction monitored by TLC was completed after 22 h, stopped and the DMF was concentrated to the remaining half of the solution. The mixture was stirred at 150 mL of saturated aqueous Na2S2O3 and filtered under reduced pressure. The filter cake was washed successively with saturated aqueous Na2S2O3 and water to colorless. The product was dried in vacuo to give the title product as a light yellow powder (33.9 g, 87.8percent yield). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H). MS m/z (ESI): 262.1 [M+H].
86% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; Inert atmosphere The 1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (953 mg, 7 . 055 mm, 1 . 0equiv), N-iodo succinimide (2.381g, 10 . 58 mm, 1 . 5equiv) suspended in N, N-dimethylformamide (15 ml) in, and in the nitrogen in 80 °C lower heating sleepovers. The reaction mixture is cooled to the room temperature, and make-up water (60 ml). Collecting solid, aqueous solution of saturated sodium sulfite are used, various washing water 2 times, and dried in air, to obtain white solid compound 2 (1.58g, yield 86percent).
84% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 2 h; Example 1. Synthesis of (i?)-l-('3-(4-Amino-3-('4-phenoxyphenyl)-lH- pyrazolo [3 A-d] pyrimidin- 1 -yQpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy 1 -one (Compound 122). Scheme 5. Preparation of Compound 122 35 36 Compound 122 [96] Step 1. 3-Iodo-lH-pyrazolo[3,4-^pyrimidin-4-amine (31). lH-Pyrazolo[3,4- d]pyrimidin-4-amine, 30 (5.0 g, 37 mmol, 1 equiv) was suspended in DMF (100 mL) and N-iodosuccinimide ( IS) (10.7 g, 45 mmol, 1.2 equiv) was added. The reaction was heated at 80 °C for 2 hours. The reaction was cooled to room temperature and then to 0 °C and was quenched by the drop-wise addition of water (200 mL). The resulting solids were collected by filtration, washed with water and cold ethanol, and dried in a vacuum oven to yield 31 (8.1 g, 84percent yield) as a beige solid. [97] Step 2. Phenoxyphenyl -lH-pyrazolo[3,4-< ]pyrimidin-4-amine (33). Compound 31 (4.0 g, 15.3 mmol, 1 equiv), boronic acid 32 (6.56 g, 30.7 mmol, 2 equiv), and potassium phosphate tribasic monohydrate (10.56 g, 45.9 mmol, 3 equiv) were dissolved in dioxane (50 mL) and water (20 mL). The mixture was sparged with nitrogen for 20 minutes and tetrakis(triphenylphosphine)palladium (2.70 g, 2.3 mmol, 0.15 equiv) was added. The mixture was sparged with nitrogen for an additional 5 minutes and then heated at reflux for 24 hours. The reaction was cooled to room temperature and stirred overnight, giving a beige precipitate. The reaction mixture was diluted with water (50 mL) and the solids were collected by filtration. The crude product was triturated with methanol (150 mL) to yield 3.9 g of 85percent pure product. The purity was further improved by trituration with ethyl acetate (100 mL), yielding 33 (3.6 g, 77percent yield, 90percent pure) as a beige solid. [98] Step 3. (R ert-Butyl 3-(4-amino-3-(4-phenoxyphenvn-lH-pyrazoror3.4- Compound 33 (1.80 g, 5.9 mmol, 1 equiv), protected piperidine, 34 (1.43 g, 7.1 mmol, 1.2 equiv), triphenylphosphine (2.33 g, 8.9 mmol, 1.5 equiv), and diisopropyl azodicarboxylate (1.80 g, 8.9 mmol, 1.5 equiv) were dissolved in THF (200 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (1 x 300 mL) and brine (1 x 300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel and purified using an Analogix automated chromatography system eluting with 0-8percent methanol in dichloromethane. All fractions containing product were combined and re- chromatographed using the above conditions to yield 35 (1.1 g, 38percent yield) as a white foam. [99] Step 4. (7?V3-(4-Phenoxyphenvn- 1 -(piperidin-3-νΠ- 1 //-pyrazoloH A- dlpyrimidin-4-amine hydrochloride (36). Compound 35 (700 mg, 1.48 mmol, 1 equiv) was dissolved in dioxane (8 mL). A solution of hydrogen chloride in dioxane (4 mL of a 4 N solution in dioxane, 16 mmol, 10.7 equiv) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with diethyl ether (20 mL) and the resulting solids were collected by filtration under a stream of nitrogen. The product was further dried in a vacuum oven to yield 36 (550 mg, 88percent yield) as an off-white solid. [100] Step 5. (_)- l-(3-(4-Amino-3-(4-phenoxyphenyl)- lH-pyrazolor3,4- ( Ipyrimidin- 1 -yDpiperidin- 1 -yl)prop-2-en-2,3 ,3 -dy- 1 -one (Compound 122). [101] A) DMF (0.003 mL, 0.03 mmol, 0.02 equiv) was added to commercially available acrylic acid-d4 (126 mg, 1.66 mmol, 1 equiv, 99 atom percent D) followed by oxalyl chloride (0.16 mL, 1.83 mmol, 1.1 equiv). The mixture was stirred for 30 minutes, at which point all gas evolution had ceased. The resulting acryloyl-d3 chloride (37) was used as such. [102] B) In a 20 mL vial, triethylamine (0.46 mL, 3.18 mmol, 3 equiv) was added to a suspension of 36 (450 mg, 1.06 mmol, 1 equiv) in dichloromethane (10 mL). The reaction was stirred for 15 minutes, resulting in a clear solution. Acryloyl-d3 chloride (37) (0.10 mL, 1.17 mmol, 1.1 equiv, prepared above) was then added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 5percent citric acid (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using an Analogix automated chromatography system eluting with 0-8percent methanol in dichloromethane. All fractions containing product were pooled and concentrated to give a colorless film which was dissolved in benzene/methanol (5 mL) and lyophilized to yield Compound 122 (170 mg, 36percent yield, [M+H]+ = 444.3) as a white powder.
80% With N-iodo-succinimide In N,N-dimethyl-formamide at 50℃; for 18 h; 1H-pyrazolo [3,4-d] pyrimidin-4-amine (12) (13.5 g, 0.1 mol) and N-iodosuccinimide (NIS) (25.8 g, 0.15 mol) In a three-necked flask, DMF (100 mL) was added, the temperature was raised to 50 ° C, and the reaction was carried out at 50 ° C for 18 hours(TLC test to confirm the disappearance of raw materials). Cooling to 0 ° C crystallization, filtration and drying to give intermediate (13) (yellow solid,20.9 g, yield 80percent).
77% With N-iodo-succinimide In N,N-dimethyl-formamide at 70℃; for 16 h; Example 1 :
Step 1 :
To the solution of 3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (5.4 g, 40.0 mmol) in DMF (100 mL) was added NIS (10.8 g, 48.0 mmol). The resulting mixture was then heated to 70°C and stirred for 16 h. Poured into ice water, the solid was collected by filtration, and washed with saturated aqueous Na2C03 solution and water. After drying, the desired product was obtained as yellow solid (9.3 g, 77percent).
77% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 12 h; Inert atmosphere 1H-[3,4-d]pyrazolopyrimidin-4-amine(5.3g, 39mmol) andN-Iodosuccinimide (13.3 g, 59 mmol) was suspended in N,N-dimethylformamide,The reaction was heated to 80°C under a nitrogen atmosphere for 12 hours.After the reaction is completed, it is cooled to room temperature, water is added, and a large amount of solids are precipitated and filtered with a Buchner funnel.Solids in turn with saturated sodium thiosulfate solution,Water and hot ethanol are washed twice each.The oil pump was drained to give 7.8 g of the target compound in a yield of 77percent.
73% With N-iodo-succinimide In N,N-dimethyl-formamide at 180℃; for 1 h; Microwave irradiation IH-pyrazolo[3 4-dJpynmidn4arnine (1 5g 1111 mmol) was suspended in 15 nil of DMF and Nodosuccnmde (1 2 eq 3 0 g 13 34 mmol) added The mixture was heated at 180 0C in the microwave for an hour. EtOH (80 m) was added to the reacUonand a precipitate began to fo rn, hich was aided by sonicaton The preuipitate wasfiltered and Washed with EtOH (x3, 20 ml) and aUowed to dry in an oven at 40 °Coveimghtto give a sand cooured soid (2115 g, 8105 mmol 730percent) ‘H NMR (500MHz, DMS06 13.80 (s, IN), 8.i(s, 1H) 7,796:.44 (m 2H);13C NMR (126 MHz,DM80) 6 157 60 (C) 156 08 CH) 155 04 (C), 102 50 (C), 89 82 (C) MS (ES +ve)[M+H)’: 283.9 (+Na), (ES -ye) [M-Hf: 259.9. 287.8 (+Na).
72% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 14 h; To a suspension of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (2.8 g, 20.7 mmol) in DMF (12 mL) was added N-iodosuccinimide (5.59 g, 24.8mrnol) at ambient temperature. The reaction mixture was heated to 80 °C and stirred for 14hr. The resulting solid was collected by filtration, rinsed with ice-cold ethanol (20 mL), and concentrated in vacuo to provide 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.9 g,72percent) as an off- white solid. MS m/z: 261.92 (M+1 ).
69% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; Inert atmosphere 87C : Compound 87B (700 mg, 5.18 mmol) and N-iodo-succinimide (1.75 g, 7.77 mmol) were dissolved in 12 mL of Ν,Ν-dimethylformamide and stirred at 80°C overnight under nitrogen atmosphere. The mixture was cooled and 30 mL of water were added. The resulting solid was filtered and rinsed with cold ethanol. The product was dried in vacuo. Compound 87C was obtained as a brown powder (935 mg, 69percent yield). NMR (ppm, DMSO): 8.17 (s, 1H). LCMS (+esi): 262.0 (M+H+).
69% With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 60℃; Step 1To a solution of lH-pyrazolo[3,4-d]pyrimidin-4-ylamine (3,0 g, 22.20 mmol, 1.0 eq) in DMF (30 mL), NIS (6.7g , 24.42 mmol, 1.1 eq) was added at room temperature. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature and 10 percent aq. NaHCOs (150 mL) was added to the reaction mixture. The solid was filtered and re-crystallization from DMF solvent to give 3-iodo- lH~pyrazo3o[3,4- d]pyrimidin-4-amme (4.0 g, 69 percent in yield).
69% With N-iodo-succinimide In N,N-dimethyl-formamide at 60℃; To a solution of 1H-pyrazoio[3,4-d]pyrimidin4’ylamine (3.0 g, 22.20 mrnol, 1.0 eq) in I)MF (30 mE), NIS (6.7g , 24.42 mmol, 1.1 eq) was added at room temperature. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature and 10 percent aq. NaHCO3 (150 added to the reaction mixture. The solid was filtered and recrystallization from DMF solvent to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin”amine (4.0 g, 69 percent in yield).
69% With N-iodo-succinimide In N,N-dimethyl-formamide at 60℃; Step 1. To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (3.0 g, 22.20 mmol, 1.0 eq) in DMF (30 mL), NIS (6.7g, 24.42 mmol, 1.1 eq) was added at room temperature. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to roomtemperature and 10 percent aq. NaHCO3 (150 mL) was added to the reaction mixture. The solid was filtered and re-crystallization from DMF solvent to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ammne (4.0 g, 69 percent in yield).
69% With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 60℃; Step 1
To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (3.0 g, 22.20 mmol, 1.0 eq) in DMF (30 mL), NIS (6.7 g, 24.42 mmol, 1.1 eq) was added at room temperature.
The reaction mixture was stirred overnight at 60° C.
The reaction mixture was cooled to room temperature and 10percent aq. NaHCO3 (150 mL) was added to the reaction mixture.
The solid was filtered and re-crystallization from DMF solvent to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.0 g, 69percent in yield).
69% With N-Iodosuccinamide In N,N-dimethyl-formamide at 80℃; for 20 h; A solution of commercially available 4-aminopyrazolo-(3,4-d)pyrimidine (3.36 g, 24.9 mmol) in 70 mL of DMF was treated with N-iodosuccinamide (8.39 g, 37.3 mmol) and stirred at 80°C for 20 h. The reaction mixture was cooled to room temperature and added into 70 mL ofice cold water. A brown precipitate formed, which was filtered and washed with ice cold ethanol. The resulting solid was dried under reduced pressure to give 3 -iodo- 1H-pyrazolo [3,4- d]pyrimidin-4-amine (4.50 g, 69percent), which was used directly in the next reaction.
54.1% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; Inert atmosphere 1 H-Pyrazolo[3,4-d]pyrimidin-4-amine (20. Og, 148.01 mmol) and /V-iodosuccinimide (60.61 g, 222.01 mmol) were combined in DMF (200mL) and the mixture heated to 80°C, under nitrogen, overnight. The bulk of the solvent was removed under reduced pressure and the residue was allowed to cool and stand for a couple of hours. The resultant material was stirred in warm water (250 ml), filtered off and washed with methanol (3 x 150 ml) to give 3-iodo-1 /-/-pyrazolo[3,4-c ]pyrimidin-4-amine (20.92g, 80.147mmol, 54.1 percent yield) LCMS (ES+, short acidic): ~0.35-0.65 min, m/z 262 [M+H]+ NMR (d6 DMSO): 13.8 (s, 1 H), 8.21 (s, 1 H), 7.20 (bs, 2H).
52% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 5 h; Step 2A mixture of lH-pyrazolo[3,4-d]pyrimidm-4-amine (150 g, 1.1 1 mo., 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80°C for 5 h. The reaction mixture was cooled to room temperature and then diluted with 10 L of water. The solid was collected by filtration, washed with 2 1 L of saturated aqueous sodium sulfite and dried under vacuum to give 50 g (52percent) of 3-iodo-lH- pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid.
52% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 5 h; Step 2A mixture of l H-pyrazolo[3,4-d]pyrimidin-4-amine (150 g, 1.1 1 mol, 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80°C for 5 h. The reaction mixture was cooled to room temperature and then diluted with 10 L of water. The solid was collected by filtration, washed with 2x1 L of saturated aqueous sodium sulfite and dried under vacuum to give 150 g (52percent) of 3-iodo-.H- pyrazolo[3,4~d]pyrimidin-4~amine as a yellow solid.
52% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 5 h; Step 2.
A mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 g, 1.11 mol, 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80° C. for 5 h.
The reaction mixture was cooled to room temperature and then diluted with 10 L of water.
The solid was collected by filtration, washed with 2*1 L of saturated aqueous sodium sulfite and dried under vacuum to give 150 g (52percent) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid.
48% With N-iodo-succinimide In N,N-dimethyl-formamide at 75℃; for 24 h; [0121] To a solution of R-1 (50.0 g, 0.37 mol) in DMF(350.0 mL) NIS (83.3 g, 0.37 mol) is added. The reactionmixture is heated to 75° C. for 24 h. The mixture is thencooled to room temperature and poured into water. The mixtureis filtered and the percipitate is washed with water, driedunder reduced pressure to afford compound I -1 ( 45.0 g, 48percent ).
150 g With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 5 h; A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (150 g, 1.1 1 mol, 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80°C for 5 h. The reaction mixture was cooled to room temperature and then diluted with 10 L of water. The solid was collected by filtration, washed with 2x1 L of saturated aqueous sodium sulfite, and dried under vacuum to give 150 g of 3-iodo-lH-pyrazolo[3,4- d]pyrimidin-4-amine as a yellow solid.
5.8 g With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 60℃; for 24 h; A solution lH-pyrazolo[3,4-d]pyrimidin-4-amine (5.0 g, 37 mmol, 1.00 eq) in DMF (50 mL) was cooled to 0 °C. To the solution was added NIS (6.1g, 38.9 mmol, 1.05 eq) portion wise. The reaction was heated at 60 °C for 24hours, then saturated sodium bicarbonate solution was added. The reaction was stirred for another 30 minutes , filtered and concentrated to dryness under vacuum to give 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid 5.8 g.
14 g With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 2 h; Inert atmosphere To a suspension of 1H-pyrazolo[3, 4-d]pyrimidin-4-amine (7.5 g, 55.50 mmol) in anhydrous DMF (50 mL) was added N-iodosuccinimide (49 g, 222.0 mmol) portionwise under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 2 h. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to RT and diluted with EtOAc (400 mL). Saturated aq. sodium thiosulfate solution (100 mL) was added, and a precipitate formed. The precipitate was collected by filtration, washed with additional amount of water, diethyl ether and then dried to obtain 14 g of 3-iodo- 1H-pyrazolo[3,4- d]pyrimidin-4-amine as an off-white solid.
4 g With N-iodo-succinimide In N,N-dimethyl-formamide at 100℃; for 4 h; 1H-Pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 14.8 mol) was charged in DMF (12 mL) and to this was added N-iodosuccinimide (6.3 g, 28.6 mmol). The reaction mixture was heated at 100 °C for 4 h. The solid obtained was filtered off and washed with cold EtOH (15 mL). The solid obtained was dried under vacuum to get (4 g) 3-iodo-1H-pyrazolo [3, 4-d]pyrimidin-4-amine.
26.8 g With N-iodo-succinimide In N,N-dimethyl-formamide at 75 - 80℃; for 16 h; A mixture of 1H-pyrazolo[3,4-djpyrimidin-4-amine (Formula II, 20 g), Niodosuccinimide (41.6 g) and dimethylformamide (300 mL) was stirred at 75°C to 80°C for 16 hours. Water (1 L) was added to the reaction mixture, and then the mixture wasstirred at 15°C for 4 hours. The solid obtained was filtered, then washed with water (100mL), and then washed with cold ethanol (60 mL). The resulting solid was dried at 45°C under vacuum for 16 hours to obtain the title compound.Yield: 26.8 g
26.8 g With N-iodo-succinimide In N,N-dimethyl-formamide at 75 - 80℃; for 16 h; Example 1 : Preparation of 3-iodo-lH-pyrazolor3.4-dlpyrimidin-4-amine (Formula III, when X is iodine) A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II, 20 g), N- iodosuccinimide (41.6 g), and dimethylformamide (300 mL) was stirred at 75°C to 80°C for 16 hours. Water (1 L) was added to the reaction mixture, and then the mixture was stirred at 15°C for 4 hours. The solid obtained was filtered, then washed with water (100 mL), and then washed with cold ethanol (60 mL). The resulting solid was dried at 45°C under vacuum for 16 hours to obtain the title compound. Yield: 26.8 g
16 g With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; Inert atmosphere Compound g (10, 1eq), NIS (25g, 2.5eq) and N,N-dimethylformamide (DMF) (100mL) were mixed and stirredovernight under nitrogen at 80 °C, and then cooled and poured into water (500mL). Solids were filtered out and washedsuccessively with saturated sodium bisulfite (50mL) and water (100mL), and then dried under vacuum for 10h at 50 °C,giving 16g of solid.

Reference: [1] Patent: US2007/293516, 2007, A1, . Location in patent: Page/Page column 12; 16
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 36, p. 10909 - 10912[3] Angew. Chem., 2016, vol. 128, p. 11069 - 11073,5
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 18, p. 7725 - 7744
[5] Patent: US2012/202785, 2012, A1, . Location in patent: Page/Page column 258
[6] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1161 - 1166
[7] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 96 - 112
[8] Patent: US2016/200730, 2016, A1, . Location in patent: Paragraph 0570; 0571
[9] Patent: WO2018/49127, 2018, A1, . Location in patent: Page/Page column 83
[10] Tetrahedron Letters, 2011, vol. 52, # 44, p. 5761 - 5763
[11] Patent: WO2010/6086, 2010, A2, . Location in patent: Page/Page column 78
[12] Patent: WO2010/51042, 2010, A1, . Location in patent: Page/Page column 128
[13] Patent: US2014/357651, 2014, A1, . Location in patent: Paragraph 0460; 0482
[14] Patent: US2016/789, 2016, A1, . Location in patent: Paragraph 0320; 0321
[15] Patent: WO2018/89786, 2018, A1, . Location in patent: Paragraph 00156
[16] Patent: WO2007/126841, 2007, A2, . Location in patent: Page/Page column 69
[17] Patent: WO2011/94628, 2011, A1, . Location in patent: Page/Page column 99
[18] Journal of Medicinal Chemistry, 2012, vol. 55, # 10, p. 4872 - 4876
[19] Patent: CN105777755, 2016, A, . Location in patent: Paragraph 0022; 0023
[20] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157
[21] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9788 - 9805
[22] Patent: US2017/305920, 2017, A1, . Location in patent: Paragraph 0145; 0146
[23] Patent: CN105315283, 2016, A, . Location in patent: Paragraph 0105; 0109; 0110; 0111
[24] Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4590 - 4609
[25] Patent: WO2014/22390, 2014, A1, . Location in patent: Paragraph 95; 96
[26] Patent: CN104557945, 2017, B, . Location in patent: Paragraph 0045; 0046; 0047
[27] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 2165 - 2172
[28] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4518 - 4522
[29] Patent: WO2015/18333, 2015, A1, . Location in patent: Page/Page column 22
[30] Patent: CN107759602, 2018, A, . Location in patent: Paragraph 0231-0233
[31] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9625 - 9638
[32] Patent: WO2016/185160, 2016, A1, . Location in patent: Page/Page column 48
[33] Patent: WO2014/63061, 2014, A1, . Location in patent: Paragraph 00336
[34] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3424 - 3430
[35] Organic and Biomolecular Chemistry, 2014, vol. 12, # 28, p. 5158 - 5167
[36] Patent: WO2012/3544, 2012, A1, . Location in patent: Page/Page column 102
[37] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 219
[38] Patent: WO2013/191965, 2013, A1, . Location in patent: Page/Page column 156; 194
[39] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 49; 99
[40] Patent: US8673925, 2014, B1, . Location in patent: Page/Page column 244
[41] Patent: WO2014/176348, 2014, A1, . Location in patent: Page/Page column 65
[42] Patent: WO2014/188173, 2014, A1, . Location in patent: Paragraph 00205
[43] Patent: WO2012/158795, 2012, A1, . Location in patent: Page/Page column 76
[44] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 165
[45] Patent: US2014/323464, 2014, A1, . Location in patent: Paragraph 0430
[46] Patent: US2014/275014, 2014, A1, . Location in patent: Paragraph 0119; 0120; 0121
[47] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 12, p. 1687 - 1690
[48] Patent: WO2009/62118, 2009, A2, . Location in patent: Page/Page column 166
[49] Patent: US2010/144705, 2010, A1, . Location in patent: Page/Page column 25
[50] Patent: WO2011/119663, 2011, A1, . Location in patent: Page/Page column 153
[51] ChemMedChem, 2013, vol. 8, # 10, p. 1673 - 1680
[52] Patent: WO2014/39899, 2014, A1, . Location in patent: Page/Page column 50
[53] Patent: WO2014/187319, 2014, A1, . Location in patent: Paragraph 0051
[54] Patent: WO2015/58084, 2015, A1, . Location in patent: Paragraph 0206; 0242
[55] Patent: WO2015/69441, 2015, A1, . Location in patent: Paragraph 0209; 0217; 0191
[56] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4697 - 4710
[57] Patent: WO2016/79693, 2016, A1, . Location in patent: Page/Page column 24; 25
[58] Patent: WO2016/151438, 2016, A1, . Location in patent: Page/Page column 10
[59] Patent: JP2015/113286, 2015, A, . Location in patent: Paragraph 0015; 0016
[60] Patent: WO2016/132383, 2016, A1, . Location in patent: Page/Page column 22
[61] Patent: WO2016/187723, 2016, A1, . Location in patent: Page/Page column 51
[62] Patent: WO2017/161344, 2017, A1, . Location in patent: Paragraph 0813; 0819
[63] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9976 - 9989
[64] Patent: EP3398950, 2018, A1, . Location in patent: Paragraph 0055; 0058
  • 13
  • [ 516-12-1 ]
  • [ 2380-63-4 ]
  • [ 151266-23-8 ]
YieldReaction ConditionsOperation in experiment
86% at 80℃; for 12 h; Pyrazolo [3,4-d] pyrimidin-4-amine (15.0 g, 111.1 mmol) was dissolved in DMF (150 mL) N-iodosuccinimide (37.5 g, 166. 6 mmol) was slowly added to the reaction mixture, and the reaction was stirred at 80 ° C for 12 h. stopWater (40 mL) was added to the reaction mixture, and the mixture was suction filtered. The solid was washed with water (80 mL), ethanol (60 mL) and dried to give to a yellow solid (24. 9 g, 86percent).
Reference: [1] Patent: CN105399756, 2016, A, . Location in patent: Paragraph 0155; 0165-0166
[2] Patent: CN105859728, 2016, A, . Location in patent: Paragraph 0073; 0074
  • 14
  • [ 2380-63-4 ]
  • [ 862730-04-9 ]
Reference: [1] Patent: WO2011/94628, 2011, A1,
[2] Patent: WO2011/119663, 2011, A1,
[3] Patent: US2016/789, 2016, A1,
[4] Patent: US2017/305920, 2017, A1,
  • 15
  • [ 2380-63-4 ]
  • [ 1022150-11-3 ]
Reference: [1] Patent: WO2012/158795, 2012, A1,
[2] Patent: WO2013/191965, 2013, A1,
[3] Patent: WO2013/191965, 2013, A1,
[4] Patent: WO2014/22569, 2014, A1,
[5] Patent: WO2014/22569, 2014, A1,
[6] Patent: WO2014/22390, 2014, A1,
[7] Patent: US8673925, 2014, B1,
[8] Patent: US8673925, 2014, B1,
[9] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157
[10] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9625 - 9638
[11] Patent: WO2016/151438, 2016, A1,
[12] Patent: WO2016/151438, 2016, A1,
[13] Patent: CN105399756, 2016, A,
[14] Patent: CN104557945, 2017, B,
[15] Patent: CN107759602, 2018, A,
Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 2380-63-4 ]

Ibrutinib Related Intermediates

Chemical Structure| 51067-38-0

[ 51067-38-0 ]

(4-Phenoxyphenyl)boronic acid

Chemical Structure| 2215-77-2

[ 2215-77-2 ]

4-Phenoxybenzoic acid

Chemical Structure| 1022150-11-3

[ 1022150-11-3 ]

(R)-tert-Butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate

Chemical Structure| 330786-24-8

[ 330786-24-8 ]

3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Chemical Structure| 151266-23-8

[ 151266-23-8 ]

3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Related Functional Groups of
[ 2380-63-4 ]

Amines

Chemical Structure| 287177-82-6

[ 287177-82-6 ]

1H-Pyrazolo[3,4-d]pyrimidin-6-amine

Similarity: 0.89

Chemical Structure| 5417-78-7

[ 5417-78-7 ]

6-Chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Similarity: 0.84

Chemical Structure| 151266-23-8

[ 151266-23-8 ]

3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Similarity: 0.83

Chemical Structure| 100644-65-3

[ 100644-65-3 ]

4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Similarity: 0.76

Chemical Structure| 862730-04-9

[ 862730-04-9 ]

3-Iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Similarity: 0.70

Related Parent Nucleus of
[ 2380-63-4 ]

Other Aromatic Heterocycles

Chemical Structure| 287177-82-6

[ 287177-82-6 ]

1H-Pyrazolo[3,4-d]pyrimidin-6-amine

Similarity: 0.89

Chemical Structure| 5417-78-7

[ 5417-78-7 ]

6-Chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Similarity: 0.84

Chemical Structure| 151266-23-8

[ 151266-23-8 ]

3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Similarity: 0.83

Chemical Structure| 23002-51-9

[ 23002-51-9 ]

6-Chloro-1H-pyrazolo[3,4-d]pyrimidine

Similarity: 0.77

Chemical Structure| 1251033-27-8

[ 1251033-27-8 ]

3-Bromo-1H-pyrazolo[3,4-d]pyrimidine

Similarity: 0.76