Home Cart 0 Sign in  
X

[ CAS No. 3469-69-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 3469-69-0
Chemical Structure| 3469-69-0
Chemical Structure| 3469-69-0
Structure of 3469-69-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 3469-69-0 ]

Related Doc. of [ 3469-69-0 ]

Alternatived Products of [ 3469-69-0 ]

Product Details of [ 3469-69-0 ]

CAS No. :3469-69-0 MDL No. :MFCD00005244
Formula : C3H3IN2 Boiling Point : -
Linear Structure Formula :- InChI Key :LLNQWPTUJJYTTE-UHFFFAOYSA-N
M.W : 193.97 Pubchem ID :77022
Synonyms :

Calculated chemistry of [ 3469-69-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.3
TPSA : 28.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.69
Log Po/w (XLOGP3) : 0.87
Log Po/w (WLOGP) : 1.01
Log Po/w (MLOGP) : 0.61
Log Po/w (SILICOS-IT) : 2.24
Consensus Log Po/w : 1.08

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.21
Solubility : 1.2 mg/ml ; 0.0062 mol/l
Class : Soluble
Log S (Ali) : -1.06
Solubility : 17.0 mg/ml ; 0.0878 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.19
Solubility : 1.26 mg/ml ; 0.00649 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.86

Safety of [ 3469-69-0 ]

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

Application In Synthesis of [ 3469-69-0 ]

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

  • Upstream synthesis route of [ 3469-69-0 ]
  • Downstream synthetic route of [ 3469-69-0 ]

[ 3469-69-0 ] Synthesis Path-Upstream   1~29

  • 1
  • [ 288-13-1 ]
  • [ 3469-69-0 ]
YieldReaction ConditionsOperation in experiment
91% With ammonium cerium(IV) nitrate; iodine In acetonitrile at 20℃; for 2.5 h; EXAMPLE 1; Preparation of 2-Amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-4-imidazol-4-one; Step a); Preparation of Compound 2; A mixture of pyrazole (3.00 g, 44.0 mmol), iodine (6.71 g, 26.4 mmol) and ceric ammonium nitrate (14.5 g, 26.4 mmol) in acetonitrile (400 mL) was stirred at room temperature for 2.5 h. The reaction was concentrated and partitioned between ethyl acetate (250 mL) and 5percent aqueous sodium bisulfite (250 mL). Water (150 mL) was added and the organic layer was separated and washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated to afford 2 (7.80 g, 91percent) as a white solid: mp 105-108° C.; 1H NMR (300 MHz, CDCl3) δ7.63 (s, 2H).
90% at 70℃; for 1 h; Raw material Pyrazole (10g) was mixed with ethanol (10 g), and iodine (22.4 g) was added in portions, (20 ° C to 30 ° C), 30percent hydrogen peroxide (16.7 g) was added dropwise, the control temperature was not higher than 70 ° C, the stirring was continued for 1 hour, the TLC was followed by the reaction, 10 g of saturated aqueous sodium bisulfite solution was added, After filtration for 1 hour, the white solid was filtered and the cake was washed with water. The filtrate was concentrated, solidified and re-filtered. The filter cake was dried and weighed 25.7g, GC purity: 99percent
89%
Stage #1: With sulfuric acid; iodine; iodic acid In acetic acid at 60℃;
Stage #2: With sodium hydrogencarbonate; sodium carbonate In acetic acid
4-lodopyrazole (1); [00188] A mixture of iodic acid (3.6g 20mmole), iodine (10.2g 40mmole), 30percent w/w sulfuric acid (4ml_) and acetic acid (30ml_) was stirred to give a solution/suspension. About half of this mix was added in portions to a solution of pyrazole (6.8g, 100 mmole) in acetic acid (60ml_) maintained at 60°C. The colour was allowed to fade after each addition before adding the next aliquot. The rest of the solution/suspension was added in one portion and the mix stirred and heated at 60°C for another 1 .75 hours. The final mix still had an iodine colour. The reaction was cooled and added to saturated sodium hydrogen carbonate (100ml_). Sodium carbonate solution (200ml of a 15percent solution) was added carefully and then solid sodium carbonate was added until there was no more carbon dioxide evolved. The product was extracted with chloroform (3x60ml_) and the combined extracts were washed with water (50ml_). The extracts were dried and evaporated and the solid obtained was dried in vacuum over sodium hydroxide to give the title compound (17.4g, 89percent), spectroscopic data for which was consistent with data reported in G.Zoppellaro, A.Geiss, V.Enkelmann, M.Baumgarten, Eur. J.Org.Chem., 2004, 2367-2374.
89% at 60℃; for 1.75 h; 4-Iodopyrazole (1) [0622] A mixture of iodic acid (3.6 g 20 mmole), iodine (10.2 g 40 mmole), 30percent w/w sulfuric acid (4 mL) and acetic acid (30 mL) was stirred to give a solution/suspension. About half of this mix was added in portions to a solution of pyrazole (6.8 g, 100 mmole) in acetic acid (60 mL) maintained at 60° C. The colour was allowed to fade after each addition before adding the next aliquot. The rest of the solution/suspension was added in one portion and the mix stirred and heated at 60° C. for another 1.75 hours. The final mix still had an iodine colour. The reaction was cooled and added to saturated sodium hydrogen carbonate (100 mL). Sodium carbonate solution (200 ml of a 15percent solution) was added carefully and then solid sodium carbonate was added until there was no more carbon dioxide evolved. The product was extracted with chloroform (3×60 mL) and the combined extracts were washed with water (50 mL). The extracts were dried and evaporated and the solid obtained was dried in vacuum over sodium hydroxide to give the title compound (17.4 g, 89percent), spectroscopic data for which was consistent with data reported in G. Zoppellaro, A. Geiss, V. Enkelmann, M. Baumgarten, Eur. J. Org. Chem., 2004, 2367-2374.
89% With iodine; n-butyltriphenylphosphonium peroxodisulfate In water; acetonitrile at 20℃; for 2 h; n-Butyltriphenylphosphonium peroxodisulfate (0.5 mmol) was added in small portions to a solution of pyrazole (1 mmol) and iodine (0.6 mmol) in CH3CN/H2O (10 : 2 mL) in a 50 mL round-bottome flask equipped with a magnetic stirrer. The reaction mixture was stirred at ambient temperature for the appropriate time (see table). Upon completion of the reaction, as indicated by TLC, the reaction mixture was poured into an aqueous sodium thiosulfate solution (1 M) and extracted with diethyl ether (3 × 15 mL). The combined organic layers were dried over MgSO4. The solvent was concentrated in vacuo, the resulting product was purified on silica gel using column chromategraphy (diethyl ether : n-hexane = 1 : 4) to afford the pure compound. 4-Iodo-1H-pyrazole (1). Yield 89percent, mp 109–110°C. 13 NMR spectrum, δ, ppm: 57.6, 138.8. Found, percent:C 18.6, H 1.57, N 14.40. C3H3IN2. Calculated, percent. C18.57, H 1.56, N 14.43.
88.6% With N-iodo-succinimide In tetrahydrofuran at 10 - 20℃; Inert atmosphere 4-Iodopyrazole (14).; A flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was charged with pyrazole (13, 450 g, 6.62 mol) and tetrahydrofuran (5 L). The mixture was cooled to 10° C. and N-iodosuccinimide (NIS, 1490 g, 6.62 mol, 1.0 equiv) was added in portions as a solid. The reaction mixture (slight suspension) was stirred at room temperature for 1 hour (longer reaction times may be necessary depending on ambient temperature). The mixture was then filtered and the THF was removed under reduced pressure. The residue was suspended in ethyl acetate (6 L) and insoluble materials were filtered. The dark filtrate was sequentially washed with aqueous saturated sodium thiosulfate solution (2.x.3 L) (organic layer lightens to a pale yellow), water (2.x.3 L), and brine (2 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-iodopyrazole (14, 1138 g, 1284.1 g theoretical, 88.6percent) as white to pale yellow solids after being dried in a vacuum oven at 30° C. overnight. For 14: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.17 (bs, 1H), 7.93 (bs,1H), 7.55 (bs,1H); C3H3IN2 (MW, 193.97), LCMS (EI) m/e 195 (M++H).
88.6% With N-iodo-succinimide In tetrahydrofuran at 10 - 20℃; for 1 h; 4-Iodopyrazole (20) [0159] A flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and a mechanical stirrer was charged with pyrazole (1, 450 g, 6.62 mol) and tetrahydrofuran (THF, 5 L) at ambient temperature. The mixture was then cooled to 10° C. and N-iodosuccinimide (NIS, 1490 g, 6.62 mol, 1.0 equiv) was added to the mixture in portions as a solid at approximately 10° C. The resulting reaction mixture was then stirred at ambient temperature for 1 hour (longer reaction times may be necessary depending on ambient temperature). The mixture was then filtered and the THF was removed under reduced pressure. The residue was suspended in ethyl acetate (6 L) and insoluble materials were filtered. The dark filtrate was sequentially washed with saturated aqueous sodium thiosulfate solution (2×3 L) (organic layer lightens to a pale yellow), water (2×3 L), and brine (2 L). The resulting organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-iodopyrazole (1138 g, 1284.1 g theoretical, 88.6percent) as a white to pale yellow solid after being dried in a vacuum oven at approximately 30° C. overnight. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (bs, 1H), 7.93 (bs, 1H), 7.55 (bs, 1H) ppm; C3H31N2 (MW, 193.97), LCMS (EI) m/e 195 (M++H).
85% With dihydrogen peroxide; iodine In water at 20℃; To a solution of pyrazole 34d (25.53 g, 375 mmol) and iodine (47.6 g, 187.5 mmol) in water (135 mL) was added 30percent H202 (25.8 mL, 225 mmol). The mixture was stirred at room temperature overnight. A cold solution of 5percent NaHS03 (100 mL) was added to the reaction mixture, affording an off-white slurry. The product was filtered and washed with water to give 4-iodo-lH-pyrazole 34e (61.9 g 85 percent), as off-white solid; mp 86.8 °C; NMR (300 MHz, CDC13) δ 9.20 (bs, 1H), 7.63 (s, 2H); 13C NMR (75 MHz, CDC13) δ 138.75, 138.75, 56.50 ; Analysis: Calculated for C3H3rN2: C, 18.58; H, 1.56; N, 14.44; Found: C, 18.70; H, 1.49; N, 14.41.

Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 5, p. 863 - 865
[2] Heterocycles, 2003, vol. 60, # 4, p. 879 - 886
[3] Journal of Organic Chemistry, 2003, vol. 68, # 21, p. 8075 - 8079
[4] Tetrahedron Letters, 2001, vol. 42, # 11, p. 2089 - 2092
[5] Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 360 - 367[6] Izv. Akad. Nauk, Ser. Khim., 2014, # 2, p. 360 - 367
[7] Patent: US2007/4786, 2007, A1, . Location in patent: Page/Page column 13-14
[8] Chimia, 2016, vol. 70, # 10, p. 704 - 708
[9] Patent: CN103601749, 2016, B, . Location in patent: Paragraph 0021; 0025-0028
[10] Patent: WO2012/123745, 2012, A1, . Location in patent: Page/Page column 63
[11] Patent: US2013/345181, 2013, A1, . Location in patent: Paragraph 0621-0622
[12] Russian Journal of General Chemistry, 2016, vol. 86, # 8, p. 1931 - 1934[13] Zh. Obshch. Khim., 2016, vol. 86, # 8, p. 1931 - 1934,4
[14] Organic Letters, 2004, vol. 6, # 26, p. 4929 - 4932
[15] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 102-103
[16] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0159
[17] Synthetic Communications, 2011, vol. 41, # 16, p. 2430 - 2434
[18] Journal fuer Praktische Chemie (Leipzig), 1989, vol. 331, # 5, p. 799 - 805
[19] Patent: WO2011/31554, 2011, A2, . Location in patent: Page/Page column 148
[20] Molecules, 2005, vol. 10, # 2, p. 401 - 406
[21] Angewandte Chemie - International Edition, 2013, vol. 52, # 32, p. 8290 - 8294[22] Angew. Chem., 2013, vol. 125, # 32, p. 8448 - 8452,5
[23] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507
[24] Tetrahedron Letters, 2008, vol. 49, # 25, p. 4026 - 4028
[25] Chemistry - A European Journal, 2015, vol. 21, # 47, p. 16801 - 16806
[26] Russian Chemical Bulletin, 2010, vol. 59, # 8, p. 1549 - 1555
[27] Monatshefte fur Chemie, 2012, vol. 143, # 4, p. 619 - 623
[28] Chemical Communications, 2015, vol. 51, # 34, p. 7305 - 7308
[29] Synlett, 2003, # 12, p. 1895 - 1897
[30] Synthesis, 1995, # 8, p. 926 - 928
[31] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 200 - 207
[32] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5164 - 5170
[33] Polyhedron, 2012, vol. 47, # 1, p. 151 - 164
[34] Russian Chemical Bulletin, 2013, vol. 62, # 4, p. 1044 - 1051[35] Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 4, p. 1043 - 1050,8
[36] Heterocycles, 2018, vol. 96, # 7, p. 1203 - 1215
  • 2
  • [ 2075-45-8 ]
  • [ 3469-69-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 1, p. 263 - 266[2] Angew. Chem., 2015, vol. 127, # 01, p. 265 - 268,4
  • 3
  • [ 288-13-1 ]
  • [ 3469-69-0 ]
  • [ 6645-70-1 ]
Reference: [1] Russian Journal of General Chemistry, 2016, vol. 86, # 8, p. 1931 - 1934[2] Zh. Obshch. Khim., 2016, vol. 86, # 8, p. 1931 - 1934,4
  • 4
  • [ 28466-26-4 ]
  • [ 3469-69-0 ]
Reference: [1] Chemische Berichte, 1904, vol. 37, p. 3501
  • 5
  • [ 3469-69-0 ]
  • [ 74-88-4 ]
  • [ 39806-90-1 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere
Stage #2: for 12 h;
Under an atmosphere of nitrogen a solution of 4-iodo-1H-pyrazole (1.58 g; 8.0 mmol) in anhyd. THF wasadded dropwise to a freshly prepared suspension of sodium hydride (0.21 g; 8.7 mmol). The reactionmixture was stirred for 3 h and then 1.0 mL of methyl iodide (2.24 g; 15.8 mmol) was added dropwise.The mixture was stirred for additional 12 h and quenched by adding approximately 50 mL of water. Thecrude product was extracted with Et2O and dried over sodium sulfate. After evaporation of the solvent theproduct was obtained as a yellowish solid. Yield: 1.64 g (98percent)
95% at 20℃; for 96 h; To a solution of 4-iodopyrazole (1.3 g, 6.8 mmol) in dioxane (10 mL) was added iodomethane (0.42 mL, 6.8 mmol) and the resulting mixture stirred at room temperature for 96 h.
The mixture was concentrated in vacuo and the residue mixed with methylene chloride and filtered.
The filtrate was concentrated in vacuo to provide 1.35 g (95percent) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.47 (s, 1H), 7.38 (s, 1H), 3.90 (s, 3H).
95.9%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.166667 h; Inert atmosphere
Stage #2: at 20℃; for 22 h; Inert atmosphere
To a solution of 4-iodo-1H-pyrazole (3.88 g, 20 mmol) in DMF (50 mL) was addedNaH (1.66 g, 55.33 mmol, 80percent dispersion in mineral oil) at 0°C under N2 atmosphere. Thereaction was stirred at 0°C for 10 min followed by the addition of CH3I (2.5 mL, 38.76 mmol)slowly. The mixture was stirred at rt for 22 h, then quenched with H20 (100 mL) and extractedwith EtOAc (200 mL). The organic phase was dried over anhydrous Na2S04 and concentrated invacuo to give the title compound as a pale yellow solid (3.99 g, 95.9percent). The title compound wascharacterized by LC-MS as shown below:LC-MS (ESI, pos. ion) m/z: 209 [M+Ht.
95.9%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.166667 h; Inert atmosphere
Stage #2: at 20℃; for 22 h;
Under the protection of nitrogen, the 4-iodo -1H-pyrazole (3.88g, 20mmol) dissolved in DMF (50 ml) in, cooling to 0 °C, adding NaH (1.66g, 55 . 33mmol, in 80percent dispersion in mineral oil), mixture in 0 °C stirring 10 minutes, to continue to slowly adding the CH 3 I (2.5 ml, 38 . 76mmol). Reaction solution stirring the mixture at room temperature for 22 hours later, water (100 ml) quenching, and using EtOAc (200 ml) extraction. Organic phase Na 2 SO 4 drying, concentrating under reduced pressure, to obtain the title compound as a buff solid (3.99g, 95.9percent).
85% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 17 h; 1-Methyl-4-iodopyrazole (18)[00203] 4-lodopyrazole (1 ); (5.0g 25.7mmole) was dissolved in DMF (50ml_), potassium carbonate (4.26g 30.9mmole) was added and stirred (2 mins) before iodomethane (1 .76ml_, 4.01 g 28.3mmole) was added. The reaction was stirred rapidly at r.t. for 17 hrs. It was filtered through a Celite pad. The filtrate was evaporated to a small volume, about 10ml_, using a rotary evaporator with a high vac. pump and the water bath at 60°C. Water (120ml_) was added to the residue. The filtered solids on the Celite pad were washed with ethyl acetate (50ml) and these washings were used to extract the product from the aqueous. The aqueous was extracted with more ethyl acetate (2x50ml_). The combined organics were washed with water (3x30ml_) and with brine; dried and evaporated to give the title compound as a solid 4.56g, 85percent. 1 H-NMR (CDCI3, 500MHz): δ 3.93 (s, 3H) 7.42 (s, 1 H), 7.50 (s, 1 H).
85%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.0333333 h;
Stage #2: at 20℃; for 17 h;
1-Methyl-4-iodopyrazole (18)
4-Iodopyrazole (1) (5.0 g 25.7 mmole) was dissolved in DMF (50 mL), potassium carbonate (4.26 g 30.9 mmole) was added and stirred (2 mins) before iodomethane (1.76 mL, 4.01 g 28.3 mmole) was added.
The reaction was stirred rapidly at r.t. for 17 hrs.
It was filtered through a Celite pad.
The filtrate was evaporated to a small volume, about 10 mL, using a rotary evaporator with a high vac.
pump and the water bath at 60° C. Water (120 mL) was added to the residue.
The filtered solids on the Celite pad were washed with ethyl acetate (50 ml) and these washings were used to extract the product from the aqueous.
The aqueous was extracted with more ethyl acetate (2*50 mL).
The combined organics were washed with water (3*30 mL) and with brine; dried and evaporated to give the title compound as a solid 4.56 g, 85percent. 1H-NMR (CDCl3, 500 MHz): δ 3.93 (s, 3H) 7.42 (s, 1H), 7.50 (s, 1H).
45%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃;
To a suspension of NaH (0.463 g, 15.47 mmol, 80percent NaH/mineral oil) in DMF (100 mL) was added 4-iodo-pyrazole (1.0 g, 5.16 mmol) at 0 °C under N2 atmosphere, the mixture was stirred at 0 °C for 30 minutes, then iodomethane (0.64 mL, 10.31 mmol, d = 2.28) was added. The resulted mixture was warmed to rt and stirred overnight, then quenched with brine (100 mL), and concentrated in vacuo. The residue was diluted with EtOAc (200 mL) and washed with water (100 mL). The separated organic phase was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a light yellowish solid (490 mg, 45percent). NMR (400 MHz, CDCb): δ 7.48 (s, 1H), 7.40 (s, 1H), 3.91 (s, 3H).
45%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
NaH (0.463 g, 15.47 mmol, 80percent NaH / mineral oil)Suspended in DMF (100 mL)Cooled to 0 ° C,Then under the protection of nitrogen,To the reaction solution was added 4-iodopyrazole (1.0 g, 5.16 mmol),After stirring at 0 ° C for 30 minutes,Further iodomethane (0.64 mL, 10.3 lmmo 1, d = 2.28) was added,Warmed to room temperature, stirred overnight,The reaction was then quenched by the addition of brine (100 mL)The residue was diluted with EtOAc (200 mL), washed with water (100 mL), separated and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 2/1) The title compound was a light yellow solid (490 mg, 45percent)
15 g With potassium carbonate In acetone at 20℃; General procedure: Step 1:
1-methyl-4-iodopyrazole
1H-4-iodopyrazole (20 g), potassium carbonate (28.45 g) and acetone (120 mL) were added into a round bottomed flask (250 mL) and agitated for 10 min.
Then iodomethane (17.56 g) was added and the mixture was agitated at room temperature over night.
After that, the mixture was filtrated and concentrated, the residue was recrystallized from n-hexane to prodce 1-methyl-1H-4-iodopyrazole (15 g) as white acicular crystal.
1H-NMR (300Hz, CDCl3) δ: 7.48 (s, 1H), 7.40 (s, 1H), 3.92 (s, 3H).
2.1 g With potassium carbonate In acetonitrile for 12 h; Reflux 4-iodopyrazole (2g, 10.3mmol), potassium carbonate (2.14g),Methyl iodide (1.72 g) and 25 mL acetonitrile,The reaction was refluxed for 12 h. Spin dry under reduced pressure and add 50 mL of water.Extracted three times with 50 mL of ethyl acetate, and the organic layers were combined.The organic layer was dried over anhydrous Na 2 SO 4 and dried under reduced pressure.1-Methyl-4-iodopyrazole (2.1 g) was obtained.

Reference: [1] Heterocycles, 2018, vol. 96, # 7, p. 1203 - 1215
[2] Patent: US6797723, 2004, B1, . Location in patent: Page/Page column 97
[3] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0186
[4] Patent: CN103539777, 2016, B, . Location in patent: Paragraph 0455;0456
[5] Patent: WO2012/123745, 2012, A1, . Location in patent: Page/Page column 70
[6] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 10045 - 10065
[7] Patent: US2013/345181, 2013, A1, . Location in patent: Paragraph 0637
[8] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6628 - 6639
[9] Patent: WO2014/193647, 2014, A2, . Location in patent: Paragraph 0276
[10] Patent: CN104119331, 2018, B, . Location in patent: Paragraph 0790; 0791; 0793; 0794
[11] Patent: EP2650293, 2013, A1, . Location in patent: Paragraph 0072; 0073; 0074
[12] Patent: CN108484609, 2018, A, . Location in patent: Paragraph 0155; 0158
[13] Patent: US2018/312523, 2018, A1, . Location in patent: Paragraph 1800; 1801
  • 6
  • [ 3469-69-0 ]
  • [ 74-87-3 ]
  • [ 39806-90-1 ]
YieldReaction ConditionsOperation in experiment
80% at 30 - 45℃; 4-iodopyrazole (20 g) and ethanol (100 ml) were added and stirred uniformly. KOH (11.6 g) and KI (0.9 g) were added and the methyl chloride gas was introduced into the liquid surface, Control temperature 30_45 ° C, GC tracking reaction end, add water 100g, dichloromethane extraction (40gX3), Concentrated to no flow liquid, with n-heptane 6ml beating, suction filter white solid, dry, weighing 17.2g, GC purity 98percent, yield 80percent;
Reference: [1] Patent: CN103601749, 2016, B, . Location in patent: Paragraph 0029-0030
  • 7
  • [ 3469-69-0 ]
  • [ 2075-46-9 ]
YieldReaction ConditionsOperation in experiment
72% With nitric acid In tetrahydrofuran; water at 20℃; for 3.5 h; General procedure: To iodopyrazole (1 mmol) dissolved in THF (10 mL), Fuajasite (250 mg) was added. Nitric acid (d 1.52 g/cm3, 10 mL) was added slowly and the mixture was stirred at room temperature for required time. The catalyst was recovered by filtration and the filtrate was extracted repeatedly with dichloromethane. The solvent was removed under vacuum to obtain nitropyrazole.
Reference: [1] Synthetic Communications, 2012, vol. 42, # 23, p. 3463 - 3471
[2] Catalysis Communications, 2013, vol. 42, p. 35 - 39
  • 8
  • [ 3469-69-0 ]
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 51105-90-9 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 115, p. 94776 - 94785
  • 9
  • [ 3469-69-0 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 37622-90-5 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 115, p. 94776 - 94785
  • 10
  • [ 3469-69-0 ]
  • [ 100-39-0 ]
  • [ 50877-42-4 ]
YieldReaction ConditionsOperation in experiment
97% With potassium carbonate In acetone for 3 h; Heating / reflux To a stirred suspension of 4-iodo-lH-pyrazole (1.50 g, 7.73 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in acetone was added benzyl bromide (0.96 mL, 8.07 mmol) and the reaction was refluxed for 3 h. After cooling to room temperature the mixture was concentrated onto silica gel in vacuo and eluted through a short silica plug (sequential elution - hexane, 10percent diethyl ether in hexanes) to provide the title compound as a white solid (2.12 g, 97percent yield). Literature reference - Tetrahedron Letters, 2001, p863.
80% With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Step 1. 1-Benzyl-4-iodo-1H-pyrazole; A 250-mL round-bottomed flask was charged with 4-iodo-1H-pyrazole (17 g, 87.63 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) To this was added sodium hydride (3.6 g, 105.00 mmol, 1.20 equiv, 70percent) in several batches at 0° C., followed by addition of 1-(bromomethyl)benzene (16.5 g, 96.49 mmol, 1.10 equiv) dropwise at 0° C. The resulting solution was allowed to warm up to room temperature and stirred for 2 hours at room temperature. The reaction was then quenched by the addition of water/ice (200 mL). The resulting solution was extracted with ethyl acetate (3.x.200 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 1-benzyl-4-iodo-1H-pyrazole as yellow solid (22 g, 80percent).
68% With potassium carbonate In acetone for 3 h; Reflux To a solution of 4-iodo-1H-pyrazole (1.40 g, 7.20 mmol) in actone (20 mL) were added (bromomethyl) benzene (1.44 g, 8.42 mmol) and potassium carbonate (2.80 g, 20.00 mmol) at rt. The mixture was refluxed for 3 h. The mixture was cooled to rt and filtered through a Celite pad. The filter cake was washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 5/1 to give a white solid product (1.40 g, 68.0) .[1084]MS (ESI, pos. ion) m/z: 285.1 [M+1]+ and[1085]1H NMR (400 MHz, CDCl3) : δ (ppm) 7.57 (s, 1H) , 7.42 (s, 1H) , 7.41-7.31 (m, 3H) , 7.27-7.20 (m, 2H) , 5.32 (s, 2H)
59%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h;
Stage #2: at 20℃; for 2 h;
a) 1-Benzyl-4-iodo- 1H-pyrazole (A 147) 4-lodo-1 H-pyrazole (1.00 g, 5.16 mmol) in DMF (15 mL) was cooled to 0 °C before sodium hydride (60percent w/w dispersion in mineral oil, 258 mg, 6.44 mmol) was added. After 15 minutes, benzyl bromide (0.674 mL, 6.44 mmol) was added and the mixture stirred at room temperature. After two hours, the mixture was added to water (200 mL), cooled at 4 °C for one hour then filtered. The collected solid was washed with cyclohexane (2 x 3 mL) and air dried to give the title compound as a white solid (0.859 g, 59percent). H NMR (400 MHz, CDCI3) δ 7.51 (s, 1 H), 7.36 (s, 1 H), 7.35-7.28 (m, 3H), 7.21-7.17 (m, 2H), 5.27 (s, 2H). LCMS-B: 3.48 min, m/z (positive ion) 285.1 [M+H]+.

Reference: [1] Organic Letters, 2017, vol. 19, # 19, p. 5114 - 5117
[2] Patent: WO2006/84338, 2006, A1, . Location in patent: Page/Page column 63
[3] Patent: US8080566, 2011, B1, . Location in patent: Page/Page column 56-57
[4] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00555
[5] Patent: WO2014/128465, 2014, A1, . Location in patent: Page/Page column 160; 161
  • 11
  • [ 3469-69-0 ]
  • [ 100-44-7 ]
  • [ 50877-42-4 ]
YieldReaction ConditionsOperation in experiment
79% at 20℃; for 48 h; 0.323 g of benzyl chloride was added dropwise to a solution of 57.0 g of 4-iodopyrazole, 20.0 g of potassium hydroxide and 2.9 g of TBAB in a solution at room temperature, After the dropwise addition, the mixture was stirred at about constant temperature for about 48 hours. The organic layer was washed three times with 40 ° C water and dried over magnesium sulfate to give 66.0 g of a yellow oil product with a GC purity of 97.0percent and a yield of 79percent.
Reference: [1] Patent: CN103601749, 2016, B, . Location in patent: Paragraph 0062-0063
[2] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 1, p. 189 - 194
  • 12
  • [ 3469-69-0 ]
  • [ 100-39-0 ]
  • [ 7646-69-7 ]
  • [ 10199-67-4 ]
  • [ 50877-42-4 ]
Reference: [1] Patent: US6214807, 2001, B1,
  • 13
  • [ 3469-69-0 ]
  • [ 76-83-5 ]
  • [ 191980-54-8 ]
Reference: [1] Synthesis, 1997, # 5, p. 563 - 566
[2] Bioorganic and medicinal chemistry, 2001, vol. 9, # 12, p. 3243 - 3253
[3] Patent: US2015/329492, 2015, A1, . Location in patent: Sheet 1/5
[4] Journal of the American Chemical Society, 2018, vol. 140, # 20, p. 6383 - 6390
[5] MedChemComm, 2014, vol. 5, # 1, p. 72 - 81
[6] Patent: US6528510, 2003, B1,
  • 14
  • [ 3469-69-0 ]
  • [ 109-92-2 ]
  • [ 575452-22-1 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With hydrogenchloride In 1,4-dioxane; toluene at 35 - 40℃; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; toluene at 20 - 30℃;
1-(ethoxyethyl)-4-iodo-1H-pyrazole (20).; A 22 L 4-neck flask equipped with an mechanical stirrer, thermowell, N2 inlet and condenser was charged with 4-iodo-1H-pyrazole (14, 1.00 Kg, 5.16 mol) and toluene (10 L) and ethyl vinyl ether (18, 557 g, 740 mL, 7.73 mol, 1.5 equiv) was added. To the suspension 4 M HCl in dioxane (32 mL, 0.128 mol, 0.025 equiv) was added over 5 min with formation of a slightly thicker white suspension. The mixture was heated carefully to 35-40° C. at which point a mild exotherm to about 40° C. occurred with rapid dissolution of all solids to give a clear light yellow solution. The reaction mixture was heated at about 40° C. for an additional 0.5 hr until the GC analysis indicated the reaction was complete. The solution was allowed to cool to 25-30° C. and solid NaHCO3 (108 g, 1.29 mol, 0.25 equiv) was added. The suspension was stirred for 1 hr at room temperature to ensure the complete neutralization of HCl. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residual liquid was fractionally distilled to afford 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 1.346 Kg, 1.373 Kg theoretical, 98percent) as a pale yellow liquid (bp 89-93° at about 1 torr). For 20: 1H NMR (CDCl3, 250 MHz) δ ppm 7.61 (s, 1H), 7.47 (s, 1H), 5.46 (q, 1H, J=6.0 Hz), 3.48-3.23 (m, 2H), 1.60 (d, 3H, J=6.0 Hz), 1.11 (t, 3H, J=7.0 Hz); C7H11IN2O (MW, 266.08), LCMS (EI) m/e 267 (M++H).
93% With trifluoroacetic acid In dichloromethane at 20 - 33℃; Large scale General procedure: To a solution of pyrazole 1-13 (1 equiv.) and trifluoroacetic acid (0.01 equiv.) in dichloromethane(for 1 mol of pyrazole - 1 L of dichloromethane were used) ethyl vinyl ether (1.27 equiv.) wasadded dropwise, keeping the temperature between 28-32 C (exothermic reaction) and left to stir atroom temperature for 12-78 hours. Dichloromethane was washed with saturated NaHCO3 solution(1 × 250 mL – for 1 L of dichloromethane) then with deionized H2O (1 × 250 mL). Organic layerwas dried with anhydrous Na2SO4, and evaporated under reduced pressure. Products were purifiedby distillation or recrystallization.
73% With hydrogenchloride; sodium bicarbonate In benzene Step 1:
1-(1-Ethoxyethyl)-4-iodo-1H-pyrazole
4-Iodo-1H-pyrazole (3.0 g) was suspended in benzene (150 mL) and the suspension was heated while stirring.
Ethyl vinyl ether (4.4 mL) was added thereto, concentrated HCl was added dropwise thereto, and the resulting mixture was stirred at 60° C. for 3 hours.
After completion of the reaction, the resulting mixture was concentrated by evaporation under a reduced pressure, and the residue was neutralized using aqueous saturated sodium hydrogen carbonate (10 mL).
The resulting mixture was extracted with ethyl acetate (50 mL) and the extract was washed successively with distilled water (100 mL).
The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure.
The resulting residue was purified by silica gel chromatography to obtain the title compound as a transparent yellow liquid (3.0 g, yield 73percent).
1H NMR (CDCl3): δ 7.54 (s, 1H), 7.41 (s, 1H), 5.40 (q, 1H, J=6.0 Hz), 3.38-3.18 (m, 2H), 1.54 (d, 3H, J=6.0 Hz), 1.05 (t, 3H, J=7.1 Hz).
73% With hydrogenchloride In water; benzene at 60℃; for 3 h; Example 2: 4-((.pound.)-2-(l-((2/?,3i?)-3-(2,4-Difluorophenyl)-3-hydroxy-4- (l/T-l,2,4-triazol-l-yl)butan-2-yl)-lflr-pyrazol-4-yl)vinyl)benzonitrileStep 1 : l-(l-Ethoxyethyl)-4-iodo-l//-pyrazole; 4-1OdO-IiZ-PyTaZoIe (3.Og) was suspended in benzene (15OmL) and the suspension was heated while stirring. Ethyl vinyl ether (4.4mL) was added thereto, concentrated HCl was added dropwise thereto, and the resulting mixture was stirred at 60 °C for 3 hours. After completion of the reaction, the resulting mixture was concentrated by evaporation under a reduced pressure, and the residue was neutralized using aqueous saturated sodium hydrogen carbonate (1OmL). The resulting mixture was extracted <n="23"/>with ethyl acetate (5OmL) and the extract was washed successively with distilled water (10OmL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound as a transparent yellow liquid (3.Og, yield 73percent). 1H NMR (CDCl3): δ 7.54(s, IH), 7.41(s, IH), 5.40(q, IH, /=6.0 Hz), 3.38-3.18(m, 2H), 1.54(d, 3H, /=6.0 Hz), 1.05(t, 3H, /=7.1 Hz).

Reference: [1] Organic Letters, 2009, vol. 11, # 9, p. 1999 - 2002
[2] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 104
[3] Synthetic Communications, 2011, vol. 41, # 16, p. 2430 - 2434
[4] Heterocycles, 2003, vol. 60, # 4, p. 879 - 886
[5] Organic Letters, 2004, vol. 6, # 26, p. 4929 - 4932
[6] Arkivoc, 2014, vol. 2014, # 6, p. 54 - 71
[7] Angewandte Chemie - International Edition, 2013, vol. 52, # 32, p. 8290 - 8294[8] Angew. Chem., 2013, vol. 125, # 32, p. 8448 - 8452,5
[9] Patent: US2010/63285, 2010, A1,
[10] Patent: WO2008/82198, 2008, A1, . Location in patent: Page/Page column 21-22
[11] Patent: WO2016/90285, 2016, A1, . Location in patent: Paragraph 00366
  • 15
  • [ 110-87-2 ]
  • [ 3469-69-0 ]
  • [ 938066-17-2 ]
YieldReaction ConditionsOperation in experiment
93% With toluene-4-sulfonic acid In dichloromethane at 20℃; for 2 h; To a stirred solution of 4-iodopyrazole (5.0 g, 25.8 mmol) in dichloromethane (10 mL) was added TsOH H2O (0.5 g, 2.9 mmol) and 3,4-dihydro-2h-pyran (4.5 g, 53.5 mmol).
The resulting mixture was stirred at room temperature for 2 h.
The reaction mixture was concentrated in vacuo.
The residue was purified by silica gel column eluted ethyl acetate/petroleum ether (1:3) to afford desired product 4-iodo-1-tetrahydropyran-2-yl-pyrazole (7 g, 93percent yield) as a colorless oil. LCMS (ESI): [M-84+H]+=195.1.
80% With toluene-4-sulfonic acid In ethyl acetate at 90℃; for 1 h; General procedure: A suspension of 6-chloro-9H-purine (or 4-iodo-1H-pyrazole) (13mmol) and 4-methylbenzenesulfonic acid (0.12g, 0.65mmol) in EtOAc (25ml) was treated with 3,4-dihydro-2H-pyran (3.54ml, 39mmol). The mixture was heated at 90°C and the solid slowly dissolved over 1h. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated under vacuum. The pale yellow residue was purified by flash chromatography to give title compound.
Reference: [1] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 2, p. 446 - 453
[2] Patent: US2018/282328, 2018, A1, . Location in patent: Paragraph 1171; 1172
[3] Journal of Organic Chemistry, 2007, vol. 72, # 9, p. 3589 - 3591
[4] European Journal of Medicinal Chemistry, 2014, vol. 73, p. 167 - 176
[5] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2014, vol. 69, # 1, p. 83 - 97
  • 16
  • [ 3469-69-0 ]
  • [ 25015-63-8 ]
  • [ 269410-08-4 ]
Reference: [1] Patent: US6680401, 2004, B1, . Location in patent: Page column 58
  • 17
  • [ 3469-69-0 ]
  • [ 1195-66-0 ]
  • [ 269410-08-4 ]
Reference: [1] Patent: CN108276418, 2018, A, . Location in patent: Paragraph 0085; 0086; 0087
  • 18
  • [ 3469-69-0 ]
  • [ 141699-59-4 ]
  • [ 877399-73-0 ]
YieldReaction ConditionsOperation in experiment
70.2%
Stage #1: With sodium hydride In dichloromethane; mineral oil at 0℃; for 1 h;
Stage #2: at 100℃; for 15 h;
To a stirred solution of 4-iodo-lH-pyrazole (8.98 g, 46.28 mmol) in DCM (160 mL) was added NaH (1.67 g, 55.53 mmol, 80percent NaH/mineral oil) portion-wise at 0 °C. The mixture was stirred at 0 °C for 1 hour, then tert-butyl 4-((methylsulfonyl)oxy)piperidine-l- carboxylate (14.22 g, 50.90 mmol) was added. The resulted mixture was stirred at 100 °C for 15 hours, then cooled to rt, quenched with H20 (30 mL) and concentrated in vacuo. The residue was diluted with H20 (150 mL), and the mixture was extracted with EtOAc (100 mL x 5). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (12.25 g, 70.2percent>). MS (ESI, pos. ion) m/z: 322.0 (M-56+1).
70.2%
Stage #1: With sodium hydride In dichloromethane; mineral oil at 0℃; for 1 h;
Stage #2: at 100℃; for 15 h;
The compound 4-iodo-1H-pyrazole (8.98 g, 46.28 mmol)Dissolve in DCM (160 mL), cool to 0 ° C, thenAfter the reaction was added NaH (1.67 g, 55.53 mmol, 80percent NaH / mineral oil) in portions,After stirring for 1 hour,To the reaction solution was further added tert-butyl 4 - ((methylsulfonyl) oxy) nicardine-1-carboxylate(14.22 g, 50.90 mmol),Heated to 100 ° C, the reaction was stirred for 15 hours,The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), concentrated under reduced pressure and the residue washed with water (150 mL). The resulting mixture was extracted with EtOAc (100 mL × 5). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (12.25 g, 70.2percent
68.7% With sodium hydride In N,N-dimethyl-formamide at 100℃; for 14 h; Cooling with ice Step 2:
1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-iodopyrazole
4-iodopyrazole (5.54 g) and anhydrous N,N-dimethylformamide (90 mL) were added in a round bottomed flask (250 mL) and 1.371 g of sodium hydride (60percent) was further added with agitating in an ice-water bath.
Then, 8.776 g of 1-tert-butoxycarbonyl-4-methylsulfonyloxy piperidine was added in the mixture when it was agitated in an ice-water bath for another 2h, and it was warmed to 100°C, agitated for 12h and cooled in an ice-water bath.
The resulted mixture was quenched by adding 300 mL of water.
The reaction solution was extracted by ethyl acetate (3x100 mL), the parts of ethyl acetate were combined, washed by saturated saline solution, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether=1:5) to produce 1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-iodopyrazole as white solid (7.43 g, yield: 68.7percent).
1H-NMR (300Hz, CDCl3) δ: 7.51 (s, 1H), 7.46 (s, 1H), 4.30 (m, 3H), 2.87 (m, 2H), 2.12 (m, 2H), 1.89 (m, 2H), 1.47 (s, 9H).
66% With NaH In N,N-dimethyl-formamide; pentane tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (3)
NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4° C.
The resulting mixture was stirred for 1 hour at 4° C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added.
The resulting mixture was heated to 100° C. for 12 h.
The reaction was quenched with H2O and extracted with EtOAc several times.
The combined organic layers were dried, filtered, and concentrated to afford an orange oil.
The residue was purified by silica gel chromatography (eluding with 5percent EtOAc in pentane) to give compound 3 as a white solid (140 g, 66percent).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 4℃; for 1 h;
Stage #2: at 100℃; for 12 h;
NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4° C. The resulting mixture was stirred for 1 hour at 4° C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100° C. for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in pentane) to give compound 3 as a white solid (140 g, 66percent).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 4℃; for 1 h;
Stage #2: at 100℃; for 12 h;
tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (23-1a)
NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4° C.
The resulting mixture was stirred for 1 hour at 4° C. and compound 23-4 (1.1 eq., 0.63 mmol) was then added.
The resulting mixture was heated to 100° C. for 12 h.
The reaction was quenched with H2O and extracted with EtOAc several times.
The combined organic layers were dried, filtered, and concentrated to afford an orange oil.
The residue was purified by silica gel chromatography (eluding with 5percent EtOAc in pentane) to give compound 23-1a as a white solid (140 g, 66percent).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 4℃; for 1 h;
Stage #2: at 100℃; for 12 h;
NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4°C. The resulting mixture was stirred for 1 hour at 4°C and compound 23-4 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100°C for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in pentane) to give compound 23-1 a as a white solid (140 g, 66percent).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 4℃; for 1 h;
Stage #2: at 100℃; for 12 h;
tert-butyl 4-(4-iodo-1 H-yrazoI- 1 -yI)i eridine-1 -carboxylate (3)NaH (1 .2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4- iodopyrazole (0.57 mmol) in DMF (2 L) at 4°C. The resulting mixture was stirred for 1 hour at 4°C and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100°C for 12 h. The reaction was quenched with H20 and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in pentane) to give compound 3 as a white solid (140 g, 66percent).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 4℃; for 1 h;
Stage #2: at 4 - 100℃; for 12 h;
tert-butyl 4-(4-iodo-1 H-pyrazol-1-yl)piperidine-1-carboxylate (3): NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4°C. The resulting mixture was stirred for 1 hour at 4°C and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100°C for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in pentane) to give compound 3 as a white solid (140 g, 66percent).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 4℃; for 1 h;
Stage #2: at 100℃; for 12 h;
tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (3)
NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4° C.
The resulting mixture was stirred for 1 hour at 4° C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added.
The resulting mixture was heated to 100° C. for 12 h.
The reaction was quenched with H2O and extracted with EtOAc several times.
The combined organic layers were dried, filtered, and concentrated to afford an orange oil.
The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in pentane) to give compound 3 as a white solid (140 g, 66percent).
60.67% With potassium carbonate In N,N-dimethyl-formamide at 60℃; Step-1: Tert-butyl4-( 4-iodo-lH-pyrazol-1-yl)piperidine-1-carboxylate 4-Iodo-lH-pyrazole (1.4 g, 7.2 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.19 g, 8.6 mmol) were dissolved in dry DMF (25 ml) and added potassiumcarbonate (1.6 g, 21.6 mmol). The resulting mixture was heated to 60 oc overnight. The reactionwas monitored by TLC (30percent ethyl acetate in hexane). The reaction mixture was diluted with icewater (150 ml) and extracted with ethyl acetate (2x50 ml). The organic layer was dried over Na2S04, and concentrated under reduced pressure to afford 1.64 g (60.67percent yield) of the pureproduct which was taken as such for next reaction.1H NMR (CDCh, 300MHz): 8 7.51 (s, lH), 7.45 (s, lH), 4.30-4.21 (m, 2H), 3.87 (s, lH), 3.48(t, lH), 2.95-2.80 (m, 2H), 2.12-2.03 (m, 2H), 1.88 (m, 2H), 1.48-1.47 (s, 9H).
60.67% With potassium carbonate In N,N-dimethyl-formamide at 60℃; 4-Iodo-1H-pyrazole (1.4 g, 7.2 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.19 g, 8.6 mmol) were dissolved in dry DMF (25 ml) and added potassium carbonate (1.6 g, 21.6 mmol). The resulting mixture was heated to 60° C. overnight. The reaction was monitored by TLC (30percent ethyl acetate in hexane). The reaction mixture was diluted with ice water (150 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 1.64 g (60.67percent yield) of the pure product which was taken as such for next reaction. [0159] 1H NMR (CDCl3, 300 MHz): δ 7.51 (s, 1H), 7.45 (s, 1H), 4.30-4.21 (m, 2H), 3.87 (s, 1H), 3.48 (t, 1H), 2.95-2.80 (m, 2H), 2.12-2.03 (m, 2H), 1.88 (m, 2H), 1.48-1.47 (s, 9H).
51% With potassium carbonate In N,N-dimethyl-formamide at 100℃; A mixture of tert-butyl 4- [(methylsulfonyl)oxy]ρiperidine-l-carboxylate: (75.5 g, 0.271 mol), 4-iodopyrazole (52.5 g, 0.271 mol), and K2CO3 (11.3 g, 0.8 mol) in 1.5 L of N, N-dimethylformamide (DMF) was stirred at 1000C overnight. After cooled to r.t., the solvent was evaporated. The residue was dissolved in DCM, filtered, and washed with water and brine. The organic layer was dried and evaporated to an oil. The crude product was purified by chromatography (MeOH/DCM 1 :40) and (EtOH/MeOH 10percent-20percent) to give 52 g of the product as a white solid after standing, in 51percent yield.
41%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1 h;
Stage #2: at 100℃; for 16 h;
Step-I:
tert-butyl 4-(4-iodopyrazol-1-yl)piperidine-1-carboxylate (Va-1-I)
NaH (60percent suspension, 1.13 g, 28.4 mmol) was added portion wise to a solution of 4-iodopyrazole (5 g, 25.7 mmol) in anhydrous DMF (30 mL) at 0° C.; and it was stirred for 1 h.
Finally, tert-butyl 4-mesylpiperidine-1-carboxylate (CAS: 141699-59-4) (6.5 g, 32.7 mmol) was added to the reaction mixture and it was stirred at 100° C. for 16 h.
It was, then, cooled and quenched with saturated solution of NH4Cl (100 mL).
Extraction was carried out using EtOAc (50 mL*2); the combined organic layers were washed with water (100 mL); brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude product, which was further purified by silica gel column chromatography (20percent EtOAc in hexanes) to give title compound Va-1-I (4 g, 41percent). LCMS: m/z 378.1 (M+1)+.
620 mg
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2 h;
Stage #2: at 100℃; for 12 h;
To a solution of 4-iodo-lH-pyrazole (467.5 mg, 2.41 mmol) was added NaH (60percent, 193 mg, 4.82 mmol) in dry DMF (8 mL) at 0 °C portion-wise, then warmed to rt and continued to stirred for 2 hours, followed by adding of a solution of the above product in DMF (4 mL). The mixture was heated at 100 °C for 12 hours, then quenched with NH4C1 (aq, 20 mL) and extracted with EtOAc (40 mL x 2). The combined organic phases were washed with brine (25 mL), dried over Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (620 mg, 68 percent). MS (ESI, pos. ion) m/z: 322.0 (M+l-56).

Reference: [1] Patent: WO2014/193647, 2014, A2, . Location in patent: Paragraph 0184
[2] Patent: CN104119331, 2018, B, . Location in patent: Paragraph 0382; 0387; 0388
[3] Patent: EP2650293, 2013, A1, . Location in patent: Paragraph 0195; 0196
[4] Patent: US2008/300273, 2008, A1,
[5] Patent: US2008/293769, 2008, A1, . Location in patent: Page/Page column 6
[6] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 69-70
[7] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 81; 82
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[9] Patent: WO2013/17989, 2013, A1, . Location in patent: Page/Page column 67
[10] Patent: EP2764866, 2014, A1, . Location in patent: Paragraph 0053
[11] Patent: US2016/206608, 2016, A1, . Location in patent: Paragraph 0264; 0265
[12] Patent: WO2014/24077, 2014, A1, . Location in patent: Page/Page column 36
[13] Patent: US2015/183781, 2015, A1, . Location in patent: Paragraph 0158
[14] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
[16] Journal of Medicinal Chemistry, 2013, vol. 56, # 6, p. 2294 - 2310
[17] Patent: WO2010/68292, 2010, A1, . Location in patent: Page/Page column 85
[18] Patent: US2015/64196, 2015, A1, . Location in patent: Paragraph 0183
[19] Patent: WO2014/89280, 2014, A1, . Location in patent: Page/Page column 50
[20] Patent: CN107417603, 2017, A, . Location in patent: Paragraph 0021
[21] Patent: CN106831720, 2017, A, . Location in patent: Paragraph 0016; 0018; 0019
  • 19
  • [ 3469-69-0 ]
  • [ 118811-07-7 ]
  • [ 877399-73-0 ]
YieldReaction ConditionsOperation in experiment
92% With caesium carbonate In N,N-dimethyl acetamide at 100℃; for 1 h; Inert atmosphere In a 2OmL reaction vial with a magnetic stirbar a mixture of 4-(toluene-4-sulfonyloxy)- piperidine-1 -carboxylic acid tert-butyl ester (1 .08 g; 3.04 mmol; 1 .00 eq.), 4-lodo-1 H-pyrazole (589.37 mg; 3.04 mmol; 1 .00 eq.) and cesium carbonate (1 .48 g; 4.56 mmol; 1.50 eq.) in DMA (7.00 mL) was heated at 100°C for ih under N2 atmosphere. LCMS at 1 hr showed indicated the reaction was complete. The reaction was diluted with ethyl acetate (50 mL) and washed with water (2x20 mL) and brine (1x20 mL).The organic layer was dried over Na2SO4, filtered, and concentrated to provide1 .06g (92percent) of 4-(4-lodo-pyrazol-1 -yl)-piperidine-1 -carboxylic acid tert-butyl ester as a colorless oil. MS (ES 1+): 378.
Reference: [1] Patent: WO2015/106058, 2015, A1, . Location in patent: Page/Page column 58; 59
  • 20
  • [ 3469-69-0 ]
  • [ 109384-19-2 ]
  • [ 877399-73-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With dmap; methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 5 h;
Stage #2: With sodium hydride In ethyl acetate; N,N-dimethyl-formamide at 20 - 100℃; for 14 h;
The compound 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (485 mg, 2.41 mmol) and DMAP (29.4 mg,0.241 mmol) was dissolved in DCM (15 mL), and Et3N (0.67 mL, 4.82 mmol) and MsCl (0.223 mL, 2.879 mmol) were slowly added to the reaction mixture at 0 °C.After the reaction mixture was stirred at room temperature for 5 hours, an aqueous solution of NaHCO3 (25 mL, 1 M) was added.The mixture was extracted with DCM (50 mL×2). The combined organic phases were washed with brine (25 mL).Dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure.The crude product obtained was used directly in the next step without further purification.The compound 4-iodo-1H-pyrazole (467.5 mg, 2.41 mmol) was dissolved in dry DMF (8 mL) then EtOAc.NaH (60percent, 193 mg, 4.82 mmol) was added portionwise to the reaction mixture. Raise the reaction to room temperature,After stirring the reaction for 2 hours at room temperature, a solution of the above crude product in DMF (4 mL) was added to the mixture.After the reaction mixture was stirred at 100 ° C for 12 hours, the reaction was quenched by the addition of aqueous NH4Cl (20 mL).The mixture was extracted with EtOAc (40 mL×2). The combined organic phases were washed with brine (25 mL).Dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure.The residue was chromatographed on silica gel (EtOAc/EtOAc)Purification to give the title compound as a yellow solid(620 mg, 68percent).
Reference: [1] Patent: CN103833753, 2017, B, . Location in patent: Paragraph 0352; 0354; 0355; 0356
  • 21
  • [ 3469-69-0 ]
  • [ 189205-49-0 ]
  • [ 877399-73-0 ]
YieldReaction ConditionsOperation in experiment
41%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 100℃; for 16 h;
Step-I: tert-biityl 4-(4-iodopyrazoI-l-yl)piperidine-l-carboxylate (Va-l-I): NaH (60percent suspension, 1.13 g, 28.4 mmol) was added portion wise to a solution of 4-iodopyrazole (5 g, 25.7 mmol) in anhydrous DMF (30 mL) at 0 °C; and it was stirred for 1 h. Finally, tert-butyl 4-mesylpiperidine-l -carboxylate (CAS: 141699-59-4) (6.5 g, 32.7 mmol) was added to the reaction mixture and it was stirred at 100 °C for 16 h. It was, then, cooled and quenched with saturated solution of NH4C1 (100 mL). Extraction was carried out using EtOAc (50 mL x 2); the combined organic layers were washed with water (100 mL); brine ( 100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to provide crude product, which was further purified by silica gel column chromatography (20percent EtOAc in hexanes) to give title compound Va-l -I (4 g, 41percent). LCMS: mlz 378.1 (M+l)+.
Reference: [1] Patent: WO2013/157022, 2013, A1, . Location in patent: Page/Page column 56-57
  • 22
  • [ 3469-69-0 ]
  • [ 24424-99-5 ]
  • [ 121669-70-3 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In tetrahydrofuran at 20℃; for 2 h; 4-Iodopyrazole (20 mmol) was treated with Et3N (30 mmol) and (Boc)2O (22 mmol) in THF (60 mL) at r.t. for 2 hours to form N-Boc-4-iodopyrazole (5.88 g, 100percent). N-Boc-4-iodopyrazolyle in THF (100 mL) was reacted with hexamethylditin (20 mmol) in the presence of Pd(Ph3P)4 (1.1 g, 1 mmol) under nitrogen at 78°C overnight. To it was added aqueous 10percent KF and the resulting mixture was stirred for 30 minutes, and then filtered through a pad of Celite. The filtrate was extracted with EtOAc. The EtOAc layer was washed with water, and dried over MgSO4. Filtration and concentration followed by purification of the mixture by column chromatography afforded the 3-trimethyltinpyrazole derivative (5 g, 75percent) as a white solid.
98% With triethylamine In tetrahydrofuran at 20℃; for 3 h; ieri-Butyl 4-iodo-1 H-pyrazole-1 -carboxylate (2); [00189] 4-lodopyrazole (1) (7.85g 40.4mmole) was dissolved in THF (120ml_) and triethylamine (8.5ml_, 6.12g 60.5mmole) and di-terf-butyl dicarbonate (9.7g, 44.5mmole) were added. The reaction was stirred at r.t. for 3 hours. The THF was evaporated and ethyl acetate (100ml_) was added. The solution was washed with water (2x50ml_) and with brine, then dried and evaporated to leave an oil (14.2g). The crude product was purified by chromatography on a pad of silica in a sinter (10cm diam, 6cm thick) eluted with 10percent ethyl acetate in cyclohexane (1 1 x90ml_), then 20percent ethyl acetate in cyclohexane (3x90ml_) to give the protected pyrazole 2 (1 1 .66g 98percent). 1H-NMR (CDCI3, 500MHz): δ 1 .68 (s, 9H), 7.73 (s, 1 H), 8.17 (s, 1 H).
98% With triethylamine In tetrahydrofuran at 20℃; for 3 h; tert-Butyl 4-iodo-1H-pyrazole-1-carboxylate (2)
4-Iodopyrazole (1) (7.85 g 40.4 mmole) was dissolved in THF (120 mL) and triethylamine (8.5 mL, 6.12 g 60.5 mmole) and di-tert-butyl dicarbonate (9.7 g, 44.5 mmole) were added.
The reaction was stirred at r.t. for 3 hours.
The THF was evaporated and ethyl acetate (100 mL) was added.
The solution was washed with water (2*50 mL) and with brine, then dried and evaporated to leave an oil (14.2 g).
The crude product was purified by chromatography on a pad of silica in a sinter (10 cm diam, 6 cm thick) eluted with 10percent ethyl acetate in cyclohexane (11*90 mL), then 20percent ethyl acetate in cyclohexane (3*90 mL) to give the protected pyrazole 2 (11.66 g 98percent).
1H-NMR (CDCl3, 500 MHz): δ 1.68 (s, 9H), 7.73 (s, 1H), 8.17 (s, 1H).
90% at 20 - 35℃; Large scale In the reaction kettle, add 4 - iodine pyrazole (1.94 kg, 10 µM) and tetrahydrofuran 5 kg, stirring to dissolve, heating to the 20 - 30 °C, slow carbon acid di-tert-butyl adds by drops two (2.18 kg, 10 µM), drop the temperature increases slightly, the control temperature of not more than 35 °C. The completion of the dropping, stirring 1 - 2 hours, TLC confirms the completion of the reaction. The reaction liquid under reduced pressure when the distillation is carried out to the does not flow the fluid, adding 1.2 kg normal heptane cooling to 0 °C beating, filtering, drying to obtain N - BOC - 4 - iodine pyrazole 2.65 kg, yield 90percent, HPLC: 97.4percent.
78.5% With triethylamine In dichloromethane at 20℃; General procedure: To a solution of pyrazole 1-5 (1 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (for 0.05mol of pyrazole – 50 mL of dichloromethane were user) Di-tert-butyl dicarbonate (1.2 equiv) wereadded at room temperature and left to stir overnight. Dichloromethane was washed with saturatedNaHCO3 solution (1×25 mL – for 50 mL of dichloromethane) then with deionized H2O (1 × 25mL). Organic layer was dried with anhydrous Na2SO4, and evaporated under reduced pressure.

Reference: [1] Patent: EP946508, 2009, B1, . Location in patent: Page/Page column 58
[2] Patent: WO2012/123745, 2012, A1, . Location in patent: Page/Page column 64
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 32, p. 8290 - 8294[4] Angew. Chem., 2013, vol. 125, # 32, p. 8448 - 8452,5
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 10045 - 10065
[6] Patent: US2013/345181, 2013, A1, . Location in patent: Paragraph 0621; 0623
[7] Patent: CN106188116, 2016, A, . Location in patent: Paragraph 0018
[8] Arkivoc, 2014, vol. 2014, # 6, p. 54 - 71
  • 23
  • [ 3469-69-0 ]
  • [ 121-44-8 ]
  • [ 121669-70-3 ]
Reference: [1] Patent: US6020357, 2000, A,
  • 24
  • [ 3469-69-0 ]
  • [ 4584-46-7 ]
  • [ 879488-19-4 ]
YieldReaction ConditionsOperation in experiment
32% With potassium carbonate In N,N-dimethyl-formamide for 24 h; (176a)
2-(4-Iodo-1H-pyrazol-1-yl)-N,N-dimethylethylamine
N,N-Dimethylformamide (15 mL) was added to a mixture of 4-iodopyrazole (0.97 g, 5.0 mmol), 2-dimethylaminoethyl chloride hydrochloride (1.4 g, 10 mmol), and potassium carbonate (2.8 g, 15 mmol).
The resulting mixture was stirred at 100°C for 24 hr.
The reaction solution was cooled to room temperature, and water was added thereto.
After extraction with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen, eluding solvent: methanol/ethyl acetate) to obtain 0.42 g (yield: 32percent) of the title compound as a brown oily material.
1H-NMR (400 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.50 (1H, s), 4.22 (2H, t, J = 6.3 Hz), 2.73 (2H, t, J = 6.3 Hz), 2.27 (6H, s).
Reference: [1] Patent: EP1798229, 2007, A1, . Location in patent: Page/Page column 159
[2] Patent: WO2014/162039, 2014, A1, . Location in patent: Page/Page column 32
  • 25
  • [ 3469-69-0 ]
  • [ 381-73-7 ]
  • [ 1041205-43-9 ]
Reference: [1] Patent: WO2008/88692, 2008, A2, . Location in patent: Page/Page column 152
  • 26
  • [ 3469-69-0 ]
  • [ 411235-57-9 ]
  • [ 1239363-40-6 ]
YieldReaction ConditionsOperation in experiment
85% With pyridine; dmap; copper diacetate In 1,4-dioxane at 100℃; for 16 h; Intermediate bA. 1-Cyclopropyl-4-iodo-1H-pyrazole: To a mixture of 4-iodo- 1H-pyrazole (645 mg, 3.33 mmol), cyclopropylboronic acid (571 mg, 6.65 mmol), copper(II) acetate (604 mg, 3.33 mmol) and DMAP (1219 mg, 9.98 mmol) in dioxane (10mL) was added pyridine (0.323 mL, 3.99 mmol). The resulting mixture was heated to 100°C for 1 6h under air. The reaction mixture was concentrated in vacuo and diluted withEtOAc. The organic layer was washed with 1M HC1. The organic layer was dried overMgSO4, filtered and concentrated in vacuo. The crude product was purified bychromatography to give Intermediate 1OA (660 mg, 2.82 mmol, 85percent yield) as a lightyellow liquid. LCMS Anal. Calc’d for C6H7N2 234.04, found [M+H] 234.9.
43% With [2,2]bipyridinyl; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 50 - 70℃; Step 1
In a flask were combined 4-iodo-1H-pyrazole (1.00 g, 5.16 mmol), cyclopropylboronic acid (886 mg, 10.3 mmol) and sodium carbonate (1.09 g, 10.3 mmol) and the mixture suspended in 1,2-dichloroethane (20 mL).
A suspension of copper (II) acetate (936 mg, 5.16 mmol) and 2,2-bipyridine (805 mg, 5.16 mmol) in 1,2-dichloroethane (40 mL) was warmed to 50° C. and added and the resulting mixture heated at 70° C. overnight.
The mixture was then cooled and filtered and the solids rinsed with EtOAc.
The combined filtrates were concentrated and the residue taken up in EtOAc and 50percent saturated aqueous NH4Cl.
The organic layer was washed with sat NH4Cl, sat NaHCO3 and sat NaCl and dried over MgSO4.
The solution was concentrated and the residue purified by SiO2 chromatography (5-35percent EtOAc/heptane) to afford 517 mg (43percent) 1-cyclopropyl-4-iodo-1H-pyrazole as a colorless oil.
Reference: [1] Patent: WO2015/134701, 2015, A1, . Location in patent: Page/Page column 58
[2] Patent: US2011/230462, 2011, A1, . Location in patent: Page/Page column 84
  • 27
  • [ 3469-69-0 ]
  • [ 4333-56-6 ]
  • [ 1239363-40-6 ]
Reference: [1] Patent: WO2012/24620, 2012, A2, . Location in patent: Page/Page column 183
  • 28
  • [ 3469-69-0 ]
  • [ 540-51-2 ]
  • [ 1408334-75-7 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1 h;
Stage #2: at 0 - 65℃; for 72 h;
Preparation 57: 2-(4-iodo-1 H-pyrazol-1 -yl)ethanol A solution of 4-iodo-1 H-pyrazole (4.50 g, 23.20 mmol) in DMF (45 mL) was treated with sodium hydride (60percent w/w, 1 .42 g, 35.5 mmol) at 0°C and stirred at room temperature. After 1 hour the resulting mixture was treated with 2-bromoethanol (2.5 mL, 35.2 mmol) at 0°C. The resulting mixture was heated to 65 °C for 3 days. The reaction quenched with brine/EtOAc and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 50percent EtOAc in cyclohexane to give the title compound (3.55 g, 64percent). 1 H NMR (500 MHz, CDCI3): δ 7.55 (s, 1 H), 7.52 (s, 1 H), 4.32 - 4.22 (m, 2H), 4.04 - 3.95 (m, 2H), 2.79 - 2.68 (br m, 1 H). LCMS (ESI) Rt = 1 .50 minutes MS m/z 238 [M+H]+
Reference: [1] Patent: WO2014/37750, 2014, A1, . Location in patent: Paragraph 00142-00144
  • 29
  • [ 96-49-1 ]
  • [ 3469-69-0 ]
  • [ 1408334-75-7 ]
YieldReaction ConditionsOperation in experiment
53% at 125℃; for 24 h; a.
2-(4-Iodo-pyrazol-1-yl)-ethanol (Intermediate Aa)
A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125° C. for 24 h.
The cooled solution was concentrated under vacuum to leave a brown oil.
The residue was purified by FCC using 30-70percent EtOAc in DCM to give the title compound (9.36 g, 53percent). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53% at 125℃; for 24 h; A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 °C for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC, using 30-70percent EtOAc in DCM, to give the title compound (9.36 g, 53percent). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53% at 125℃; for 24 h; A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125°C for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC using 30-70percent EtOAc in DCM to give the title compound (9.36 g, 53percent). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53% at 125℃; for 24 h; A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylenecarbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 °C for 24 h.The cooled solution was concentrated under vacuum to leave a brown oil. Theresidue was purified by FCC, using 30-70percent EtOAc in DCM, to give the titlecompound (9.36 g, 53percent).

Reference: [1] Patent: US2014/364411, 2014, A1, . Location in patent: Paragraph 0423; 0424
[2] Patent: WO2014/194956, 2014, A1, . Location in patent: Page/Page column 42
[3] Patent: WO2014/195400, 2014, A1, . Location in patent: Page/Page column 92
[4] Patent: KR2016/16973, 2016, A, . Location in patent: Paragraph 0221-0223
Recommend Products
Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 3469-69-0 ]

Crizotinib Related Intermediates

Chemical Structure| 141699-59-4

[ 141699-59-4 ]

tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Chemical Structure| 7379-35-3

[ 7379-35-3 ]

4-Chloropyridine hydrochloride

Chemical Structure| 877397-70-1

[ 877397-70-1 ]

(R)-3-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine

Chemical Structure| 877399-50-3

[ 877399-50-3 ]

tert-Butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

Chemical Structure| 73183-34-3

[ 73183-34-3 ]

4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane)

Related Parent Nucleus of
[ 3469-69-0 ]

Pyrazoles

Chemical Structure| 39806-90-1

[ 39806-90-1 ]

4-Iodo-1-methyl-1H-pyrazole

Similarity: 0.83

Chemical Structure| 15802-75-2

[ 15802-75-2 ]

4-Iodo-3-methyl-1H-pyrazole

Similarity: 0.79

Chemical Structure| 6647-97-8

[ 6647-97-8 ]

4-Iodo-1,3-dimethyl-1H-pyrazole

Similarity: 0.68

Chemical Structure| 288-13-1

[ 288-13-1 ]

1H-Pyrazole

Similarity: 0.68

Chemical Structure| 1354703-91-5

[ 1354703-91-5 ]

4-Iodo-1H-pyrazole-5-carbonitrile

Similarity: 0.65