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Product Details of [ 2075-45-8 ]

CAS No. :2075-45-8 MDL No. :MFCD00075602
Formula : C3H3BrN2 Boiling Point : -
Linear Structure Formula :- InChI Key :WVGCPEDBFHEHEZ-UHFFFAOYSA-N
M.W : 146.97 Pubchem ID :16375
Synonyms :
Chemical Name :4-Bromo-1H-pyrazole

Calculated chemistry of [ 2075-45-8 ]

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 : 26.29
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) : -7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.74
Log Po/w (XLOGP3) : 0.28
Log Po/w (WLOGP) : 1.17
Log Po/w (MLOGP) : 0.41
Log Po/w (SILICOS-IT) : 1.95
Consensus Log Po/w : 0.91

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.54
Solubility : 4.2 mg/ml ; 0.0286 mol/l
Class : Very soluble
Log S (Ali) : -0.44
Solubility : 52.9 mg/ml ; 0.36 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.07
Solubility : 1.26 mg/ml ; 0.00859 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.15

Safety of [ 2075-45-8 ]

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

Application In Synthesis of [ 2075-45-8 ]

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

  • Upstream synthesis route of [ 2075-45-8 ]
  • Downstream synthetic route of [ 2075-45-8 ]

[ 2075-45-8 ] Synthesis Path-Upstream   1~34

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Reference: [1] Chemische Berichte, 1970, vol. 103, p. 1942,1943, 1948
[2] Justus Liebigs Annalen der Chemie, 1956, vol. 598, p. 186,197
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YieldReaction ConditionsOperation in experiment
100% With N-Bromosuccinimide In water at 20 - 25℃; Step 1[00249j To a slurry of 1H-pyrazole (10 g, 147 mmol) in water (150 mL) at room temperature was added NBS (26.1 g, 147 mmol) in one portion. Reaction became milky white and was allowed to stir at room temperature for 24 h. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with aqueous Na25203 and brine then dried over Na2504, and concentrated under reduced pressure to afford a light tan oil as 21.5 g (100percent) of as a light tan oil that solidified upon standing. HPLC Peak RT = 0.87 mm.
100% With N-Bromosuccinimide In water at 20℃; step 1To a solution of lH-pyrazole (10 g, 147 mmol)NBS (26.1 g, 147 mmol) was added to the slurry in water (150 mL) at one time (note: exotherm) and the mixture became milky white and stirred overnight at rt. The reaction mixture was then extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with aqueous Na2S2O3 and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the desired product as 4-bromo-lH-pyrazole (21.5 g, 146 mmol, 100percent yield), which solidifies after standing.
99%
Stage #1: With bromine In water for 1 h; Heating / reflux
Stage #2: With sodium carbonate In water at 20℃;
A solution of 150 g (2.2 mol) of pyrazole and 703 g (4.4 mol, 2.0 eq.) of bromine in 3 L of water was refluxed for 1 h.
The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution and the product was extracted into ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated.
The residue was triturated with hexanes to give 322 g (99percent) of 4-bromo-1H-pyrazole.
99% With tetrapropylammonium nonabromide In dichloromethane at 0 - 23℃; for 0.166667 h; Inert atmosphere General procedure: A round-bottom flask equipped with a magnetic stir bar and a rubber septum was charged with Pr4NBr9 (0.66 mmol, 0.33 molpercent) and CH2Cl2 (1 mL). The homogeneous solution was stirred and cooled to 0 °C if not described otherwise (partial precipitation of the nonabromide can occur at this point). The substrate (2.0 mmol, 1.0equiv) was added and the reaction allowed to warm to 23 °C (attention: exothermic reaction) After the reported reaction time the dark-red color of the nonabromide had vanished and TLC control showed completion of the reaction. The reaction was quenched by addition of sat. aq Na2S2O3 (2 mL) and transferred to a separation funnel. H2O was added (15 mL) followed by extraction with Et2O (4 × 20 mL) if not described otherwise. The organic layers were combined, washed with H2O (4 × 15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude product.
98% With N-Bromosuccinimide In water at 20℃; 4-Bromopyrazole (21).; Pyrazole (13, 34.0 g, 0.5 mol) and NBS (89.0 g, 0.5 mol, 1.0 equiv) were suspended in water (625 ml). The resulting suspension was stirred over night at room temperature. The reaction mixture was then extracted with EtOAc (2.x.100 mL). The combined EtOAc extracts was washed with aqueous Na2S2O3 and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 4-bromopyrazole (21, 72.0 g, 73.5 g theoretical, 98percent yield) as a white solid (GC purity: >98percent).
98% With N-Bromosuccinimide In water at 20℃; 4-Bromopyrazole (22) [0163] Pyrazole (19, 34.0 g, 0.5 mol) and NBS (89.0 g, 0.5 mol, 1.0 equiv) were suspended in water (625 ml) at ambient temperature. The resulting suspension was stirred at ambient temperature for overnight. The reaction mixture was then extracted with EtOAc (2×100 mL). The combined EtOAc extracts were washed with aqueous Na2S2O3 and brine, dried over Na2SO4, and concentrated under reduced pressure to afford crude 4-bromopyrazole (72.0 g, 73.5 g theoretical, 98percent yield) as white solids (GC purity: >98percent), which was directly used in the subsequent reaction without further purification.
94%
Stage #1: With bromine In water at 15℃; for 3 h;
Stage #2: at 10℃;
4-bromo-l H-pyrazole (A)Bromine (76.4 mL, 1.49 mol) was added dropwise over a period of 2 h to a stirred and cooled (<15 0C; ice bath cooling) solution of pyrazole 3 (97.26 g, 1.43 mol) in water (450 mL). The mixture was stirred for additional 1 h, cooled to 10 0C. Excess of acid was neutralized with 50percent aqueous NaOH (total of about 120 mL) followed by saturated aqueous NaHCO3 (150 mL). The solid was filtered off, washed with cold water (300 mL) and dried in vacuum overnight to afford 4 (196.49 g, 94percent) as white-pink powder. 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 2H), 11.70 (bs, IH).
80% With oxone; sodium bromide In water at 20℃; for 48 h; General procedure: 1-benzyl-4-chloro-3,5-dimethyl-1H-pyrazole. To a 16 mL vial containing 1-benzyl-3,5-dimethyl-1H-pyrazole (196 mg, 1.05 mmol) and a magnetic stir bar, 0.7 mL of water and 0.3 mL of ethyl acetate was added. Next, NaCl (123 mg, 2 mmol) was added and the vial was placed in a room temperature water bath to control exotherms. Finally, Oxone (322 mg, 0.52 mmol or 1.05 mmol KHSO5) was added and the vial was capped. The reaction proceeded with continuous and vigorous stirring until no starting material remained as indicated by TLC (1 h). The remaining oxidants were reduced with solid sodium bisulfite until starch iodide paper tested negative. Water (5 mL) was added and the mixture was extracted with 1:1 hexanes/diethyl ether (3 x 5 mL). The combined organic fractions were dried (MgSO4) and concentrated to yield crude product that was purified by flash chromatography (14 x 1 cm), 9:1 hexane/ethyl acetate eluent. Pure 1-benzyl-4-chloro-3,5-dimethyl-1H-pyrazole was obtained as a pale yellow oil (215 mg, 93percent yield).

Reference: [1] Heterocycles, 2010, vol. 81, # 6, p. 1509 - 1516
[2] Patent: WO2014/74661, 2014, A1, . Location in patent: Paragraph 00249
[3] Patent: TWI582077, 2017, B, . Location in patent: Page/Page column 81
[4] Patent: US2008/261975, 2008, A1, . Location in patent: Page/Page column 12
[5] Synthesis (Germany), 2014, vol. 46, # 6, p. 740 - 747
[6] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 105
[7] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0163
[8] Patent: WO2008/95944, 2008, A1, . Location in patent: Page/Page column 225
[9] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2954 - 2958
[10] Tetrahedron Letters, 2017, vol. 58, # 43, p. 4111 - 4114
[11] Canadian Journal of Chemistry, 1991, vol. 69, # 3, p. 432 - 439
[12] Synthetic Communications, 2007, vol. 37, # 1, p. 137 - 147
[13] Chem.Abstr., 1961, # 23942,
[14] Patent: WO2015/69310, 2015, A1, . Location in patent: Paragraph 00173
[15] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4405 - 4411
[16] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 2239 - 2245
[17] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 2239 - 2245
[18] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10200 - 10211
[19] Advanced Synthesis and Catalysis, 2018, vol. 360, # 4, p. 626 - 630
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Reference: [1] Patent: WO2014/140073, 2014, A1, . Location in patent: Page/Page column 13; 28
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Reference: [1] Chemische Berichte, 1895, vol. 28, p. 688[2] Journal fuer Praktische Chemie (Leipzig), 1896, vol. &lt;2&gt; 53, p. 127
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Reference: [1] Russian Journal of General Chemistry, 2007, vol. 77, # 9, p. 1652 - 1653
  • 6
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
  • 7
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  • [ 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
  • 8
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Reference: [1] Patent: EP1000062, 2004, B1, . Location in patent: Page 56
[2] Patent: US2010/144695, 2010, A1, . Location in patent: Page/Page column 40
[3] Patent: EP1186604, 2002, A1, . Location in patent: Page 106
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  • [ 15803-02-8 ]
Reference: [1] Patent: US6511974, 2003, B1,
[2] Patent: US6831079, 2004, B1, . Location in patent: Page/Page column 69
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  • [ 74-83-9 ]
  • [ 15803-02-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 6, p. 931 - 939
[2] Patent: WO2010/10184, 2010, A1, . Location in patent: Page/Page column 60; 77
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  • [ 37718-11-9 ]
Reference: [1] Patent: US5066479, 1991, A,
  • 12
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  • [ 591-51-5 ]
  • [ 37718-11-9 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
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  • [ 591-50-4 ]
  • [ 15115-52-3 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 6, p. 2067 - 2070
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  • [ 98-80-6 ]
  • [ 15115-52-3 ]
Reference: [1] ChemCatChem, 2016, vol. 8, # 18, p. 2953 - 2960
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  • [ 71-43-2 ]
  • [ 15115-52-3 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 72, p. 18161 - 18165
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YieldReaction ConditionsOperation in experiment
87%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 2 h;
Step 1: Preparation of l-benzyl-4-bromo-lH-pyrazole [00167] Sodium hydride (0.2 g, 60 percent, 5.1 mmol) was added to a solution of 4-bromo-lH- pyrazole (0.5 g, 3.4 mmol) in N,N-dimethylformamide (10 mL) at 0 °C and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 °C, added benzyl bromide (0.485 mL, 4.08 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with ice-water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 7percent ethyl acetate in hexane to afford the title compound l-benzyl-4-bromo-lH-pyrazole (0.7 g, 87percent yield) as a colorless liquid. Calculated M+H: 236.99; Found M+H: 236.9.
Reference: [1] Angewandte Chemie - International Edition, 2006, vol. 45, # 8, p. 1282 - 1284
[2] Patent: WO2016/49165, 2016, A1, . Location in patent: Paragraph 00167
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YieldReaction ConditionsOperation in experiment
95%
Stage #1: for 0.25 h; Sonication
A 100 mL round bottom flask was charged with 4-bromopyrazole (4.41 g, 30 mmol), tetrabutylammonium bromide [(484] mg, 1.5 mmol) and potassium hydroxide pellets (3.37 g, 60 mmol). After the mixture was sonicated for 15 min, benzyl chloride (5.2 [ML,] 45 mmol) was added dropwise and the resulting mixture was stirred overnight. Ethyl ether (20 mL), water (20 mL), and diluted hydrochloric acid (1 [ML,] [10percent)] were added under stirring. The organic layer was washed with water [(2X20] mL) and dried over MgS04. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica gel (hexane/ethyl acetate 10: 1) to provide the desired product as a white solid (6.74 g, 95percent yield). Mp [51-52 °C] (lit. [44-45 °C,] See Jones, R. G. [J.] Am. [CHEM.] Soc. 1949, [71,] [3994).APOS;H NMR] (400 MHz, CDC13) : [8] 7.53 (s, 1H), 7.42-7. 33 (m, 4H), 7.28-7. 22 (m, 2H), 5.29 (s, 2H); [13C] NMR (100 MHz, CDC13) : [6] 140.4, 136.2, 129. 8, 129.4, 128.8, [128.] 3,93. 9, 57.1.
Reference: [1] Journal of the American Chemical Society, 2003, vol. 125, # 10, p. 2890 - 2891
[2] Patent: WO2004/13094, 2004, A2, . Location in patent: Page 99-100
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Reference: [1] Patent: WO2005/113513, 2005, A2, . Location in patent: Page/Page column 180
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Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10035 - 10039[2] Angew. Chem., 2013, vol. 125, # 38, p. 10219 - 10223
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Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 2, p. 648 - 651
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YieldReaction ConditionsOperation in experiment
98.2% With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere A 500 mL Schlenk flask backfilled with N2was added 4-bromo-1H-pyrazole (10.0g, 68.0 mmol) and dry THF (250 mL). The resulting solution was cooled to 0 °C understirring before 60percent NaH dispersion (3.3 g, 81.6 mmol) was added slowly. Once H2evolution had ceased, trityl chloride (20.9 g, 74.8 mmol) was added slowly, andthe resulting mixture was stirred overnight at RT before quenching with H2O(5 mL) and drying in vacuo.Theresulting residue was triturated in dichloromethane (5 mL) and methanol (200mL) for 2 hours.The resulting suspension wasfiltered and dried overnight at 50°C to give4-bromo-1-trityl-1H-pyrazole(26.0g, 66.8 mmol, 98.2percent) as a white solid.1HNMR (300 MHz, DMSO-d6)δ = 7.03 – 7.06 (m, 6 H), 7.34 – 7.40 (m, 9 H), 7.51 (s, 1 H), δ 7.76 (s, 1H).
96% With pyridine In dichloromethane at 20℃; for 16 h; A solution of 150 g (1.0 mol) of 4-bromo-1H-pyrazole, 334 g (1.2 mol, 1.2 eq.) of trityl chloride, 158 g (2.0 mol, 2.0 eq.) of pyridine and 6.1 g (0.05 mol, 5 mol percent) of 4-dimethylaminopyridine in 2 L of dichloromethane was stirred at room temperature for 16 h.
The resulting mixture was washed with water and saturated aqueous ammonium chloride solution.
The organic layer was dried over sodium sulfate and concentrated.
The residue was triturated with hexanes to give 380 g (96percent) of 4-bromo-1-trityl-1H-pyrazole.
87% With triethylamine In N,N-dimethyl-formamide at 70℃; for 3 h; Manufacturing Example 32-1-1 4-Bromo-1-trityl-1H-pyrazole; To a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N,N-dimethylformamide (100 mL) was added dropwise triethylamine (23.7 mL, 170 mmol) under nitrogen atmosphere at room temperature. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution on an ice bath (0° C.), and stirred for 3 hours at 70° C. Water (400 mL) was added to the reaction solution to precipitate the solids. The precipitated solids were filtered and dried under a reduced pressure. The solids were then azeotropically dried with toluene to obtain the title compound (22.9 g, 87percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 7.04-7.07 (6H, m), 7.35-7.38 (9H, m), 7.52 (1H, d, J=0.4 Hz), 7.76 (1H, d, J=0.8 Hz).
87% With triethylamine In N,N-dimethyl-formamide at 0 - 70℃; for 3 h; To a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N,N-dimethylformamide (100 mL) was added dropwise triethylamine (23.7 mL, 170 mmol) under nitrogen atmosphere at room temperature. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution on an ice bath (0° C.), and stirred for 3 hours at 70° C. Water (400 mL) was added to the reaction solution to precipitate the solids. The precipitated solids were filtered and dried under a reduced pressure. The solids were then azeotropically dried with toluene to obtain the title compound (22.9 g, 87percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 7.04-7.07 (6H, m), 7.35-7.38 (9H, m), 7.52 (1H, d, J=0.4 Hz), 7.76 (1H, d, J=0.8 Hz).

Reference: [1] Tetrahedron Letters, 2016, vol. 57, # 8, p. 895 - 898
[2] Patent: US2008/261975, 2008, A1, . Location in patent: Page/Page column 12
[3] Journal of the American Chemical Society, 2011, vol. 133, # 31, p. 12285 - 12292
[4] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 81
[5] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 78
[6] Heterocycles, 2010, vol. 81, # 6, p. 1509 - 1516
[7] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[8] Synthesis, 1997, # 5, p. 563 - 566
[9] Organic Letters, 2015, vol. 17, # 5, p. 1142 - 1145
[10] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2954 - 2958
[11] Patent: US6492416, 2002, B1,
[12] Patent: US6200978, 2001, B1,
[13] Patent: WO2007/52943, 2007, A1, . Location in patent: Page/Page column 20-21
[14] Patent: US2008/287440, 2008, A1, . Location in patent: Page/Page column 5
[15] Patent: WO2003/104200, 2003, A1, . Location in patent: Page 20
[16] Patent: WO2003/104189, 2003, A2, . Location in patent: Page 16
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Reference: [1] Journal of Materials Chemistry, 2006, vol. 16, # 26, p. 2736 - 2745
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
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YieldReaction ConditionsOperation in experiment
84% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h; a) 4-Bromo- 1 -ethyl- 1 H-pyrazoleTo a solution of 4-bromo-l H-pyrazole (5 g, 34 mmol) in DMF were added K2C03 (11.75 g, 85.03 mmol, 2.5 eq.) and iodoethane (8 g, 51 mmol, 1.5 eq.) and the mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 40 percent ethyl acetate in hexane) to yield the product in 84 percent yield (5 g). Ή NMR (300 MHz, DMSO-i¾): δ 8.02 (s, 1H), 7.55 (s, 1H), 4.15 (q, 2H), 1.37 (t, 3H); LC-MS (ESI): Calculated mass: 175.03;Observed mass: 177.0 [M+H]+ (rt: 0.56 min).
84% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h; a
To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF were added K2CO3 (11.75 g, 85.03 mmol, 2.5 eq.) and iodoethane (8 g, 51 mmol, 1.5 eq.) and the mixture was stirred at RT for 12 h.
The mixture was quenched and extracted as in Intermediate Example 5(c).
The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 40percent ethyl acetate in hexane) to yield the product in 84percent yield (5 g).
1H NMR (300 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.55 (s, 1H), 4.15 (q, 2H), 1.37 (t, 3H); LC-MS (ESI): Calculated mass: 175.03; Observed mass: 177.0 [M+H]+ (rt: 0.56 min).
75%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.333333 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 2 h;
4-Bromo-1-ethyl-1H-pyrazole_: To a suspension of NaH (0.196 g, 8.16 mmol) in THF (15 ml_) was added 4-bromo- 1 H-pyrazole (1 g, 6.80 mmol) in THF (5 ml_) at 0 °C, under nitrogen atmosphere, and strirred for 20 min. Ethyl iodide (0.825 ml_, 10.21 mmol) was added at 0 °C and stirred at RT for 2 h. The reaction mixture was quenched with cold water, and extracted with EtOAc (2X). The organic layer washed with brine, dried under anhydrous Na2S04and filtered. The filtrate was concentrated and was purified by column chromatography to afford 4- bromo-1-ethyl-1 H-pyrazole (900 mg, 5.12 mmol, 75 percent yield). LC-MS m/z 174 (M+H)+, 1.84 min (ret. time).
72%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 16 h;
Step 3: Synthesis of 4-bromo-1-ethyl-1H-pyrazole (4):j00341j To a stirred solution of NaH (34.0 g, 0.85 mol; 60percent in mineral oil) in THF (400 mL) was added a solution of 4-bromo-1H-pyrazole (50 g, 0.34 mol) in THF (100 mL) at 0 °C under inert atmosphere. The reaction mixture was warmed to RT and maintained at same temperature for 1 h. The reaction mixture was cooled again to 0 °C and added EtI (63.67 g, 0.408 mol) slowly for 5 mm. The resultant solution was allowed to warm to RT and then stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 250 mL). The combined organic extracts were dried over Na2504, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 4-6percent EtOAc/Hexanes) to afford compound 4 (43 g, 72percent) as a pale yellow liquid. 1H NMR (500 MHz, CDC13): ö 7.45 (s, 1H), 7.41 (s, 1H), 4.15 (q, J = 7.5 Hz, 2H), 1.47 (t, J = 7.5 Hz, 3H); MS (ES): mlz 175.0 (M + Hj.
72%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 16 h; Inert atmosphere
Step 3:
Synthesis of 4-bromo-1-ethyl-1H-pyrazole (4)
To a stirred solution of NaH (34.0 g, 0.85 mol; 60percent in mineral oil) in THF (400 mL) was added a solution of 4-bromo-1H-pyrazole (50 g, 0.34 mol) in THF (100 mL) at 0° C. under inert atmosphere.
The reaction mixture was warmed to RT and maintained at same temperature for 1 h.
The reaction mixture was cooled again to 0° C. and added EtI (63.67 g, 0.408 mol) slowly for 5 min.
The resultant solution was allowed to warm to RT and then stirred for 16 h.
After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3*250 mL).
The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude.
The crude was purified (silica gel chromatography; 4-6percent EtOAc/Hexanes) to afford compound 4 (43 g, 72percent) as a pale yellow liquid. 1H NMR (500 MHz, CDCl3): δ 7.45 (s, 1H), 7.41 (s, 1H), 4.15 (q, J=7.5 Hz, 2H), 1.47 (t, J=7.5 Hz, 3H); MS (ESI): m/z 175.0 (M+H+).
72%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 16 h;
To a stirred solution of NaH (34.0 g, 0.85 mol; 60percent in mineral oil) in THF (400 mL) was added a solution of 4-bromo-1H-pyrazole (50 g, 0.34 mol) in THF (100 mL) at 0 °C under inert atmosphere. The reaction mixture was warmed to RT and maintained at same temperature for 1 h. The reaction mixture was cooled again to 0 °C and added EtI (63.67 g, 0.408 mol) slowly for 5 mm. The resultant solution was allowed to warm to RT and then stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 250 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 4-6percent EtOAc/Hexanes) to afford compound 4 (43 g, 72percent) as a pale yellow liquid. 1H NMR (500 MHz, CDC13): ö 7.45 (s, 1H), 7.41 (s, 1H), 4.15 (q, J = 7.5 Hz, 2H), 1.47 (t, J = 7.5 Hz, 3H); MS (ES): m/z 175.0 (M + H).

Reference: [1] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 36
[2] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0150
[3] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 403
[4] Patent: WO2015/77503, 2015, A1, . Location in patent: Paragraph 00341
[5] Patent: US9051320, 2015, B1, . Location in patent: Paragraph 0258
[6] Patent: WO2016/191427, 2016, A1, . Location in patent: Paragraph 00324; 00327
[7] Patent: EP1186604, 2002, A1, . Location in patent: Page 113
  • 25
  • [ 2075-45-8 ]
  • [ 74-96-4 ]
  • [ 71229-85-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 6, p. 931 - 939
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 770 - 792
  • 26
  • [ 2075-45-8 ]
  • [ 73183-34-3 ]
  • [ 269410-08-4 ]
YieldReaction ConditionsOperation in experiment
94% With bis-triphenylphosphine-palladium(II) chloride; tetrabutylammomium bromide; potassium carbonate In 1,4-dioxane for 12 h; Inert atmosphere; Reflux Under a nitrogen atmosphere, 7.35 g of 1-H-4-bromopyrazole, 14.0 g of diboronic acid pinacol ester, 6.0 g of potassium acetate, 2.15 g of tetrabutylammonium bromide, 0.1 g were placed in a 500 ml four-necked flask. Pd(PPh3)2Cl2, and 100 ml of 1,4-dioxane was added thereto, and the mixture was stirred under reflux with heating for 12 hours, and was subjected to HPLC. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was filtered under reduced pressure.Swirled white product 8.8g,Yield 94.0percent,HPLC 98.4percent.
Reference: [1] Patent: CN108997309, 2018, A, . Location in patent: Paragraph 0016
[2] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 43; 44
  • 27
  • [ 2075-45-8 ]
  • [ 540-51-2 ]
  • [ 214614-81-0 ]
YieldReaction ConditionsOperation in experiment
86% With potassium hydroxide; potassium iodide In ethanol at 155℃; for 8 h; microwave The mixture of 8d (400mg, 2.72mmol), KI (671mg, 4.04mmol), KOH (290mg, 5.2mmol) and 22a (625mg, 5.0mmol) in EtOH (1OmL) were reacted under microwave condition at 1550C for 8h. After the reaction was complete, the mixture was cooled, filtered and evaporated. The residue was dissolved in 2OmL of EtOAc 15 and washed with 2OmL of water, dried over Na2SO4 and concentrated to give 22b (0.45g, 86percent yield) as yellow oil.
65% With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 90℃; for 2 h; To a solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol) in 20 mL of DMF was successively added 2-bromoethanol (0.53 mL, 7.48 mmol), Cs2CO3 (2.66 g, 8.16 mmol) and TBAI (503 mg, 1.36 mmol). The resulting mixture was heated at 90 °C for 2 h and diluted with 60 mL of water. The mixture was extracted with EA (3 × 100 mL). The combined organic layer was washed with water (3 × 50 mL), brine (60 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash column chromatography (0-30percent EA/PE gradient) to afford 27 as light yellow oil in 65percent yield. 1H NMR (300 MHz, CDCl3) δ 7.49 (s, 1H), 7.48 (s, 1H), 4.23 (t, J = 4.8 Hz, 2H), 3.99 (t, J = 4.8 Hz, 2H), 2.73 (br, 1H).
Reference: [1] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 47
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
  • 28
  • [ 96-49-1 ]
  • [ 2075-45-8 ]
  • [ 214614-81-0 ]
YieldReaction ConditionsOperation in experiment
34%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 20℃;
General Procedure 77
To a stirred solution of 4-bromo-1H-pyrazole in DMF was added sodium hydride at room temperature.
The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature.
The reaction was monitored by TLC.
After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated.
The residue was purified by silica gel, eluants EtOAc and DCM 10percent, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34percent. 1H NMR (400 MHz, chloroform-D) δ ppm 7.49 (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).
34%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 20℃;
To a stirred solution of 4-bromo-1 H-pyrazole in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel, eluants EtOAc and DCM 10percent, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34percent. 1H NMR (400 MHz, chloroform-D) 6 ppm 7.49 (s, 1 H) 7.46 (s, 1 H) 4.18 - 4.23 (m, 2 H) 3.93 - 3.98 (m, 2 H) 3.09 (s, 1 H).
Reference: [1] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 71
[2] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 84
  • 29
  • [ 2075-45-8 ]
  • [ 1072-53-3 ]
  • [ 214614-81-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4115 - 4134
  • 30
  • [ 2075-45-8 ]
  • [ 141699-59-4 ]
  • [ 877399-50-3 ]
YieldReaction ConditionsOperation in experiment
77% at 80℃; for 12 h; Large scale 2.08 kg of cesium carbonate,0.78 kg of 4-bromopyrazole was dissolved in 4 liters of N-methylpyrrolidone,Heated to 80 degrees,A 5 liter solution of N-methylpyrrolidone was added to 1.8 kg of compound (CZT-7)Reaction for 12 hours.Cooled to room temperature,Add 50 litersMethyl tert-butyl etherwith50 liters of water,Stir for 1 hour.After dispensing,The organic phase was washed with 20 liters of * 4 water and dried 50percentLiter of hexane and stirred at room temperature for 2 hours. Filtered and dried to give 1.35 kg of compound (CZT-8) in a yield of 77percent
58%
Stage #1: With sodium hydride In dichloromethane at 0℃; for 1 h;
Stage #2: at 110℃;
B. To a cold solution (0 °C) of 4-bromo-lH-pyrazole (14.9 g, 0.10 mol) in 80 mL of dichloromethane was added sodium hydride (8.13 g, 0.20 mol) portion wise. The mixture was stirred at 0 °C for 1 hour, followed by the addition of a solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (34.0 g, 0.12 mol) in 30 mL of N,N-dimethylformamide. The resulting mixture was heated at 110 °C overnight. Purification by column chromatography afforded tert-butyl 4-(4-bromo-lH- pyrazol-l-yl)piperidine-l-carboxylate as a yellow oil in 58percent yield (19.5 g). 1H NMR (400 MHz, CDC13) δ 7.48 (s, 1H), 7.44 (s 1H), 4.35-4.20 (m, 3H), 2.95-2.85 (m, 2H), 2.15-2.05 (m, 2H), 1.92-1.81 (m, 2H), 1.48 (s, 9H).
45%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 100℃;
To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0° C., was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol).
The solution was stirred for 1 hour at 0° C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g, 71.03 mmol) was added slowly and the reaction was heated to 100° C. overnight or until consumption of the pyrazole by NMR.
The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc.
The combined extracts were washed with saturated aqueous NaCl (4*20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil.
The oil was purified using silica gel chromatography eluding with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a Rf=0.4 (25percent EtOAc/hexanes, using iodine as the stain).
1H NMR (CDCl3, 400 MHz) δ 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H).
45%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 100℃;
To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0°C, was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0°C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g , 71.03 mmol) was added slowly and the reaction was heated to 100°C overnight or until consumption of the pyrazole by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCI (4 x 20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil. The oil was purified using silica gel chromatography eluting with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a R^= 0.4 (25percent EtOAc/hexanes, using iodine as the stain). 1H NMR (CDCI3, 400 MHz) 8 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88(m, 2H), 1.47(s, 9H).

Reference: [1] Patent: CN106317024, 2017, A, . Location in patent: Paragraph 0060; 0061
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
[3] Patent: WO2015/81257, 2015, A2, . Location in patent: Page/Page column 81
[4] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[5] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 64-65
[6] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 74; 75
[7] Patent: WO2008/148867, 2008, A2, . Location in patent: Page/Page column 51-52
[8] Patent: WO2010/48131, 2010, A1, . Location in patent: Page/Page column 54
[9] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 31
[10] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[11] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0136
[12] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[13] Patent: WO2009/150240, 2009, A1, . Location in patent: Page/Page column 119
  • 31
  • [ 2075-45-8 ]
  • [ 141699-58-3 ]
  • [ 877399-34-3 ]
YieldReaction ConditionsOperation in experiment
98% With sodium hydride In N,N-dimethyl-formamide at 110℃; for 0.5 h; Microwave irradiation A 5 mL microwave tube was charge with compound (2-4) (304 mg, 1.21 mmol); 4-bromopyrazole (2-5, 178 mg, 1.21 mmol) and NaH 60percent in mineral oil (73 mg, 1.82 mmol.) with 2 mL of DMF. The resulting mixture was microwaved at 110 C. for 30 minutes. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2x50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then concentrated by vacuum to afford 360 mg of (L) as yellow oil (98percent). 1H NMR (400 MHz, DMSO-D6) ? ppm 1.36-1.43 (m, 9H) 4.08 (s, 2H) 4.18-4.31 (m, 2H) 5.12-5.22 (m, 1H) 7.67 (s, 1H) 8.14 (s, 1H).
98% With sodium hydride In N,N-dimethyl-formamide at 110℃; for 0.5 h; Microwave irradiation A 5 mL microwave tube was charge with compound (2-4) (304 mg, 1.21 mmol); 4-bromopyrazole (2-5. 178 mg, 1.21 mmol) and NaH 60percent in mineral oil (73 mg, 1.82 mmol.) with 2 mL of DMF. The resulting mixture was microwaved at 110°C for 30 minutes. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x 50 mL);brine (50 mL). The organic layer was dried (Na2SO4), then concentrated by vacuum to afford 360 mg of (2-6) as yellow oil (98percent). 1H NMR (400 MHz, DMSO-D6) 6 ppm 1.36 - 1.43 (m, 9 H) 4.08 (s, 2 H) 4.18 - 4.31 (m, 2 H) 5.12 - 5.22 (m, 1 H) 7.67 (s, 1 H) 8.14 (s, 1 H).
Reference: [1] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 57-58
[2] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 62-63; 64
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
  • 32
  • [ 2075-45-8 ]
  • [ 4333-56-6 ]
  • [ 1151802-23-1 ]
YieldReaction ConditionsOperation in experiment
68% With caesium carbonate In N,N-dimethyl-formamide at 180℃; for 1.5 h; Microwave irradiation Step 1 : 4-Bromo- 1 -cyc A mixture of 4-bromo-lH-pyrrazole (1.0 g, 6.8 mmol), bromo cyclopropane (1.3 g, 10.7 mmol), cesium carbonate (3.5 g. 10.7 mmol), and DMF (6 mL) in a 30 mL microwave vial is heated to 180 °C under radiation for 1.5 hr. After cooled to room temperature, the reaction mixture is filtered. The filtrate is concentrated and the residue is purified on a silica gel flash chromatography with ethyl acetate/petroleum ether (1 :5) to get a brown liquid (0.87 g, 68percent yield). (MS: [M+l] 259)
Reference: [1] Patent: WO2014/32498, 2014, A1, . Location in patent: Page/Page column 14
[2] Patent: US2015/31673, 2015, A1, . Location in patent: Paragraph 0334
  • 33
  • [ 2075-45-8 ]
  • [ 624-92-0 ]
  • [ 1393128-21-6 ]
YieldReaction ConditionsOperation in experiment
3300 mg
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 1.33333 h;
Stage #2: at 0℃;
Step 1 : 4-(Methylthio)-1H-pyrazole A suspension of 4-bromopyrazole (4 g, 27 mmol) in tetrahydrofuran (68 mL) was cooled to 0°C and n-butyllithium (2.5 M in hexanes, 35.9 mL, 90 mmol) was added dropwise over a period of 20 min. The reaction mixture was stirred at room temperature for 1 h and then was cooled to 0°C. 1 ,2-Dimethyldisulfide (2.66 mL, 30.0 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1.5 h. The reaction mixture was poured into water (150 mL) and then it was acidified to pH~8 with a saturated aqueous solution of ammonium chloride and a solution of aqueous hydrochloric acid (1 N). The mixture was extracted with ethyl acetate (150 mL x 3) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(methylthio)-1 H-pyrazole (3300 mg). 1H NMR (500 MHz, CDCI3) δ 2.36 (s, 3H), 7.63 (s, 2H).
Reference: [1] Patent: WO2013/150416, 2013, A1, . Location in patent: Page/Page column 102
[2] Patent: WO2014/169833, 2014, A1, . Location in patent: Page/Page column 131
  • 34
  • [ 2075-45-8 ]
  • [ 24424-99-5 ]
  • [ 1150271-23-0 ]
YieldReaction ConditionsOperation in experiment
98% With dmap; triethylamine In acetonitrile at 20℃; for 2 h; Step 1: Preparation of tert-butyl 4-bromo-lH-pyrazole-l-carboxylate B [00161] Boc anhydride (2.34 niL, 10.2 mmol) was added to a solution of 4-bromo-lH- pyrazole (1 g, 6.8 mmol), triethylamine (3.3 raL, 23.8 mmol) and 4-dimethylaminopyridine (0.166 g, 1.36 mmol) in acetonitrile (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (100 niL x 3). The combined organic extract was washed with water (100 mL), brine (100 raL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 10percent ethyl acetate in hexane to afford the title compound tert-butyl 4- bromo-1 H-pyrazole- 1 -carboxylate (1.65 g, 98percent yield) as a colorless liquid. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDCls) δ 8.09 (s, 1H), 7.66 (s, 1H), 1.65 (s, 9H).
93% With triethylamine In dichloromethane at 20℃; 4-Bromo-1H-pyrazole, 5.00 g (34.0 mmol), di-tert-butyl dicarbonate, 8.17 g (37.4 mmol), and triethylamine, 7.57 g (74.8 mmol), were added into 50 mL of dichloromethane. The resulting mixture was stirred at room temperature for overnight. The resulting mixture was purified by silica gel column chromatography to give 8.00 g (93percent) of the product as an off-white solid. MS (ESIpos): m/z = 247 [M+H]+. LC-MS [method 4, gradient starting with water (0.1 percentHCOOH)-Acetonitrile, 10percentB]: Rt = 1.75 min.
92% at 30 - 45℃; Large scale In the reaction kettle, add 4 - brompyrazole (1.47 kg, 10 µM) and tetrahydrofuran 6 kg, stirring to dissolve, heating to 30 - 40 °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 45 °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 - brompyrazole 2.01 kg, yield 92percent, HPLC: 98.3percent.
86% With triethylamine In dichloromethane at 25℃; for 1 h; To a mixture of 4-bromo- lH-pyrazole (500 mg, 3.40 mmol) in DCM (10 mL) was added Boc20 (0.790 mL, 3.40 mmol) and Et3N (0.948 mL, 6.80 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to afford fert-butyl 4-bromo- lH-pyrazole-l-carboxylate (800 mg, 2.91 mmol, 86percent yield). TLC (PE/EA = 2: 1, Rf = 0.6): lH NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.77 (s, 1H), 1.63 (s, 9H). ES-LCMS m/z 148.0 (M-Boc+H).
79.6% 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: WO2016/49165, 2016, A1, . Location in patent: Paragraph 00161
[2] Patent: WO2018/172250, 2018, A1, . Location in patent: Page/Page column 300
[3] Patent: CN106188116, 2016, A, . Location in patent: Paragraph 0016
[4] Patent: WO2014/141187, 2014, A1, . Location in patent: Page/Page column 142
[5] Arkivoc, 2014, vol. 2014, # 6, p. 54 - 71
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