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Chemical Structure| 269410-08-4
Chemical Structure| 269410-08-4
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Product Details of [ 269410-08-4 ]

CAS No. :269410-08-4 MDL No. :MFCD03453063
Formula : C9H15BN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :TVOJIBGZFYMWDT-UHFFFAOYSA-N
M.W : 194.04 Pubchem ID :2774010
Synonyms :
Chemical Name :4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Calculated chemistry of [ 269410-08-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.67
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 55.06
TPSA : 47.14 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.2
Log Po/w (WLOGP) : 0.71
Log Po/w (MLOGP) : 0.0
Log Po/w (SILICOS-IT) : 0.87
Consensus Log Po/w : 0.55

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.0
Solubility : 1.95 mg/ml ; 0.0101 mol/l
Class : Very soluble
Log S (Ali) : -1.79
Solubility : 3.17 mg/ml ; 0.0164 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.84
Solubility : 0.282 mg/ml ; 0.00145 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.76

Safety of [ 269410-08-4 ]

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 [ 269410-08-4 ]

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

  • Upstream synthesis route of [ 269410-08-4 ]
  • Downstream synthetic route of [ 269410-08-4 ]

[ 269410-08-4 ] Synthesis Path-Upstream   1~71

  • 1
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Reference: [1] Patent: WO2008/116620, 2008, A1, . Location in patent: Page/Page column 171
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  • [ 74-88-4 ]
  • [ 761446-44-0 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 4 h; To the solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.06 mmol) in THF (10 mL) was added NaH (0.1.00 g, 4.12 mmol) followed by methyl iodide (0.25 mL, 4.12 mmol) at 0° C and the reaction mixture was stirred at ambient temperature for 4 hr. The reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and distilled under reduced pressure to obtain Intermediate 108 (0.40 g, 93.00percent) as yellow viscous liquid.1H NMR (400 MHz, CDCl3) δ ppm 1.31 (s, 12 H), 3.91 (s, 3 H), 7.65 (s, 1 H), 7.77 (s, 1 H). LCMS (Method-D): retention time 1.58 min, [M+1] 209.1.
90% With sodium hydride In tetrahydrofuran at 20℃; To the solution of 4-pinacolatoboron-lH-pyrazole (1.0 g, 5.0 mmol) in THF (30 mL) was added NaH (0.4 g, 10 mmol). After addition of NaH was completed, to the reaction mixture was added CH3I (1.42 g, 10 mmol) and stirred overnight at room temperature. The reaction was quenched <n="139"/>with MeOH (1 mL). The result mixture was concentrated to give residues, purification by chromatography (EA:PE=l : 10) to give compound l-methyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.9 g, 90percent) as light yellow solid. MS (m/z) (M++Η): 209
72% With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 3 h; To a solution of 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H- pyrazole (0. 19g, 1.0 mmol) in 4 ml DMF was added Mel (0. 067 ml, 1.1 eq) and Cs2C03 (0.39g, 1.2 eq). The reaction mixture was stirred at RT for 3h. The solution was taken up into EtOAc, washed with water, brine, dried over Na2SO4 and concentrated. 150mg crude product was obtained (yield 72percent).
Reference: [1] Patent: WO2018/93569, 2018, A1, . Location in patent: Page/Page column 189
[2] Patent: WO2009/155527, 2009, A2, . Location in patent: Page/Page column 137-138
[3] Patent: WO2005/85227, 2005, A1, . Location in patent: Page/Page column 90-91
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  • [ 761446-44-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 7934 - 7937
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  • [ 75-03-6 ]
  • [ 847818-70-6 ]
YieldReaction ConditionsOperation in experiment
77% With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h; To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.0 g, 5.2 mmol) in DMF (10 mL) were added cesium carbonate (2.5 g, 7.7 mmol) and iodoethane (1.2 mL, 15 mmol) . The mixture was stirred at rt for 12 h and diluted with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combinded orgainc layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 2/1 to give a colorless oily product (880 mg, 77) .[1505]MS (ESI, pos. ion) m/z: 223.25 [M+1]+
74%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: at 20℃; for 72 h;
(107a)
1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Sodium hydride (55percent, oil, 0.54 g, 12 mmol) was suspended in N,N-dimethylformamide (20 mL), and a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10 mmol) in N,N-dimethylformamide (5 mL) was added thereto.
The resulting mixture was stirred at room temperature for 1 hr, and then iodoethane (2.4 g, 16 mmol) was slowly added dropwise thereto.
The resulting mixture was stirred at room temperature for 3 days.
To this reaction solution, water was added.
After extraction with diethyl ether, the organic layer was washed with water and brine, and then dried with anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Yamazen, eluding solvent: hexane and ethyl acetate) to obtain 1.7 g (yield: 74percent) of the title compound as a colorless oily material.
1H-NMR (400 MHz, CDCl3) δ ppm: 7.78 (1H, s), 7.70 (1H, s), 4.19 (2H, q, J = 7.3 Hz), 1.49 (3H, t, J = 7.3 Hz), 1.32 (12H, s).
38% With potassium carbonate In N,N-dimethyl acetamide at 60℃; Step 8
1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.0 g), N,N-dimethylacetamide (50 ml), potassium carbonate (5.3 g) and ethyl iodide (2.1 ml) were mixed, and the mixture was stirred at 60° C. overnight.
The reaction mixture was cooled to room temperature, water (100 ml) and ethyl ether (100 ml) were added, and the mixture was partitioned in a separatory funnel.
The aqueous layer was further extracted with ethyl ether (100 ml), and the organic layers were combined.
The organic layer was washed 3 times with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was partitioned in a separatory funnel.
The organic layer was washed 3 times with water (40 ml) and once with saturated brine (40 ml), dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give the title compound (2.1691 g, 38percent).
1H-NMR (CDCl3) δ: 7.79 (1H, s), 7.70 (1H, s), 4.19 (2H, q, J=7.3 Hz), 1.49 (3H, t, J=7.3 Hz), 1.32 (12H, s).
27%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h;
Stage #2: for 48 h;
NaH 60percent dispersion in mineral oil (50.0 mg, 1.24 mmol) was suspended in DMF (2 mL) followed by the addition of a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1H-pyrazole (200 mg, 1.03 mmol) in DMF (550 pL). The resulting mixture was stirred at r.t. for ihour. lodomethane (132 pL, 1.6Smmol) was added dropwise and stirring was continued for 2 days. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. Dried Mg504, filtered and concentrated in vacuo. The product was purified by flash chromatography (dry packing) on silica gel using a gradient 0 to 30percent EtOAc in hexanes and afforded the title compound (62.7 mg, 0.28 mmol, 27percent) as a yellow oil.

Reference: [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00655
[2] Patent: EP1798229, 2007, A1, . Location in patent: Page/Page column 130
[3] Patent: US2010/240634, 2010, A1, . Location in patent: Page/Page column 67-68
[4] Patent: WO2018/102452, 2018, A2, . Location in patent: Paragraph 425; 426
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5299 - 5302
[6] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 163
[7] Patent: WO2013/91096, 2013, A1, . Location in patent: Page/Page column 67
[8] Patent: WO2014/111871, 2014, A1, . Location in patent: Page/Page column 162; 163
[9] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 270 - 285
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  • [ 74-96-4 ]
  • [ 847818-70-6 ]
Reference: [1] Patent: WO2011/79804, 2011, A1, . Location in patent: Page/Page column 41
[2] Patent: US2012/245178, 2012, A1, . Location in patent: Page/Page column 25
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  • [ 269410-08-4 ]
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Reference: [1] Patent: WO2016/196644, 2016, A1, . Location in patent: Paragraph 441; 442
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  • [ 425-75-2 ]
  • [ 847818-70-6 ]
Reference: [1] Patent: WO2017/178416, 2017, A1, . Location in patent: Page/Page column 115; 116
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Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 270 - 285
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  • [ 6482-24-2 ]
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YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In N,N-dimethyl-formamide at 160℃; for 2 h; Microwave irradiation A mixture of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (1.94 g, 10 mmol), 2-bromoethyl methyl ether (1.68 g, 12 mmol) and K2C03 (2.76 g, 20 mmol) in DMF (16 mL) was stirred at 160 °C for 2 h in the microwave. The reaction mixture was concentrated and purified by silica gel chromatography (30percent EA:PE) to give 2.2 g (90percent) of the title compound as yellow oil. ‘H NMR (400 MHz, CDC13): ö 1.32 (12H, s), 3.32 (3H, s), 3.75 (2H, t, J= 5.2 Hz), 4.30 (2H, t, J= 5.2 Hz), 7.77 (1H, s), 7.79 (1H, s). [M+H] Calc’d for C,2H2,BN203, 253; Found, 253.
68% With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 0.5 h; Microwave irradiation Example A68Preparation of intermediate 68: l-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl- [l,3,21dioxaborolan-2-yl)-7H-pyrazoleA mixture of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-7H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150 °C for 30 min. under microwave irradiation. The mixture was partitioned between water and diethyl ether. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
68% With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 0.5 h; microwave irradiation Example A68
Preparation of intermediate 68: 1-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150° C. for 30 min. under microwave irradiation.
The mixture was partitioned between water and diethyl ether.
The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70).
The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
57% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; 2-Bromoethyl methyl ether (0.93 g, 6.70 mmol, 0.64 mL) was added to a mixture of 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine(3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method L7; 12 g; heptane, 10percent-30percent ethyl acetate) afforded 0.74 g (2.92 mmol; 57percent of theory) of the title compound.GO-MS (Method L9): R1 = 4.21 mm; m/z = 251 MH NMR (300 MHz, Ohloroform-d, Method M2) 6 7.79 (s, 1 H), 7.76 (s, 1 H), 4.29 (t, J = 5.3 Hz,2H), 3.75 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H), 1.31 (s, 12H).
56%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.25 h;
Stage #2: at 80℃; for 1 h; Microwave irradiation
General procedure: Preparation 122: 1 -(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- Method H NaH (60percent, 83 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 - -pyrazole (204 mg, 1 .05 mmol) in DMF (4 mL). After stirring for 15 minutes, 1 -bromo-2-methoxyethane (175 mg, 1 .26 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80°C under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2S04j and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (148 mg, 56percent). 1 H NMR (500 MHz, CDCI3): δ 7.80 (d, J = 0.7 Hz, 1 H), 7.77 (d, J = 0.7 Hz, 1 H), 4.31 (t, = 5.3 Hz, 2H), 3.76 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 1.32 (s, 12H). LCMS (ESI) Rt = 2.17 minutes MS m/z 253 [M+H]+
26%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h;
Stage #2: at 0 - 20℃; for 1 h;
To a solution of 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .00 g, 5.1 mmol) in DMF (5 mL) was added sodium hydride (245 mg of a 60percent dispersion in mineral oil, 6.1 mmol) at room temperature. The mixture was then stirred at room temperature for 60 minutes. The mixture was cooled to 0 ° C and 2-bromoethyl methyl ether (0.72 mL, 7.7 mmol) was added drop wise via syringe. After complete addition, the mixture was allowed to warm to room temperature and stirred for an hour prior to addition of ethyl acetate (70 mL) and water (30 mL). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 mL), dried (Na2S04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50percent EtOAc in heptane] to give the title compound (333 mg, 26percent yield) as a colourless oil. 1H NMR (250 MHz, DMSO-d6) δ [ppm] 7.88 (s, 1 H), 7.57 (s, 1 H), 4.32 - 4.20 (m, 2H), 3.73 - 3.60 (m, 2H), 3.21 (s, 3H), 1 .25 (s, 12H). LCMS (Analytical Method A): Rt = 1 .01 mins, MS (ESIPos): m/z = 253 (M+H)\
20% With potassium hydroxide In ethanol at 50℃; for 76 h; Intermediate 1171 -[2-(Methyloxy)ethyl]-4-(4,4,5,5-tetrameth l-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazolA solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10 g, 51 .5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61 .8 mmol) and 1 -bromo-2- (methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50°C under nitrogen for 16 h then cooled to room temeprature. 1 -Bromo-2- (methyloxy)ethane (2 ml_, 21 .3 mmol) was added and the resulting mixture was stirred at 50°C for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1 -[2-(methyloxy)ethyl]-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+ = 252.9
20% With potassium hydroxide In ethanol at 50℃; for 66 h; Inert atmosphere A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61.8 mmol) and 1-bromo-2-(methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50° C. under nitrogen for 16 h then cooled to room temperature. 1-Bromo-2-(methyloxy)ethane (2 mL, 21.3 mmol) was added and the resulting mixture was stirred at 50° C. for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+=252.9
25.4 g With caesium carbonate In N,N-dimethyl-formamide at 80℃; 4-(4,4,5,5-Tetramethyl-[1 ,3,2]clioxaborolan-2-yl)-1 H-pyrazole (19.4 g, 0.10 mol), 1- bromo-2-methoxy-ethane (14.18 ml, 0.15 mol), and caesium carbonate (32.58 g, 0.1 mol) are dissolved in DMF (200 ml). The suspension is stirred for 16 h at 80°C, filtered and the solvent is removed in vacuum. The residue is treated with tert-butyl methyl ether (200 ml), filtered over Celite and then the solvent is removed in vacuum; yield: 25.4 g 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa- borolan-2-yl)-1H-pyrazole; HPLC/MS: 1.82 min, [M+H] = 253.
1.31 g With caesium carbonate In acetonitrile at 50℃; Inert atmosphere 1H-pyrazole-4-boronic acid pinacol ester (1.0 g, 5.155 mmol),2-Bromoethyl methyl ether (0.788 g, 5.669 mmol)And cesium carbonate (5.04 g, 15.469 mmol) were dissolved in acetonitrile (20 mL),The mixture was stirred under nitrogen at 50 ° C overnight,filter,Concentrate to dryness to give 1- (2-methoxyethyl) -1H-pyrazole-4-boronic acid pinacol ester (1.310 g).

Reference: [1] Patent: WO2014/151106, 2014, A1, . Location in patent: Paragraph 00179
[2] Patent: WO2011/51342, 2011, A1, . Location in patent: Page/Page column 95
[3] Patent: US2011/269752, 2011, A1, . Location in patent: Page/Page column 42
[4] Patent: WO2017/178416, 2017, A1, . Location in patent: Page/Page column 115
[5] Patent: WO2014/37751, 2014, A1, . Location in patent: Paragraph 00416-00418
[6] Patent: WO2018/114786, 2018, A1, . Location in patent: Page/Page column 142
[7] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 106-107
[8] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 48
[9] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 154
[10] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 169
[11] Patent: WO2012/167423, 2012, A1, . Location in patent: Page/Page column 35-36
[12] Patent: WO2013/117285, 2013, A1, . Location in patent: Page/Page column 82; 83
[13] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0166; 0167
[14] Patent: CN107312005, 2017, A, . Location in patent: Paragraph 0474; 0475; 0476; 0477
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YieldReaction ConditionsOperation in experiment
100% With caesium carbonate In N,N-dimethyl-formamide at 160℃; for 0.5 h; Microwave irradiation 4-( 4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 00 mg, 0.52mmol), 1-chloro-2-methoxyethane (0.056 mL, 0.62 mmol) and cesium carbonate (252mg, 0.73 mmol) in DMF (1 mL) were heated in microwave reactor at 160 °C for 30 min.The reaction mixture was concentrated under reduced pressure and purified by silica gelchromatography (ISCO, hexanes/ethyl acetate 0-100percent over 15 min) to isolate CompoundB162a (130 mg, 100percent yield). HPLC: RT = 1.0 min (LCMS Method M). MS (ES): m/z= 253.0 [M+H( 1H NMR (500MHz, CHLOROFORM-d) 8 8.04 (s, 1H), 7.83 (d,J=18.4 Hz, 1H), 4.37 (t, J=5.2 Hz, 1H), 3.78 (t, J=5.2 Hz, 1H), 3.38-3.31 (m, 2H), 2.98(s, 3H), 2.90 (s, 3H), 1.34 (s, 6H), 1.26 (s, 3H).
72% With caesium carbonate In N,N-dimethyl-formamide at 160℃; for 0.5 h; microwave irradiation 2-Chloroethyl methyl ether (0.050 ml, 0.63 mmol) was added to a stirred solution of 4- (4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.77 mmol) and cesium carbonate (12.59 g, 38.65 mmol) in DMF (27 ml). The mixture was stirred at 160 °C for 30 min. under microwave irradiation and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 2/98). The desired fractions were collected and evaporated in vacuo to yield intermediate 67 (4.6 g, 72percent) as a pale yellow oil.
72% With caesium carbonate In N,N-dimethyl-formamide at 160℃; for 0.5 h; Microwave irradiation Example A67
1-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
2-Chloroethyl methyl ether (0.050 ml, 0.63 mmol) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 25.77 mmol) and cesium carbonate (12.59 g, 38.65 mmol) in DMF (27 ml).
The mixture was stirred at 160° C. for 30 min. under microwave irradiation and then the solvent was evaporated in vacuo.
The crude product was purified by flash column chromatography (silica; MeOH in DCM 2/98).
The desired fractions were collected and evaporated in vacuo to yield intermediate 67 (4.6 g, 72percent) as a pale yellow oil.
Reference: [1] Patent: WO2014/15088, 2014, A1, . Location in patent: Paragraph 00223
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4196 - 4212
[3] Patent: WO2011/110545, 2011, A1, . Location in patent: Page/Page column 95-96
[4] Patent: US2012/329792, 2012, A1, . Location in patent: Page/Page column 46
  • 11
  • [ 269410-08-4 ]
  • [ 5407-04-5 ]
  • [ 847818-72-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
  • 12
  • [ 269410-08-4 ]
  • [ 109-54-6 ]
  • [ 847818-72-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5299 - 5302
  • 13
  • [ 269410-08-4 ]
  • [ 76-83-5 ]
  • [ 863238-73-7 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 1, p. 211 - 217
  • 14
  • [ 1029716-44-6 ]
  • [ 269410-08-4 ]
YieldReaction ConditionsOperation in experiment
94% With hydrogenchloride; 2,3-dimethyl-2,3-butane diol In water at 10 - 25℃; for 4.083 h; 1 -( 1 -Ethoxyethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-l H-pyrazole (60.00 g, 224 mmol) is combined with CPME (120 mL) and 2,3-dimethylbutane-2,3-dtol (26.49 g, 224 mmol). The reaction is cooled to 5-10 °C then a solution of anhydrous HQ in CPME (3.1 M, 86.8 mL, 269 mmol) is added over 15 minutes, followed by additional CPME (15 mL). The reaction is stirred at 20-25 °C and monitored for completion. After 7 hours, additional HCI solution (3 mL, 9.3 mmol) is added to the reaction and stirring is continued for an additional 15 hours to give 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l H-pyrazole hydrochloride salt, which is not isolated.mL) is added over 10 minutes. The reaction mixture temperature increases to 20 °C following the addition. Additional CPME (10 mL) is added and the reaction mixture is stirred for 15 minutes then cooled in an ice bath. After 3 hours the reaction mixture is filtered and the solid (triethylamine hydrochloride) is washed with cold CPME (3 x 60 mL). The filtrate and washes are combined to give 426 g of solution containing 102,3 mg of 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazo]e/g solution (total 8.15 g, 94percent )yield of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyTazole) which is used directly in the next step.
77.3% With hydrogenchloride; 2,3-dimethyl-2,3-butane diol In tert-butyl methyl ether; 1,2-dichloro-ethane at 0 - 20℃; Large scale 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1) [0166] To a mixture of 2,3-dimethylbutane-2,3-diol (25.0 kg, 211.6 mol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24, 55.0 kg, 206.7 mol) in 1,2-dichloroethane (750 kg) was slowly added a solution of HCl in MTBE (25.0 kg, 20-30percent of HCl) at 0-5° C. The resulting reaction mixture was then stirred at 10-20° C. for 3-5 hours. After the selective deprotection reaction was complete as monitored by HPLC (1: below 1percent), the reaction mixture was degassed and refilled with nitrogen before being cooled to −15° C. The cooled reaction mixture was then added triethylamine (TEA, 30.0 kg, 296.5 mol) to adjust pH to 7-8. The mixture was then gradually warmed to ambient temperature before being treated with water (150 kg). The two phases were separated and the organic layer was washed with brine (60 kg) and dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the resulting solution was concentrated under reduced pressure at 40-50° C. to a thick oil. The residue was warmed to 60-70° C. and diluted with petroleum ether (100 kg) at the same temperature. The resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C. and stirred at the same temperature for 3 hours. The solids was collected by centrifugation and dried at 50-60° C. under vacuum to afford the crude desired product (1, 33.75 kg, 40.11 kg theoretical, 84.1percent). The crude desired product was then suspended in 1,2-dichloroethane (30 kg) and the resulting mixture was heated to reflux until a clear solution was formed. To the hot solution was then added petroleum ether (150 kg) at the same temperature. The resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C. and stirred and the same temperature for 3 hours. The solids were collected by centrifugation and dried under vacuum at 50-60° C. to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 31.0 kg, 40.11 kg theoretical, 77.3percent) as an off-white solid, which is identical in every comparable aspect to the material synthesized by the synthetic method as described above in Example 5.
Reference: [1] Patent: WO2016/205487, 2016, A1, . Location in patent: Page/Page column 27-28
[2] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0166
  • 15
  • [ 557087-01-1 ]
  • [ 1150271-23-0 ]
  • [ 269410-08-4 ]
YieldReaction ConditionsOperation in experiment
76% With n-Bu3MgLi In tetrahydrofuran at -20 - -10℃; Large scale In the reaction kettle, adding tetrahydrofuran 4.5 kg and 1 - BOC - 4 - brompyrazole (2.01 kg, 9.2 µM), stirring 0.5 hours, cooling to -20 °C, maintain -10 °C -0 °C dropwise 3.2molBu3MgLi [preparation method: 1.0eq butyl magnesium chloride in -10 °C -0 °C lower drop by adding 2.0 equivalent butyl lithium in], TLC detection reaction, maintain the exchange completion -10 °C -0 °C dropwise dimethylamine fundamental frequency that mellow boron ester (1.61 kg, 9.4 µM) dissolved in 1 kg of the mixed solution in tetrahydrofuran, the completion of the dropping, thermal insulation 2 hours, natural heating stirring overnight. The control temperature of not more than 30 °C after adding glacial acetic acid, after detecting the protecting group removal, stop stirring filtration, the mother liquor recovered, solid add triethylamine (1.01 kg, 10 µM) and ethyl acetate 8 kg after, heating to reflux reaction, the proportion of internal standard detecting product is not increased when, after lowering the filtering, the filtrate obtained after the distillation is a kind of white solid, by adding heptane cooling to 0 °C beating, filtering, 50 - 60 °C vacuum drying to obtain white solid pyrazole -4 - boric acid frequency that alcohol ester 1.36 kg, GC: 99.1percent, HNMR consistent with the literature value, yield 76percent.
Reference: [1] Patent: CN106188116, 2016, A, . Location in patent: Paragraph 0016; 0017
  • 16
  • [ 121669-70-3 ]
  • [ 557087-01-1 ]
  • [ 269410-08-4 ]
YieldReaction ConditionsOperation in experiment
79% With iPrBu2MgLi In 2-methyltetrahydrofuran at -20 - -10℃; Large scale In the reaction kettle, add 2 - methyl tetrahydrofuran 4.5 kg and 1 - BOC - 4 - iodine pyrazole (2.65 kg, 9.0 µM), stirring 0.5 hours, cooling to -20 °C, maintain -10 °C -0 °C dropwise 2.95 µM Bu3MgLi [preparation method: 1.0eq isopropyl magnesium chloride in -10 °C -0 °C lower drop by adding 2.0 equivalent butyl lithium in], TLC detection reaction, maintain the exchange completion -10 °C -0 °C dropwise dimethylamine fundamental frequency that mellow boron ester (1.57 kg, 9.2 µM) dissolved in 1 kg of the mixed solution in tetrahydrofuran, the completion of the dropping, thermal insulation 2 hours, natural heating stirring overnight. The control temperature of not more than 20 °C hydrogen chloride gas, after detecting the protecting group removal, stop stirring filtration, the mother liquor recovered, solid add triethylamine (1.01 kg, 10 µM) and ethyl acetate 10 kg after, heating to reflux reaction, the proportion of internal standard detecting product is not increased when, after lowering the filtering, the filtrate obtained after the distillation yellow solid, adding hexane cooling to 0 °C beating, filtering, 50 - 60 °C vacuum drying to obtain white solid pyrazole -4 - boric acid frequency that alcohol ester 1.38 kg, GC: 99.5percent, HNMR consistent with the literature value, yield 79percent.
Reference: [1] Patent: CN106188116, 2016, A, . Location in patent: Paragraph 0018; 0019
  • 17
  • [ 61676-62-8 ]
  • [ 269410-08-4 ]
YieldReaction ConditionsOperation in experiment
54.8%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -6 - 0℃; Inert atmosphere
Stage #2: at 0 - 20℃; Inert atmosphere
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17).; A flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel and thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (15, 225.1 g, 0.85 mol) and THF (2200 mL). This mixture was cooled to -6° C. in an ice/salt/brine bath and isopropyl magnesium chloride (2 M in THF, 510 ml, 1.02 mol, 1.2 equiv) was added at a rate such that the temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropylpinacolborate, 16, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about 1/2 of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to room temperature over 1 hr and stirred at room temperature for an additional 1 hr. The reaction was cooled to 6° C. and saturated aqueous ammonium chloride solution (2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6.x.2.2 L), brine (2.x.2.2 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Residual toluene was co-evaporated with heptane to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17, 90.3 g, 164.9 g theoretical, 54.8percent) as a white solid. For 17: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.08 (bs, 1H), 7.94 (s,1H), 7.62 (s,1H), 1.23 (s, 12H); C9H15BN2O2 (MW, 194.04), LCMS (EI) m/e 195 (M++H).
54.8%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -6 - 0℃; for 0.166667 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 2 h; Inert atmosphere
Stage #3: With water; ammonium chloride In tetrahydrofuran at -6 - 0℃;
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1) [0161] A flask equipped with a mechanical stirrer, a nitrogen inlet, an addition funnel and a thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (225.1 g, 0.85 mol) and THF (2200 mL) at ambient temperature. This mixture was cooled to approximately −6° C. in an ice/salt/brine bath before a solution of isopropyl magnesium chloride in THF (2 M solution in THF, 510 mL, 1.02 mol, 1.2 equiv) was added at a rate such that the internal temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was then added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropylpinacolborate, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about half of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to ambient temperature over 1 h and stirred at ambient temperature for an additional 1 h. The reaction mixture was cooled to approximately 6° C. and the saturated aqueous ammonium chloride solution (NH4Cl, 2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6×2.2 L) and brine (2×2.2 L) before being dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the solution was concentrated under reduced pressure. Residual toluene was co-evaporated with n-heptane to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 90.3 g, 164.9 g theoretical, 54.8percent) as a white solid. For 1: 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 1.23 (s, 12H) ppm; C9H15BN2O2 (MW, 194.04), LCMS (EI) m/e 195 (M++H).
Reference: [1] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 103
[2] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0161
  • 18
  • [ 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
  • 19
  • [ 3469-69-0 ]
  • [ 25015-63-8 ]
  • [ 269410-08-4 ]
Reference: [1] Patent: US6680401, 2004, B1, . Location in patent: Page column 58
  • 20
  • [ 3469-69-0 ]
  • [ 1195-66-0 ]
  • [ 269410-08-4 ]
Reference: [1] Patent: CN108276418, 2018, A, . Location in patent: Paragraph 0085; 0086; 0087
  • 21
  • [ 15878-00-9 ]
  • [ 73183-34-3 ]
  • [ 269410-08-4 ]
Reference: [1] RSC Advances, 2018, vol. 8, # 25, p. 13643 - 13648
  • 22
  • [ 288-13-1 ]
  • [ 25015-63-8 ]
  • [ 269410-08-4 ]
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 49, p. 12915 - 12919[2] Angew. Chem., 2013, vol. 125, # 49, p. 13153 - 13157,5
  • 23
  • [ 288-13-1 ]
  • [ 73183-34-3 ]
  • [ 269410-08-4 ]
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299
  • 24
  • [ 552846-17-0 ]
  • [ 269410-08-4 ]
Reference: [1] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9199 - 9201
  • 25
  • [ 269410-08-4 ]
  • [ 24424-99-5 ]
  • [ 552846-17-0 ]
YieldReaction ConditionsOperation in experiment
85% With dmap In dichloromethane at 20℃; for 4 h; 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrazole (1.16 g, 6.0mmol) in methylene chloride (40 mL) was added di-tert-butyl dicarbonate (1.58 g, 7.2 mmol), was added a catalytic amount of 4-dimethylaminopyridine (102 mg, 0.84 mmol), reaction at room temperature for 4 hours.Water was added to the system, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, the organic Xiangde removed by rotary evaporation the crude product (1.5 g, 85percent yield).
76% at 20℃; for 12 h; Di-tert-butyl dicarbonate (7.2 molar equivalent), 4-(dimethylamino)pyridine (0.84 molar equivalent) were added to a solution of 4,4,5,5-tetramethyl-2-(1H-pyrazole-4-yl)-1,3,2-dioxaborolane (6 mmol) in 40 mL of DMF. The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrate was evaporated to give a brown yellow oil residue as compound 21-1 (1.32 g; 4.56 mmol; 76percent). 1H NMR (400 MHz, chloroform-D) δ ppm 1.32 (s, 12H) 1.63 (s, 9H) 7.91 (s, 1H) 8.37 (s, 1H). The residue was used for the next step reaction without further purification.
64% With dmap In acetonitrile at 20℃; for 18 h; To a mixture of 4-pyrazoleboronic acid pinacol ester (0.485 g, 2.5mmol) and DMAP (0.153 g, 1.25 mmol) in MeCN (12.5 ml) was added di-tert-butyldicarbonate (0.709 g, 3.25 mmol). The resulting mixture was stirred at rt for 18 h before itwas concentrated under reduced pressure. The obtained residue was purified by flashcolumn chromatography (silica gel, 0-10percent EtOAc in petroleum ether) to afford the titlecompound (0.473 g, 64percent yield) as a white solid. 1H NMR (400 MHz, CDCb) o 8.38 (s, 1 H),7.92 (s, 1H), 1.64 (s, 9H), 1.33 (s, 12H).
57% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 48 h; To a solution of 33a (l .Og, 5.15mmol) in CH2Cl2 (3OmL) was added DIEA (2.0g, 15.5mmol), followed by (Boc)2O (1.55g, 7.4mmol) drop-wise at O0C. The resulting mixture was stirred at room temperature for 2 days. After the reaction was complete detected by TLC, the mixture was evaporated and the residue was purified by silica column chromatography (PE:EA=4:1) to provide 35a (0.86g, 57percent yield).

Reference: [1] Patent: CN103936728, 2016, B, . Location in patent: Paragraph 0177; 0203; 0204; 0205
[2] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 68
[3] Patent: WO2018/154466, 2018, A1, . Location in patent: Paragraph 001162; 001164; 001165
[4] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 58
[5] Patent: WO2004/56727, 2004, A2, . Location in patent: Page 97
[6] Patent: WO2013/107291, 2013, A1, . Location in patent: Page/Page column 66
[7] Patent: WO2013/166015, 2013, A1, . Location in patent: Paragraph 0108 - 0110
[8] Patent: WO2015/6100, 2015, A1, . Location in patent: Page/Page column 185
[9] Patent: WO2015/10626, 2015, A1, . Location in patent: Page/Page column 67
[10] Patent: WO2015/10297, 2015, A1, . Location in patent: Page/Page column 66
[11] Patent: WO2016/73652, 2016, A1, . Location in patent: Page/Page column 76
[12] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 43; 44
  • 26
  • [ 269410-08-4 ]
  • [ 552846-17-0 ]
Reference: [1] Patent: US2013/190249, 2013, A1, . Location in patent: Page/Page column
[2] Patent: US2015/31627, 2015, A1, . Location in patent: Page/Page column
  • 27
  • [ 269410-08-4 ]
  • [ 4584-46-7 ]
  • [ 877149-80-9 ]
YieldReaction ConditionsOperation in experiment
95% With caesium carbonate In acetonitrile for 5 h; Reflux Intermediate 115yV,yV-Dimethyl-2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yljethanamine4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (2 g, 10.31 mmol), cesium carbonate (6.72 g, 20.61 mmol) and 2-chloro-/V,/V-dimethylethanamine hydrochloride (2.227 g, 15.46 mmol) were suspended in acetonitrile (30 mL) and the mixture was heated at reflux for 5 h, then cooled to room temperature, diluted with Et20 and filtered. The filtrate was concentrated in vacuo to give N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazol-1 -yl]ethanamine dimethyl{2-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazol-1 -yl]ethyl}amine (2.61 g, 9.84 mmol, 95 percent yield) as an amber oil which was used in the next step without further purification.
88% With caesium carbonate In acetonitrile at 90℃; A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.0 mg, 0.309 mmol), 3-dimethylaminoethyl chloride hydrochloride (49.0 mg, 0.340 mmol) and cesium carbonate (0.302 g, 0.928 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with methylene chloride. The combined organic layers were dried over Mg504, then filtered and concentrated under reduced pressure to give the desired product (60 mg, 88percent). LCMS calculated for C13H25BN3O2 (M+H)+: m/z=266.2. Found: 266.2.
66% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 72.5 h; 2-Dimethylaminoethyl chloride hydrochloride (0.97 g, 6.70 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesiumcarbonate (5.54 g, 17.01 mmol) in dry N,N-dimethylformamide (20 mL) at 0°C. After stirring for30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperaturefor three days. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to afford 1 .00 g (3.41 mmol; 66percent of theory) of the title compound.GO-MS (Method L9): R1 = 4.48 mm; (no mass detected)1 H NMR (300 MHz, Chloroform-d, Method M2) 6 7.78 (s, 1 H), 7.74 (s, 1 H), 4.23 (t, J = 6.8 Hz,2H), 2.76 (t, J = 6.8 Hz, 2H), 2.26 (s, 6H), 1.31 (s, 12H).
56% With caesium carbonate In acetonitrile at 90℃; for 72 h; A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (100 mg, 0.515 mmol), 2-chloro-A/,A/-dimethylethanamine hydrochloride (82 mg, 0.567 mmol), and Cs2C03 (504 mg, 1.546 mmol) in acetonitrile (2 ml_) was heated at 90 °C for 3 d. After cooling to RT, the reaction mixture was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined extracts were washed (water), dried (MgS04), and concentrated in vacuo to give the title compound (76 mg, 56percent) as a colourless oil. LCMS (Method B): RT = 0.61 min, m/z = 266 [M+H]+.

Reference: [1] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 105
[2] Patent: US2014/45814, 2014, A1, . Location in patent: Paragraph 0257; 0258
[3] Patent: WO2017/178416, 2017, A1, . Location in patent: Page/Page column 116; 117
[4] Patent: WO2018/73602, 2018, A1, . Location in patent: Page/Page column 99
[5] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 47
[6] Patent: WO2014/111871, 2014, A1, . Location in patent: Page/Page column 164; 167
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  • [ 269410-08-4 ]
  • [ 2862-39-7 ]
  • [ 877149-80-9 ]
YieldReaction ConditionsOperation in experiment
20% With caesium carbonate In N,N-dimethyl-formamide at 70℃; A mixture of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.7 mmol) , 2-bromo-N, N-dimethylethanamine hydrobromide (4 g, 20 mmol) and Cs2CO3(9 g, 17.6 mmol) in DMF (15 mL) was stirred at 70 overnight. The reaction mixture was concentrated to remove DMF. The residue was diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM/MeOH (v/v) 25/1 to give a white solid product (0.5 g, 20) .[1634]MS (ESI, pos. ion) m/z: 266.1 [M+1]+.
Reference: [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00686
  • 29
  • [ 269410-08-4 ]
  • [ 107-99-3 ]
  • [ 877149-80-9 ]
Reference: [1] Patent: US2006/293358, 2006, A1, . Location in patent: Page/Page column 48
[2] Patent: WO2014/64131, 2014, A2, . Location in patent: Page/Page column 128
  • 30
  • [ 269410-08-4 ]
  • [ 4584-46-7 ]
  • [ 76-09-5 ]
  • [ 877149-80-9 ]
Reference: [1] Patent: US2011/218198, 2011, A1, . Location in patent: Page/Page column 15-16
  • 31
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  • [ 877149-80-9 ]
Reference: [1] Patent: US2013/59835, 2013, A1,
[2] Patent: US2014/249132, 2014, A1,
  • 32
  • [ 69966-55-8 ]
  • [ 269410-08-4 ]
  • [ 864754-21-2 ]
YieldReaction ConditionsOperation in experiment
6.33% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8 h; 3- (Bromomethyl) pyridine (2.67 g, 15.5 mmol)And 4-pyrazole boronic acid pinacol ester(3.01 g, 15.5 mmol) was dissolved in DMF (20 mL)Potassium carbonate (2.2 g, 16 mmol) was added to the system, and the mixture was heated to 80 ° C. for 8 h.The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3)Saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed.The residue was subjected to column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1.5)This gave 280 mg of a pale yellow oil, yield: 6.33percent.
Reference: [1] Patent: CN106749268, 2017, A, . Location in patent: Paragraph 0607; 0608
  • 33
  • [ 269410-08-4 ]
  • [ 6959-48-4 ]
  • [ 864754-21-2 ]
Reference: [1] Patent: WO2010/10186, 2010, A1, . Location in patent: Page/Page column 57
  • 34
  • [ 269410-08-4 ]
  • [ 864754-21-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
  • 35
  • [ 269410-08-4 ]
  • [ 141699-58-3 ]
  • [ 877399-35-4 ]
Reference: [1] Patent: WO2008/148867, 2008, A2, . Location in patent: Page/Page column 59-60
[2] Patent: WO2009/106577, 2009, A1, . Location in patent: Page/Page column 117-118
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
  • 36
  • [ 269410-08-4 ]
  • [ 254454-54-1 ]
  • [ 877399-35-4 ]
Reference: [1] Patent: WO2016/134320, 2016, A1, . Location in patent: Page/Page column 116
  • 37
  • [ 269410-08-4 ]
  • [ 142253-57-4 ]
  • [ 877399-31-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
  • 38
  • [ 269410-08-4 ]
  • [ 141699-59-4 ]
  • [ 877399-74-1 ]
YieldReaction ConditionsOperation in experiment
44% With caesium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere Step 2: Compound 96-2 (134 mg, 0.5 mmol) and cesium carbonate (245 mg, 0.75 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (97 mg, 0.5 mmol) in DMF, the reaction mixture was stirred at 90° C. for 12-16 h, and the reaction solution was cooled to room temperature, diluted with water, extracted with EA, and the combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product which was purified by Combi-flash column chromatography [PE:EA=100:0-50:50] to give the title compound 96-3 (2 g, yield 44percent), MS m/z (ESI): 378.2[M+1]+.
39% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; Step B: ferf-butyl 4-[4-(4l4l5l5-tetramethyl-1 l3l2-dioxaborolan-2-yl)-1 -/-pyrazol-1-yllpiperidine- 1-carboxylate (Title Compound)A mixture of terf-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (7.33 g, 26.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.09 g, 26.2 mmol), and Cs2C03 (12.8 g, 39.3 mmol) in DMF (50 mL) was heated at 100 °C for 24 h. The mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with water (3 x 50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography (20 to 40percent ethyl acetate:hexanes) to afford 3.84 g (39percent) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3): 57.81 (s, 1H), 7.74 (s, 1H), 4.17-4.35 (m, 3H), 2.89 (m, ^-.-12 Hz, 2H), 2.14 (d, =14.65 Hz, 2H), 1.90 (qd, J=12.25, 4.42 Hz, 3H), 1.48 (s, 9H), 1.33 (s, 12H); MS (ESI): 379.15 [M+H]+; HPLC tR = 3.17 min.
35.2% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; Tert-butyl-1-carboxylate 4-methanesulfonyloxy piperidine (2.00 g, 7.16 mmol)Was added to a solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.50 g, 7.70 mmol) andCesium carbonate (3.50 g, 11.00 mmol)In N, N-dimethylformamide (15 mL)The reaction solution was reacted at 100 ° C for 24 h,Cooled to room temperature,Extracted with water (100 mL) and ethyl acetate (100 mL)The aqueous phase was extracted with ethyl acetate (100 mL x 3), the organic phases were combined and washed with saturated brine (100 mL x 3)Dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was passed through a column (petroleum ether / ethyl acetate (v / v) = 2/1)To give 950 mg of a colorless solid in a yield of 35.2percent.
28.74%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
Stage #2: at 90℃;
Step 2: tert-butyl 4-[4-(4,4, 5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l- carboxvlate\\ S; To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (4.12 g, 21.2 mmol,Aldrich, Cat. 525057) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.78 g, 44.5 mmol) at 0 0C. The resulting solution was stirred at r.t. for one hour, and then tert-butyl 4- [(methylsulfonyl)oxy]ρiρeridine-l-carboxylate (6.3 g, 22 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 9O0C overnight. Then the reaction mixture was cooled to r.t., quenched with water, 0 and extracted with AcOEt. The organic layer was washed with NaHCO3 aqueous solution and brine successively, dried with MgSO4, and concentrated. The residue was purified by flash column chromatography on a silica gel column using 30percent ethyl acetate in hexane as eluent to afford the desired compound (2.30 g, 28.74percent). LCMS (M+H)+: m/z = 378.4.
884 mg With caesium carbonate In N,N-dimethyl-formamide at 100℃; To tert-butyl 4-hydroxypiperidine-1-carboxylate (402 mg, 2.0 mmol) in methylene chloride (20 mL) and triethylamine (303 mg, 3.0 mmol) at 4° C. was added methanesulfonyl chloride (274 mg, 2.4 mmol) drop-wise.
The reaction was brought to ambient temperature and was stirred for 1 hour.
The reaction mixture was concentrated in vacuo and diluted in diethyl ether (20 mL).
The solution was washed with 1N hydrochloric acid (3 mL), water (3 mL), and saturated sodium bicarbonate (3 mL).
The organics were dried (sodium sulfate) and concentrated in vacuo to afford tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate in quantitative yield.quantitative yield. The product was used directly in the next step without thrther purification. A mixture of 4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl-1H-pyrazole (427 mg, 2.2 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.0 mmol), and cesium carbonate (847 mg, 2.6 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3x). The combined organic layers were dried over Na2S04, filtered and concentrated to provide crude pale yellow oil 884 mg. MS (mlz): 378 (M+H).

Reference: [1] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0309; 0311
[2] Patent: WO2011/100502, 2011, A1, . Location in patent: Page/Page column 37
[3] Patent: CN106336413, 2017, A, . Location in patent: Paragraph 0509; 0510; 0511; 0512
[4] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 68-69
[5] Patent: WO2011/143646, 2011, A1, . Location in patent: Page/Page column 41-42
[6] Patent: US2012/165305, 2012, A1, . Location in patent: Page/Page column 29
[7] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299
[8] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0333; 0334
[9] Patent: WO2010/59771, 2010, A1, . Location in patent: Page/Page column 30-31
  • 39
  • [ 269410-08-4 ]
  • [ 76513-69-4 ]
  • [ 894807-98-8 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 16 h; Inert atmosphere Synthesis of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2~yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 t-15a)lnt-15aTo a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- H- pyrazole (8.2 g, 41 mmol) in NMP (60 mL) was added K2C03 (12 g, 82 mmoi) and 2-(trimethylsilyi)ethoxymethy. chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at r.t. under N2 for 16 h. Then, the reaction mixture was diluted and filtered, and then the filtrate was diluted with EtOAc (300 mL). The resulting solution was washed with sat. NaHC03 (aq) (3 x 200 mL), H20 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S04, filtered, concentrated and dried in vacuo to yield intermediate .nt-15a (11.4 g, 86 percent) as a clear yellowish oil.
86%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 0 - 20℃;
[96] SEM-pyrazolo-4-boronic acid pinacol ester was prepared according the procedure from WO2011/130146, page 84. A solution of pyrazolboronic acid pinacolester (20 g, 103 mmol) in DMF (180 mL) was cooled to 0° C and treated with sodium hydride (60 percent dispersion in oil) (6.2 g, 150 mmol) in nitrogen athmosphere. [97] The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0° C and (2-(chloromethoxy)ethyl)trimethylsilane (23.65 ml, 134 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. [98] The reaction mixture was poured into aqueous saturated ammonium chloride (200 mL) containing ice (approximately 200 mL) and stirred until the ice melted. The cold mixture was extracted with ethyl acetate twice. The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford SEM-pyrazolo-4-boronic acid pinacol ester (27.6 g, 86 percent yield).
72% With sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere Compound 280.1. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole.
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.82 g, 30.0 mmol) in tetrahydrofuran (80 mL). This was followed by the addition of NaH (70percent) (2.05 g, 85.4 mmol) in portions at 0 °C. To this was added SEMC1 (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirred overnight at room temperature, then quenched with 50 mL of NH4CI (sat). The aqueous phase was extracted with 2 x 100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72percent) of the title compound as colorless oil.
65.94% With caesium carbonate In tetrahydrofuran; acetonitrile at 20℃; for 2 h; 13.2 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-p razole To a solution of 1H-pyrazole-4-boronic acid pinacol ester (0.5 g, 2.57 mmol), in tetrahydrofuran/acetonitrile (3:2, 20ml), 2-(chloromethoxylethyl)trimethyl- silane (0.51 g, 3.09 mmol) and cesium carbonate (1.67 g, 5.15 mmol) are added and stirred for 2 hours at room temperature. The reaction mixture is filtered through celite, and concentrated, the crude mass is taken in ethylacetate (30 ml), washed with water, brine solution, dried over anhydrous MgS04 and concentrated to get the product as brown oil (0.55 g, 65.94 percent); TLC: Pet ether/ethyl acetate(8/2) R - 0.5; 1H NMR: 400 MHz, DMSO-d6: δ [ppm] 8.08 (s, 1H), 7.64 (s, 1 H), 5.40 (s, 2H), 3.48-3.54 (m, 2H), 1.24 (s, 12H), 0.81-0.85 (m, 2H), -0.049(s, 9H);
61%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 0.333333 h;
Stage #2: for 16.0833 h;
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60percent dispersion, 86 mg, 2.15 mmol) added and the mixture heated to 60° C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 μL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5percent lithium chloride (5.x.), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61percent) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).
56% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h; To a solution of methyl 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .238 g, 6.316 mmol) in DMF (20 mL) was added potassium carbonate (2.62 g, 18.95 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1 .68 mL, 9.48 mmol) at room temperature. The mixture was stirred for 3 hours and then partitioned between TBME (100 ml.) and water (50 ml_). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 ml_), dried (Na2S04) and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50percent EtOAc in heptane]. The product containing fractions were combined, concentrated in vacuo to give the title compound (1 .20 g, 56percent yield) as colourless oil. 1H NMR (500 MHz, chloroform-d) δ [ppm] 7.88 (s, 1 H), 7.84 (s, 1 H), 5.46 (s, 2H), 3.61- 3.55 (m, 2H), 1 .35 (s, 12H), 0.96 - 0.90 (m, 2H), 0.00 (s, 9H). LCMS (Analytical Method A): Rt = 1 .34 mins; MS (ESIPos) m/z = 324.95 (M+H)\
46%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333 h;
Stage #2: at 20℃; for 2 h;
32-(a) 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazole; Under argon atmosphere, to 20 ml of tetrahydrofuran solution containing 1.09 g (5.62 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole was added 443 mg (11.1 mmol) of 60percent sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 3 ml (17.0 mmol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, and the solutions were washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 832 mg of the title compound as a colorless oil. (46percent) Mass Spectrum (CI, m/z): 325 (M++1). 1H-NMR Spectrum (CDCl3, δ ppm): -0.03 (s, 9H), 0.86-0.94 (m, 2H), 1.32 (s, 12H), 3.51-3.59 (m, 2H), 5.43 (s, 2H), 7.81 (d, J=0.5 Hz, 1H), 7.86 (d, J=0.5 Hz, 1H).
0.9 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 10 - 35℃; for 1 h; Cooling with ice
Stage #2: at 10 - 35℃; for 15 h;
A) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [1064] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (770 mg) in DMF (10 mL) was added sodium hydride (60percent, 114 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise (2-(chloromethoxy)ethyl)(trimethyl)silane (990 mg) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5percent aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.90 g). MS(ESI+): [M+H]+ 325.2. MS(ESI+), found: 325.2.

Reference: [1] Patent: WO2011/149874, 2011, A2, . Location in patent: Page/Page column 81-82
[2] Patent: WO2016/25918, 2016, A1, . Location in patent: Paragraph 96-98
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 10, p. 3075 - 3080
[4] Patent: WO2015/95767, 2015, A1, . Location in patent: Page/Page column 325
[5] Patent: WO2013/131609, 2013, A1, . Location in patent: Page/Page column 112
[6] Patent: US2008/153813, 2008, A1, . Location in patent: Page/Page column 7
[7] Patent: WO2018/114786, 2018, A1, . Location in patent: Page/Page column 141-142
[8] Patent: EP1982986, 2008, A1, . Location in patent: Page/Page column 233
[9] Patent: WO2008/57512, 2008, A2, . Location in patent: Page/Page column 97
[10] Patent: US2007/82900, 2007, A1, . Location in patent: Page/Page column 153
[11] Patent: US2007/105864, 2007, A1, . Location in patent: Page/Page column 205
[12] Patent: US2007/117804, 2007, A1, . Location in patent: Page/Page column 137-138
[13] Patent: WO2011/130146, 2011, A1, . Location in patent: Page/Page column 83-84
[14] Patent: WO2012/58174, 2012, A1, . Location in patent: Page/Page column 43; 44
[15] Patent: EP2857400, 2015, A1, . Location in patent: Paragraph 315.A
[16] Patent: WO2016/123391, 2016, A1, . Location in patent: Page/Page column 87; 88
  • 40
  • [ 269410-08-4 ]
  • [ 100-39-0 ]
  • [ 761446-45-1 ]
YieldReaction ConditionsOperation in experiment
79% With potassium carbonate In N,N-dimethyl-formamide at 20℃; A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 15.5 mmol), bromomethyl-benzene (3.2 g, 18.7 mmol) and K2CO3 (4.3 g, 31.2 mmol) in DMF (30 mL) was stirred at room temp overnight.
After dilution with EtOAc (50 mL) and H2O (50 mL), the organic layer was separated and washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum.
The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (5:1) to give the compound 1-benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (3.5 g, 12.3 mmol) as a light yellow solid in 79percent yield. 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.66 (s, 1H), 7.37-7.29 (m, 3H), 7.24-7.22 (m, 2H), 5.30 (s, 2H), 1.29 (s, 12H). LCMS (M+H)+ 285.
66%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h;
Stage #2: at 20℃;
Compound 244.1. l-Benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole. _:Into a 100-mL three neck round-bottom flask, was placed a solution of 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3.60 g, 18.6 mmol) in THF (50 mL). Sodium hydride (742 mg, 18.6 mmol, 60percent dispersion in mineral oil) was carefully added in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C, then benzyl bromide (2.21 mL, 18.6 mmol) was added. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (10 mL). The pH of the mixture was adjusted to 9-10 with aqueous HC1 (2 M) and the aqueous phase was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (2 x 150 mL), dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/2) as eluent to yield the title compound as a yellow oil (3.47 g, 66percent).
59%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 16 h;
1 -benzyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (i34): To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (3.0 g, 15.46 mmol) in THF (50 ml_), NaH (0.408 g, 17.01 mmol) was added at 0°C and the reaction was stirred for 30 min. Benzyl bromide (2.9 g, 17.01 mmol) was then added at the same temperature and the reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion, the mixture was diluted with water and the pH adjusted to 7 using 2 M HCI. The aqueous layer was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 8percent ethyl acetate in n-hexanes as eluent to afford 1-benzyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (i34) (2.6 g, Yield 59percent). 1H NMR (400 MHz, DMSO-d6) δ 1 .24 (s, 12H), 5.33 (s, 2H), 7.38-7.20 (m, 5H), 7.60 (s, 1 H), 8.03 (s, 1 H), MS (ESI) m/e (M+1 )+: 285.00
0.28 g With caesium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere 0.25g 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole was dissolved in 5mL of DMF and 0.63g cesium carbonate was added. To this suspension was added 0.17mL of benzyl bromide and the reaction was stirred overnight at room temperature. The reaction was allowed to settle and the DMF was decanted into a flask. The remaining residue was washed and decanted twice with ethyl acetate and these washes were added to the flask with the DMF. Water was added to the ethyl acetate and DMF and the organic layer removed. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgS04 and concentrated to give 0.28g of l -benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole which was used without further purification.

Reference: [1] Patent: US2018/296543, 2018, A1, . Location in patent: Paragraph 0573; 0574; 0600
[2] Patent: WO2015/95767, 2015, A1, . Location in patent: Page/Page column 284; 285
[3] Patent: WO2016/124508, 2016, A1, . Location in patent: Page/Page column 55
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[5] Patent: WO2014/60395, 2014, A1, . Location in patent: Page/Page column 35
  • 41
  • [ 269410-08-4 ]
  • [ 78-77-3 ]
  • [ 827614-66-4 ]
YieldReaction ConditionsOperation in experiment
88% With caesium carbonate In acetonitrile at 80℃; for 4 h; A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol, 1.00 equiv), 1-bromo-2-methylpropane (1.05 g, 7.66 mmol, 1.49 equiv) and Cs2CO3 (3.36 g, 10.31 mmol, 2.00 equiv) in acetonitrile (60 mL) was stirred at 80° C. for 4 h. The reaction was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with ethyl acetate (30 mL) and then washed with brine (40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.14 g (88percent) of 1-iso-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.78 (s, 1H), 7.65 (s, 1H), 3.91 (d, J=7.2 Hz, 2H), 2.24-2.19 (m, 1H), 1.32 (s, 12H), 0.90 (d, J=7.2 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.51 min, m/z=251.0 [M+H]+.
31.8% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole 1a (5.00 g, 25.77 mmol) in DMF(50 mL) was added Cs2CO3 (16.79 g, 51.54 mmol) and 1-bromo-2-methylpropane (7.06 g, 51.54 mmol). The mixturewas stirred at 100°C for 2h. It was cooled to room temperature, water (10 mL) was added and extracted with EA (100mL*3). The combined organic phases was washed with water (100 mL*2) and brine (100 mL*2), dried over Na2SO4,filtrated and evaporated. The residue was purified by silica gel chromatography to give 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1b (2.05 g, yield:31.8percent) as a yellow liquid.1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.58 (s, 1H), 3.84 (d, 1H), 4.08-4.00 (m, 1H), 2.05-2.20 (m, 1H), 1.25 (s, 12H),0.82 (d, 6H)
Reference: [1] Patent: US2014/288105, 2014, A1, . Location in patent: Paragraph 0216-0217
[2] Patent: EP3042907, 2016, A1, . Location in patent: Paragraph 0277; 0278
[3] Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 7934 - 7937
  • 42
  • [ 75-30-9 ]
  • [ 269410-08-4 ]
  • [ 879487-10-2 ]
YieldReaction ConditionsOperation in experiment
57% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; 2-lodopropane (1.14 g, 6.70 mmol, 0.67 mL)was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol) and caesium carbonate (3.49 g,10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice- water bath was removed. The reaction mixture was stirred at room temperature overnight. Thereaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (3x100 mL).The organic layer was dried with sodium sulfate and concentrated in vacuo. Purification byflash column chromatography (Method L7; 12 g; heptane, 10percent-30percent ethyl acetate) afforded0.69 g (2.32 mmol; 57percent of theory) of the title compound.GO-MS (Method L9): R1 = 3.86 mm; m/z = 236 M1 H NMR (300 MHz, Ohloroform-d, Method M2) 6 7.79 (s, 1 H), 7.74 (s, 1 H), 4.52 (p, J = 6.7 Hz,1H), 1.50 (d, J = 6.7 Hz, 6H), 1.32 (s, 12H).
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[2] Patent: WO2017/178416, 2017, A1, . Location in patent: Page/Page column 114
[3] Patent: US2009/197862, 2009, A1, . Location in patent: Page/Page column 46-47
[4] Patent: US2011/152273, 2011, A1, . Location in patent: Page/Page column 73
[5] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 270 - 285
[6] Patent: WO2009/154557, 2009, A1, . Location in patent: Page/Page column 116-117
[7] Patent: WO2010/59771, 2010, A1, . Location in patent: Page/Page column 36
  • 43
  • [ 269410-08-4 ]
  • [ 75-26-3 ]
  • [ 879487-10-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4196 - 4212
[3] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 160-161
[4] Patent: WO2014/111871, 2014, A1, . Location in patent: Page/Page column 163; 164
  • 44
  • [ 269410-08-4 ]
  • [ 74-88-4 ]
  • [ 1020174-04-2 ]
Reference: [1] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 137
  • 45
  • [ 269410-08-4 ]
  • [ 96-32-2 ]
  • [ 959585-44-5 ]
YieldReaction ConditionsOperation in experiment
62% With caesium carbonate In N,N-dimethyl-formamide at 90℃; To a solution of 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (5.0 g, 25.8 mmol) in DMF (52 mL) was added Cs2CO3 (8.396 g, 25.8 mmol) and bromo-acetic acid methyl ester (2.52 mL, 25.8 mmol). The reaction mixture was heated at 9O0C under nitrogen for overnight. After cooling, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water for three times and brine, dried over Na2SO4., and concentrated to provide 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid methyl ester (4.27 g, 62percent yield).
47% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 18 h; Inert atmosphere Intermediate 10: Methyl [4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yI)-1 Hpyrazol-1 -yI]acetate Methyl [4-(4,4, 5, 5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl]acetate was prepared according to the synthetic route shown in Scheme 5. To a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (560 mg, 2.9 mmol) in anhydrous DMF (10 mL) was added 052003 (1.03 g, 3.16 mmol) and methyl bromoacetate (0.30 mL, 3.16 mmol) and the reaction was stirred at 9000 under a nitrogen atmosphere for 18 hrs. The reaction was cooled, diluted with EtOAc (50 mL), washed with water (2 x 25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (50percent EtOAc/heptane) to give the title compound as a colourless oil (360 mg, 47percent).LCMS: m/z 267 [M+H].
Reference: [1] Patent: WO2007/138472, 2007, A2, . Location in patent: Page/Page column 32
[2] Patent: WO2014/1802, 2014, A1, . Location in patent: Page/Page column 42; 43
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[4] Patent: US2012/115861, 2012, A1, . Location in patent: Page/Page column 22
  • 46
  • [ 269410-08-4 ]
  • [ 7051-34-5 ]
  • [ 1000801-75-1 ]
YieldReaction ConditionsOperation in experiment
85% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; N-N(Bromomethyl)cyclopropane (0.95 mg, 6.70 mmol, 0.70 mL, 95 percent) was added to a mixture of4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to afforded 1.30 g (4.38 mmol, 85percent of theory) of the title compound. GO-MS (Method L9): R1 = 4.35 mm; mlz = 247 M1 H NMR (300 MHz, Ohloroform-d, Method M2) 6 7.81 (s, 1 H), 7.79 (s, 1 H), 3.99 (d, J = 7.1 Hz,2H), 1.32 (s, 12H), 1.27 (m, 1 H), 0.71 - 0.58 (m, 2H), 0.41 - 0.33 (m, 2H).
49%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.333333 h; Inert atmosphere
Stage #2: for 24 h; Inert atmosphere
To a reaction vessel containing sodium hydride (60 wtpercent dispersion in mineral oil)(3.09 g, 77.32 mmol) was added NN-dimethylformamide (30 mL) under a stream of nitrogen followed by 4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10 g, 51.55 mmol) and the reaction mixture was stirred for 20 min at room temperature. Cyclopropylmethylbromide (8.7 g, 61.86 mmol) was then added and the reaction mixture was stirred for 24 h under an atmosphere of nitrogen. The reaction mixture was slowly poured over saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0percent-100percent EtOAc in cyclohexane) to afford 1- (cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.29 g, 49percent). LCMS (ESI): [M+H]+ = 249.2; lH NMR (400 MHz, CDC13) δ 7.80 (d, J= 7.4 Hz, 2H), 3.99 (d, J = 7.0 Hz, 2H), 1.32 (s, 12H), 1.29 - 1.26 (m, 1H), 0.69 - 0.60 (m, 2H), 0.41 - 0.33 (m, 2H).
48% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 14 h; To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (8.00 g,41.2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and(bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 600 C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 percent yield) of the titlecompound.LC-MS (Method 2): Rt = 1.12 mm; MS (ESIpos): mlz = 249 [M+H]1HNMR (400 MHz, DMSO-d6) O [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65),0.471 (0.53), 0.476 (0.61), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1.219 (1.70), 1.224 (16.00),3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1.07), 7.544 (1.08), 7.932 (1.09).
48% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 14 h; To a stirred solution of 4-(4, 4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (purchased from Acros, CAS 269410-08-4, 8.00 g, 41 .2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and (bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 60° C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 percent yield) of the title compound. LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 249 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) _ [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65), 0.471 (0.53), 0.476 (0.61 ), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1 .219 (1 .70), 1 .224 (16.00), 3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1 .07), 7.544 (1 .08), 7.932 (1.09).

Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4196 - 4212
[2] Patent: WO2017/178416, 2017, A1, . Location in patent: Page/Page column 114; 115
[3] Patent: WO2014/210354, 2014, A1, . Location in patent: Page/Page column 47; 48
[4] Patent: WO2017/102091, 2017, A1, . Location in patent: Page/Page column 435
[5] Patent: WO2017/207534, 2017, A1, . Location in patent: Page/Page column 180
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 9080 - 9093
[7] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 158
[8] Patent: WO2009/154557, 2009, A1, . Location in patent: Page/Page column 113-114
  • 47
  • [ 269410-08-4 ]
  • [ 3647-69-6 ]
  • [ 864754-18-7 ]
YieldReaction ConditionsOperation in experiment
47% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; 4-(2-Ohloroethyl)morpholine hydrochloride (1 .25 mg, 6.70 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (5.54 g, 17.01 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature for four days. The reaction mixture was diluted with ethyl acetate (150 mL) and washed withbrine (3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo.Purification by flash column chromatography (Method L7; 12 g; ethyl acetate) afforded 0.75 g(2.44 mmol; 47percent of theory) of the title compound.GO-MS (Method L9): R1 = 5.49 mm; (no mass detected)1 H NMR (300 MHz, Ohloroform-d, Method M2) 6 7.80 - 7.75 (m, 1 H), 7.73 (s, 1 H), 4.25 (t, J =6.8 Hz, 2H), 3.73 - 3.64 (m, 4H), 2.81 (t, J = 6.8 Hz, 2H), 2.50 - 2.42 (m, 4H), 1.32 (s, 12H).
Reference: [1] Patent: WO2017/178416, 2017, A1, . Location in patent: Page/Page column 116
[2] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 160
  • 48
  • [ 89583-07-3 ]
  • [ 269410-08-4 ]
  • [ 864754-18-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 7934 - 7937
  • 49
  • [ 269410-08-4 ]
  • [ 5292-43-3 ]
  • [ 1006875-83-7 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate In acetone at 65℃; for 13 h; Inert atmosphere A mixture of 4-(4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (2.0 g, 10.31 mmol), tert-butyl 2-bromoacetate (2.212 g, 11.34 mmol) and K2C03 (1.709 g, 12.37 mmol) in acetone (20 mL) was stirred at 65 °C for 13 hours under nitrogen. The reaction was poured into ice water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give the title compound (3 g, 8.76 mmol, 85 percent yield) as an oil. LCMS (Method C): m/z 309.2 (M+H), retention time: 1.946 minutes; ‘H NIVIR (400 MHz, CDC13) ö 7.82 (s, 1H), 7.75 (s, 1H), 4.82 (s, 1H), 1.47 (s, 9H), 1.28 (s, 12H).
84% With caesium carbonate In N,N-dimethyl-formamide at 90℃; To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 0.0077 mol) in DMF (25 mL) was added 2-bromoacetic acid 1,1-dimethylethyl ester (1.2 mL, 0.0085 mol) and cesium carbonate (3.8 g, 0.012 mol).
The suspension was stirred at 90° C. overnight.
The reaction mixture was cooled to RT and partitioned with ethyl acetate and water.
The organic layer was washed with water, brine, and dried over MgSO4.
The solution was concentrated to afford the desired compound (2.0 g, 84percent).
Analytical LC/MS: (M+H)+=309.4.
81%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 0.0833333 h;
Stage #2: at 0 - 20℃; for 2 h;
1.0 M Potassium tert-butoxide in THF (2.4 mL, 2.4 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.39 g, 2.0 mmol) in N,N-dimethylformamide (6.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 min. After cooled to 0° C., to the mixture was added t-butyl bromoacetate (0.5 mL, 3 mmol). The reaction was stirred at room temperature for 2 h, then diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product (0.5 g, 81percent) was purified by chromatography eluting with hexanes/EtOAc (max. EtOAc 30percent). LCMS calculated for C15H26BN2O4 (M+H)+: m/z=309.2; Found: 309.1
81%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 0.0833333 h;
Stage #2: at 0 - 20℃; for 2 h;
Step 1.
tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate
1.0M Potassium tert-butoxide in THF (2.4 mL, 2.4 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.39 g, 2.0 mmol) in N,N-dimethylformamide (6.0 mL) at 0° C.
The reaction mixture was stirred at room temperature for 5 min.
After cooled to 0° C., to the mixture was added t-butyl bromoacetate (0.5 mL, 3 mmol).
The reaction was stirred at room temperature for 2 h, then diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated.
The product (0.5 g, 81percent) was purified by chromatography eluting with hexanes/EtOAc (max. EtOAc 30percent). LCMS calculated for C15H26BN2O4 (M+H)+: m/z=309.2. Found: 309.1
77% With potassium carbonate In N,N-dimethyl acetamide at 20℃; for 4 h; Example 2; Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol (compound No. 595); Step 1; [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid t-butyl ester; 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (10 g), N,N-dimethylacetamide (100 ml), potassium carbonate (17.8 g) and t-butyl bromoacetate (9.9 ml) were mixed, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through celite. Water and ethyl ether were added to the filtrate, and the mixture was partitioned in a separatory funnel. The aqueous layer was extracted with ethyl ether, and the organic layers were combined. The organic layer was washed 3 times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was stirred. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (12.23 g, 77percent).1H-NMR (DMSO-D6) δ: 7.92 (1H, d, J=0.7 Hz), 7.59 (1H, d, J=0.5 Hz), 4.95 (2H, s), 1.42 (9H, s), 1.25 (12H, s).
63% With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 8 h; 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (0.5 g, 2.6 mmol) Cesium carbonate (1.3 g, 3.9 mmol) was dissolved in N, N-dimethylformamide (10 mL) Tert-butyl bromoacetate (0.6 mL, 3.9 mmol) was added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, distilled water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give the title compound 56-a (1.1 g, 63percent) as a yellow solid.
12.23 g With potassium carbonate In N,N-dimethyl-d6-formamide at 20℃; for 4 h; Step 8
t-Butyl[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)[1,3,2]dioxaborolane (10 g), N,N-dimethylacetamide (100 ml), potassium carbonate (17.8 g) and t-butyl bromoacetate (9.9 mL) were mixed, and the mixture was stirred at room temperature for 4 hr.
The reaction mixture was filtered through celite.
Water and diethylether were added to the filtrate, and the mixture was poured into a separating funnel and partitioned.
The aqueous layer was extracted again with diethyl ether, and combined with the organic layer.
The obtained organic layer was washed three times with water, once with saturated brine, and dried over anhydrous sodium sulfate.
The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
To the obtained residue was added hexane (50 ml) and the mixture was slurry washed (suspension stirred).
The suspension was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (12.23 g).
1H-NMR (400 MHz, DMSO-D6) δ: 7.92 (1H, d, J=0.7 Hz), 7.59 (1H, d, J=0.5 Hz), 4.95 (2H, s), 1.42 (9H, s), 1.25 (12H, s).

Reference: [1] Patent: WO2016/123796, 2016, A1, . Location in patent: Page/Page column 49; 50
[2] Patent: US2008/39457, 2008, A1, . Location in patent: Page/Page column 36
[3] Patent: US2013/59835, 2013, A1, . Location in patent: Paragraph 1146
[4] Patent: US2014/249132, 2014, A1, . Location in patent: Paragraph 0424
[5] Patent: US2010/240634, 2010, A1, . Location in patent: Page/Page column 57-58
[6] Patent: KR101798840, 2017, B1, . Location in patent: Paragraph 1111-1114
[7] Patent: WO2008/64157, 2008, A1, . Location in patent: Page/Page column 87
[8] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 126-127
[9] Patent: US2014/296316, 2014, A1, . Location in patent: Paragraph 0286; 0287; 0288
  • 50
  • [ 269410-08-4 ]
  • [ 4399-47-7 ]
  • [ 1002309-48-9 ]
YieldReaction ConditionsOperation in experiment
5.21%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.333333 h; Inert atmosphere
Stage #2: at 20℃; for 2 h;
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.55 mmol) was dissolved in DMF (5 mL) at 0 °C under Ar. NaH (60percent in oil, 40.8 mg, 1.70 mmol) was added portionwise, and the reaction mixture was then stirred for 20 minutes at rt. A solution of bromocyclobutane (209 mg, 1.55 mmol) in 1 mL of DMF was added, and stirring was continued 2 h at rt. The reaction mixture was quenched with saturated aq. NH4Cl, and then extracted 3x with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography to provide pyrazole boronate 20A (40 mg, 5.21 percent) . MS (ESI): m/z 249.0 (M+H).
Reference: [1] Patent: WO2017/160632, 2017, A1, . Location in patent: Page/Page column 96
[2] Patent: WO2018/114786, 2018, A1, . Location in patent: Page/Page column 152-153
  • 51
  • [ 110-87-2 ]
  • [ 269410-08-4 ]
  • [ 1003846-21-6 ]
YieldReaction ConditionsOperation in experiment
94% With trifluoroacetic acid In toluene at 90℃; for 2 h; 3,4-Dihydro-2H-pyran (5.6 g, 67 mmol) and trifluoroacetic acid (1.17 g, 10.3 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (10.0 g, 51.5 mmol) in toluene (200 mL), and the reaction mixture was heated to 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonatesolution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10percent to 50percent ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 13.4 g, 48.2 mmol, 94percent. 1H NMR (400 MHz, CDCl3) 7.94 (s, 1H), 7.83 (s, 1H), 5.41 (dd, J=9.5, 2.5 Hz, 1H), 4.01-4.08 (m, 1H), 3.65-3.74(m, 1H), 1.98-2.18 (m, 3H), 1.6-1.76 (m, 3H), 1.32 (s, 12H).
90% With toluene-4-sulfonic acid In dichloromethane at 20℃; for 4 h; To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (110.00 g, 566.89 mmol) in DCM (1000 mL) was added dihydropyran (95.37 g, 1.13 mol, 103.66 mL) and TsOH .H2O (53.92 g, 283.45 mmol). The mixture was stirred at 20 °C for 4 h. TLC (petroleum ether/EtOAc = 5/1) indicated starting material was consumed completely and one main new spot (Rf=0.4) formed. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove volatiles. The residue was diluted with sat. NaHCCb (350 mL) and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography with petroleum ether/ethyl acetate (from 20/1 to 15/1) to afford the title compound (142.00 g, 90percent) as colorless oil. 1H NMR (400 MHz, DMSO-d6) 400 MHz δ 8.06 (s, 1H), 7.61 (s, 1H), 5.42 (dd, J= 10.0, 2.0 Hz, 1H), 3.94-3.86 (m, 1H), 3.66-3.54 (m, 1H), 2.17- 2.03 (m, 1H), 1.96- 1.82 (m, 2H), 1.77-1.37 (m, 3H), 1.33-1.18 (m, 12H). MS (ES+) m/e 279 (M+H).
73% With toluene-4-sulfonic acid In dichloromethane at 30℃; for 4 h; To a solution of 4-(4,4, 5, 5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (10.00 g, 51.54 mmol) in CH2C12 (100.00 mL) was added DHP (8.67 g, 103.08 mmol, 9.42 mL) and TsOHH20 (4.90 g, 25.77 mmol). The mixture was stirred at 30 °C for 4 hour. LCMS showed 4-(4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazolewas consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with sat.NaHCO3 (35 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 20/1 to 1/1) to afford the title compound (10.5 g, 73percent) as colorless oil. ‘H NIVIR (400 MHz, DMSO-d6) ö 8.06 (s, 1H), 7.62 (s, 1H), 5.44-5.41 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.58 (m, 2H), 3.46-3.41 (m, 1H), 2.15-2.06 (m, 1H), 1.95-1.84 (m, 2H), 1.76-1.40 (m, 9H), 1.26 (s, 12H).
73% With toluene-4-sulfonic acid In dichloromethane at 30℃; for 4 h; [0406] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10.00 g, 51.54 mmol) in CH2C12 (100.00 mL) was added DHP (8.67 g, 103.08 mmol, 9.42 mL) and TsOH H20 (4.90 g, 25.77 mmol). The mixture was stirred at 30 °C for 4 hour. LCMS showed 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazolewas consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with sat.NaHCC (35 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 20/1 to 1/1) to afford the title compound (10.5 g, 73percent) as colorless oil. 1H NMR (400 MHz, DMSO-i/6) δ 8.06 (s, 1H), 7.62 (s, 1H), 5.44-5.41 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.58 (m, 2H), 3.46-3.41 (m, 1H), 2.15-2.06 (m, 1H), 1.95-1.84 (m, 2H), 1.76-1.40 (m, 9H), 1.26 (s, 12H).
5.04 g With toluene-4-sulfonic acid In 1,2-dichloro-ethane at 50℃; for 2 h; To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.76 mmol) in dry dichloroethane (128 ml), 3,4-dihydro-2H-pyran (4.71 ml, 51.52 mmol) was added followed by p-toluenesulfonic acid (490 mg, 2.576 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with aqueous saturated solution of sodium bicarbonate (75 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate. The mixture was evaporated under reduced pressure and residue obtained was purified by column chromatography to yield 5.04 g of product as a white solid. 1H NMR (300 MHz, CDCI3): δ I .31 (s, 12H), 1.54-1.70 (m, 3H), 1.98-2.20 (m, 3H), 3.68 (t, / = 10.2 Hz, 1H), 4.04 (d, / = I I .7 Hz, 1H), 5.35-5.45 (m, 1H), 7.82 (s, 1H), 7.93 (s, 1H).

Reference: [1] Patent: WO2014/1973, 2014, A1, . Location in patent: Page/Page column 60; 61; 62
[2] Patent: WO2018/201006, 2018, A1, . Location in patent: Paragraph 0125; 0126
[3] Patent: WO2016/210331, 2016, A1, . Location in patent: Paragraph 0225; 0226
[4] Patent: WO2016/210330, 2016, A1, . Location in patent: Paragraph 0405-0406
[5] Patent: WO2009/71509, 2009, A1, . Location in patent: Page/Page column 80-81
[6] Patent: WO2014/24119, 2014, A1, . Location in patent: Page/Page column 72
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[8] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0328; 0329
  • 52
  • [ 96-49-1 ]
  • [ 269410-08-4 ]
  • [ 1040377-08-9 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydroxide In N,N-dimethyl-formamide at 140℃; for 16 h; Intermediate 1182-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxa H-pyrazol-1 -yl]ethanolA solution of 1 ,3-dioxolan-2-one (2.496 g, 28.3 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (5 g, 25.8 mmol) and sodium hydroxide (0.103 g, 2.58 mmol) in N,N-Dimethylformamide (DMF) (18 mL) was stirred at 140°C for 16 h. then cooled to room temperature and treated with activated charcoal (200mg). The resulting mixture was stirred at room temperature for 1 h then filtered through celite (10 g). The insoluble were washed with EtOAc (50 mL) and EtOH (50ml_). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 50 G silica cartyridge (gradient: 0 to 40percent MeOH in DCM) gave a residue which was further purified by SP4 using a 100 G silica cartridge (eluant: 0 to 20percent MeOH in DCM) to give 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yl]ethanol (5.58 g, 23.44 mmol, 91 percent yield) as a colourless oil which was used in the next step without further purification.LCMS (method A): Retention time 0.68 min, [M+H]+ = 239.13
85% With sodium hydroxide In N,N-dimethyl-formamide for 2.5 h; Heating / reflux INTERMEDIATE 34; 2-[4-f4.4.5.5-Tetramethyl-ri.3.21dioxaborolan-2-ylVρyrazol-l-yl1-ethanol; 4-Pyrazoleboronic acid pinacol ester (0.25 g, 1.29 mmol), ethylene carbonate(0.125 g, 1.42 mmol) and sodium hydroxide (5 mg, 0.13 mmol) were dissolved in DMF (1 mL) and the reaction mixture was heated to reflux for 2 Vi h. It was cooled to r.t. before addition of activated charcoal (25 mg). The resulting suspension was stirred at r.t. for Ih and then filtered through celite, washed with DMF (6 mL) and concentrated in vacuo to give the title compound (0.26g, 85percent) as a yellow oil. LCMS (ES+) 239.18 (M+H)+.
76% With caesium carbonate In N,N-dimethyl-formamide at 140℃; for 0.5 h; 100 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 91 mg of 1,3-dioxolan-2-one weredissloved in 2 ml of dimethylformamide. 336 mg of cesium carbonate was heated to 140 °C, stirred for 0.5 h and thencooled to room temperature and concentrated. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 30: 70) to give 93 mg of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol aspale yellow oil. Yield: 76percent.1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.25 (s, 12H), 3.71 (q, J= 5.4 Hz, 2H), 4.15 (t, J = 5.4 Hz, 2H), 4.87 (t, J = 5.4Hz, 1H), 7.57 (s, 1H), 7.88 (s, 1H).
7.53 g With sodium hydroxide In N,N-dimethyl-formamide at 140℃; A solution of I ,3-dioxolan-2-one (1 .902 mL, 28.5 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-IH-pyrazole (5.0239 g, 25.9 mmol) and sodium hydroxide (0.0998 g, 2.495 mmol) in N,Ndimethylformamide (DMF) (20 mL) was heated to 140 °C overnight. The mixture was cooled down to rt and then activated charcoal (200 mg) was added and this was stirred for 4 h before filtering through celite cartridge (10 g). The mixture was washed with EtOAc (50 mL) and EtCH (50 mL andthe combined filtrate was concentrated in vacuo to afford 7.53 g of brown oil. This was used crude in further reactions. LCMS: Not recorded.

Reference: [1] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 107
[2] Patent: WO2008/44022, 2008, A1, . Location in patent: Page/Page column 35
[3] Patent: EP3112351, 2017, A1, . Location in patent: Paragraph 0041
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3208 - 3212
[5] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 155
[6] Patent: US2010/144783, 2010, A1, . Location in patent: Page/Page column 15
[7] Patent: US2011/281842, 2011, A1, . Location in patent: Page/Page column 45
[8] Patent: US2011/281868, 2011, A1, . Location in patent: Page/Page column 21
[9] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 48
[10] Patent: WO2014/140076, 2014, A1, . Location in patent: Page/Page column 208
  • 53
  • [ 269410-08-4 ]
  • [ 540-51-2 ]
  • [ 1040377-08-9 ]
YieldReaction ConditionsOperation in experiment
63% With caesium carbonate In N,N-dimethyl-formamide at 70℃; 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (1 .00 g, 5.15 mmol) and cesium carbonate (5.04 g, 15.47 mmol) were suspended in 10 mL of dimethylformamide. 2-Bromoethanol (0.73 mL, 10.30 mmol) was added and the mixture was stirred at 70 °C for 3 hours. Additional amounts of cesium carbonate (5.04 g, 15.47 mmol) and 2-bromoethanol (0.73 mL, 10.30 mmol) were added and the mixture was left at 70 °C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to give 770 mg (63percent yield) of a yellowish oil that was used in the next step without further purification.LRMS (m/z): 239 (M+1 )+.
31.47% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 48 h; Inert atmosphere; Sealed Step A: Preparation of 2-(4-(4 A5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- pyrazol- 1 -yDethanol : To a flask charged with 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole (1.000 g, 5.154 mmol), Cs2C03 (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100 °C for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100percent ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)ethanol (0.4290 g, 1.622 mmol, 31.47percent yield). MS (apci) m/z = 239.2 (M+H).
Reference: [1] Patent: WO2014/60432, 2014, A1, . Location in patent: Page/Page column 129
[2] Patent: WO2011/130146, 2011, A1, . Location in patent: Page/Page column 82-83
[3] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0281; 0282; 0283
  • 54
  • [ 269410-08-4 ]
  • [ 109-92-2 ]
  • [ 1029716-44-6 ]
YieldReaction ConditionsOperation in experiment
97.3%
Stage #1: With hydrogenchloride In 1,4-dioxane; toluene at 35 - 40℃; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; toluene for 1 h;
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19).; A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, condenser and N2 inlet was charged with 4-(4,4,5,5-tetra-methyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (17, 1.42 kg, 7.32 mol), toluene (9.5 L) and ethyl vinyl ether (18, 790.5 g, 1050 mL, 10.98 mol, 1.50 equiv). A 4 M HCl in dioxane (50 mL) was added via an addition funnel over 10 minutes and the resulting reaction mixture was heated at 35-40° C. for 7 hr to give a clear homogeneous solution. When the reaction was shown to be complete by GC, solid NaHCO3 (130 g) was added and the mixture was stirred for 1 hr before being filtered. The filtrate was concentrated under reduced pressure. Heptane (200 mL) was added to the residue to affect crystallization. The solid was collected by filtration and dried in a vacuum oven to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 1.896 Kg, 1.948 Kg theoretical, 97.3percent) as a white to off-white solid. For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s,1H), 7.62 (s,1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
Reference: [1] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 103-104
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8336 - 8357
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 8, p. 1357 - 1362
  • 55
  • [ 269410-08-4 ]
  • [ 156380-34-6 ]
  • [ 1029715-63-6 ]
Reference: [1] Patent: WO2008/64157, 2008, A1, . Location in patent: Page/Page column 90
[2] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 164
  • 56
  • [ 269410-08-4 ]
  • [ 941685-26-3 ]
  • [ 941685-27-4 ]
YieldReaction ConditionsOperation in experiment
64% With potassium carbonate In 1,4-dioxane; water at 90℃; for 2 h; Inert atmosphere 4-(1H-Pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5).; Method A.; To a flask equipped with a reflux condenser, a nitrogen inlet, mechanical stirrer, and a thermowell was added 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 817 g, 2.88 mol) and dioxane (8 L). To this solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4, 728 g, 3.75 mol, 1.30 equiv) followed by a solution of potassium carbonate (K2CO3, 1196 g, 8.67 mol, 3.0 equiv) in water (4 L). The solution was degassed by passing a stream of nitrogen through the solution for 15 minutes before being treated with tetrakis(triphenylphosphine)palladium(0) (167 g, 0.145 mol, 0.05 equiv) and the resulting reaction mixture was heated at reflux (about 90° C.) for 2 hours. When the reaction was deemed complete by TLC (1:1 heptane/ethyl acetate) and LCMS, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (24 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (4 L). The combined organic layers were washed with water (2.x.2 L), brine (2 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was suspended in toluene (4 L) and the solvent was removed under reduced pressure. The residue was finally triturated with methyl tert-butyl ether (MTBE, 3 L) and the solids were collected by filtration and washed with MTBE (1 L) to afford 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 581.4 g, 908.5 g theoretical, 64percent yield) as white crystalline solids. For 5: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H); C15H21N5OSi (MW, 315.45), LCMS (EI) m/e 316 (M++H).
27%
Stage #1: With potassium carbonate In 1,4-dioxane; water at 20℃; for 0.166667 h; Inert atmosphere
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane; waterInert atmosphere
At room temperature, 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12f) (800 mg, 2.82 mmol) and 4-pyrazoleboronic acid pinacol ester (842 mg, 4.34 mmol) were dissolved in dioxane (10 mL), water (2 mL) and potassium carbonate (857 mg, 6.2 mmol) were then added, nitrogen atmosphere protection was applied, and the reaction was stirred at room temperature for 10 min.
Under protection of nitrogen, Pd(dppf)Cl2 (227 mg, 0.31 mmol) was added.
The reaction was placed in an oil bath at 95°C, and stirred overnight. TLC indicated starting materials substantially disappeared.
The reaction was quenched with water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, and purified by preparative flash chromatography (PE:EA=2:3), to afford 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12g) (240 mg, brown solid), yield: 27percent. MS (ESI, m/z): 316 [M+H]+.
166.4 g
Stage #1: With potassium carbonate In water at 25 - 30℃; Inert atmosphere
Stage #2: at 78 - 80℃; for 2 h; Inert atmosphere
Nitrogen gas was purged through a mixture of 4-chloro-7- { [2- (0224) (trimemylsilyl)ethoxy]memyl}-7H-pyIτolo[2,3-
Reference: [1] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 75-76
[2] Patent: EP3360878, 2018, A1, . Location in patent: Paragraph 0140; 0145
[3] Patent: WO2016/35014, 2016, A1, . Location in patent: Page/Page column 27
  • 57
  • [ 269410-08-4 ]
  • [ 134419-59-3 ]
  • [ 1040377-03-4 ]
YieldReaction ConditionsOperation in experiment
80% at 90℃; for 2 h; A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30.0 mg, 0.154 mmol), and tetrahydro-2H-pyran-4-yl methanesulfonate (0.150 g, 0.460 mmol) in acetonitrile (1.0 mL) was stirred at 90° C. for 2 hours. The reaction was quenched with water, extracted with ethyl acetate. The combined organic layer was dried over MgSO4, then filtered and concentrated under reduced pressure to afford the desired product (35 mg, 80percent), which was used directly in the next step without further purification. LCMS calculated for C14H24BN2O3 (M+H)+: m/z=279.2. Found: 279.2.
40%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h;
Stage #2: at 110℃;
To a solution of 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (1.0 g, 5.2 mmol) in DMF (10 mL) was added NaH (0.3 g, 7.5 mmol) at 0 °C and the mixture was stirred at rt for 30 mi Tetrahydro-2H-pyran-4-yl methanesulfonate (1.1 g, 6.1 mmol) was added and the mixture was stirred at 110 °C overnight. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (30percent EA:PE) to give 550 mg of the title compound (40percent). [M+H] Calc’d for C,4H23BN203, 279; Found, 279.
38% With caesium carbonate In N,N-dimethyl-formamide at 100℃; A mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (2.8 g, 16 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.01 g, 10.4 mmol) and cesium carbonate (5.4 g, 17 mmol) in DMF (30 mL) was stirred at 100 overnight. The reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by pre-HPLC to give a light yellow oily product (1.1 g, 38) .[1589]MS (ESI, pos. ion) m/z: 279.3 [M+1]+.
16.4% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h; Inert atmosphere; glass bomb Step B: Preparation of 1 -(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole: In 8 mL of Ν,Ν-dimethylformamide were combined 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.75 g, 3.87 mmol), tetrahydro- 2H-pyran-4-yl methanesulfonate (1.04 g, 5.80 mmol), and CS2CO3 (2.01 g, 6.18 mmol) in a glass bomb and then sealed under nitrogen and heated to 100 °C. After one hour the reaction was cooled and water was added to dissolve all solids. The solution was diluted with water and then extracted with EtOAc (250 mL). The organic layer was then washed with water and brine. The combined aqueous layer was then extracted with EtOAc (200 mL). The organic layers were combined, dried over MgS04, filtered, and concentrated under reduced pressure. The crude material was dried overnight on high vacuum. The crude was purified by way of silica gel chromatography eluting with a gradient of 15-25percent EtOAc in DCM to afford 1- (tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.176 g, 0.633 mmol, 16.4percent yield). MS (apci) m/z = 279.2 (M+H).

Reference: [1] Patent: US2014/45814, 2014, A1, . Location in patent: Paragraph 0247; 0248
[2] Patent: WO2014/151106, 2014, A1, . Location in patent: Paragraph 00188
[3] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00675
[4] Patent: WO2011/130146, 2011, A1, . Location in patent: Page/Page column 81
[5] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 149
[6] Patent: WO2014/37751, 2014, A1, . Location in patent: Paragraph 00419
  • 58
  • [ 269410-08-4 ]
  • [ 590-17-0 ]
  • [ 1093307-35-7 ]
YieldReaction ConditionsOperation in experiment
63% With potassium carbonate; sodium iodide In acetonitrile at 70℃; A mixture of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH- pyrazole (0.50 g, 2.58 mmol), sodium iodide (39 mg, 0.26 mmol) bromoacetonitrile (1 .3 g, 10.8 mmol) and potassium carbonate (1.0 g, 7.8 mmol) in acetonitrile (10 mL) was heated at 70 °C overnight. Water was added and the solution was extracted with EtOAc (3x). The organic was dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography ( 10percent to 100percent EtOAc/hexane) to obtain 2-(4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetonitrile (0.38g, 63percent yield). MS (ESI) m/z: 234.1 (M+H+).
39% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; A solution of 4-(4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H- pyrazole (5.11 g, 26.3 mmol) in DMF (50 mL) was treated with bromoacetonitrile (2.20 mL, 31.6 mmol) and K2CO3() (5.46 g, 39.5 mmol). The resulting suspension was stirred for 24 h at 100 °C. The reaction mixture was cooled to ambient temperature, diluted with water (100 mL) then extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with water (3 x 50 mL) and brine (50 mL) then dried over anhydrous Na2SO4(). Following filtration, the organic extracts were concentrated under vacuum then purified by silica chromatography (10-60percent Hexanes/EtOAc as the gradient eluent) to afford the title compound (2.42 g, 39percent yield). ‘H NIVIR (400 MHz, DMSO-d6) 8.04 (s, 1H), 7.71 (s, 1H), 5.49 (s, 2H), 1.25 (s, 12H).
Reference: [1] Patent: WO2011/139891, 2011, A1, . Location in patent: Page/Page column 61-62
[2] Patent: WO2017/70708, 2017, A1, . Location in patent: Paragraph 00405
[3] Patent: WO2015/51241, 2015, A1, . Location in patent: Paragraph 00769
  • 59
  • [ 269410-08-4 ]
  • [ 2417-90-5 ]
  • [ 1022092-33-6 ]
Reference: [1] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 150
  • 60
  • [ 269410-08-4 ]
  • [ 107-13-1 ]
  • [ 1022092-33-6 ]
Reference: [1] Patent: WO2008/154241, 2008, A1, . Location in patent: Page/Page column 159
  • 61
  • [ 269410-08-4 ]
  • [ 683-57-8 ]
  • [ 1083326-46-8 ]
YieldReaction ConditionsOperation in experiment
67% With caesium carbonate In acetonitrile at 90℃; for 3 h; Step 1: Preparation of 2-(4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazol- 1 -vi) acetamide (Intermediate 24) A mixture of 4- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole(200 mg, 1.03 mmol), 2-bromoacetamide (213 mg, 1.54 mmol) and Cs2CO3 (1.27 g,3.92 mmol) in CH3CN (5.0 mL) was stirred at 90 °C for 3 hours. After being cooledto room temperature, the reaction mixture was diluted with water and extracted withEtOAc twice. The combined organic layers were dried over Na2SO4, filtered andconcentrated in vacuo to obtain the title compound (174 mg, 67percent) as a white solid, which was used for the next reaction without further purification.1H-NMR (400 MHz, CDC13): ö 7.89 (s, 1H), 7.76 (s, 1H), 6.21 and 5.41 (brs,2H), 4.83 (s, 2H), 1.32 (s, 12H).
70 mg With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 0.583333 h; Sealed tube; Microwave irradiation To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1a (100 mg, 0.52 mmol) in DMF(3 mL) was added 2-bromoacetamide 1b (143.5 mg, 1.04 mmol) and Cs2CO3 (253.5 mg, 0.78 mmol) in a sealed tubeat RT. Reaction mixture was stirred at 100 °C for 35 min under microwave irradiation. After cooling at room temperature,the mixture was diluted with EA (10 mL) and water (10 mL), extracted with EA (10 mL*3), and the organic layers werecombined and washed with water (30 mL*3) and brine (50 mL), dried over Na2SO4, filtrated and evaporated to afford2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide 1c (70 mg) as a yellow oil and used in thenext step directly.MS m/z (ESI): 252.2 [M+1]1H NMR (100 MHz, CDCl3) δ 7.9 (d, 2 H), 2.05 (s, 2 H), 1.32 (s, 12 H)
Reference: [1] Patent: WO2015/156601, 2015, A1, . Location in patent: Page/Page column 51; 52
[2] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 170
[3] Patent: WO2015/95128, 2015, A1, . Location in patent: Paragraph 0222; 0223
[4] Patent: EP3042907, 2016, A1, . Location in patent: Paragraph 0286; 0287
[5] Patent: WO2008/154241, 2008, A1, . Location in patent: Page/Page column 160
  • 62
  • [ 269410-08-4 ]
  • [ 1146629-75-5 ]
  • [ 1146629-77-7 ]
YieldReaction ConditionsOperation in experiment
82.27% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water for 14 h; Heating (4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate (10 g; Formula V), water (50 mL), and potassium carbonate (15.5 g) were added into a reaction vessel at ambient temperature. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (8.7 g; Formula VIII), 1,4-dioxane (100 mL), and tetrakis(triphenylphosphine)palladium(0) (0.08 g) were added to the reaction mixture. The reaction mixture was heated to a temperature of 80°C to 85°C, and then stirred at the same temperature for 14 hours. The progress of the reaction was monitored by thin layer chromatography. On completion, ethyl acetate (100 mL) was added to the reaction mixture. The contents were stirred for 1 hour,then filtered through a Hyflo, and then washed with ethyl acetate (40 mL). The organic layer was separated, and then concentrated under reduced pressure to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate. Yield: 82.27percent
Reference: [1] Patent: WO2016/88094, 2016, A1, . Location in patent: Page/Page column 10
  • 63
  • [ 269410-08-4 ]
  • [ 1895-39-2 ]
  • [ 1206640-82-5 ]
YieldReaction ConditionsOperation in experiment
84% With 18-crown-6 ether In acetonitrile for 18 h; Reflux Step 1: l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole [00218] A 100 mL round bottom flask was charged with 4-pyrazoleboronic acid pinacol ester (1.0 g, 5.15 mmol), 18-crown-6 (0.27 g, 1.03 mmol) and anhydrous acetonitrile (25 mL). The reagents were stirred until a colorless solution formed then sodium chlorodifluoroacetate (0.94 g, 6.18 mmol) was added and the reaction mixture heated to reflux for 18 h. After this time the reaction mixture was cooled to r.t. and the precipitated solid removed by filtration through celite, washing with EtOAc (3 x 20 mL). Combined organics were filtered through a hydrophobic frit and condensed to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution ο-hexane to 33percent EtOAc in /so-hexane) to give the title compound as a colorless solid (1.06 g, 84percent). MS (ES+) consistent with target (M+H)+.
84% With 18-crown-6 ether In acetonitrile for 18 h; Reflux Step 1 : 1 -(difluoromethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole [00256] A 100 mL round bottom flask was charged with 4-pyrazoleboronic acid pinacol ester (1 .0 g, 5.15 mmol), 18-crown-6 (0.27 g, 1 .03 mmol) and anhydrous acetonitrile (25 mL). The reagents were stirred until a colorless solution formed then sodium chlorodifluoroacetate (0.94 g, 6.18 mmol) was added and the reaction mixture heated to reflux for 18 h. After this time the reaction mixture was cooled to r.t. and the precipitated solid removed by filtration through Celite, washing with EtOAc (3 x 20 mL). Combined organics were filtered through a hydrophobic frit and condensed to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution, 0-33percent EtOAc in /so-hexane) to give the title compound as a colorless solid (1 .06 g, 84percent). MS (ES+) consistent with target (M+H)+.
80% for 24 h; Reflux; Inert atmosphere Step 1: To acetonitrile (100 ml) was added compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 101-1 (4.0 g, 0.21 mol), sodium chlorodifluoroacetate (3.77 g 0.25 mol, 15-crown-5 (103.8 g, 0.65 mol), and the reaction mixture was heated to reflux under nitrogen and stirred for 24 h, cooled to room temperature, the reaction mixture was poured into water (50 ml) to quench the reaction, and extracted with EA (100 ml×3), washed with saturated brine (20 ml), dried over Na2SO4, and filtered, and the filtrate was evaporated to give compound 101-2 (4.1 g, yield 80percent) as a white solid. MS m/z (ESI): 245.1 [M+H]+.
47% With 18-crown-6 ether In acetonitrile for 20 h; Reflux Reference Example 1711-(Difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester A suspension of 1H-pyrazole-4-boronic acid pinacol ester (5.16 g, 26.6 mmol), CF2ClCO2Na (4.86 g, 31.9 mmol), and 18-crown-6 (1.41 g, 5.32 mmol) in CH3CN (100 mL) was refluxed for 20 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (3.03 g, 47percent yield) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ ppm 1.33 (12H, s), 7.22 (1H, t, J=60.7 Hz), 7.89 (1H, s), 8.13 (1H, s).
500 mg With 18-crown-6 ether In acetonitrile for 20 h; Reflux A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (516 mg, 2.66 mmol), CF2ClCO2Na (486 mg, 3.19 mmol), and 18-crown-6 (141 mg, 0.532 mmol) in CH3CN (150 mL) was heated to reflux for 20 hours. After cooled to room temperature, thereaction mixture was poured into water and extracted with EtOAc. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford a crude 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg), which was used for the next step without further purification. MS (ESI) m/z: 245 [M+H]+.
1.54 g With 18-crown-6 ether In acetonitrile at 90℃; for 16 h; E)
1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.50 g), sodium chlorodifluoroacetate (1.41 g) and acetonitrile (35 mL) was added 18-crown-6 (0.409 g).
The reaction mixture was stirred at 90° C. for 16 hr, poured into water, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to give the title compound (1.54 g).
MS (API+): [M+H]+245.1.

Reference: [1] Patent: WO2014/159218, 2014, A1, . Location in patent: Paragraph 00218
[2] Patent: WO2014/159224, 2014, A1, . Location in patent: Paragraph 00256
[3] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0324; 0325
[4] Patent: US2010/197651, 2010, A1, . Location in patent: Page/Page column 84
[5] Patent: WO2014/1377, 2014, A1, . Location in patent: Page/Page column 119; 120
[6] Patent: US2016/159808, 2016, A1, . Location in patent: Paragraph 1374; 1375
[7] Patent: US2017/44132, 2017, A1, . Location in patent: Paragraph 0697; 0698
[8] Patent: TW2017/14883, 2017, A, . Location in patent: Paragraph 0198
  • 64
  • [ 269410-08-4 ]
  • [ 75-45-6 ]
  • [ 1206640-82-5 ]
Reference: [1] Patent: WO2010/10184, 2010, A1, . Location in patent: Page/Page column 91; 92
  • 65
  • [ 269410-08-4 ]
  • [ 383-62-0 ]
  • [ 1206640-82-5 ]
Reference: [1] Patent: WO2018/13867, 2018, A1, . Location in patent: Paragraph 654
  • 66
  • [ 269410-08-4 ]
  • [ 7250-67-1 ]
  • [ 1000802-52-7 ]
YieldReaction ConditionsOperation in experiment
50.1% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6 h; A mixture of 1- (2-chloroethyl) pyrrolidine hydrochloride (1.48 g, 8.70 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.7 g, 8.8 mmol) and potassium carbonate (3.7 g, 27.00 mmol) in DMF (15 mL) was stirred at 80 for 6 h. The reaction mixture was diluted with water (50 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM/EtOAc (v/v) 20/1 to give a light yellow liquid product (1.27 g, 50.10) .[1772]MS (ESI, pos. ion) m/z: 292.10 [M+1]+
Reference: [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00719
[2] Patent: US2010/273796, 2010, A1, . Location in patent: Page/Page column 20-21
[3] Patent: US2011/34474, 2011, A1, . Location in patent: Page/Page column 22
[4] Patent: US2011/71153, 2011, A1, . Location in patent: Page/Page column 21
[5] Patent: US2011/92498, 2011, A1, . Location in patent: Page/Page column 20-21
[6] Patent: WO2011/95196, 2011, A1, . Location in patent: Page/Page column 93
[7] Patent: US2011/269765, 2011, A1, . Location in patent: Page/Page column 24
[8] Patent: US2011/281842, 2011, A1, . Location in patent: Page/Page column 40
[9] Patent: US2011/257173, 2011, A1, . Location in patent: Page/Page column 23
[10] Patent: US2012/295902, 2012, A1, . Location in patent: Paragraph 0306; 0307; 0308
  • 67
  • [ 269410-08-4 ]
  • [ 5392-81-4 ]
  • [ 1086111-20-7 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.5 h;
Stage #2: With potassium iodide In tetrahydrofuran at 50℃;
To a solution of 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (250 mg, 1.29 mmol) and sodium hydride (61.8 mg, 2.58 mmol) in tetrahydrofuran at 0° C. was added 2-bromo-N,N-diethylethanamine (558 mg, 2.58 mmol). The reaction was allowed to warm up to room temperature and was monitored by LCMS. After 90 minutes there was still no reaction and potassium iodide (1.71 g, 10.3 mmol) was added and the reaction was heated at 50° C. overnight. The reaction mixture was diluted with a large volume of ethyl acetate and water and partitioned. The organic layer containing the product was washed with brine and concentrated in vacuo to give clear thick oil confirmed by LCMS to be 100percent pure N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine (340 mg, yield 90percent, M+1 294.2)
Reference: [1] Patent: US2012/245144, 2012, A1, . Location in patent: Page/Page column 118
  • 68
  • [ 269410-08-4 ]
  • [ 869-24-9 ]
  • [ 1086111-20-7 ]
Reference: [1] Patent: WO2014/159224, 2014, A1, . Location in patent: Paragraph 00276
  • 69
  • [ 269410-08-4 ]
  • [ 13057-19-7 ]
  • [ 1301198-65-1 ]
YieldReaction ConditionsOperation in experiment
26% With potassium carbonate In acetonitrile at 35℃; for 3 h; Inert atmosphere Intermediate 941 -[(Methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35°C for 5 min under nitrogen atmosphere then cooled to room temperature, lodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35°C for 3 h then cooled to room temeprature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgS04 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silca cartridge (gradient: 0 to 50percent AcOEt in hexanes) gave 1 -[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (6.45 g, 50percent pure by LCMS, 26percent) as a yellow liquid which was used in the next step without further purification.LCMS (method G): Retention time 0.85 min, [M+H]+ = 238.8
260 mg With potassium carbonate In acetonitrile at 35℃; for 4.5 h; Intermediate 12: 1-[(Methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[0399]4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 2.061 mmol) (Aldrich) was dissolved in acetonitrile (25 ml) and stirred for 5 min at 35° C. Iodomethyl methyl ether (0.873 ml, 10.31 mmol) and potassium carbonate (1424 mg, 10.31 mmol) were added and the mixture was allowed to stir at 35° C. for 3 h.[0401]The LCMS showed incomplete reaction. The mixture was left to stir at 35° C. for one additional hour. The LCMS showed no progression so 2 eq (349 μl) of the alkylating agent was added and the mixture was allowed to stir at 35° C. for 30 min. Ammonium chloride was then added. The mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were washed with water, dried using a hydrophobic frit and concentrated to an oil. The oil was purified on 50 g silica using an SP4 and eluted with a 0-100percent ethyl acetate/cyclohexane gradient. The product was found in the waste, which was concentrated to give the title compound as an oil (260 mg).[0402]LCMS (Method B): Rt=0.84 min, MH+=238.85
Reference: [1] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 91-92
[2] Patent: WO2011/134971, 2011, A1, . Location in patent: Page/Page column 12; 56; 57
[3] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 41
[4] Patent: US2013/40984, 2013, A1, . Location in patent: Paragraph 0399-0402
  • 70
  • [ 269410-08-4 ]
  • [ 26272-83-3 ]
  • [ 1339890-99-1 ]
Reference: [1] Patent: WO2014/37751, 2014, A1, . Location in patent: Paragraph 00419
  • 71
  • [ 269410-08-4 ]
  • [ 535-11-5 ]
  • [ 1220968-24-0 ]
YieldReaction ConditionsOperation in experiment
61% With caesium carbonate In acetonitrile at 90℃; for 4 h; A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.1 mmol, Aldrich, Cat. 525057), ethyl 2-bromopropanoate (290 μL, 2.3 mmol), and cesium carbonate (1.5 g, 4.6 mmol) in acetonitrile (8 mL) was stirred at 90° C. for 4 h. After cooling, the reaction mixture was worked up with aqueous Na2CO3, extracted with ethyl acetate (3.x.20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50percent) to afford the desired product (0.42 g, 61percent). LCMS (M+H)+: m/z=295.1.
21.6 g With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 14 h; Step 9
Ethyl 2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate
To a suspension of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added ethyl 2-bromopropionate (13 ml), and the mixture was stirred at 80° C. for 14 hr.
The reaction mixture was cooled to 0° C., and toluene (100 ml) and water (150 ml) were successively added dropwise.
The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml).
The combined organic layer was successively washed once with 10percent aqueous potassium carbonate solution (50 ml), twice with water (50 ml) and once with saturated brine (50 ml).
The obtained organic layer was dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give the title compound (21.6 g).
1H-NMR (400 MHz, CDCl3) δ: 7.85 (1H, s), 7.81 (1H, s), 5.10 (1H, q, J=7.3 Hz), 4.19 (2H, q, J=7.1 Hz), 1.78 (3H, d, J=7.4 Hz), 1.32 (12H, s), 1.25 (3H, t, J=7.2 Hz).
Reference: [1] Patent: US2012/165305, 2012, A1, . Location in patent: Page/Page column 43
[2] Patent: US2014/296316, 2014, A1, . Location in patent: Paragraph 0193; 0194; 0195