Home Cart 0 Sign in  

[ CAS No. 761446-44-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 761446-44-0
Chemical Structure| 761446-44-0
Structure of 761446-44-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 761446-44-0 ]

Related Doc. of [ 761446-44-0 ]

Alternatived Products of [ 761446-44-0 ]

Product Details of [ 761446-44-0 ]

CAS No. :761446-44-0 MDL No. :MFCD03789259
Formula : C10H17BN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :UCNGGGYMLHAMJG-UHFFFAOYSA-N
M.W :208.07 Pubchem ID :2773987
Synonyms :

Calculated chemistry of [ 761446-44-0 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.7
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 59.96
TPSA : 36.28 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) : -6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.22
Log Po/w (WLOGP) : 0.72
Log Po/w (MLOGP) : 0.3
Log Po/w (SILICOS-IT) : 0.29
Consensus Log Po/w : 0.51

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.08
Solubility : 1.73 mg/ml ; 0.00833 mol/l
Class : Soluble
Log S (Ali) : -1.58
Solubility : 5.48 mg/ml ; 0.0264 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.4
Solubility : 0.823 mg/ml ; 0.00395 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.81

Safety of [ 761446-44-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 761446-44-0 ]

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

  • Upstream synthesis route of [ 761446-44-0 ]
  • Downstream synthetic route of [ 761446-44-0 ]

[ 761446-44-0 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 761446-44-0 ]
  • [ 78242-20-3 ]
YieldReaction ConditionsOperation in experiment
98% With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran at 0 - 25℃; for 3 h; Inert atmosphere General procedure: To a cold (0 °C, ice bath) solution of 1-alkyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 g, 120.2 mmol) in tetrahydrofuran (600.9 mL, 0.2 M) was slowly added aqueous sodium hydroxide (80.1 mL, 3 M, 240.3 mmol) followed by Hydrogen peroxide (27.3 mL, 240.3 mmol). The reaction mixture was stirred at 0-25 °C for 3 h. The mixture was carefully neutralized with 12N HCl (18.6 mL) and diluted with a mixture of dichloromethane and methanol (90:10, 200 mL). The aqueous layer was extracted with a mixture of dichloromethane and methanol (90:10, 3*200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-alkyl-1H-pyrazol-4-ol 12.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 49, p. 4587 - 4590
[2] Patent: WO2016/11930, 2016, A1, . Location in patent: Page/Page column 138
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
  • 2
  • [ 269410-08-4 ]
  • [ 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
  • 3
  • [ 15803-02-8 ]
  • [ 73183-34-3 ]
  • [ 761446-44-0 ]
YieldReaction ConditionsOperation in experiment
27.1% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 5 h; Inert atmosphere A suspension of 4-bromo-l -methyl- lH-pyrazole (2 g, 12.42 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (3.47 g, 13.66 mmol), KOAc (2.438 g, 24.84 mmol), PdCl2(dppf) (0.909 g, 1.242 mmol) in 1,4-dioxane (20 mL) was heated to 100 °C for 5 h under N2 atmosphere. The mixture was concentrated to give the residue which was extracted with DCM (15 mL x 2). The organic extract was washed with brine (20 mL ), dried over Na2S04, filtered and concentrated, and then the crude product was purified by silica column chromatography (10percent EA: 90percent Petroleum ether, 4 g silica column). All fractions found to contain product by TLC (EA : Petroleum ether = 1 : 1, Rf = 0.3) were combined and concentrated to yield a yellow solid of 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (700 mg, 3.36 mmol, 27.1percent yield): NMR (400 MHz, CDC13) δ 7.77 (s, 1H), 7.66 (s, 1H), 3.92 (s, 3H), 1.32 (s, 12H). ES- LCMS m/z 209 (M+H).
Reference: [1] Patent: WO2014/141187, 2014, A1, . Location in patent: Page/Page column 163
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 12, p. 5053 - 5074
  • 4
  • [ 39806-90-1 ]
  • [ 61676-62-8 ]
  • [ 761446-44-0 ]
YieldReaction ConditionsOperation in experiment
1 g
Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 1.5 h;
To 1-methyl-4-iodopyrazole (1.0 g) and 10 mL of THF,Under the protection of nitrogen, slowly add isopropylmagnesium chloride/lithium chloride solution (3.97mL), the temperature during the dropwise addition does not exceed 0 °C,After the addition, stir for 1 h, then at 0 ° C,Slowly add isopropyl pinacol borate (1.11g) to control the temperature not to exceed 0 ° C, and then stir at room temperature for 1.5 h after the addition.After the reaction was completed, 10 mL of a saturated ammonium chloride solution was added dropwise.Quenched.Then add 50 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution.The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layer was combined and dried over anhydrous Na2SO?Dry under reduced pressure,The title product (1 g) was obtained.
Reference: [1] Patent: CN108484609, 2018, A, . Location in patent: Paragraph 0155; 0156; 0157; 0159
  • 5
  • [ 76-09-5 ]
  • [ 847818-55-7 ]
  • [ 761446-44-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 6, p. 931 - 939
  • 6
  • [ 930-36-9 ]
  • [ 76-09-5 ]
  • [ 761446-44-0 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858
  • 7
  • [ 76-09-5 ]
  • [ 22038-72-8 ]
  • [ 761446-44-0 ]
Reference: [1] Patent: CN105440067, 2016, A, . Location in patent: Paragraph 0016
  • 8
  • [ 35852-81-4 ]
  • [ 73183-34-3 ]
  • [ 761446-44-0 ]
Reference: [1] RSC Advances, 2018, vol. 8, # 25, p. 13643 - 13648
  • 9
  • [ 269410-08-4 ]
  • [ 74-83-9 ]
  • [ 761446-44-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 7934 - 7937
  • 10
  • [ 135034-10-5 ]
  • [ 761446-44-0 ]
  • [ 943541-20-6 ]
YieldReaction ConditionsOperation in experiment
82% With potassium phosphate; N-benzyl-N,N,N-triethylammonium chloride; triphenylphosphine In tetrahydrofuran; water at 65℃; for 16 h; Step 5: 3-chloro-6-(1-methyl-1/-/-pyrazol-4-yl)pyridazineWater (253 mL) and THF (842 mL) were put in the reaction balloon. The reagents were added one by one to the stirred reaction mixture: potassium phosphate monohydrate 86,2 g (374 mmol) and BTEAC 2,25g (9,88 mmol). Then 3-chloro-6-iodopyhdazine, 45 g (187,2 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole, 46,73g(224,6 mmol) were added and finally triphenylphosphine, 1 ,96g (7,49 mmol) and palladiumdiacetate, 420 mg (1 ,87 mmol) were added. The reaction mixture was heated at 65°C for 16h . The reaction mixture was allowed to cool to 600C. Then 935 mL water and301 , 5g sodium chloride were added. The mixture was stirred for 15 minutes and allowed <n="74"/>to cool to 450C. The phases were separated and the organic layer was washed with a solution of 45 g sodium chloride in 374 mL water. The organic layer was separated and stirred with magnesium sulphate (225 g) and charcoal (4,5 g). The mixture was filtered and evaporated. The evaporation residue was co-evaporated with toluene twice and evaporated further till a final volume of 200 ml. This residue was stirred for 16 h at room temperature. The resulting solids were collected by filtration. The solids were dried at reduced pressure affording 29,7 g of the title compound (152,6 mmol, yield 82percent).1 H NMR (600 MHz, CHLOROFORM-c/) δ ppm 4.00 (s, 3 H) 7.46 (d, J=8.69 Hz, 1 H) 7.56 (d, J=9.06 Hz, 1 H) 7.98 (s, 1 H) 8.11 (s, 1 H)
Reference: [1] Patent: WO2008/155378, 2008, A1, . Location in patent: Page/Page column 72-73
[2] Patent: US2011/92498, 2011, A1, . Location in patent: Page/Page column 19
[3] Patent: US2011/257181, 2011, A1, . Location in patent: Page/Page column 21
  • 11
  • [ 141-30-0 ]
  • [ 761446-44-0 ]
  • [ 943541-20-6 ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate In 1,4-dioxane; water at 80℃; for 4 h; Example 2 : 6-(l-methyI-li/-pyrazol-4-yl)-[l ,2,4] triazolo [4,3-6] pyridazine-3-thiol; Step 1: 3-Chloro-6-(l-methyl-lHr-pyrazol-4-yl)-pyridazine; [0345] A mixture of 3,6-dichloropyridazine (20. Ig, 135 mmol), l-methyl-4- pyrazoleboronic acid pinacol ester (22.46 g, 108 mmol) and K2CO3 (44.71 g, 324 mmol) in 50OmL of dioxane and 20OmL of H2O was degassed with nitrogen. To this mixture was added dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.28 g, 7.2 mmol) and the resulting mixture was bubbled with nitrogen for another 20 min. The reaction mixture was heated at 8O0C for 4h, then concentrated in vacuo. The residue was purified by flash column chromatography with dichloromethane as eluent to provide 21g of 3-chloro-6-(l-methyl-lH-pyrazol-4-yl)-pyridazine (76percent yield): 1H NMR(CDCl3) δ 3.99 (s, 3H), 7.45 (d, IH), 7.56 (d, IH), 7.97 (s, IH), 8.11 (s, IH).
75% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water at 90℃; for 5 h; To a solution of 3,6-dichloropyridazine (500 mg, 3.4 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (560 mg, 2.7 mmol), K2CO3 (1.1 g, 8.1 mmol) in 1,4-dioxane/H2O (2.5:1, 5 mL) was added PdCl2(dppf)2. After stirred at 90 °C for 5 h, the reaction mixture was was extracted with CH2Cl2 (40 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (494 mg, 75 percent). 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (1a) 1HNMR (300 MHz, CDCl3) δ 8.20 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 3.95 (s, 3H).
68% With sodium carbonate In 1,4-dioxane; water at 80℃; A flask was charged with 3,6-dichloropyridazine (AJdrich, 23.91 g, 160.5 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2idioxaborolan-2-yl)-lH-pyrazole (20 g, 96 mmol), 2.0 M Na23 (96 mL) and dioxane (65 mL). Nitrogen was bubbled through the reaction for 60 seconds followed by the addition of Dichlorobis(triphenylphosphine)palladium (0) (6.75 g, 9.6 mmol). The reaction was heated to 800C overnight followed by aqueous work up using AcOEt and a solution of K2CO3. After filtration over celite, the organic layer was dried (MgSO4) and concentrated in vacuo. A first fraction of compound (10.2g) was obtained by crystallization in the solvent (dichoromethane). The filtrate was purified by column chromatography (CH2Cl2 100percent and CH2Cl2ZMeOH : 95/5) . The two fractions were gathered and washed with diisopropylether to give the title compound as a yellow solid (12.7 g, 68 percent).
63.1% With potassium carbonate In 1,4-dioxane; water at 80℃; for 16.3 h; Inert atmosphere Preparation 1
3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine
To a 3000 mL round bottom flask containing a solution of 1-methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (76 g, 365.3 mmol), 3,6-dichloropyridazine (68 g, 456.4 mmol) in 1,4-dioxane (1200 mL) is added a aqueous solution of K2CO3 (127 g, 919 mmol) in water (480 mL).
After [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (7.5 g, 9.2 mmol) is added, the mixture is purged with N2 for 20 min and stirred at 80° C. for 16 h.
The reaction mixture is poured into water (300 mL) and dichloromethane (2000 mL), and the aqueous layer is extracted with DCM (3*800 mL).
The combined organic layers are dried over anhydrous Na2SO4 and concentrated under vacuum.
The crude product is purified with silica gel column eluting with DCM/methanol (40:1) to give the title compound as a pale yellow solid (56 g, 63.1percent). MS (m/z): 195.1 (M+H).
47% With sodium carbonate In 1,4-dioxane; water at 80℃; A flask was charged with 3,6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (499 mg, 2.4 mmol), 2 M Na2COs (4 mL) and dioxane (4 mL). Argon was bubbled through the reaction for 60 seconds followed by the addition ofTetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol). The reaction was heated to 80 0C overnight followed by aqueous work up using EtOAc and brine. The organic layer was dried (MgSO4) and concentrated in vacuo followed by column chromatography purification (20 percent Ethyl Acetate in Hexanes) resulting in the title compound as a white solid (183 mg, 47 percent). 1H-NMR (CD3OD): δ 8.23 (IH, s), 8.08 (IH, s), 7.84 (IH, br s), 7.34 (IH, br s), 4.00 (3H, s).
44%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane for 0.0166667 h;
Stage #2: With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 80℃; for 15 h;
A solution of 3,6-dichloropyridazine (4.57 g, 0.003 1 mol), (1-methyl-1H-pyrazol-4- yl)boronic acid pinacol ester (3.82 g, 0.0 184 mol) and a solution ofNa2CO3 2M (18.3 mL) in dioxane (18.4 mL) was stirred for 1 minute. PdC12(PPh3)2 (1.29 g, 0.0018 mol) was added and the solution was heated at 80°C for 15 hours. The mixture was cooled to room temperature and poured into water. K2C03 was added and the mixture wasfiltered through a short pad of Celite®. The organic layer was dried (Mg504), filtered and evaporated to dryness. The Celite® was washed with CH2C12, the filtrate was dried (Mg504) and evaporated. The residue was crystallized from CH2C12. The precipitate was filtered and dried to give 1.5 g of a first batch of intermediate 5 (42percent). The filtrate was purified by chromatography over silica gel (30 g of SiOHl5-40jim,mobile phase : gradient from CH2C12 100percent to CH2C12 95percent/CH3OH 5percent). The pure fractions were collected and evaporated until dryness to give 1.58 g of a second batch of intermediate 5 (44percent)

Reference: [1] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 96
[2] Archives of Pharmacal Research, 2016, vol. 39, # 4, p. 453 - 464
[3] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 119
[4] Patent: US2012/28984, 2012, A1, . Location in patent: Page/Page column 2
[5] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 69
[6] Patent: WO2016/87586, 2016, A1, . Location in patent: Page/Page column 17; 18
[7] Patent: WO2013/85957, 2013, A1, . Location in patent: Page/Page column 55
  • 12
  • [ 89402-43-7 ]
  • [ 761446-44-0 ]
  • [ 1151801-90-9 ]
YieldReaction ConditionsOperation in experiment
85% With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); tetrabutylammomium bromide In 2-methyltetrahydrofuran at 70℃; Inert atmosphere [00316] 3-fluoro-2-hydrazinyl-5- (i-methyl-i H-pyrazol-4-yl)-pyridine was synthesized according to Scheme 14 by the following procedure. A 60 L jacketed reactor was fitted with a 5 L addition funnel and the jacket temperature was set to 20±5 °C. 36.0 L (15 Vol) of 2- methyltetrahydrofuran was added to the reactor via a 20 tm inline filter with vacuum using polypropylene transfer lines. The solution was sparged by bubbling nitrogen through a dipstick in the solution for 1±0.5 h with agitation. After 1 h the dipstick was removed but the nitrogen sweep continued. 1.55 kg of sparged 2-MeTHF was removed to be used as rinse volumes. 36.7 g of Pd2dba3, 75.6 g X-Phos, 259 g of tetrabutylammonium bromide, and 7397 g of potassium phosphate tribasic were added to the reactor. The manhole was rinsed with 0.125 kg of sparged 2-MeTHF. The reactor was agitated and the nitrogen sweep continued for 1±0.5 h. Then the nitrogen sweep was stopped and the reaction left under a positive pressure of nitrogen.[00317] 3.6 L (1.5 Vol) of sparged water was prepared in advance by bubbling nitrogen through a 4 L bottle of water for 1±0.5 h. The nitrogen sparged water was transferred to the 5 L addition funnel via a 20 tm inline filter with vacuum using polypropylene transfer lines, then slowly added to the reaction while maintaining the internal temperature at 20±5 °C. The 5 L addition funnel was replaced with a 2 L addition funnel. 2412 g of 5-chloro-2,3-difluoropyridine was added to the 2 L addition funnel. The 5-chloro-2,3-difluoropyridine was then added to the reaction through the 2 L addition funnel. The 2L addition funnel was rinsed with 0.060 kg of sparged 2-MeTHF. 83.8 g (1.15 equivalents) of 1-methylpyrazole-4-boronic acid, pinacol ester was added to reactor, the reactor was swept with nitrogen for 1±0.5 h, then left under a positive pressure of nitrogen. The internal temperature of the reactor was adjusted to 70±5 °C. The batch was agitated at 70±5 °C for at least 4 hours after the final reagent was added. A sample was taken from the reaction and the reaction progress assayed for conversion. The progress of the reaction was checked every 2 hours until the reaction was completed (e.g., greater than 99percent conversion). The batch was cooled to 20±5 °C.[00318] A 20percent w/v sodium bisulfite solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water then 2411 g sodium bisulfite to an appropriate container and agitating until homogeneous. The 20percent sodium bisulfite solution was transferred into the reactor and agitated for 30 minutes. The agitation was stopped, the phases allowed to settle, and the aqueous phase was removed. A 0.5 M potassium fluoride solution (12.0 L, 5 Vol) was prepared by charging 12.0 L of water and 348 g of potassium fluoride to an appropriate container and agitating until homogenous. The 0.5 M potassium fluoride solution was transfened into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed. A 25percent w/v sodium chloride solution (12.0 L, 5 Vol) was prepared by charging an appropriate container with 12.0 L of water and 2999 g of sodium chloride and agitating until homogeneous. The 25percent sodium chloride solution was transferred into the reactor and agitated for 30 mm. The agitation was stopped, the phases were allowed to settle, and the aqueous phase was removed from the reactor.[00319] The organic phase was distilled at constant volume (36 L, 15 Vol) while maintaining the internal temperature of the reactor at 50±5 °C by adjusting the vacuum pressure until no more than 0.3percent of water remained. 2-Methyltetrahydrofuran was added to the reactor as needed to maintain constant volume. The batch was cooled to 20 °C and transferred into drums. The batch was transfeffed using a polish filter (using a 5 tm inline filter) into a 60 L jacketed reactor withbatched concentrator attached. 1.2 L of 2-MeTHF was used to rinse the drums. The batch was concentrated to about 9 Vol while maintaining the internal temperature of the vessel at 50±5adjusting the vacuum pressure. The batch was then distilled at constant volume (22.0 L, 9Vol) while maintaining the internal temperature of the vessel at 50±5 °C by adjusting the vacuum pressure. Heptane was added with residual vacuum until a 15percent 2-MeTHF:heptane supernatant mixture was obtained. The pressure was brought to atmospheric pressure under nitrogen. The reactor was cooled to 20±5 °C over 2±2 h. The batch was agitated at 20±5 °C until an assay of the supernatant indicated that the amount of product was 7 mg/mL 2,3-difluoro-1-methyl-i H-pyrazol-4-yl)pyridine.[00320] A 10percent 2-MeTHF:heptane (7.2 L, 3 Vol) wash solution was prepared by mixing 720 mL of 2-MeTHF and 6.5 L of heptane. The batch sluffy was filtered through an Aurora filter fitted with a 25 tm polypropylene filter cloth, resulting in heavy crystals that required pumping with a diaphragm pump using polypropylene transfer lines through the top of the reactor while stirring. The mother liquor was recycled to complete the transfer. The reactor and filter cake were washed with two portions of the 10percent 2-MeTHF:heptane wash solution (3.6 L each). The product cake was dried on a frit under a nitrogen stream at ambient temperature. The 2,3- difluoro-5-(i-methyl-1H-pyrazol-4-yl)pyridine was detennined to be dry when the ‘H NMR assay was 0.05±0.05. 2.635 kg was isolated as an off white crystalline solid (85percent yield).
Reference: [1] Patent: WO2014/210042, 2014, A2, . Location in patent: Paragraph 00316-00320
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2328 - 2342
  • 13
  • [ 761446-44-0 ]
  • [ 1151801-90-9 ]
YieldReaction ConditionsOperation in experiment
57.4% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In N,N-dimethyl-formamide at 80℃; for 10.16 h; Inert atmosphere A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.038 g, 9.79 mmol), Na2C03 (2.076 g, 19.59 mmol) and Pd(PPh3)4 (1 .131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N2 for 10 min and was then heated to 80°C for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA,washed with water and brine, dried over anhydrous MgS04. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100percent to 20percent) to afford the title compound as a white solid (1 .5 g, 57.4percent yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, 3H), 7.99 (d, 1 H), 3.87 (s, 3H). LCMS (method B): [M+H]+ = 196, tR = 1 .91 min.
57.4% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (2.038 g, 9.79 mmol), Na2CO3 (2.076 g, 19.59 mmol) and Pd(PPh3)4 (1.131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N2 for 10 min and was then heated to 80° C. for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA, washed with water and brine, dried over anhydrous MgSO4. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100percent to 20percent) to afford the title compound as a white solid (1.5 g, 57.4percent yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, 3H), 7.99 (d, 1H), 3.87 (s, 3H). LCMS (method B): [M+H]+=196, tR=1.91 min.
Reference: [1] Patent: WO2013/38362, 2013, A1, . Location in patent: Page/Page column 78; 79
[2] Patent: US2013/245002, 2013, A1, . Location in patent: Paragraph 0719
  • 14
  • [ 106-37-6 ]
  • [ 761446-44-0 ]
  • [ 1191616-45-1 ]
YieldReaction ConditionsOperation in experiment
75% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 3 h; Inert atmosphere Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 1-methyl-4-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 9.61 mmol), 1 ,4-dibromobenzene (2.30 g, 9.75 mmol), Pd(PPh3)4 (550 mg, 0.48 mmol), potassium carbonate (2.60 g, 18.8 mmol), dioxane (40 ml_) and water (10 ml_). The resulting solution was stirred for 3 h at 80°C. The resulting mixture was evaporated to dryness. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 1.70 g (75percent) of 4-(4- bromophenyl)-1-methyl-1 H-pyrazole as a yellow solid.
Reference: [1] Patent: WO2016/41618, 2016, A1, . Location in patent: Page/Page column 69
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 761446-44-0 ]

Organoboron

Chemical Structure| 847818-70-6

[ 847818-70-6 ]

1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.92

Chemical Structure| 269410-08-4

[ 269410-08-4 ]

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.90

Chemical Structure| 1040377-08-9

[ 1040377-08-9 ]

2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol

Similarity: 0.90

Chemical Structure| 827614-69-7

[ 827614-69-7 ]

1-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.90

Chemical Structure| 879487-10-2

[ 879487-10-2 ]

1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.89

Related Parent Nucleus of
[ 761446-44-0 ]

Pyrazoles

Chemical Structure| 847818-70-6

[ 847818-70-6 ]

1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.92

Chemical Structure| 269410-08-4

[ 269410-08-4 ]

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.90

Chemical Structure| 1040377-08-9

[ 1040377-08-9 ]

2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol

Similarity: 0.90

Chemical Structure| 827614-69-7

[ 827614-69-7 ]

1-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.90

Chemical Structure| 879487-10-2

[ 879487-10-2 ]

1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.89