Home Cart 0 Sign in  
X

[ CAS No. 407-20-5 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 407-20-5
Chemical Structure| 407-20-5
Chemical Structure| 407-20-5
Structure of 407-20-5 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 407-20-5 ]

Related Doc. of [ 407-20-5 ]

Alternatived Products of [ 407-20-5 ]

Product Details of [ 407-20-5 ]

CAS No. :407-20-5 MDL No. :MFCD04112555
Formula : C5H3BrFN Boiling Point : -
Linear Structure Formula :- InChI Key :HNNNBQRRIHKFLI-UHFFFAOYSA-N
M.W : 175.99 Pubchem ID :820206
Synonyms :

Calculated chemistry of [ 407-20-5 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 31.89
TPSA : 12.89 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.73
Log Po/w (XLOGP3) : 1.64
Log Po/w (WLOGP) : 2.4
Log Po/w (MLOGP) : 1.68
Log Po/w (SILICOS-IT) : 2.54
Consensus Log Po/w : 2.0

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.52
Solubility : 0.532 mg/ml ; 0.00302 mol/l
Class : Soluble
Log S (Ali) : -1.52
Solubility : 5.27 mg/ml ; 0.0299 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.15
Solubility : 0.124 mg/ml ; 0.000703 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.52

Safety of [ 407-20-5 ]

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 [ 407-20-5 ]

* 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 [ 407-20-5 ]
  • Downstream synthetic route of [ 407-20-5 ]

[ 407-20-5 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 13535-01-8 ]
  • [ 407-20-5 ]
YieldReaction ConditionsOperation in experiment
55% With tetrafluoroboric acid; sodium nitrite In water at -8℃; for 1 h; Step 2:
3-Bromo-5-fluoropyridine
A at -10° C. cooled solution of 10.0 g (0.058 mol) of 3-Amino-5-bromopyridine in 59 ml of 50percent Tetrafluoroboric acid was treated by dropwise addition of a solution of 4.19 g (0.06 mol) of sodium nitrite in 13 ml of water.
After stirring for 1 h at -8° C., 150 ml of ether was added to the brown suspension.
The crude diazonium salt was filtered off, and washed with ether.
This crude salt was then added in portions to 200 ml of toluene heated at 80° C.
After stirring for 1 h at 90° C., the organic phase was concentrated.
The light yellow residue was suspended in 150 ml of water and the pH was adjusted to 11 with 32percent sodium hydroxide solution.
The resulting solution was extracted three times with 200 ml of methylene chloride.
The combined organic phases were washed with water, dried over magnesium sulfate and concentrated.
The crude material 15.4 g (brown oil) was purified by vaccum distillation (10 mBar, 35° C.) and yielded 5.6 g (0.032 mol, 55percent) of the title compound as a colorless oil (ISP): m/e=176.1, 178.1 (M+H+).
Reference: [1] Patent: US2006/199960, 2006, A1, . Location in patent: Page/Page column 21
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
  • 2
  • [ 625-92-3 ]
  • [ 407-20-5 ]
Reference: [1] Synthesis, 2010, # 14, p. 2490 - 2494
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 12, p. 2215 - 2218
[3] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
  • 3
  • [ 2546-52-3 ]
  • [ 372-47-4 ]
  • [ 407-20-5 ]
Reference: [1] Tetrahedron, 1986, vol. 42, # 8, p. 2253 - 2262
  • 4
  • [ 557-21-1 ]
  • [ 407-20-5 ]
  • [ 696-42-4 ]
Reference: [1] Patent: WO2013/43520, 2013, A1, . Location in patent: Page/Page column 37
  • 5
  • [ 407-20-5 ]
  • [ 452972-09-7 ]
YieldReaction ConditionsOperation in experiment
87.4%
Stage #1: With n-butyllithium; isopropyl boric acid In tetrahydrofuran at -90 - -80℃; for 2.5 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at -20 - 10℃; for 0.5 h;
Preparation of 5-Fluoropyridine-3-boronic acid (2b): 3-bromo-5- fluoropyridine (2a) (25 kg, 142 moles, 1.0 equiv.), THF (222.5 kg) and isopropyl borate (28 kg, 149.3 moles, 1.05 equiv.) were added to a 700 L low temperature reactor. The resulting mixture was cooled to -90 0C ~ -80 0C while stirred. Then n-BuLi (40.2 kg, 2.5 M, 142 moles, 1.0 equiv.) was added dropwise (2 kg/h) maintaining the temperature below -87 0C. After the addition was complete, the mixture was maintained at -88 ~ -83 0C for 2.5 h. When the reaction was deemed complete by HPLC analysis, it was quenched by addition of 9 percent aqueous HCl (7.7 kg). The mixture was transferred to a1000 L glass-lined reactor and the temperature returned to -20 ~ -10 0C. Additional HCl <n="57"/>solution (122.3 kg) was then added until pH was adjusted to 1-2 maintaining the temperature at 0-10 0C. The mixture was then held for 0.5 h in order to allow layers to separate. The organic layer was separated and washed with saturated brine (38 kg). It was stirred for 0.5 h and then held again for 0.5 h to allow layer separation. The aqueous 5 layer was separated and the combined aqueous layers were extracted with EtOAc twice (51+25 kg). The organic phase was separated and pH was adjusted to a value of 6 by using 30 percent aqueous NaOH solution (27.4 kg). At this pH a solid precipitated out. The slurry was filtered by centrifuge and allowed to dry in a tray dryer at 40-45 0C. Title compound (2b) was obtained as a white solid (17.5 kg, 87.4 percent, purity: 98.6 percent AUC o using method B).
Reference: [1] Patent: WO2009/76200, 2009, A2, . Location in patent: Page/Page column 54-55
  • 6
  • [ 407-20-5 ]
  • [ 73183-34-3 ]
  • [ 719268-92-5 ]
Reference: [1] Patent: WO2015/94119, 2015, A1, . Location in patent: Paragraph 0365 - 0367
  • 7
  • [ 407-20-5 ]
  • [ 124-38-9 ]
  • [ 955372-86-8 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -70 - 0℃; for 1 h; Inert atmosphere
Stage #2: for 0.5 h; Inert atmosphere
n-BuLi (250 mL, 0.62 mol, 2.5 equiv) was added dropwise into a solution of bis(propan-2-yl)amine (76 g, 0.75 mmol, 3 equiv) and tetrahydrofuran (1 L) at 0 °C under nitrogen. The mixture was stirred for 30 min at 0 °C. To this was added 3-bromo-5- fluoropyridine (44 g, 0.25 mol, 1 equiv) dropwise with stirring at -70 °C. The resulting solution was stirred for lh at -70 °C. The reaction mixture was then poured into a mixture of dry ice in 500 mL of THF. The resulting mixture was stirred for 30 min and then concentrated under vacuum. The residue was dissolved in water. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 mol/L). The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to give the product (40 g, 72percent) as yellow solid.
Reference: [1] Patent: WO2018/96159, 2018, A1, . Location in patent: Paragraph 0202-0205
  • 8
  • [ 407-20-5 ]
  • [ 1032943-43-3 ]
Reference: [1] Patent: WO2018/11628, 2018, A1,
  • 9
  • [ 407-20-5 ]
  • [ 872041-86-6 ]
YieldReaction ConditionsOperation in experiment
87.4%
Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran at -90 - -80℃; for 2.5 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at -20 - 10℃;
Stage #3: With sodium hydroxide In water
To a 700 L low temperature reactor were added 3-bromo-5-fluoropyridine (2a) (25 Kg, 142 moles, 1.0 equiv.), THF (222.5 Kg) and isopropyl borate (28 Kg, 149.3 moles, 1.05 equiv.). The resulting mixture was cooled to -90 0C ~ -80 0C while stirred. Then n-BuLi (40.2 Kg, 2.5 M, 142 moles, 1.0 equiv.) was added dropwise (2Kg/h) maintaining the temperature below -87 0C. After the addition was complete, the mixture was maintained at -88 - 83 0C for 2.5 h. When the reaction was deemed complete by HPLC analysis, it was quenched by addition of 9 percent aqueous HCl (7.7 Kg). The mixture was transferred to a 1000 L glass-lined reactor and the temperature returned to -20 ~ -10 0C. Additional HCl solution (122.3 Kg) was then added until pH was adjusted to 1-2 maintaining the temperature at 0-10 0C. The mixture was then held for 0.5 h in order to allow layers to separate. The organic <n="38"/>layer was separated and washed with saturated brine (38 Kg). It was stirred for 0.5 h and then held again for 0.5 h to allow layer separation. The aqueous layer was separated and the combined aqueous layers were extracted with EtOAc twice (51+25 Kg). The organic phase was separated and pH was adjusted to a value of 6 by using 30 percent aqueous NaOH solution (27.4 Kg). At this pH a solid precipitated out. The slurry was filtered by centrifuge and allowed to dry in a tray dryer at 40-45 0C. Title compound 2b was obtained as a white solid (17.5 Kg, 87.4 percent, purity: 98.6 percent AUC using method B)
Reference: [1] Patent: WO2009/61875, 2009, A2, . Location in patent: Page/Page column 36-37
  • 10
  • [ 407-20-5 ]
  • [ 68-12-2 ]
  • [ 1227573-02-5 ]
YieldReaction ConditionsOperation in experiment
60.3%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -65℃; for 0.5 h;
Stage #2: for 0.5 h;
Diisopropylamine (5.7 g, 28.4 mmol, 2.0 eq) was dissolved in anhydrous THF (200.0 mL), and the reaction mixture was cooled to -60 °C~ -65 °C, then n-ButLi (35.5 mL, 56.8 mmol, 2.0 eq) was added dropwise. The reaction mixture was stirred at the same temperature for 30.0 min, then 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol, 1.0 eq) in anhydrous THF (50.0 mL) was added to the reaction mixture at -60 °C~-65 °C and stirred at this temperature for 30 min. then DMF (2.5 g, 34.1 mmol, 1.2 eq) was added to the reaction mixture in one portion and stirred at this temperature for 30 min. The reaction was quenched by MeOH, then H4C1 solution was added, diluted by EA (200.0 mL), extracted by EA (200.0 mL X 3), washed by brine, concentrated. The resulting residue was purified by column chromatography (PE:EA = 3 : 1) to provide 3-bromo-5- fluoroisonicotinaldehyde (3.5 g, 60.3percent) as brown oil. LCMS (M+H+) m/z calculated 204.1, found 204.2.
22%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78℃; for 0.5 h;
Step 1:
3-Bromo-5-fluoroisonicotinaldehyde
To a LDA solution (1M in hexanes/THF, 12.55 mL, 12.55 mmol) was added a solution of 3-bromo-5-fluoropyridine (1.84 g, 10.46 mmol) in THF (20 ml) at -78° C. dropwise.
The mixture was stirred at -78° C. for 1 h.
Then DMF (1.62 mL, 1.53 g, 20.91 mmol) was added to the reaction mixture.
After stirring at -78° C. for 30 min, the reaction mixture was quenched with aq. sat.
NaHCO3 solution followed by extracting with EtOAC three times and DCM twice.
All the organic layers were combined and dried over anhydrous Na2SO4.
The solid was filtered out.
Volatiles were removed under reduced pressure and the residue was purified with silica-gel chromatography (DCM) to afford the title compound (0.478 g, 22percent).
1H NMR (400 MHz, chloroform-d3) δ ppm=10.36 (s, 1H), 8.75 (s, 1H), 8.63-8.57 (m, 1H).
Reference: [1] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00661
[2] Patent: US2018/111932, 2018, A1, . Location in patent: Paragraph 0406; 0407
[3] Patent: WO2010/130773, 2010, A2, . Location in patent: Page/Page column 77-78
[4] Patent: WO2011/61168, 2011, A1, . Location in patent: Page/Page column 61
  • 11
  • [ 407-20-5 ]
  • [ 109-94-4 ]
  • [ 1227573-02-5 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.5 h;
Stage #2: at -78℃; for 1.45 h;
n-BuLi (5.5 mL, 14 mmol) was added to a stirred solution of N,N-diisopropylamine (1.5 g, 15 mmol) in THF (50 mL) slowly at -78 °C. The temperature was allowed to reach -50 °C and stirred at this temperature for 30 minutes. The solution was cooled to -78 °C and to it was added a solution of 3-Bromo-5-fluoropyridine (2.09, 1.1 mmol) in THF (15 mL). The resulting mixture was stirred at this temperature for 45 minutes. A solution of ethyl formate (8.4 g, 113 mmol) in THF (15 mL) was added over 15 minutes and the resulting mixture was stirred at this temperature for 1 .5 hours. A saturated solution of NH4CI was added and the resulting mixture was partitioned with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel to afford a bright yellow solid characterised as 3-bromo-5-fluoro- pyridine-4-carbaldehyde (1.4 g, 60percent yield). 1H NMR (CDCI3, 400 MHz) O: 10.32 (5, 1H), 8.71 (5, 1H), 8.567 (5, 1H).
Reference: [1] Patent: WO2016/59412, 2016, A1, . Location in patent: Page/Page column 00194; 00195
  • 12
  • [ 407-20-5 ]
  • [ 342602-55-5 ]
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 2, p. 279 - 291
  • 13
  • [ 407-20-5 ]
  • [ 74-88-4 ]
  • [ 1211517-76-8 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; cyclohexane; ethylbenzene at -78℃; for 0.666667 h;
Stage #2: at -78 - 30℃; for 2.5 h;
Step 1 : To a solution of LDA (2M solution in Cy/ethylbenzole THF, 21.3 mL, 42.6 mmol) in dry THF (23 mL) was added dropwise over 10 min a solution of 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol) in dry THF (23 mL) at -78°C and stirring continued at -78°C for 30 min. Subsequently a solution of CH3I (2.6 mL, 42.6 mmol) in dry THF (23 mL) was added very slowly dropwise and again stirring continued for 30 min at -78°C. The RM was stirred for another 2 h at rt before it was quenched with sat. NH4CI solution. After further 30 min at rt the RM was extracted with EtOAc. The combined organic layers were dried, volatiles removed under reduced pressure and the residue purified by CC (Si02, EtOAc/Cy) to yield the desired product (3.6 g, 66percent).
52%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.666667 h;
Stage #2: at -78 - 20℃; for 1.58333 h;
Stage #3: With ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene
Step 1
In a 250 mL round-bottomed flask, LDA, 2.0M in heptane/THF/ethylbenzene (9.4 ml, 18.8 mmol, Eq: 1.10) was combined with THF (15 ml) to give an orange solution.
The mixture was cooled to -78° C. and 3-bromo-5-fluoropyridine (3 g, 17.0 mmol, Eq: 1.00) in THF (15 ml) was added dropwise over 10 min.
The brown reaction mixture was stirred at -78° C. for 30 min.
A solution of iodomethane (3.63 g, 1.6 ml, 25.6 mmol, Eq: 1.5) in THF (15.0 ml) was added dropwise over 5 min.
The mixture was stirred at -78° C. for 30 minutes.
Cooling was removed and stirring continued for 1 h. aq.
A saturated ammonium chloride solution was added cautiously followed by ethyl acetate.
The ethyl acetate layer was separated and the aqueous layer was extracted 2* with ethyl acetate.
The organic layers were combined, washed with aq, sodium thiosulfate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
The crude material was purified by flash chromatography (silica gel, 120 g, 0percent to 5percent EtOAc in hexanes).
Fraction were pooled and evaporated to yield 1.69 g (52percent) of 3-bromo-5-fluoro-4-methylpyridine as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 8.53 (s, 1H), 8.35 (s, 1H), 2.41 (d, J=2.1 Hz, 3H). LC-MS (ES) calculated for C6H5BrFN, 190.02. found m/z 189.7 [M+H]+.
1.4 g
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.75 h;
Stage #2: at -78℃; for 0.5 h;
A solution of diisopropylamine (1.9 mL, 13.7 mmol) in 20 mL of THF is cooled to 0°C and treated with n-butyllithium (6.7 mL, 13.6 mmol). The mixture is stined at 0°C for 15 minutes then cooled to -78°C. 3-Bromo-5-fluoropyridine (2.0 g, 11.4 mmol) is added drop-wise as a solution in 20 mL of THF. This mixture is stined at -78°C for 45 minutes. A separate solution of iodomethane (2.1 mL, 34.1 mmol) in 20 mL of THF is cooled to -78°C. The anion solution is then cannulated into the iodomethane solution. Once the transfer is complete, the mixture is stirred at -78°C for 30 minutes. The cooling bath is removed and the mixture is stined for 30 minutes and then quenched with saturated NH4C1 solution. The mixture is diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified via silica gel flash column chromatography eluting with 0-10 percent EtOAc/heptane to afford 1.4 g of the title compound.
Reference: [1] Patent: WO2015/22073, 2015, A1, . Location in patent: Page/Page column 49
[2] Patent: US2013/109720, 2013, A1, . Location in patent: Paragraph 0092; 0093
[3] Patent: WO2012/12478, 2012, A1, . Location in patent: Page/Page column 48-49
[4] Patent: WO2012/148808, 2012, A1, . Location in patent: Page/Page column 49
[5] Patent: WO2013/43520, 2013, A1, . Location in patent: Page/Page column 36
[6] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 573 - 578
[7] Patent: WO2016/61161, 2016, A1, . Location in patent: Page/Page column 34; 35
  • 14
  • [ 407-20-5 ]
  • [ 1211540-92-9 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -70℃; for 1 h;
Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78 - 20℃;
To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78°C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20°C then cooled back down to -78°C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70°C (approx 30 mins). The reaction mixture was stirred at - 78°C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 niL) was then added dropwise, keeping temperature below -70°C (over approx 30 mins). The mixture was stirred at -78°C for 20 minutes, allowed to warm to room temperature, cooled back to 0°C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown011 that turned to a crystalline solid on standing, 11.85 g, 89percent). XH NMR (DMSO-d6) δ 8.78 (s, 1H), 8.76 (s, 1H). [00372] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60percent). XH NMR (DMSO-d6) δ 8.77 (s, 1H), 8.75 (s, 1H).
89%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -70℃; for 1 h;
Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78 - -70℃; for 0.833333 h;
Preparation 10: (l-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-l- yl)methanone (hydrochloride) 17b Scheme 5 Step 1: 3-bromo-4-chloro-5-fluoropyridine hydrochloride 18 [00261] To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78°C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20°C then cooled back down to -78°C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70°C (approx 30 mins). The reaction mixture was stirred at - 78°C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70°C (over approximately 30 mins). The mixture was stirred at -78°C for 20 minutes, allowed to warm to room temperature, cooled back to 0°C and quenched with water (100 rnL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for 10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown oil that turned to a crystalline solid on standing, 1 1.85 g, 89percent). lH NMR (DMSO-d6) δ 8.78 (s, 1H), 8.76 (s, 1H). [00262] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60percent). XH NMR (DMSO-d6) δ 8.77 (s, 1H), 8.75 (s, 1H).
89%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -70℃; for 1 h;
Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78 - -70℃; for 0.833333 h;
Preparation 9: (l-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-l- yl)methanone (hydrochloride) 17 Scheme 4 Step 1: 3-bromo-4-chloro-5-fluoropyridine hydrochloride 18 [00264] To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78°C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20°C then cooled back down to -78°C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70°C (approx 30 mins). The reaction mixture was stirred at - 78°C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70°C (over approx 30 mins). The mixture was stirred at -78°C for 20 minutes, allowed to warm to room temperature, cooled back to 0°C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for 10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown 011 that turned to a crystalline solid on standing, 11.85 g, 89percent). 1H NMR (DMSO-d6) δ 8.78 (s, 1H), 8.76 (s, 1H). [00265] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60percent). 1H NMR (DMSO-d6) δ 8.77 (s, 1H), 8.75 (s, 1H).
89%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -70℃; for 1 h;
Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78 - -70℃; for 0.833333 h;
To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78°C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20°C then cooled back down to -78°C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70°C (approx 30 mins). The reaction mixture was stirred at - 78°C for 30 mm and a solution of 1,1,1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70°C (over approx 30 mins). The mixture was stirred at -78°C for 20 minutes, allowed to warm to room temperature, cooled back to 0°C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (Mg504), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for 10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown oil that turned to a crystalline solid on standing, 11.85 g, 89percent). ‘H NMR (DMSO-d6) ö 8.78 (s, 1H), 8.76 (s, 1H).
89%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -70℃; for 1 h;
Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78 - -70℃; for 0.833333 h;
To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78° C., was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol).
The reaction mixture was allowed to warm to -20° C. then cooled back down to -78° C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70° C. (approx 30 mins).
The reaction mixture was stirred at -78° C. for 30 min and a solution of 1,1,1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70° C. (over approx 30 mins).
The mixture was stirred at -78° C. for 20 minutes, allowed to warm to room temperature, cooled back to 0° C. and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2*), brine (1*), dried (MgSO4), filtered and concentrated in vacuo to leave a brown solid.
The solid was triturated in pentane (100 mL) for 10 minutes, then filtered.
The filtrate was concentrated in vacuo to afford product as a brown oil that turned to a crystalline solid on standing, 11.85 g, 89percent).
1H NMR (DMSO-d6) δ 8.78 (s, 1H), 8.76 (s, 1H).
70% With lithium diisopropyl amide In tetrahydrofuran; hexachloroethane at -78 - 20℃; for 2.25 h; To a solution of LDA (2.0 mol/L THF solution, 8.9 mL, 18 mmol) in THF (45 mL) which was cooled to -78°Cwas added dropwise a solution of compound (VII-16) (2.60 g, 14.8 mmol) in THF (12 mL), and the mixture was stirredat -78°C for 45 min. To the reaction mixture was added dropwise a solution of hexachloroethane (3.85 g, 16.3 mmol) inTHF (12 mL), and the mixture was stirred at -78°C for 30 min, warmed to room temperature and stirred for 1 hr. Thereaction was discontinued by adding saturated aqueous ammonium chloride solution, and the mixture was extractedwith ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution andsaturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 97:3 →85:15) to give compound(VII-17) (yield 2.18 g, 70percent) as a pale-yellow solid
70%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.75 h;
Stage #2: With hexachloroethane In tetrahydrofuran at -78 - 20℃; for 1.5 h;
LDA (2.0 mol / L THF solution cooled to -78 ° C.,8.9 mL, 18 mmol) in THF (45 mL)Compound (VII-16) (2.60 g, 14.8 mmol)In THF (12 mL) was added dropwise,And the mixture was stirred at -78 ° C. for 45 minutes.A solution of hexachloroethane (3.85 g, 16.3 mmol) in THF (12 mL) was added dropwise to the reaction solution,After stirring at -78 ° C. for 30 minutes,The mixture was warmed to room temperature and stirred for 1 hour.A saturated aqueous solution of ammonium chloride was added to stop the reaction, followed by extraction with ethyl acetate.The organic layer was washed with a saturated aqueous ammonium chloride solution,And then washed successively with saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97: 3 → 85: 15)To give Compound (VII-17)(Yield 2.18 g, Yield 70percent)As a pale yellow solid.

Reference: [1] Patent: WO2014/89379, 2014, A1, . Location in patent: Paragraph 00371; 00372
[2] Patent: WO2014/143240, 2014, A1, . Location in patent: Paragraph 00260-00261
[3] Patent: WO2014/143242, 2014, A1, . Location in patent: Paragraph 00263-00264
[4] Patent: WO2015/84384, 2015, A1, . Location in patent: Paragraph 00243
[5] Patent: US2015/158868, 2015, A1, . Location in patent: Paragraph 0309; 0310
[6] Patent: EP3351533, 2018, A1, . Location in patent: Paragraph 0282; 0283
[7] Patent: JP2018/145180, 2018, A, . Location in patent: Paragraph 0283; 0284; 0285
[8] Patent: WO2012/148808, 2012, A1, . Location in patent: Page/Page column 54
[9] Patent: US2015/158872, 2015, A1,
  • 15
  • [ 407-20-5 ]
  • [ 75-03-6 ]
  • [ 1374655-69-2 ]
Reference: [1] Patent: WO2013/43521, 2013, A1, . Location in patent: Page/Page column 37
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 407-20-5 ]

Fluorinated Building Blocks

Chemical Structure| 156772-60-0

[ 156772-60-0 ]

2,5-Dibromo-3-fluoropyridine

Similarity: 0.88

Chemical Structure| 1162674-74-9

[ 1162674-74-9 ]

5-Bromo-3-fluoro-2-methylpyridine

Similarity: 0.85

Chemical Structure| 89402-44-8

[ 89402-44-8 ]

5-Bromo-2,3-difluoropyridine

Similarity: 0.81

Chemical Structure| 748812-37-5

[ 748812-37-5 ]

5-Bromo-3-fluoropyridin-2-amine

Similarity: 0.81

Chemical Structure| 831203-13-5

[ 831203-13-5 ]

5-Bromo-2-chloro-3-fluoropyridine

Similarity: 0.80

Bromides

Chemical Structure| 156772-60-0

[ 156772-60-0 ]

2,5-Dibromo-3-fluoropyridine

Similarity: 0.88

Chemical Structure| 1162674-74-9

[ 1162674-74-9 ]

5-Bromo-3-fluoro-2-methylpyridine

Similarity: 0.85

Chemical Structure| 89402-44-8

[ 89402-44-8 ]

5-Bromo-2,3-difluoropyridine

Similarity: 0.81

Chemical Structure| 748812-37-5

[ 748812-37-5 ]

5-Bromo-3-fluoropyridin-2-amine

Similarity: 0.81

Chemical Structure| 831203-13-5

[ 831203-13-5 ]

5-Bromo-2-chloro-3-fluoropyridine

Similarity: 0.80

Related Parent Nucleus of
[ 407-20-5 ]

Pyridines

Chemical Structure| 156772-60-0

[ 156772-60-0 ]

2,5-Dibromo-3-fluoropyridine

Similarity: 0.88

Chemical Structure| 1162674-74-9

[ 1162674-74-9 ]

5-Bromo-3-fluoro-2-methylpyridine

Similarity: 0.85

Chemical Structure| 89402-44-8

[ 89402-44-8 ]

5-Bromo-2,3-difluoropyridine

Similarity: 0.81

Chemical Structure| 748812-37-5

[ 748812-37-5 ]

5-Bromo-3-fluoropyridin-2-amine

Similarity: 0.81

Chemical Structure| 831203-13-5

[ 831203-13-5 ]

5-Bromo-2-chloro-3-fluoropyridine

Similarity: 0.80