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Chemical Structure| 149806-06-4
Chemical Structure| 149806-06-4
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Product Details of [ 149806-06-4 ]

CAS No. :149806-06-4 MDL No. :MFCD04115419
Formula : C6H4BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :PVUKGNBRJFTFNJ-UHFFFAOYSA-N
M.W : 186.01 Pubchem ID :11769234
Synonyms :

Calculated chemistry of [ 149806-06-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 37.32
TPSA : 29.96 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) : -6.48 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.38
Log Po/w (XLOGP3) : 1.34
Log Po/w (WLOGP) : 1.66
Log Po/w (MLOGP) : 0.56
Log Po/w (SILICOS-IT) : 2.2
Consensus Log Po/w : 1.43

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.26
Solubility : 1.01 mg/ml ; 0.00544 mol/l
Class : Soluble
Log S (Ali) : -1.57
Solubility : 5.0 mg/ml ; 0.0269 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.83
Solubility : 0.278 mg/ml ; 0.00149 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.47

Safety of [ 149806-06-4 ]

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

Application In Synthesis of [ 149806-06-4 ]

* 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 [ 149806-06-4 ]
  • Downstream synthetic route of [ 149806-06-4 ]

[ 149806-06-4 ] Synthesis Path-Upstream   1~34

  • 1
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  • [ 53014-84-9 ]
Reference: [1] Patent: WO2008/16968, 2008, A2, . Location in patent: Page/Page column 70
  • 2
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  • [ 100-55-0 ]
YieldReaction ConditionsOperation in experiment
78% With hydrogen; sodium acetate; palladium dichloride In methanol at 35℃; for 4 h; Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 °C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78percent).
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 29, p. 3798 - 3801
  • 3
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  • [ 6311-35-9 ]
Reference: [1] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
  • 4
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  • [ 26218-78-0 ]
Reference: [1] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
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  • [ 58553-48-3 ]
Reference: [1] Patent: US2015/307465, 2015, A1,
  • 6
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  • [ 101990-45-8 ]
Reference: [1] Patent: WO2012/177603, 2012, A2,
  • 7
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  • [ 131747-68-7 ]
YieldReaction ConditionsOperation in experiment
236 mg at 120℃; for 1.5 h; A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol) and copper (I) cyanide (679 mg, 7.58 mmol) in DMF (8.4 mL) was stirred at 120° C. for 1.5 hours, cooled to RT, and partitioned between water and EtOAc. The solids were removed from the aqueous layer by filtration, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with a gradient of 40percent-60percent (40percent ethyl acetate in heptane) in heptane, to provide the title compound (236 mg, 1.786 mmol) as white solid. LC/MS (ESI+) m/z=133 (M+H)
236 mg at 120℃; for 1.5 h; A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol) and copper (I) cyanide (233 xL, 7.58 mmol) in DMF (8.4 mL) was stirred at 120°C for 1.5 hours, cooled to RT, and partitioned between water and EtOAc. The solids were removed from the aqueous layer by filtration, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with a gradient of 40percent-60percent (40percent ethyl acetate in heptane) in heptane, to provide the title compound (236mg, 1.786 mmol) as white solid. LC/MS (ESI+) m/z = 133 (M+H) +
236 mg at 120℃; for 1.5 h; A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol) and copper (I) cyanide (233 μL, 7.58 mmol) in DMF (8.4 mL) was stirred at 120° C. for 1.5 hours, cooled to RT, and partitioned between water and EtOAc. The solids were removed from the aqueous layer by filtration, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with a gradient of 40percent-60percent (40percent ethyl acetate in heptane) in heptane, to provide the title compound (236 mg, 1.786 mmol) as white solid. LC/MS (ESI+) m/z=133 (M+H).
4.55 g at 120℃; for 3 h; Inert atmosphere Step 1: (0581) A mixture of 6-bromonicotinaldehyde (11.2 g, 60 mmol) and CuCN (8.06 g, 90 mmol) in DMF (100 mL) was heated at 120° C. for 3 h under N2. The mixture was cooled to rt and diluted with EtOAc and filtered through a pad of celite. The organic layer was washed with water and brine and then dried (MgSO4) and concentrated. The product 5-formylpicolinonitrile (4.55 g) was obtained by silica gel chromatography (elution with 0-20percent EtOAc/Hex).
236 mg at 120℃; for 1.5 h; A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol) and copper (I) cyanide (233 µL, 7.58 mmol) in DMF (8.4 mL) was stirred at 120°C for 1.5 hours, cooled to RT, and partitioned between water and EtOAc. The solids were removed from the aqueous layer by filtration, and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with a gradient of 40percent-60percent (40percent EtOAc in heptane) in heptane, to provide the title compound (236mg, 1.786 mmol) as white solid. LC/MS (ESI+) m/z = 133 (M+H) +.

Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 559 - 576
[2] Patent: US2014/107109, 2014, A1, . Location in patent: Page/Page column
[3] Patent: US2014/213581, 2014, A1, . Location in patent: Paragraph 0645
[4] Patent: US2014/249104, 2014, A1, . Location in patent: Page/Page column
[5] Patent: WO2014/138484, 2014, A1, . Location in patent: Page/Page column 146; 147
[6] Patent: US2015/38497, 2015, A1, . Location in patent: Paragraph 0808
[7] Patent: US2015/307465, 2015, A1, . Location in patent: Paragraph 0581
[8] Patent: WO2016/22724, 2016, A1, . Location in patent: Page/Page column 320
[9] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 44, p. 5260 - 5270
  • 8
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Reference: [1] Patent: US2013/65905, 2013, A1,
  • 9
  • [ 154321-32-1 ]
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YieldReaction ConditionsOperation in experiment
92% With calcium carbonate In water at 105℃; for 16 h; A solution of intermediate Ia (3.650 g, 11.07 mmol), calcium carbonate (2.437 g,24.35 mmol) in water (80m1) was stirred at 105°C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc twice. The combined organics were washed with water, with saturated solution of NaC1, dried over MgSO4, filtered and evaporated to give intermediate lb (1.890 g, 92percent). ‘H NMR (500 MHz, CDC13) ö 10.05 (s, 1H), 8.78(d, J= 2.2 Hz, 1H), 7.98 (dd, J= 8.2, 2.4 Hz, 1H), 7.65 (d, J= 8.2 Hz, 1H).
Reference: [1] Patent: WO2016/124747, 2016, A1, . Location in patent: Page/Page column 58; 59
[2] Patent: US2018/202388, 2018, A1,
[3] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[4] Synthesis, 1994, # 1, p. 87 - 92
  • 10
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  • [ 68-12-2 ]
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YieldReaction ConditionsOperation in experiment
70%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 1 h;
40.0 g (168.8 mmol) of 2,5-dibromopyridine are placed in 2 L of anhydrous ethyl etherand maintained at -78 ° C. Slowly add 70.9 mL (177.2 mmol) of n-butyllithium (2.5 M,n-butyllithium) and keep for 1 hour. To the reaction mixture slowly add 14.3 mL (185.6mmol) of anhydrous dimethylformamide. The reaction mixture is maintained at -78 ° Cfor 1 hour and then slowly raised to room temperature. To the reaction was added a 1.0M aqueous hydrochloric acid solution (1.0 M aq. HCl) is added and stirred for 15minutes, and then the organic layer is separated. The resulting aqueous layer isextracted again with anhydrous ethyl ether. The resulting organic layers are combined,washed with water and dried over MgSO4. The organic layer was concentrated underreduced pressure to obtain 22.1 g (yield: 70percent) of a solid compound (intermediate (1)).
70%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 1 h;
40.0 g (168.8 mmol) of 2,5-dibromopyridine was added to the solution, Add 2 L of anhydrous ethyl ether and keep at -78 ° C. 70.9 mL (177.2 mmol) of n-butyllithium (2.5 M, n-butyllithium)Go slowly and keep for 1 hour.To the reaction mixture slowly add 14.3 mL (185.6 mmol) of anhydrous dimethylformamide. The reaction mixture was -78 up slowly to room temperature, the mixture was kept for 1 hour.100 mL of a 1.0 M aqueous hydrochloric acid solution (1.0 M aq. HCl) was added to the reaction mixture, followed by stirring for 15 minutes, followed by separation of the organic layer.The resulting aqueous layer is extracted again with anhydrous ethyl ether.The resulting organic layers are combined, washed with water and dried over MgSO4.The organic layer was concentrated under reduced pressure to obtain 22.1 g (yield: 70percent) of a solid compound (intermediate (7)).
70%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h;
Stage #2: at -78℃; for 1 h;
40.0 g (168.8 mmol) of 2,5-dibromopyridine is placed in 2 L of anhydrous ethyl ether and the temperature is maintained at -78 ° C. Slowly add 70.9 mL (177.2 mmol) of n-butyllithium (2.5 M, n-butyllithium) and keep for 1 hour. To the reaction mixture slowly add 14.3 mL (185.6 mmol) of anhydrous dimethylformamide. The reaction mixture is maintained at -78 & lt; 0 & gt; C for 1 hour and then slowly raised to room temperature. 100 mL of a 1.0 M aqueous hydrochloric acid solution (1.0 M aq. HCl) was added to the reaction mixture, followed by stirring for 15 minutes, followed by separation of the organic layer. The resulting aqueous layer is extracted again with anhydrous ethyl ether. The resulting organic layers are combined, washed with water and dried over MgSO4. The organic layer was concentrated under reduced pressure to obtain 22.1 g (yield: 70percent) of a solid compound (intermediate (1)).
66%
Stage #1: With n-butyllithium In diethyl ether; hexane at -80℃; for 1 h; Inert atmosphere
Stage #2: at -80℃; for 1 h; Inert atmosphere
Stage #3: With hydrogenchloride In diethyl ether; hexane at 0℃; for 0.25 h; Inert atmosphere
To a suspension of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in dry diethyl ether (25 mL) was added n-BuLi (3.55 mL, 8.87 mmol, 2,5 M solution in hexane) at -80°C under a nitrogen atmosphere. After stirring for 1 h at -80°C dry DMF (0.68 mg, 9.28 mmol) was added. After stirring for an additional hour at -80°C the reaction mixture was allowed to warm to 0°C and HCI (18.0 mL, 1 M) was added. After stirring for 15 minutes the phases were separated and aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over MgS04. The organic phase was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica-gel using a mixture of hexane / ethyl acetate (8: 1) as eluent. White solid. Yield: 1.03 g, 66 percent. 1 H NMR (CDCI3, 500 MHz): δΗ (ppm) = 7.67 - 7.71 ppm (m, 1 H), 8.02 (dd, J = 8.2, 2.5 Hz, 1 H), 8.84 (dd, J = 2.5, 0.6 Hz, 1 H), 10.10 (s, 1 H); 13C NMR (CDCI3, 125 MHz): 5C (ppm) =129.0, 130.6, 137.5, 148.3, 152.5, 189.4; MS (ESI): m/z = 187.19 [M+H]+.
56%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.666667 h; Inert atmosphere
Stage #2: at -78℃; for 2 h;
6-bramonicotinaldeiwde (DL i To a stirred solution of 2, 5-dihromepyridine A (99 mL, 105.53 mmoi) in diethyl ether (250 mL) under argon atmosphere was added jj-BuLi (99 mL, 158.30 moL 1.6 M hexanes) at -78 °C and stiixed for 40 rain. Then DMF (16 mL, 211.06 mol) was added to the reaction mixture at -78 °C and stirred for another 2 h. The progress of the reaction was monitored by TLC. The reaction was quenched with aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 rnL), dried over anhydrous Na?SC>4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (elueii 20percent EtOAc Hexane) to afford compound DL (11 g. 59.13 mmoL 56percent) as paie yellow solid. H NMR (500 MHz, CDCl3): 5 10.07 (s, IH), 8.80 (s, IH), 8.00 (dd, J = 8.1, 2.3 Hz, IH), 7.66 (d, J= 8.1 Hz, 1H).
45%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃;
Stage #2: With ammonium chloride In diethyl ether; hexane
EXAMPLE 17 2-(2,4-Difluorophenyl)-l,l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(2,2,2- trifluoroethyl)pyridin-2-yl)propan-2-ol (17)To a stirred solution of 2,5-dibromopyridine (20 g, 84.1 mmol) in dry ether (400 mL) was added w-BuLi (1.6 M solution in hexane; 62.98 mL, 100.77 mmol) slowly at -78 °C. After being stirred for 45 min, DMF (12.28 g, 168.2 mmol) was added to the reaction mixture at - 78 °C, and the stirring was continued for another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with saturated (satd) NH4C1 solution and extracted with EtOAc (4 x 500 mL). The combined organic extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 15percent EtOAc/hexane) afforded aldehyde J (7.0 g, 37.8 mmol, 45percent) as a yellow solid. 1H NMR (500 MHz, CDC13): δ 10.09 (s, 1H), 8.83 (d, / = 2.0 Hz, 1H), 8.02 (dd, / = 8.0, 2.0 Hz, 1H), 7.68 (d, / = 8.0 Hz, 1H). MS (ESI): m/z 186 [M+].To a stirred solution of aldehyde J (1.0 g, 5.40 mmol) in 1,2-dimethoxyethane (DME; 10 mL) was added trimethyl(trifluoromethyl)silane (TMSCF3; 1.3 mL, 8.10 mmol) followed by cesium fluoride (CsF; 821 mg, 5.40 mmol) slowly at 0 °C under inert atmosphere. The resulting solution was stirred for 12 h at RT; progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was quenched with 1 N hydrochloric acid (HC1; 5.0 mL), stirred for 30 min and then extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with water and satd NaHC03 solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 20percent EtOAc/hexane) afforded compound K (0.6 g, 2.34 mmol, 43percent) as a yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.09-5.06 (m, 1H), 3.27 (br s, 1H). MS (ESI): m/z 258 [M++2] . HPLC: 97.05percent.To a stirred solution of compound K (5.0 g, 19.53 mmol) in dry THF (60 mL) was added sodium hydride (NaH; 935 mg, 39.06 mmol) portionwise at 0 °C under inert atmosphere. After being stirred for 1 h, carbon disulfide (CS2; 2.35 mL, 39.06 mmol) was added to the reaction mixture drop wise, and the mixture was stirred for 1 h at 0 °C. To the resulting reaction mixture iodomethane (CH I; 2.43 mL, 39.06 mmol) was added at 0 °C, and then the mixture was stirred for 2 h at RT. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water and extracted with CH2C12 (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure to afford dithionate L (7.0 g) that was used in the next step without any further purification. 1H NMR (400 MHz, CDC13): δ 8.47 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.0, 2.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.88 (q, J = 6.8 Hz, 1H), 2.61 (s, 3H). MS (ESI): m/z 348 [M++2] .To a stirred solution of compound L (7.0 g, crude) in dry toluene (40 mL) was added tributyltin stannane (Bu SnH; 10.5 mL, 30.34 mmol) followed by 2,2'- azobis(isobutyronitrile) (AIBN; 728 mg, 3.03 mmol) at RT under inert atmosphere. The reaction mixture was gradually heated up to 90 °C and stirred for 2 h. After consumption of the starting material (by TLC), the volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 8percent EtOAc/Hexane) afforded compound M (3.0 g, 12.5 mmol, 61percent) as a pale-yellow liquid. This material contained a small amount of tin impurity and was used in the next step without any further purification. 1H NMR (400 MHz, CDC13): δ 8.31 (s, 1H), 7.51 (s, 2H), 3.36 (q, J = 10.4 Hz, 2H). MS (ESI): m/z 240 [M+] .To a stirred suspension of copper powder (3.17 g, 50 mmol) in DMSO (30 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.07 g, 25 mmol) and the mixture was stirred for 1 h at RT. To the resulting reaction mixture compound M (3.0 g, 12.5 mmol) was added, and the mixture was stirred for 12 h at RT. After completion of reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 8percent EtOAc/Hexane) afforded ester N (2.5 g, 8.83 mmol, 70percent) as a pale-yellow liquid. 1H NMR (400 MHz, CDC13): 58.58 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 4.37 (q, J = 1.2 Hz, 2H), 3.46 (q, J = 10.4 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 284.2 [M++l] .To a stirred solution of l-bromo-2,4-difluorobenzene (818 mg, 4.24 mmol) in dry ether (15 mL) was added w-BuLi (1.6 M solution in hexane; 2.65 mL, 4.24 mmol) at -78 °C under inert atmosphere. After being stirred for 45 min, a solution of ester N (1.0 g, 3.53 mmol) in ether (5 mL) was added to the reaction mixture and stirring was continued for another 1 h at -78 °C. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution and extracted with CH2C12 (2 x 150 mL). The combined organic extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure to afford ketone O (1.5 g) as brownish crude liquid. This crude material was used in the next step without any purification. 1H NMR (500 MHz, CDC13): δ 8.51 (s, 1H), 8.10-8.05 (m, 1H), 7.88-7.83 (m, 2H), 7.01-6.98 (m, 1H), 6.84-6.80 (m, 1H), 3.46 (q, J = 10.5 Hz, 2H).To a stirred solution of ketone O (0.9 g, crude) in ether (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (2.64 g, 25.64 mmol) in a 1 : 1 mixture of 10percent KOH solution (100 mL) and ether (100 mL) at 0 °C followed by separation and drying of the organic layer using KOH pellets] at 0 °C, and the mixture was stirred for 30 min. The resulting reaction mixture was stirred for 12 h at RT; progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (eluting with 10percent EtOAc/hexane) afforded the epoxide P (0.3 g, 0.82 mmol) as a brownish liquid. 1H NMR (400 MHz, CDC13): δ 8.59 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.40-7.34 (m, 1H), 6.85-6.80 (m, 1H), 6.76-6.70 (m, 1H), 3.48-3.40 (m, 3H), 2.97 (d, J = 4.8 Hz, 1H). MS (ESI): m/z 366 [M++l] .To a stirred solution of epoxide P (0.3 g, 0.82 mmol) in dry DMF (8 mL) was added 1H- tetrazole (113.4 mg, 1.23 mmol) followed by K2C03 (113.4 mg, 0.82 mmol) at RT under inert atmosphere. The reaction mixture was then stirred for 14 h at 65 °C. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 50percent EtOAc/hexane) afforded 17 (0.18 g, 0.41 mmol, 50percent) as a brownish liquid. 1H NMR (500 MHz, CDC13): δ 8.75 (s, 1H), 8.48 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.34-7.30 (m, 2H), 6.78-6.74 (m, 1H), 6.68-6.65 (m, 1H), 5.57 (d, J = 14.5 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H), 3.45 (q, J = 10.5 Hz, 2H). MS (ESI): m/z 434 [M+-l] . HPLC: 98.09percent.
30%
Stage #1: With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - -30℃; for 1.5 h;
Example 38; 4-({3-[6-(2-Methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-3-carboxylic Acid; a) -Bromo-pyridineS-carbaldehyde; 2,5-Dibromopyridine (10.0 g, 0.0422 mol) was dissolved in the mixture solvent of ether (150.0 mL) and tetrahydrofuran (100.0 mL). The resulting solution was cooled to -780C, and ra-butyllithium (1.60 M in hexane, 26.4 mL) was added slowly. The reaction mixture was stirred at -78 0C for another 30 min before N,N-dimethylformamide (6.5 mL, 0.084 mol) was added slowly. The mixture was stirred at -78 0C for 1 hr and then warmed up to -300C over 30 min. LC-MS showed no starting material. The reaction was quenched with water. The organic phase was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with 10percentEtOAC/Hexane on silica gel to afford the desired product as a white solid (2.4 g, 30percent). LC-MS,[M+1] 186.2;188.2.
28%
Stage #1: With n-butyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 2 h;
Stage #3: With water In tetrahydrofuran; diethyl ether
Step A6-Bromo-pyridine-3-carbaldehyde. 2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to - 78 °C, 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at -78 °C for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30- 40percent EtOAc in hexane, 2.80g white solid was obtained (28percent yield), MS: (M+H)+ 186.0, 188.0.
11%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -90℃; for 0.0833333 h;
Stage #2: at -50℃; for 0.25 h;
To a cooled (-90°C) solution of 2,5-dibromopyridine (10 g) and THF (264 mL) was added, dropwise, nBuLi (16.9 mL of a 2.5 M solution in hexanes) and the resulting solution was stirred for 5 min. DMF (3.27 mL) was added dropwise and the resulting solution was warmed to - 50°C and stirred for 15 min at that temperature. The reaction solution was poured onto ice and extracted with EtOAc (3 * 75 mL). The combined EtOAc extracts were dried over MgSO4, filtered and evaporated to give 7.8 g of crude material which was purified by silica gel chromatography (4:1 hexane:EtOAc as eluant). After combining the desired fractions and evaporating the solvents, the desired aldehyde 5 was isolated as a solid (0.89 g) in 11 percent yield.

Reference: [1] Chemistry - A European Journal, 2003, vol. 9, # 20, p. 5011 - 5022
[2] Journal of Materials Chemistry C, 2017, vol. 5, # 35, p. 9053 - 9065
[3] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
[4] Patent: KR2017/72856, 2017, A, . Location in patent: Paragraph 0083-0086
[5] Patent: KR2017/58623, 2017, A, . Location in patent: Paragraph 0096-0099
[6] Patent: KR2017/58618, 2017, A, . Location in patent: Paragraph 0078-0081
[7] Patent: WO2012/52540, 2012, A1, . Location in patent: Page/Page column 59
[8] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6022 - 6032
[9] Tetrahedron Letters, 1999, vol. 40, # 5, p. 859 - 862
[10] Dalton Transactions, 2015, vol. 44, # 18, p. 8419 - 8432
[11] Patent: WO2017/117393, 2017, A1, . Location in patent: Page/Page column 165; 166
[12] Angewandte Chemie - International Edition, 2015, vol. 54, # 27, p. 7949 - 7953[13] Angew. Chem., 2015, vol. 127, # 27, p. 8060 - 8064,5
[14] Patent: WO2012/177603, 2012, A2, . Location in patent: Page/Page column 68-72
[15] Patent: WO2007/15744, 2007, A1, . Location in patent: Page/Page column 55-56
[16] Patent: WO2012/114223, 2012, A1, . Location in patent: Page/Page column 42
[17] Patent: EP1091956, 2004, B1, . Location in patent: Page 11
[18] Journal of Organic Chemistry, 2004, vol. 69, # 2, p. 250 - 262
[19] Organic Letters, 2004, vol. 6, # 26, p. 4929 - 4932
[20] Patent: EP1577288, 2005, A1, . Location in patent: Page/Page column 104
[21] Dalton Transactions, 2013, vol. 42, # 16, p. 5697 - 5705
  • 11
  • [ 68-12-2 ]
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YieldReaction ConditionsOperation in experiment
60.8%
Stage #1: With n-butyllithium; butyl magnesium bromide In tetrahydrofuran; hexane; toluene at -10 - 0℃; for 5.5 h;
Stage #2: at -10 - -5℃; for 1 h;
40.1 ml of a 2M solution of n-butylmagnesium chloride in THF (80.2 mmol) were added to a solution 100.2 ml of a 1.6M solution of n-butyllithium in hexane (160.41 mmol) in 50 ml of toluene and 50 ml of THF at -10 °C to 0 °C over 0.5 h, and the mixture was stirred at -10 °C for 0.5 h. A solution of 50 g (211 mmol) of 2,5-dibromopyridine in 200 ml of toluene and 200 ml of THF was added dropwise over 1 h while maintaining the temperature of the mixture below -5 °C. The resulting suspension was stirred at -10 °C for 2.5 h and then transferred into a cooled (-10 °C) solution of 21.2 ml of DMF (274.3 mmol) in 100 ml of toluene and 100 ml of THF over 0.5 h. The mixture was left at -10 °C to -5 °C for 0.5 h and then quenched with 400 ml of water. After stirring the mixture below 20 °C for 10 min, the organic layer was separated and the aqueous layer was extracted three times with 400 ml each of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, cyclohexane/ethyl acetate 9:1) to give 23.9 g (60.8 percent) of the title compound as a white solid. Mp. (melting point): 106 °C. 1H-NMR (400 MHz, CDCl3): δ (ppm) = 7.6 (d, 1 H), 7.95 (d, 1H), 8.75(s, 1 H), 10 (s, 1 H)..
44.8% With n-butyllithium In hexanes; diethyl ether at -78 - -70℃; for 1 h; In a 2 L round-bottomed flask was charged n-butyllithium 2.5M hexanes (99 ml, 248 mmol) in Et2O (1680 ml) to give a colorless solution. The reaction was cooled to -78° C. n-Butyllithium 2.5M hexanes (99 ml, 248 mmol) was added dropwise keeping the temperature below -70° C. The reaction was stirred for 1 hour and N,N-dimethylformamide (36.6 ml, 473 mmol) was added keeping the temperature below -70° C. The reaction was stirred for 1 hour and quenched with saturated ammonium chloride solution (2 L). The organic layer was washed with brine, dried over sodium sulfate and solvent removed under reduced pressure. The crude residue was purified by column chromatography eluting with 0-30percent ethyl acetate to give 6-bromonicotinaldehyde. Yield 19.7 g, 44.8percentIn a 2 L round-bottomed flask was added Methyltriphenylphosphonium bromide (42.9 g, 120 mmol) in THF (600 ml) and cooled to -20° C. n-Butyllithium 2.5M hexanes (48.0 ml, 120 mmol) was added dropwise keeping the temperature below 0° C. The reaction was warmed to room temperature for 20 minutes and cooled back to 0° C. A solution of 6-bromonicotinaldehyde (18.6 g, 100 mmol) in THF (40 mL) was added. The reaction was warmed to room temperature and stirred overnight. The reaction was partitioned between water and diethyl ether (1 L) and the organic layer was dried over sodium sulfate, filtered and solvent removed at room temperature under reduced pressure. The product, 2-bromo-5-vinylpyridine, was purified by bulb to bulb distillation (600 mTorr, 80-100° C.). Yield 17.2 g, 93percent2-Bromo-5-vinylpyridine (17.2 g, 40.1 mmol) was dissolved in ethanol (150 mL) and Adam's Catalyst (PtO2, 75percent, 1.4 g) was added. The mixture was hydrogenated at 3 psi of hydrogen, continually checking the progress of the reaction by LC and 1H NMR between each charge of hydrogen. After 10 psi was consumed, the data showed completion of the reaction with <5percent of reduction of the bromine. The catalyst was filtered off and the solvent was removed under reduced pressure at 20° C. to give 2-bromo-5-ethylpyridine. Yield 17 g, 98percent.In a 1 L round-bottomed flask was compound 6 (10 g, 53.8 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (13.83 g, 59.1 mmol) in Dioxane (300 ml) followed by saturated sodium bicarbonate (150 ml). The mixture was degassed by passing a stream of nitrogen through the mixture for 20 minutes. Tetrakis(triphenylphosphine) palladium(0) (3.36 g, 2.91 mmol) was added and the mixture was heated to reflux becoming very thick then finally going to solution. The reaction was heated for 2 hours, cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and solvent removed under reduced pressure. The residue was purified by column chromatography 0-100percent ethyl acetate/heptane to give 3-(5-ethylpyridin-2-yl)-4-methylaniline. Yield 8.7 g, 77percentThe urea was formed from 3-(5-ethylpyridin-2-yl)-4-methylaniline and 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3,3-dimethylpiperazine-2-one.
28%
Stage #1: With n-butyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 2 h;
Stage #3: With water In tetrahydrofuran; diethyl ether
6-Bromo-pyridine-3-carbaldehyde. 2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to -78° C., 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at -78° C. for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30-40percent EtOAc in hexane, 2.80 g white solid was obtained (28percent yield), MS: (M+H)+ 186.0, 188.0.
Reference: [1] Patent: EP1741708, 2007, A1, . Location in patent: Page/Page column 47
[2] Patent: US2010/41642, 2010, A1, . Location in patent: Page/Page column 26-27
[3] Patent: US2005/192302, 2005, A1, . Location in patent: Page/Page column 24
  • 12
  • [ 73290-22-9 ]
  • [ 68-12-2 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: With n-butyllithium In diethyl ether at -78℃;
Stage #2: for 1 h;
Stage #3: With hydrogenchloride; water In diethyl ether at 20℃;
Preparation of 2-Bromo-5-formylpyridine (8)The compound was prepared following the literature procedure [van den Heuvel et al J. Org. Chem. 2004, 69, (2), 250-262.]. To a suspension of 2-bromo-5-iodopyridine (3 g, 11 mmol) is dry Et2O (10O mL) at -78 0C was added /1-BuLi (2.2 M, 5.3 mL, 1.1 eq). The reaction mixture was stirred for 1 h prior to the addition of dry DMF (1 mL). After stirring for an additional 1 h, the mixture was warmed to room temperature and quenched by the addition of dilute HCI (1 M, 20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et2O (2 x 20 mL). The combined organic fraction was dried with MgSO4, filtered, and the solvent removed in vacuo. Column chromatography on silica using a gradient (7-60percent EtOAc, hexanes) yielded the product as a white solid (1.25 g, 64percent yield). Rf (1 : 1 EtOAc/hexanes): 0.39. Mp 100-101 0C. (lit. 100 0C). 1H NMR (CDCI3): δ 7.69 (d, J = 8 Hz, 1H), 8.01 (dd, J = 8 Hz and 2 Hz, 1H), 8.83 (d, J = 2 Hz, 1H), 10.10 (s, 1H1 CHO).
Reference: [1] Patent: WO2010/24783, 2010, A1, . Location in patent: Page/Page column 81; 82
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 2314 - 2318
  • 13
  • [ 624-28-2 ]
  • [ 50-00-0 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
56% With n-butyllithium In diethyl ether; acetone at -75℃; Inert atmosphere 2,5-dibromopyridine 4.7 g(20 mmol) is added to purified ether (150 ml) and sufficiently stirred.In order to remove the 5 bromes of 2,5-dibromopyridine in the substitution reaction of aldehyde, the reaction temperature is maintained at -75 ° C or less using an ice bath using liquid nitrogen / acetone. When the temperature of the reactor falls below -75 ,9.6 ml (24 mmol) of n-BuLi was slowly added thereto, followed by reaction for about 90 minutes. Then, 3.1 ml (40 mmol) of DMF was added and reacted for 24 hours to obtain a reaction product. The reactants were extracted with Eehtyl acetate (EA) and water, and the remaining water was removed using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The extracted reaction product was purified by column chromatography (silica gel, n-hexane / ethyl acetate = 10: 1) and dried. 56percent yield: 1 H-NMR (CDCl 3, ppm):? 10.1 (s, 1 H); 8.8 (s, 1 H); 8.0 (d, 1 H); 7.2 (d, 1 H).
Reference: [1] Patent: KR101610226, 2016, B1, . Location in patent: Paragraph 0022-0023
  • 14
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  • [ 693-04-9 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
66% With n-butyllithium; acetic acid In tetrahydrofuran; hexane; N,N-dimethyl-formamide; toluene WORKING EXAMPLE 5
Production of 6-bromo-3-formylpyridine
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (20 mL).
The mixture was stirred at 0° C. for 15 minutes to give a suspension.
The suspension was added to a mixture of toluene (15 mL) and tetrahydrofuran (10 mL) containing 2,5-dibromopyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more while keeping the temperature below -5° C. to give a dark orange solution.
The solution was stirred at 0° C. for 1.25 hours and then at 20° C. for one hour.
The solution was cooled to 0° C., and N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto.
After the mixture was stirred at 0° C. for 30 minutes, 1M aqueous acetic acid solution (20 mL) was added.
The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL).
The organic phases were combined, washed with saturated aqueous sodium chloride (15 mL), dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent.
The resultant residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (20:1, v/v) to give the title compound (1.229 g, 66percent yield) as a colorless solid. 1H-NMR(CDCl3) δppm:7.69 (1H, d, J=8.4 Hz), 8.02 (1H, dd, J=2.4, 8.4 Hz), 8.84 (1H, d, J=2.4 Hz), 10.10 (1H, s).
Reference: [1] Patent: US2003/130511, 2003, A1,
  • 15
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  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
64.8% With hydrogenchloride; n-butyllithium In N,N-dimethyl-formamide a.
2-Bromo-pyridine-5-carboxaldehyde.
To a suspension of 2,5-dibromopyridine (10.28 g, 0.043 mol) in dry ether (150 mL) cooled to -78° C. under argon was added dropwise a solution of n-BuLi (17.4 mL, 0.043 mol, 2.5M in hexanes) while maintaining an internal reaction temperature below -78° C.
The resulting dark red suspension was stirred for 30 min. and a solution of DMF (4.0 mL, 0.0521 mol) in 5 mL dry ether was added dropwise.
After 45 min. the bath was removed and the mixture was allowed to warm to RT.
The mixture was cooled to 0° C. and 1N HCl was added and stirred for 15 min.
The resulting layers were separated and the aqueous layer washed with ether (twice) and combined with the original organics.
The organics were washed with water, brine and dried (MgSO4).
The mixture was filtered and evaporated to give a solid that was purified by column chromatography (silica gel, CH2Cl2) to afford the product as a white solid, 5.23 g (64.8percent yield).
1H NMR (300 MHz; CDCl3) δ7.69 (d, J=8.0 Hz, 1 H), 8.03 (dd, J1=8.0 Hz, J2=2.0 Hz, 1 H), 8.84 (d, J=2.0 Hz, 1 H), 10.10 (s, 1 H).
Reference: [1] Patent: US2003/83357, 2003, A1,
  • 16
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  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
58.6 g With disodium hydrogenphosphate; potassium iodide In dimethyl sulfoxide at 90 - 100℃; for 8 h; Inert atmosphere Take 100g of 2-bromo-5-bromomethyl pyridine,500 g of DMSO and 55 g of disodium hydrogen phosphate were added,5g potassium iodide, stirring, bubbling nitrogen under the surface. Heating to 90 ~ 100 reaction. The reaction was completed for 8 hours. After completion of the reaction, the DMSO was distilled off, the mixture was cooled and 100 g of water and 300 g of MTBE were added, and the mixture was washed and separated to obtain MTBE. The remaining 2-bromo-5-aldehyde pyridine 58.6 g with a purity of more than 95percent.
Reference: [1] Patent: CN107253930, 2017, A, . Location in patent: Paragraph 0078; 0081; 0084; 0087; 0090
  • 17
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  • [ 1068-55-9 ]
  • [ 149806-06-4 ]
Reference: [1] Patent: US2002/120144, 2002, A1,
  • 18
  • [ 23100-12-1 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
28.7 g at 80 - 90℃; Autoclave Take 30g of 2-chloro-5-aldehyde pyridine in a Hastelloy autoclave,Add 40percent hydrobromic acid/acetic acid solution 240g,The reaction vessel was sealed and heated to 80-90°C with stirring.After the reaction is completed, the acetic acid is recovered by desolvation.The residue is added to 100g DCM,Adjust to neutral with saturated sodium bicarbonate.After separation and separation of the organic phase, 34.4 g of 2-bromo-5-aldehyde pyridine was obtained, with a yield of about 87percent.After desolvation, 100ml n-hexane was added to reflux for 30min. After cooling down to 0-10°C, it was filtered and dried to obtain 28.7g of a brown-yellow solid. The GC detection content was 99.2percent, and 2-chloro-5-aldehyde pyridine was 0.5percent in the product.
Reference: [1] Patent: CN107698497, 2018, A, . Location in patent: Paragraph 0086; 0087; 0088; 0089
  • 19
  • [ 3510-66-5 ]
  • [ 149806-06-4 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[2] Synthesis, 1994, # 1, p. 87 - 92
[3] Synthesis, 1994, # 1, p. 87 - 92
[4] Patent: WO2016/124747, 2016, A1,
[5] Patent: US2018/202388, 2018, A1,
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  • [ 149806-06-4 ]
Reference: [1] Synthesis, 1994, # 1, p. 87 - 92
  • 21
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  • [ 149806-06-4 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 45, p. 7889 - 7892
  • 22
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  • [ 149806-06-4 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[2] Synthesis, 1994, # 1, p. 87 - 92
[3] Synthesis, 1994, # 1, p. 87 - 92
  • 23
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  • [ 107-31-3 ]
  • [ 149806-06-4 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 19, p. 4972 - 4975
  • 24
  • [ 154321-17-2 ]
  • [ 149806-06-4 ]
Reference: [1] Synthesis, 1994, # 1, p. 87 - 92
  • 25
  • [ 70258-18-3 ]
  • [ 149806-06-4 ]
Reference: [1] Patent: CN107698497, 2018, A,
  • 26
  • [ 149806-06-4 ]
  • [ 122306-01-8 ]
YieldReaction ConditionsOperation in experiment
92% With sodium tetrahydroborate In methanol at 20 - 30℃; for 2 h; To a solution of 6-bromonicotinaldehyde (20.0 g, 0.1 1 mol) in MeOH (108 mL) was added portionwise NaBH4 (4.88 g, 0.026 mol) at 20-30°C and the reaction mixture was stirred at room temperature for 2 hours then diluted with saturated aqueous NH4CI solution. The combined mixture was concentrated to remove MeOH and resultant aqueous solution was extracted with EtOAc. The extract was washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, filtered and concentrated to afford title compound 94 (18.61 g, 92 percent yield) as an pale yellow solid. ?-NMR (300 MHz, CDC13) ? (ppm): 8.36 (d, J = 2.7 Hz, 1 H), 7.60 (dd, J = 8.1 , 2.7 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1H), 4.72 (s, 2H), 1.95 (s, 1 H).
69% at 0℃; EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH3OH (30 mL) was added NaBH4 (0.53 g, 13.97 mmol) portionwise at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40percent EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69percent) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M+] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et20 (20 mL) was added phosphorus tribromide (PBr3; 1.5 mL, 15.95 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC03 and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10percent EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62percent) as a colorless liquid. 1H NMR (400 MHz, CDC13): δ 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs2C03 (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10percent EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94percent) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]+.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49percent) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]+.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et20 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 °C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et20 (30 mL) was added to the reaction mixture at -78 °C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]+.To a stirred solution of crude AZ (650 mg, crude) in Et20 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10percent KOH solution (100 mL) and Et20 (100 mL) at 0 °C followed by separation and drying of the organic layer using KOH pellets] at -5 °C and the mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for another 16 h; progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexanes) afforded compound BA (250 mg, 0.60 mmol, 37percent) as a yellow liquid. 1H NMR (400 MHz, CDC13): δ 8.73 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65-7.53 (m, 3H), 7.38-7.36 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.86-6.71 (m, 2H), 5.18 (s, 2H), 3.45 (d, J = 5.2 Hz, 1H), 2.98 (t, J = 5.2 Hz, 1H). MS (ESI): m/z 415 [M+H]+.To a stirred solution of compound BA (250 mg, 0.60 mmol) in dry DMF (8 mL) was added iH-tetrazole (62.5 mg, 0.90 mmol) followed by K2C03 (83.3 mg, 0.60 mmol) at RT under inert atmosphere. The reaction mixture was heated to 65 °C and stirred for 16 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography afforded 80 (40 mg, 0.15 mmol, 13percent; eluent: 35percent EtOAc/hexanes) as a yellow liquid and 79 (75 mg, 0.28 mmol, 25percent; eluent: 60percent EtOAc/hexanes) as a thick yellow solid. Compound 79: 1H NMR (400 MHz, CDC13): δ 8.74 (s, 1H), 8.58 (s, 1H), 7.90 (dd, J = 8.0, 2,0 Hz, 1H), 7.66-7.62 (m, 3H), 7.45 (br s, OH), 7.40-7.34 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.80-6.65 (m, 2H), 5.52 (d, J = 14.0 Hz, 1H), 5.18 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]+. HPLC: 97percent. Compound 80: 1H NMR (400 MHz, CDC13): δ 8.63 (s, 1H), 8.31 (s, 1H), 7.90 (dd, J = 8.4, 1.6 Hz, 1H), 7.66-7.62 (m, 3H), 7.44-7.38 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.83-6.67 (m, 2H), 6.63 (br s, OH), 5.82 (d, J = 14.0 Hz, 1H), 5.40 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]+. HPLC: 97percent.
1.9 g With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 2 h; At 0 °C ice bath, add NaBH4 (1.640 g) to a solution of 2-bromo-5-mercaptopyridine (2.010 g) in THF (20 mL), after adding NaBH4, remove the ice bath, warm naturally to room temperature. After stirring at room temperature for 2 hours, The reaction mixture was quenched with water (50 mL) Extracted with EA (50 mL × 2), The combined organic phases were dried over anhydrous Na2SO4 and concentrated. Purified by column chromatography (PE/EA=5/1), 1.900 g of (6-bromopyridin-3-yl)methanol were obtained.
Reference: [1] Patent: WO2013/44360, 2013, A1, . Location in patent: Paragraph 000299-000300
[2] Patent: WO2006/114213, 2006, A1, . Location in patent: Page/Page column 29-30
[3] Patent: WO2012/177603, 2012, A2, . Location in patent: Page/Page column 105-108
[4] Journal of Organic Chemistry, 2004, vol. 69, # 2, p. 250 - 262
[5] Dalton Transactions, 2012, vol. 41, # 3, p. 1074 - 1081
[6] Inorganic Chemistry, 2016, vol. 55, # 16, p. 7944 - 7953
[7] Journal of Biological Inorganic Chemistry, 2018, vol. 23, # 7, p. 1139 - 1151
[8] Patent: TW2018/29406, 2018, A, . Location in patent: Page/Page column 31
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  • [ 656827-76-8 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 2, p. 250 - 262
  • 28
  • [ 149806-06-4 ]
  • [ 386704-12-7 ]
Reference: [1] RSC Advances, 2016, vol. 6, # 79, p. 75465 - 75469
  • 29
  • [ 110-91-8 ]
  • [ 149806-06-4 ]
  • [ 364793-93-1 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 0.666667 h;
Stage #2: With sodium hydrogencarbonate In 1,2-dichloro-ethane
To a RB flask containing formylpyridine (9.347 g, 1 equiv.) in 175 mL 1,2-dichloroethane (3.5 mL/mmol) was added morpholine (4.7 mL, 1.07 equiv.) followed by NaBH(OAc)3 (14.819 g, 1.4 equiv.) and acetic acid (3.1 mL, 1.07 equiv.). The flask was loosely capped and the mixture was stirred at r.t. Mixture gets slightly warm. After 40 min, the reaction was quenched with saturated NaHCO3. When the gas evolution was greatly reduced, 1M NaOH was added to bring the pH to 8-9. The two layers were separated and the aqueous layer was extracted with DCM (.x.3). The organic layer was dried over Na2SO4, filtered and solvent was removed in vacuo. The product was filtered through silica with 1000 mL 100:1 EtOAc:NH4OH to remove baseline material. The material was dissolved in 15 mL EtOAc and 150 mL hexanes was added. The mixture was allowed to sit overnight at 4° C. to crystallize. The supernatant was decanted off and the crystals were washed with a little hexanes which was decanted off. The crystals were transferred to another flask using DCM. LC-MS showed only product. The solvent from the supernatant was removed in vacuo. The remaining mixture was purified by flash column (6.5.x.8.5 cm silica) using 500 mL 8:2 EtOAc; 1400 mL 100:1 EtOAc:NH4OH. All product fractions were combined giving 10.931 g (85percent) of the 4-((6-bromopyridin-3-yl)methyl)morpholine as a yellow solid.In a RB flask, a mixture of 4-((6-bromopyridin-3-yl)methyl)morpholine (10.959 g, 1 equiv.), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10.478 g, 1.05 equiv.), 2M potassium phosphate solution (42.5 mL, 2 equiv.) and Pd(PPh3)4 (2.479, 0.050 equiv.)) in 210 mL dioxane (5 mL/mmol) was sparged with argon for 5 min. The flask was fitted with a septum and argon balloon and the mixture was stirred at 100° C. (amber solution). After 27 h, the mixture was allowed to cool then volume was reduced by at least half in vacuo. The remainder was diluted with water and extracted with EtOAc (.x.3). The organic layers were washed with brine, dried over Na2SO4, filtered and solvent was removed in vacuo. The material was purified by column chromatography on silica eluting with DCM:MeOH to give 10.268 g (85percent) of 4-methyl-3-(5-(morpholinomethyl)pyridin-2-yl)aniline as a very viscous dark amber oil.
72% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 0 - 20℃; for 5 h; 4-[(6-bromopyridin-3-yl)methyl]morpholine
In a 50-mL round bottom flask, 6-bromopyridine-3-carbaldehyde (1.200 g, 6.45 mmol, 1.00 equiv) and morpholine (843 mg, 9.68 mmol, 1.50 equiv) were dissolved in 1,2-dichloroethane (15 mL), to which were added NaBH(OAc)3 (4.102 g, 19.35 mmol, 3.00 equiv) and acetic acid (416 mg, 10.35 mmol 1.07 equiv) at 0° C.
The resulting solution was warmed up to room temperature and stirred for 5 h at room temperature.
When the reaction was done, it was quenched by the addition of 20 mL sat.
sodium bicarbonate solution and the pH value of the resulting mixture was adjusted to 9 using sodium hydroxide solution (1 M).
The mixture was then extracted with ethyl acetate (3*30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (5percent to 50percent gradient) to afford 4-[(6-bromopyridin-3-yl)methyl]morpholine (1.2 g, 72percent) as light yellow solid.
57.9% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 2 h; To a solution of 6-bromonicotinaldehyde (1.0 g, 5.4 mmol) and morpholine (0.50 g, 5.7 mmol) in 1,2-dichloroethane (30 mL) was added sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified via ISCO (eluted with MeOH in H20 0-100percent) to afford the title compound as a yellow solid (0.80 g, 57.9percent yield). MS (m/z): 256.9/258.9 (M+H)+.
57.9% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 2 h; To a solution of 6-bromonicotinaldehyde (1.0 g, 5.4 mmol) and morpholine (0.50 g, 5.7 mmol) in 1 ,2-dichloroethane (30 mL) was added sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified via ISCO (eluted with MeOH in H20 0-100percent) to afford the title compound as a yellow solid (0.80 g, 57.9percent yield). MS (m/z): 256.9/258.9 (M+H)+.
43% With sodium cyanoborohydride; acetic acid In ethanol at 20℃; for 3 h; (181a)
4-[(6-Bromopyridin-3-yl)methyl]morpholine
2-Bromo-5-formylpyridine (0.86 g, 4.6 mmol) was dissolved in ethanol (20 mL), and morpholine (0.48 mL, 5.5 mmol), acetic acid (0.37 mL, 6.4 mmol), and sodium cyanoborohydride (0.43 g, 6.9 mmol) were added thereto.
The resulting mixture was stirred at room temperature for 3 hr.
The solvent was evaporated under reduced pressure.
To the residue, a saturated sodium carbonate aqueous solution was added.
After extraction with methylene chloride, the organic layer was dried with anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen, eluding solvent: ethyl acetate) to obtain 0.51 g (yield: 43percent) of the title compound as a white solid.
1H-NMR (400 MHz, CDCl3) δ ppm: 8.28 (1H, d, J = 2.3 Hz), 7.54 (1H, dd, J = 2.3, 8.0 Hz), 7.43 (1H, d, J = 8.0 Hz), 3.69 (4H, t, J = 4.7 Hz), 3.45 (2H, s), 2.43 (4H, t, J = 4.7 Hz).

Reference: [1] Patent: US2010/41642, 2010, A1, . Location in patent: Page/Page column 20
[2] Patent: US2016/96834, 2016, A1, . Location in patent: Paragraph 0735
[3] Patent: WO2014/139145, 2014, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2014/139465, 2014, A1, . Location in patent: Page/Page column 37; 38
[5] Patent: EP1798229, 2007, A1, . Location in patent: Page/Page column 162
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4242 - 4247
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 19, p. 5325 - 5329
  • 30
  • [ 149806-06-4 ]
  • [ 168173-56-6 ]
Reference: [1] Inorganic Chemistry, 2016, vol. 55, # 16, p. 7944 - 7953
[2] Journal of Biological Inorganic Chemistry, 2018, vol. 23, # 7, p. 1139 - 1151
[3] Patent: TW2018/29406, 2018, A,
  • 31
  • [ 149806-06-4 ]
  • [ 1180132-17-5 ]
Reference: [1] Patent: WO2015/130540, 2015, A1,
[2] Patent: CN106608879, 2017, A,
[3] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 974 - 978
[5] Patent: EP3385262, 2018, A1,
  • 32
  • [ 5308-25-8 ]
  • [ 149806-06-4 ]
  • [ 1180132-17-5 ]
Reference: [1] Patent: CN105622638, 2016, A,
[2] Patent: CN107266421, 2017, A,
  • 33
  • [ 5308-25-8 ]
  • [ 149806-06-4 ]
  • [ 1231930-25-8 ]
YieldReaction ConditionsOperation in experiment
92% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 5 h; To 100ml of anhydrous DCM was added 6a (10 g, 54 mmol) and 7a (6.20 g, 54.00 mmol),.followed NaHB(OAc)3 (17.20 g, 81.00 mmol) was added in parts, The mixture was stirred at RT for 5hdiluted with DCM (100 mL), Saturated Na2CO3 solution was added to the mixture until the pH reached 8–10. The mixture was partitioned between water and dichloromethane. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM/MeOH = 50:1) to give compound 8a (14.00 g, 92.00percent) as yellow soild. MS (ESI): mass calcd. for C12H18BrN3 283, m/z found 284 [M+H] +.
91.4%
Stage #1: for 2 h;
Stage #2: With sodium tetrahydroborate; acetic acid In dichloromethane for 16 h;
6-bromo-pyridine-3-carbaldehyde (5 g, 26.9 mmol, 1.0 eq.) and 4-ethyl-piperidine was dissolved in dichloromethane (100 ml), stirred for 2 hours, acetic acid was added portionwise inside borohydride sodium (6.2 g, 29.2 mmol, 1.1 eq). After 16 hours of reaction, an aqueous solution of sodium hydroxide was added thereto 2 mol/L to adjust the PH to alkaline, extracted with dichloromethane, and concentrated under reduced pressure to give a white solid of 1-(6-bromopyridin-3-yl)methyl-4-ethylpiperidine (6.98g, yield: 91.4percent).
80% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 12 h; 1-ethylpiperazine (1.8 g, 16 mmol), 6-bromo-pyridine-3-carbaldehyde (3 g, 16 mmol) and dichloromethane (50 mL) were added to the reaction flask,Sodium triacetoxyborohydride (3.7 g, 17.5 mmol) was added portionwise with stirring,The mixture was stirred at room temperature for 12 hours.Dichloromethane (20 mL) and aqueous sodium hydroxide (2N, 15 mL) were added to the reaction solution.The aqueous phase was extracted with dichloromethane (20 mL x 2). Combine organic phase,Saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, suction filtration,The filtrate was concentrated under reduced pressure to give the title compound (3.6 g, yellow oil) in 80percent yield.
71% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; NaHB(OAc)3 (2.60g, 12.23mmol) was added to a solution of 137 6-bromonicotinaldehyde (1.50g, 8.15mmol) and 92 1-ethylpiperazine (0.90g, 8.15mmol) in 103 DCM (15mL). The mixture was allowed to stir at RT overnight, after which it was filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1–10:1) to obtain 138 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (1.65g; yield, 71percent) as a yellow oil. Lithium bis(trimethylsilyl)amide (1N) (20mL, 20.0mmol) under N2 was added to a solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.80g, 10.0mmol), Cy-John-Phos (700.0mg, 2.0mmol), and Pd2(dba)3 (915.0mg, 1.0mmol) in dry toluene (30mL). Then the mixture was heated to 80°C overnight, cooled to RT, filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1–10:1) to give INT-7 (1.52g; yield, 69percent) as a brown solid. ESI-MS: m/z 221.2 [M+H]+.
11.5 kg With sodium tris(acetoxy)borohydride In dichloromethane at 20 - 30℃; for 12 h; Large scale Add neat 1-ethylpiperazine (5.6 kg) to a mixture of 6-bromo-pyridine-3- carbaldehyde (8.3 kg) and dichloromethane (186 kg). Then, add sodium (0086) triacetoxyborohydride (10.9 kg) in portions and stir at 20-30 °C for 12 hours. Quench the reaction into a mixture of dichloromethane (36 kg) and aqueous solution of sodium hydroxide 2 N (46 kg). Separate the layers and extract twice the aqueous layer with dichloromethane (24 X 2 kg). Combine the organic layers, wash with brine (50 X 2 kg) and remove the solvent under vacuum to afford 11.5 kg of the title compound. MS (ES+): m/z= 285 (M+H)+.
1.48 g With formic acid; trimethyl orthoformate In acetonitrile for 4 h; Reflux; Inert atmosphere N-ethylpiperazine (1.59 g, 13.95 mmol), 2-bromo-5-pyridinecarbaldehyde (3.14 g, 16.88 mmol) were added successively to acetonitrile,To a solution of formic acid (2.10 mL, 55.80 mmol)Trimethyl orthoformate (3.07 mL, 27.90 mmol).Heating under reflux under nitrogen,After 4 hours the reaction solution was cooled to room temperature,Add 30 mL of water,15 mL of ethyl acetate,Liquid separation.The organic layer is the remaining 2-bromo-5-pyridinecarboxaldehyde.The aqueous layer was added with saturated sodium hydroxide to adjust the pH to 10,30 mL of ethyl acetate was added,Liquid separation,The aqueous layer was again added with 30 mL of ethyl acetate,Combined organic layer,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.The product of formula XII-1 (1.48 g) was purified by column chromatography,As a colorless liquid.
1.48 g With formic acid; trimethyl orthoformate In acetonitrile for 4 h; Reflux; Inert atmosphere N-Ethylpiperazine (1.59 g, 13.95 mmol) and 2-bromo-5-pyridinecarbaldehyde (3.14 g, 16.88 mmol) were sequentially added to acetonitrile and formic acid (2.10 mL, 55.80 mmol) Ester (3.07 mL, 27.90 mmol).The mixture was heated to reflux under nitrogen and the reaction was cooled to room temperature after 4h. 30mL of water and 15mL of ethyl acetate were added to separate the layers.The organic layer is the remaining 2-bromo-5-pyridinecarboxaldehyde.The aqueous layer was added with saturated sodium hydroxide to adjust the pH to 10, added with 30 mL of ethyl acetate, separated and the aqueous layer was added with 30 mL of ethyl acetate again. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.Purification by column chromatography gave 1.48 g of a colorless liquid.1H-NMR (300 MHz, CDCl 33)?: 8.29 d, J = 1.74Hz), 7.53-7.55 (1H, dd, J = 1.98Hz, 8.10Hz), 7.43 (1H, d, J = 8.10Hz), 3.47 (2H, s) , 2.38-2.48 (10H, m), 1.08 (3H, t, J = 7.14 Hz).HRMS (ESI): m / z 283.0684
1.64 g With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; 2-bromo-5-formylpyridine (1.5 g, 8.15 mmol), 1-ethylpiperazine (0.93 g, 8.15 mmol), and
dichloromethane (15 mL) were added to the reaction flask, and then NaHB(OAc)3 (2.58 g, 12.23 mmol) was added in batches.
Reaction was carried out at room temperature overnight.
The reaction product was filtered, concentrated and separated by column chromatography (DCM/MeOH = 100:1 to 10:1) to obtain the titled product (1.64g, yellow oil).
MS (ESI): mass calcd. for C12H18BrN3 285.1, m/z found 286.1 [M+H]+.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 974 - 978
[2] Patent: CN105622638, 2016, A, . Location in patent: Paragraph 0220
[3] Patent: CN106608879, 2017, A, . Location in patent: Paragraph 0142-0145
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1892 - 1915
[6] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 9
[7] Patent: WO2015/130540, 2015, A1, . Location in patent: Page/Page column 20-21
[8] Patent: WO2016/14904, 2016, A1, . Location in patent: Page/Page column 21; 23; 24
[9] Patent: CN106467517, 2017, A, . Location in patent: Paragraph 0107; 0108; 0109; 0110; 0111; 0112
[10] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1447 - 1451
[11] Patent: CN107266421, 2017, A, . Location in patent: Paragraph 0164; 0165; 0166
[12] Patent: EP3385262, 2018, A1, . Location in patent: Paragraph 0097; 0098; 0099; 0100
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Reference: [1] Patent: WO2015/130540, 2015, A1,
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