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CAS No. :2591-86-8 MDL No. :MFCD00006483
Formula : C6H11NO Boiling Point : -
Linear Structure Formula :- InChI Key :FEWLNYSYJNLUOO-UHFFFAOYSA-N
M.W : 113.16 Pubchem ID :17429
Synonyms :

Safety of [ 2591-86-8 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P280-P305+P351+P338-P312 UN#:2810
Hazard Statements:H302-H311-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 2591-86-8 ]

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

  • Upstream synthesis route of [ 2591-86-8 ]
  • Downstream synthetic route of [ 2591-86-8 ]

[ 2591-86-8 ] Synthesis Path-Upstream   1~64

  • 1
  • [ 288-47-1 ]
  • [ 2591-86-8 ]
  • [ 10200-59-6 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 4, p. 442 - 444
  • 2
  • [ 872-31-1 ]
  • [ 2591-86-8 ]
  • [ 930-96-1 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: for 1 h;
A solution of 3-bromothiophene (30.0 g, 184 mmol) in THF (200 mL) cooled to 0 °C was added slowly to a 2.0 M solution of LDA in THF (92 mL, 184 mmol; Aldrich Chemicals). The orange solution was stirred at 0 °C for 30 min, then piperidine-1-carbaldehyde (20.4 mL, 184 mmol) was added. The mixture was stirred for a further1 h then diluted with Et2O (300 mL), washed with brine (100 mL), dried, and concentrated. The resulting orange oil was purifiedby chromatography (silica gel, heptane–EtOAc). Product containing fractions were combined and concentrated to give an orange liquid; 21 yield: 29.3 g (85percent).
85%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 1.5 h;
Stage #2: at 0 - 20℃; for 2 h;
Commercially available lithium diisopropylamide (LDA) solution (2 M, 27 mL, 53.4 mmol) wasdiluted in THE (100 mL)solution at0 °C. A solution of compound 6d (5.0 mL, 53.4 mmol) in THE(5 mL) was added drop wise to the dilute LDA solution at 0 °C over 60 minutes using a droppingfunnel. The reaction mixture was allowed to stir at 0 °C for 30 minutes. After 30 mins, 1-formyl-piperidine was added drop-wise to the reaction mixture. The resultant mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with NH4CI (150 mL) and extracted with Et20 (3 x 100 mL). The combined organic layers were washed with brine and concentrated to give yellow oil, which was purified by col15 umn chromatography on silica gel using DCM: hexane (v/v 1:1)to yield compound 8a as a yellow oil (8.7 g, 85percent). 1H NMR (400 MHz, CDCI3) ö 9.99 (s, 1 H), 7.71 (d, 1 H, J = 5.2 Hz), 7.15 (d, 1H, J = 5.2 Hz).
79.2%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0 - 2℃; for 0.5 h;
Stage #2: for 2 h;
Experimental procedure3-Bromo-thiophene (6.523 g, 40 mmol) was dissolved under N2 in THF (100 mL). After cooling to 0-2 °C it was mixed dropwise with a 2M LDA solution (20 mL, 40 mmol) and stirred for 0.5 h. Following that 1-Formylpiperidin (4.52 g, 40 mmol) was added. After 2 h the reaction was stopped by adding a surplus of a saturated solution of NH4CI. For purification it was extracted three times with Et2O (10 mL) and the pooled organic phases subsequently dried over Na2SO4. After filtration the solvent was removed under vacuum. The crude product (approx. 8.3 g) was purified using flash-chromatography (8 cm, cyclohexane:ethylacetate 9:1 , 30 mL, Rf = 0.65) and by distillation under vacuum (Bp. 62 0C, 5.6 -10"2 mbar).Colourless liquid, yield 6.05 g (79.2 percent). <n="42"/>C5H3BrOS (191.1)MS (EI): m/z = 190/192 [M+], 162 [M+ -CHO].IR (Film): v (crτT1) = 3103 (C-H)1 2843 (C-H), 1657 (C=O).1H-NMR (CDCI3):δ (ppm) = 7.15 (d, J = 5.5 Hz, 1 H, 4-H-Th), 7.71 (dd, J = 5.1/1.5 Hz, 1 H, 5-H-Th)1 9.99 (d, J = 1.5 Hz, 1 H, Th-CHO).
54%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 0℃; for 12 h;
[00174] To a solution of lithium diisopropylamide (31.6 mmol) in 50 mL of THF at -78 °C was added 3-bromothiophene (3.0 g, 31 mmol) (1). After stirring for 1 h, formylpiperidine (3.50 g, 31.6 mmol) (2) was added and the reaction was warmed to 0 °C. After 12 h, the reaction mixture was partitioned between DCM and sat. NH4C1 and the organic layer was separated, dried over MgS04, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to afford 1.90 g (54percent) of the title compound as a yellow oil. 'H NMR (400 MHz, CDCI3) δ 9.99 (s, 1H), 7.71 (d, J= 5.2 Hz, 1H), 7.15 (d, J= 4.8 Hz, 1H).

Reference: [1] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 6, p. 1132 - 1136
[2] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2248 - 2255
[3] Synthesis (Germany), 2014, vol. 46, # 1, p. 96 - 100
[4] Patent: WO2015/128779, 2015, A1, . Location in patent: Page/Page column 28
[5] Advanced Functional Materials, 2012, vol. 22, # 1, p. 48 - 60
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6531 - 6537
[7] Patent: WO2008/155132, 2008, A1, . Location in patent: Page/Page column 40-41
[8] Heterocyclic Communications, 2016, vol. 22, # 1, p. 1 - 5
[9] Patent: WO2015/197861, 2015, A1, . Location in patent: Paragraph 00173-00174
[10] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3465 - 3470
[11] Molecules, 2012, vol. 17, # 10, p. 12163 - 12171
[12] Patent: KR101540066, 2015, B1, . Location in patent: Paragraph 0021; 0022; 0023
  • 3
  • [ 3140-93-0 ]
  • [ 2591-86-8 ]
  • [ 109-72-8 ]
  • [ 930-96-1 ]
Reference: [1] Patent: US4876271, 1989, A,
  • 4
  • [ 3140-93-0 ]
  • [ 2591-86-8 ]
  • [ 930-96-1 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1805 - 1818
  • 5
  • [ 2591-86-8 ]
  • [ 2402-78-0 ]
  • [ 113293-70-2 ]
  • [ 55304-73-9 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4793 - 4796
[2] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4793 - 4796
  • 6
  • [ 2591-86-8 ]
  • [ 136613-57-5 ]
  • [ 63136-60-7 ]
Reference: [1] Tetrahedron, 1998, vol. 54, # 47, p. 14327 - 14340
  • 7
  • [ 110-89-4 ]
  • [ 124-38-9 ]
  • [ 122-51-0 ]
  • [ 100-74-3 ]
  • [ 2591-86-8 ]
  • [ 5325-94-0 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 2, p. 455 - 458
  • 8
  • [ 109-09-1 ]
  • [ 2591-86-8 ]
  • [ 36404-88-3 ]
Reference: [1] European Journal of Organic Chemistry, 2006, # 9, p. 2181 - 2196
[2] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
[3] Synthesis, 1996, # 8, p. 986 - 990
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 20, p. 4421 - 4426
  • 9
  • [ 109-09-1 ]
  • [ 2591-86-8 ]
  • [ 591-50-4 ]
  • [ 36404-88-3 ]
YieldReaction ConditionsOperation in experiment
54% With n-butyllithium; diisopropylamine In tetrahydrofuran EXAMPLE 13
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)thieno[2,3-b]pyridine-2-carboxamide Dihydrochloride
Preparation of the Acid:
THF (200 mL) in a dry flask under N2 is chilled by placing the flask in a dry-ice/acetone bath at -78° C. Butyllithium (125 mL, 200 mmol) is added drop-wise, followed by the drop-wise addition of iodobenzene (11.19 mL, 100 mmol) in THF (10 mL).
The solution is allowed to stir for 30 min at -78° C. Diisopropylamine (0.70 mL, 5 mmol) in THF (3 mL) and 2-chloropyridine (9.46 mL, 100 mmol) in THF (30 mL) are added successively in a drop-wise manner, and the solution is stirred for 1 h at -40° C. Formyl piperidine (11.1 mL, 100 mmol) in THF (25 mL) is added drop-wise, and the solution is stirred for 1 h at -40° C.
The reaction is quenched with 40 mL 6N HCl, diluted with 250 mL ether, and a small amount of sodium thiosulfate solution is added to remove the iodine color.
The solution is neutralized with saturated NaHCO3, filtered, and extracted with ether (3*150 mL).
The combined organic layer is dried over Na2SO4, filtered, and concentrated in vacuo.
The crude material is chromatographed over 600 g slurry-packed silica, eluding with 20percent EtOAc/hexane.
The fractions with the desired compound are collected and concentrated to afford 2-chloronicotinaldehyde (C90) as a pale orange solid (54percent yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.
Reference: [1] Patent: US2003/45540, 2003, A1,
  • 10
  • [ 626-55-1 ]
  • [ 2591-86-8 ]
  • [ 70201-43-3 ]
YieldReaction ConditionsOperation in experiment
48%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.25 h; Inert atmosphere
Stage #2: at -78 - 20℃; for 2.33333 h; Inert atmosphere
Under an N2 atmosphere, a 1.6 M solution of n-butyllithium in hexane (7.06 mL, 11.3 mmol) was added slowly to a cooled (-78 °C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol) in THF (25 mL). After 30 min stirring at 0 °C, the mixture was cooled to -78 °C and a solution of 3-bromopyridine 5c (1.63 g, 1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixture was stirred at -78 °C for 15 min, and then a solution of N-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was added slowly. The solution was stirred at -78 °C for 50 min. Then it was allowed to warm to room temperature and it was stirred for another 1.5 h. A satd. NH4Cl solution (40 mL) was added. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (60 mL) and dried over Na2SO4. Filtration and evaporation afforded crude product, which was purified by fc (5.5 cm, EtOAc:cyclohexane 1:4).
Yellow solid (EtOAc:cyclohexane 2:1, Rf = 0.55), yield 914 mg (48percent). 1H NMR (600 MHz, CDCl3): δ (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72 (d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO).
48%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.25 h; Inert atmosphere
Stage #2: at -78℃; for 0.833333 h; Inert atmosphere
Under an N2 atmosphere, a 1.6 M solution of n-butyllithium inhexane (7.06 mL, 11.3 mmol) was added slowly to a cooled(78 C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol)in THF (25 mL). After 30-min stirring at 0 C, the mixture wascooled to 78 C and a solution of 3-bromopyridine (5, 1.63 g,1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixturewas stirred at 78 C for 15 min, and then a solution ofN-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was addedslowly. The solution was stirred at 78 C for 50 min. Then itwas allowed to warm to room temperature and stirred for another1.5 h. Saturated NH4Cl solution (40 mL) was added. The aqueouslayer was extracted with EtOAc (3 30 mL). The combined organiclayers were washed with brine (60 mL) and dried over Na2SO4.Filtration and evaporation afforded crude product, which waspurified by fc (5.5 cm, EtOAc/cyclohexane 1:4). Yellow solid(EtOAc/cyclohexane2:1, Rf = 0.55), yield 914 mg (48percent). 1H NMR(600 MHz, CDCl3): d (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72(d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO).
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 83, p. 709 - 716
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 15, p. 4277 - 4284
  • 11
  • [ 2591-86-8 ]
  • [ 217813-03-1 ]
  • [ 32040-06-5 ]
  • [ 148-53-8 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With tetrabutyl ammonium fluoride In acetonitrile at 20℃; for 3 h; Inert atmosphere
Stage #2: at 20℃;
General procedure: To a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate 1 (53 μL, 0.20 mmol) and 1-formylpiperidine 4, N,N-dibenzylformamide 6, or N-methylformamide 8 (2.0 mmol) in CH3CN (1.4 mL) was added TBAF (1.0 M solution in CH3CN, 0.60 mL, 0.60 mmol) under argon atmosphere at room temperature. After being stirred at the same temperature for 3 h, H2O (0.1 mL) was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt/hexane=1/20 to 1/8 with 2percent CH2Cl2) afforded the products 2, 5, 7, and 9.
Reference: [1] Tetrahedron, 2012, vol. 68, # 1, p. 179 - 189
  • 12
  • [ 2591-86-8 ]
  • [ 71112-64-6 ]
  • [ 4707-71-5 ]
Reference: [1] Angewandte Chemie, 1981, vol. 93, # 10, p. 925 - 926
  • 13
  • [ 2591-86-8 ]
  • [ 150-78-7 ]
  • [ 7310-97-6 ]
YieldReaction ConditionsOperation in experiment
51%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane; ethyl acetate at 0℃; Inert atmosphere; Reflux
Stage #2: at 0 - 20℃; for 1 h;
To a solution of 1-1 1 ,4-dimethoxybenzene (11.5 g, 83.26 mmol, 1 eq) in distilled Et20(276 mL) was added TMEDA (37,4 mL, 249.78 mmol, 3 eq). At 000, nBuLi at 2.5 M inhexane (100 mL, 249.78 mmol, 3 eq) was added dropwise. The mixture was stirred atreflux overnight under inert atmosphere. At 000, 1-formylpiperidine (27.74 mL, 249.78mmol, 3 eq). was added dropwise. The mixture was stirred at room temperature for 1 h.Following the addition of distilled water (300 mL) and HCI 3 M (57.5 mL), the mixture was extracted with hot CHCI3 (300 mLx4). The organic phase was dried over an hydrous Na2SO4 and filtered. After removing the solvent, the remaining residue was purified by recrystallization in CHCI3 to give an orange solid (9.51 g, 51 percent).1H NMR (300 MHz, ODd3) 6 ppm = 10.51 (s, 2 H, CHO), 7.46 (s, 2 H, Ar), 3.95 (s, 6 H,OH3) data matched with literature reference
Reference: [1] Patent: WO2017/211985, 2017, A1, . Location in patent: Page/Page column 35; 36
  • 14
  • [ 2591-86-8 ]
  • [ 96797-15-8 ]
  • [ 33016-47-6 ]
Reference: [1] Organic Preparations and Procedures International, 1996, vol. 28, # 6, p. 709 - 710
  • 15
  • [ 2591-86-8 ]
  • [ 56686-16-9 ]
  • [ 52606-02-7 ]
Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 8, p. 1494 - 1497
  • 16
  • [ 2591-86-8 ]
  • [ 251-41-2 ]
  • [ 31486-86-9 ]
Reference: [1] Synlett, 2011, # 15, p. 2151 - 2156
  • 17
  • [ 109-09-1 ]
  • [ 2591-86-8 ]
  • [ 54087-03-5 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 26, p. 6166 - 6171
  • 18
  • [ 2591-86-8 ]
  • [ 53939-30-3 ]
  • [ 23100-12-1 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With n-butyllithium In diethyl ether; hexane at -50 - -45℃; Inert atmosphere
Stage #2: at -70 - 20℃;
5-Bromo-2-chloropyridine (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to -50 °C under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of -50 °C to -45 °C, and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to -70 °C, formylpiperidine (9.70 g) was added dropwise in the temperature range of -70 °C to -65 °C, and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68percent.
Reference: [1] Patent: EP2351741, 2011, A1, . Location in patent: Page/Page column 53
[2] Patent: KR101512525, 2015, B1, . Location in patent: Paragraph 0133-0135
  • 19
  • [ 2591-86-8 ]
  • [ 1628-89-3 ]
  • [ 71255-09-9 ]
Reference: [1] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
  • 20
  • [ 2591-86-8 ]
  • [ 2402-78-0 ]
  • [ 55304-73-9 ]
YieldReaction ConditionsOperation in experiment
40%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.333333 h;
Under N2, to a solution of 2,6-dichloroyridine (6.00 g, 40.5 mmol) in anhydrous THF (75 mL) cooled at -78 0C was added LDA (2.0 M in heptane/THF/ethylbenzene, 20.5 mL, 41.0 mmol). After the mixture was stirred at -78 0C for 30 min, 1-formylpiperidine (4.64 g, 41.0 mmol) was added. The mixture was stirred at -78 0C for 20 min, and at -780C aqueous EPO <DP n="63"/>HCl (1 N, 60 mL) and Et2O (50 mL) were added. The organic layer was collected and the aqueous layer was extracted with Et2O (3 X 100 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (CH2Cl2/hexanes, 1 :2 v/v) to afford 2,6-dichloro-pyridine- 3-carbaldehyde as a white solid (2.85 g, 40percent).
Reference: [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 61-62
[2] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
  • 21
  • [ 2591-86-8 ]
  • [ 2402-78-0 ]
  • [ 113293-70-2 ]
  • [ 55304-73-9 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4793 - 4796
[2] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4793 - 4796
  • 22
  • [ 2591-86-8 ]
  • [ 17347-32-9 ]
  • [ 106-93-4 ]
  • [ 6386-80-7 ]
Reference: [1] Patent: US4664693, 1987, A,
[2] Patent: EP125059, 1991, B1,
  • 23
  • [ 2591-86-8 ]
  • [ 85609-09-2 ]
  • [ 40150-98-9 ]
Reference: [1] Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 2001, vol. 491, # 1-2, p. 195 - 209
  • 24
  • [ 2591-86-8 ]
  • [ 2039-88-5 ]
  • [ 28272-96-0 ]
Reference: [1] Chemistry - A European Journal, 2013, vol. 19, # 15, p. 4849 - 4857
[2] Journal of Organic Chemistry, 1985, vol. 50, # 14, p. 2427 - 2431
[3] Patent: US4587253, 1986, A,
  • 25
  • [ 2591-86-8 ]
  • [ 24591-33-1 ]
  • [ 31825-29-3 ]
Reference: [1] Journal of Natural Products, 2014, vol. 77, # 9, p. 2134 - 2137
  • 26
  • [ 2591-86-8 ]
  • [ 90609-47-5 ]
  • [ 874-63-5 ]
  • [ 19447-00-8 ]
Reference: [1] Australian Journal of Chemistry, 1995, vol. 48, # 5, p. 1055 - 1058
  • 27
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  • [ 4111-55-1 ]
  • [ 74-88-4 ]
  • [ 7560-83-0 ]
Reference: [1] Journal of Organic Chemistry, 2000, vol. 65, # 6, p. 1629 - 1635
  • 28
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  • [ 456-49-5 ]
  • [ 458-50-4 ]
  • [ 331-64-6 ]
  • [ 450-83-9 ]
Reference: [1] Archiv der Pharmazie, 1994, vol. 327, # 9, p. 547 - 561
  • 29
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  • [ 452-08-4 ]
  • [ 19415-51-1 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 6, p. 1385 - 1392
[2] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 5955 - 5963
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  • [ 90609-47-5 ]
  • [ 874-63-5 ]
  • [ 19447-00-8 ]
Reference: [1] Australian Journal of Chemistry, 1995, vol. 48, # 5, p. 1055 - 1058
  • 31
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  • [ 59557-93-6 ]
  • [ 1971-81-9 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 2, p. 297 - 303
  • 32
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  • [ 456-49-5 ]
  • [ 331-64-6 ]
  • [ 146137-74-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 72 - 83
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Reference: [1] Archiv der Pharmazie, 1994, vol. 327, # 9, p. 547 - 561
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  • [ 456-49-5 ]
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Reference: [1] Archiv der Pharmazie, 1994, vol. 327, # 9, p. 547 - 561
  • 35
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  • [ 456-49-5 ]
  • [ 331-64-6 ]
  • [ 450-88-4 ]
  • [ 450-83-9 ]
Reference: [1] Archiv der Pharmazie, 1994, vol. 327, # 9, p. 547 - 561
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  • [ 456-49-5 ]
  • [ 458-50-4 ]
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Reference: [1] Archiv der Pharmazie, 1994, vol. 327, # 9, p. 547 - 561
  • 37
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  • [ 456-49-5 ]
  • [ 331-64-6 ]
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Reference: [1] Archiv der Pharmazie, 1994, vol. 327, # 9, p. 547 - 561
  • 38
  • [ 2591-86-8 ]
  • [ 372-48-5 ]
  • [ 36404-90-7 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With trimethylsilylmethyllithium; diisopropylamine In tetrahydrofuran; hexane at -50℃; for 3 h;
Stage #2: at -50 - 20℃;
A solution of (trimethylsilylmethyl) lithium (22 mL, 13.8 weight percent in hexanes) was charged to a 100 mL 3-NECK round-bottom flask and cooled TO-50 °C. A solution of 2-fluoropyridine (2.0 g), THF (25 mL) and DIISOPROPYLAMINE (0.13 mL) was added at less than-50 °C in 1 minute. After 3 hours, 1-formylpiperidine (2.4 g) was added in 1 min at less THAN-50 °C. The mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was quenched with acetic acid (3 mL) and water (7 mL). The aqueous layer was separated and washed with 3x25 mL MTBE. All organic layers were combined, dried over MGS04 and concentrated in vacuo to leave 3.79 g of brown oil. This oil was chromatographed through silica gel, eluting with 15 percent EtOAc in hexanes, to afford 2. 24 g of 92. 4percent pure 2-FLUORO-3-PYRIDINECARBOXALDEHYDE (90percent yield, corrected for assay).
Reference: [1] Patent: WO2004/92125, 2004, A2, . Location in patent: Page 7-8
[2] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
  • 39
  • [ 2591-86-8 ]
  • [ 82257-14-5 ]
  • [ 82257-15-6 ]
Reference: [1] Patent: WO2004/92125, 2004, A2, . Location in patent: Page 7
  • 40
  • [ 2591-86-8 ]
  • [ 17228-64-7 ]
  • [ 95652-80-5 ]
  • [ 95652-81-6 ]
Reference: [1] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
  • 41
  • [ 2591-86-8 ]
  • [ 17228-64-7 ]
  • [ 95652-80-5 ]
  • [ 95652-81-6 ]
Reference: [1] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
  • 42
  • [ 2591-86-8 ]
  • [ 459-60-9 ]
  • [ 105728-90-3 ]
Reference: [1] European Journal of Medicinal Chemistry, 1993, vol. 28, # 2, p. 103 - 115
  • 43
  • [ 2591-86-8 ]
  • [ 26452-80-2 ]
  • [ 134031-24-6 ]
YieldReaction ConditionsOperation in experiment
54%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 0℃; for 3.5 h;
Stage #2: at -78℃; for 1.5 h;
Intermediate 12,4-Dichloro-pyridine-3-carbaldehydeTo a solution of n-butyllithium (1.6 M in hexane, 64 ml, 101 mmol) in THF (150 ml) at -78 °C was added diisopropylamine (14.3 ml, 101 mmol) dropwise. The reaction mixture was allowed to warm to 0 °C over 1 h, and then cooled down to -78 °C. 2,4-Dichloropyridine (11 ml, 101 mmol) was added dropwise and the solution was stirred at -78 °C for 2.5 h. N-Formylpiperidine (11.2 ml, 101 mmol) was then added dropwise and the mixture stirred at -78 °C for a further 1.5 h. The solution was quenched at -78 °C with saturated NH4CI (aq) and then allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M HCI (aq), the organic phase was separated, washed with saturated NaHC03 (aq), dried (MgS04) and evaporated to dryness. The crude residue was purified by flash chromatography, eluting with 0 to 20percent ethyl acetate/petroleum ether gradient to give a yellow solid (9.7 g, 54percent). 1H NMR (400 MHz, DMSO-cfe) δ ppm 7.78 (d, J=5.04 Hz, 1 H), 8.56 (d, J=5.50 Hz, 1 H), 10.31 (s, 1 H). Rf (20percent ethyl acetate in petroleum ether) = 0.70.
54%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 2.5 h;
Stage #2: at -78℃; for 1.5 h;
Intermediate 10
2,4-Dichloro-pyridine-3-carbaldehyde
To a solution of n-butyllithium (1.6 M in hexane, 64 ml, 101 mmol) in THF (150 ml) at -78 0C was added diisopropylamine (14.3 ml, 101 mmol) dropwise. The reaction mixture was allowed to warm to 0 0C over 1 h, and then cooled down to -78 0C. 2,4-DichIoropyridine (11 ml, 101 mmol) was added dropwise and the solution was stirred at-78°C for 2.5 h. N- Formylpiperidine (11.2 ml, 101 mmol) was then added dropwise and the mixture stirred at -78 0C for a further 1.5 h. The solution was quenched at -78 0C with saturated NH4CI (aq) and then allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M HCI (aq), the organic phase was separated, washed with saturated NaHCO3 (aq), dried (MgSO4) and evaporated to dryness. The crude residue was purified by flash chromatography, eluting with 0 to 20percent ethyl acetate/petroleum ether gradient to give a yellow solid (9.7 g, 54percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J=5.04 Hz, 1 H), 8.56 (d, J=5.50 Hz, 1 H), 10.31 (s, 1 H). Rf (20percent ethyl acetate in petroleum ether) = 0.70.
7 g
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78℃; for 2 h;
A) 2,4-dichloropyridine-3-carbaldehyde [1031] To a solution of 2,4-dichloropyridine (10 g) in THF (100 mL) was added dropwise lithium diisopropylamide solution (2M, 37 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 hr. To the reaction mixture was added dropwise 1-formylpiperidine (7.7 g) at -78°C. The reaction mixture was stirred at -78°C for 2 hr. The reaction mixture was added to 10percent aqueous acetic acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (7.0 g). 1H NMR (400 MHz, DMSO-d6) δ 7.78 (1H, d, J = 5.6 Hz), 8.56 (1H, d, J = 5.6 Hz), 10.32 (1H, s).
Reference: [1] Patent: WO2012/38743, 2012, A1, . Location in patent: Page/Page column 81-82
[2] Patent: WO2010/106333, 2010, A1, . Location in patent: Page/Page column 77-78
[3] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4793 - 4796
[4] Patent: EP2857400, 2015, A1, . Location in patent: Paragraph 1031
  • 44
  • [ 2591-86-8 ]
  • [ 4175-76-2 ]
  • [ 139670-00-1 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 2, p. 215 - 219
  • 45
  • [ 626-61-9 ]
  • [ 2591-86-8 ]
  • [ 114077-82-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 662 - 667
  • 46
  • [ 2591-86-8 ]
  • [ 15231-91-1 ]
  • [ 78119-82-1 ]
Reference: [1] Dyes and Pigments, 2012, vol. 94, # 2, p. 175 - 182
[2] Tetrahedron, 1999, vol. 55, # 18, p. 5821 - 5830
  • 47
  • [ 2591-86-8 ]
  • [ 456-49-5 ]
  • [ 331-64-6 ]
  • [ 146137-74-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 72 - 83
  • 48
  • [ 2591-86-8 ]
  • [ 402-52-8 ]
  • [ 146539-83-5 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 6, p. 1385 - 1392
  • 49
  • [ 2591-86-8 ]
  • [ 116026-95-0 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With n-butyllithium In tetrahydrofuran; pentane at -78 - -20℃; for 1.75 h;
Stage #2: at -15 - 20℃;
A solution of tert-butyl pyridin-3-ylcarbamate (17.7 g, 91.1 mmol) in THF (300 mL) was cooled to -78 0C and treated with 1.70 M te^butyllithium in pentane (129 mL). Upon completion of the addition, the reaction was stirred at -78 0C for an additional 15 min and then at -20 0C for 1.5 h. 1-piperidinecarboxaldehyde (30.4 mL, 0.273 mol) was added while the temperature was maintained below at -15 0C, and then the mixture was allowed to stir at room temperature overnight. The solution was cooled to 0 0C and was quenched by the addition of 1 M HCl to bring the pH to 2. Solid Na2CO3 was then added to adjust the pH to 7. The solution was extracted with ethyl acetate three times, and the combined organic solutions were washed with water (3x) and brine. The organic layer was dried, filtered, and volatiles evaporated. The residue was purified by silica gel chromatography (50percent ethyl EPO <DP n="106"/>acetate/hexanes) to give the desired product as a yellow solid (12.2 g, 60percent). LCMS for CnH15N2O3 (M+H)+: m/z = 223.1.
Reference: [1] Patent: WO2007/38215, 2007, A1, . Location in patent: Page/Page column 104-105
  • 50
  • [ 2591-86-8 ]
  • [ 56700-70-0 ]
  • [ 116026-95-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
  • 51
  • [ 2591-86-8 ]
  • [ 38427-94-0 ]
  • [ 116026-94-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
[2] Synthetic Communications, 2004, vol. 34, # 1, p. 109 - 118
  • 52
  • [ 2591-86-8 ]
  • [ 116026-98-3 ]
  • [ 116026-99-4 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere
Stage #2: at 0℃; for 1 h;
Step 2: fert-Butyl 2-formylpyridin-3-ylcarbamate (10b)To a solution of compound 10a (2.9 g, 10.7 mmol) in THF (30 mL) was added n-BuLi (2.5M, 8.5 mL, 21.4 mmol) at -78°C under N2 atmosphere and the resulting mixture was stirred for 1 h at this temperature. /V-Formylpiperidine (1.3 mL, 11.8 mmol) was added with rapid stirring. The mixture was stirred at 0°C for 1 h and then partitioned with 1.5M HCI solution. The pH was adjusted to 7 by the addition of solid Na2C03. The aqueous layer was extracted with EA twice and the combined organic layers were dried over Na2S04, concentrated under reduced pressure and purified by CC (PE/EA = 3/1) to give compound 10b (1.5 g, 65percent) as a white solid.
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5032 - 5043
[3] Patent: WO2013/64231, 2013, A1, . Location in patent: Page/Page column 51
  • 53
  • [ 2591-86-8 ]
  • [ 400-72-6 ]
  • [ 106312-36-1 ]
Reference: [1] Synthesis, 2009, # 12, p. 2040 - 2060
  • 54
  • [ 2591-86-8 ]
  • [ 454-90-0 ]
  • [ 106312-36-1 ]
  • [ 1017778-98-1 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 72 - 83
  • 55
  • [ 2591-86-8 ]
  • [ 1513-65-1 ]
  • [ 155601-65-3 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.333333 h;
Under N2, to a solution of 2,6-difluoropyridine (4.95 g, 43.0 mmol) in anhydrous THF (100 mL) cooled at- -78°C was added LDA (2.0 M in heptane/THF/ethylbenzene, 23.0 mL, 46.0 mmol). After the mixture was stirred at -780C for 30 min 1-formylpiperidine (4.98 g, 44.0 mmol) was added. The mixture was stirred at -78°C for 20 min, and at -78°C aqueous HCl (3 N, 60 mL) and Et2O (50 mL) were added. The ether layer was collected and the aqueous layer was extracted with Et2O (3 X 100 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (CH2Cl2/hexanes, 1:1 v/v) to afford 2,6-difluoro-pyridme-3- carbaldehyde as a pale yellow liquid (1.41 g, 60percent).
Reference: [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 61
  • 56
  • [ 2591-86-8 ]
  • [ 315204-36-5 ]
Reference: [1] Nucleosides, Nucleotides and Nucleic Acids, 2000, vol. 19, # 9, p. 1397 - 1411
  • 57
  • [ 2591-86-8 ]
  • [ 105942-08-3 ]
  • [ 101048-76-4 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -10℃; for 3 h; Inert atmosphere
Stage #2: at -10 - 20℃; for 1.5 h;
Synthesis of intermediate Vll-a: 2-Fluoro-4-formyl-benzonitrileA solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) in dry THF (50 mL) at - 10°C under argon was treated with a solution of isopropylmagnesium chloride (2M in THF, 15.0 mL, 30.0 mmol) dropwise before stirring at this temperature for 3 h. A solution of N-formylpiperidine (3.89 g, 35.0 mmol) in dry THF (15 mL) was added dropwise and the mixture allowed to warm to room temperature before stirring for 1.5h. The resultant solution was treated with 4M aq HC1 (250 mL each) and the organics extracted with EtOAc. The combined organics were dried (MgS04), filtered and evaporated before purification of the residue by column chromatography (Si02; eluting with 30percent to 50percent EtOAc in cyclohexane) to afford 2-fluoro-4-formyl-benzonitrile VH-a as a pale yellow solid (2.73 g, 73percent).1H NMR (300 MHz, CDC13) δ 10.07 (d, J = 1.7 Hz, 1H), 7.90 - 7.79 (m, 2H), 7.74 (dd, J= 8.5, 0.8 Hz, 1H).
53.1%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 0℃; for 2.33333 h; Inert atmosphere
Stage #2: at 0℃; for 2 h; Inert atmosphere
General procedure: To a solution of 4-halogen-2-chlorobenzonitrile (23.10mmol) in dry 35 THF under Argon at 0°C was added 36 isopropyl magnesium chloride (30.03mmol, 2M solution in ether) dropwise during 20min, and the reaction mixture was stirred for 2h, keeping the temperature around 0°C. Then 37 1-formyl piperidine (30.03mmol) was added dropwise at 0°C and stirred for additional 2h at 0°C. The reaction mixture was quenched with saturated 38 NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=3:1) to afford 39 compound 10a and 10b.
Reference: [1] Patent: WO2013/14170, 2013, A1, . Location in patent: Page/Page column 84
[2] Bioorganic Chemistry, 2019, vol. 82, p. 41 - 57
  • 58
  • [ 2591-86-8 ]
  • [ 123843-67-4 ]
  • [ 433939-88-9 ]
Reference: [1] Patent: WO2016/132134, 2016, A1, . Location in patent: Page/Page column 67
  • 59
  • [ 2591-86-8 ]
  • [ 452-08-4 ]
  • [ 426831-32-5 ]
  • [ 1441770-51-9 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 5955 - 5963
  • 60
  • [ 2591-86-8 ]
  • [ 360576-04-1 ]
Reference: [1] Patent: WO2005/105772, 2005, A1, . Location in patent: Page/Page column 56
  • 61
  • [ 2591-86-8 ]
  • [ 461-96-1 ]
  • [ 537013-51-7 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 0.5 h;
Stage #2: at -70 - 0℃;
55 ml (0.11 mmol) of 2 M lithium diisopropylamide are added with stirring at -70° C. to a solution of 19.3 g (0.1 mmol) of 1-bromo-3,5-difluorobenzene in 120 ml of dried tetrahydrofuran.After 30 minutes, N-formylpiperidine is added dropwise at this temperature.The mixture is allowed to warm to 0° C.
At about 0° C., the reaction mixture is poured into cold water, acidified using 10percent HCl and extracted twice with methyl tert-butyl ether.The combined organic phases are washed with water, dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure.The residue is filtered through SiO2 (heptane/dichloromethane 1:1), (yield: 17.6 g, 78percent).
Reference: [1] Patent: US2004/6235, 2004, A1, . Location in patent: Page 11
  • 62
  • [ 2591-86-8 ]
  • [ 102-54-5 ]
  • [ 1271-48-3 ]
Reference: [1] Inorganica Chimica Acta, 2009, vol. 362, # 6, p. 2068 - 2070
  • 63
  • [ 2591-86-8 ]
  • [ 766-11-0 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #2: at -78℃;
Intermediate 1; Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridine; a) 5-bromo-2-fluoro-3-pyridinecarbaldehyde; Following the procedure described in WO2006015124 and trituration of the crude product in hexanes instead of crystallization from cyclohexane afforded the title compound as an off-white solid (68percent). MS (ES)+ m/e 203.8, 205.7 [M+H]+.
52%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexanes at -78℃; for 1.75 h;
Stage #2: at -78℃; for 0.0166667 h;
A solution of lithium di-iso-propylamine (5 mL, 35 mmol) in anhydrous THF (40 mL) was cooled to -78° C. under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30 mmol) was added. The mixture was then stirred at -78° C. for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78° C. for 90 min. N-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspension at -78° C. and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10percent (w/v) aqueous solution of citric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude product from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52percent yield) as pale beige flaky crystals. 1H-NMR (500 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.70 (dd, 1H), 8.55 (dd, 1H). MS: m/z 236, 238 [MNa+], 204, 206 [MH+], 176, 178 [MH-CO+].
Reference: [1] Patent: US2008/293706, 2008, A1, . Location in patent: Page/Page column 27; 85
[2] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 73-74
  • 64
  • [ 2591-86-8 ]
  • [ 16063-69-7 ]
  • [ 1261269-66-2 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 73℃; for 1 h;
Stage #2: at -78℃; for 1 h;
Intermediate 1 A solution of 2,4,6-trichloropyridine (9.85 g, 53.8 mmol) in THF (100 ml) was added dropwise to a solution of n-butyllithium, 1.6M in hexane (33.6 ml, 53.8 mmol) in THF (40 ml) whilst maintaining the temperature below -73°C. After the addition was complete, the mixture was stirred at -78°C for 1 hour. A solution of 1-formylpiperidine (6.0 ml, 53.8 mmol) in THF (10 ml) was added dropwise and the mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with sat. NH4CI(aq) at -78°C and allowed to warm to rt. The mixture was extracted with ether and was washed successively with 1 HCI(aq), water, sat. NH4HC03(aq), water and brine. The organic phase was dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10:1 petrol-ethyl acetate to provide a yellow solid (5.18 g, 45percent). 1H NMR (400 MHz, DMSO-ay δ ppm 8.09 (s, 1 H), 10.27 (s, 1 H).
2.94 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 1 h;
To a solution of 2,4,6-trichloro-pyridine (5.00 g) in tetrahydrofuran (anhydrous, 50,00 mL) at -78 00 under a nitrogen atmosphere was added n-butyl lithium (2.5M in hexane) (10,96 ml) dropwise. The mixture was stirred at -78 00 for 1 h and then piperidine-1- carbaldehyde (3.04 mL) was added drop wise. The reaction was stirred at -78 00 for 1 h. The reaction mixture was quenched with sat NH4CI aq (50 ml). The mixture was extracted with TBME (3 x 40 mL) and the organic phase washed successively with 1 M HCI (75 mL) and sat. ammonium carbonate (75 mL). The organic phase were dried (Na2504) and concentrated and the residue purified by Biotage Isolera FCC (5i02: 50 g) eluting with 10-50percent TBME in cyclohexane to give 2.94 g of product as a yellow solid.Analysis: HPLC-MS: R1 = 1.27 mm (method P)1H NMR (DMSO, 250 MHz) 68.07 (1H, s), 10.28 (1H, s)
Reference: [1] Patent: WO2011/141756, 2011, A1, . Location in patent: Page/Page column 48-49
[2] Patent: WO2017/42100, 2017, A1, . Location in patent: Page/Page column 49
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