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Product Details of [ 4394-85-8 ]

CAS No. :4394-85-8 MDL No. :MFCD00006170
Formula : C5H9NO2 Boiling Point : -
Linear Structure Formula :(CH2CH2)2ONCHO InChI Key :LCEDQNDDFOCWGG-UHFFFAOYSA-N
M.W : 115.13 Pubchem ID :20417
Synonyms :

Calculated chemistry of [ 4394-85-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.52
TPSA : 29.54 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.33
Log Po/w (XLOGP3) : -0.64
Log Po/w (WLOGP) : -0.91
Log Po/w (MLOGP) : -0.38
Log Po/w (SILICOS-IT) : 0.58
Consensus Log Po/w : 0.0

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.08
Solubility : 94.8 mg/ml ; 0.823 mol/l
Class : Very soluble
Log S (Ali) : 0.49
Solubility : 358.0 mg/ml ; 3.11 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.04
Solubility : 127.0 mg/ml ; 1.1 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.27

Safety of [ 4394-85-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P261-P272-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P333+P313 UN#:N/A
Hazard Statements:H316-H320-H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4394-85-8 ]

* 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 [ 4394-85-8 ]
  • Downstream synthetic route of [ 4394-85-8 ]

[ 4394-85-8 ] Synthesis Path-Upstream   1~29

  • 1
  • [ 3034-53-5 ]
  • [ 4394-85-8 ]
  • [ 10200-59-6 ]
Reference: [1] Synthesis, 1987, # 11, p. 998 - 1001
[2] Journal of Materials Chemistry, 1998, vol. 8, # 4, p. 833 - 835
  • 2
  • [ 4394-85-8 ]
  • [ 116045-56-8 ]
  • [ 1003-32-3 ]
Reference: [1] Patent: US2009/170907, 2009, A1, . Location in patent: Page/Page column 59
  • 3
  • [ 3581-89-3 ]
  • [ 4394-85-8 ]
  • [ 13838-78-3 ]
YieldReaction ConditionsOperation in experiment
70.8%% With n-butyllithium In hexane (a)
To a solution of n-butyllithium (24 ml, 0.06 mol, 2.5M in hexane) in 50 ml of ether under argon at -78° C. was added dropwise a solution of 5-methylthiazole (5 g, 0.05 mol) in 25 ml of ether.
The mixture was stirred at -78° C. for 1 h, and then a solution of N-formyl-morpholine (5.5 ml 0.055 mol) in 30 ml of ether was added within 15 min.
The mixture was stirred for 1 h at -78° C., then at 0°--5° C. overnight.
The reaction mixture was then extracted with 4N HCl (4*10 ml), the aqueous layers were combined, cooled in an ice-bath, and neutralized with sodium bicarbonate solution (pH 9).
The aqueous layer was extracted with ether (4*20 ml), the organic layer was dried over magnesium sulfate and concentrated in vacuo.
The residue was dried in vacuo to afford 4.5 g (70.8percentpercent) of 5-methyl-2-thiazolylcarboxaldehyde.
Reference: [1] Patent: US5569655, 1996, A,
  • 4
  • [ 4394-85-8 ]
  • [ 136613-57-5 ]
  • [ 63136-60-7 ]
Reference: [1] Tetrahedron, 1998, vol. 54, # 47, p. 14327 - 14340
  • 5
  • [ 110-91-8 ]
  • [ 4394-85-8 ]
  • [ 38952-62-4 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 18, p. 5861 - 5865
  • 6
  • [ 15159-40-7 ]
  • [ 109-72-8 ]
  • [ 4394-85-8 ]
  • [ 22342-18-3 ]
  • [ 38952-62-4 ]
Reference: [1] Organic Letters, 2004, vol. 6, # 21, p. 3703 - 3706
  • 7
  • [ 15159-40-7 ]
  • [ 598-30-1 ]
  • [ 4394-85-8 ]
  • [ 38952-62-4 ]
  • [ 6342-79-6 ]
  • [ 212190-87-9 ]
Reference: [1] Organic Letters, 2004, vol. 6, # 21, p. 3703 - 3706
[2] Organic Letters, 2004, vol. 6, # 21, p. 3703 - 3706
  • 8
  • [ 4394-85-8 ]
  • [ 100-14-1 ]
  • [ 6425-46-3 ]
YieldReaction ConditionsOperation in experiment
98% With potassium hydroxide In water at 50℃; for 3 h; Green chemistry General procedure: KOH (2.4mmol), H2O (1.0mL), (pseudo)halides 1 (0.8mmol), and formamides 2 (1.6mmol) were successively added into a reaction tube. Then the reaction mixture was stirred under the conditions shown in Tables 1–5. After the reactions were completed, the mixture was extracted by ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography to give products 3.
97% With NHC-Pd(II)-Im; sodium hydroxide In water at 50℃; for 3 h; Inert atmosphere; Schlenk technique General procedure: Under a N2 atmosphere, NaOH (3.0 equiv), NHC-Pd(II)-Im complex 1 (1.0 molpercent), water (1.0 mL), benzyl chloride 2a (0.8 mmol), and N-formylmorpholine 3a (2.0 equiv) were successively added into a Schlenk reaction tube. The mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. Then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (eluent: PE/EA = 5:1) to give the pure products 4a. 4-(4-Nitro-benzyl)-morpholine (4l):16 Yellow solid, m.p. 76–78 °C; 1H NMR (500 MHz): δ 8.17 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 3.73 (t, J = 4.5 Hz, 4H), 3.62 (s, 2H), 2.48 (t, J = 4.5 Hz, 4H); 13C NMR (125 MHz): δ 147.0, 145.7, 129.4, 123.3, 66.7, 62.2, 53.4.
Reference: [1] Tetrahedron, 2014, vol. 70, # 4, p. 880 - 885
[2] Journal of Chemical Research, 2013, vol. 37, # 10, p. 611 - 614
  • 9
  • [ 626-55-1 ]
  • [ 4394-85-8 ]
  • [ 70201-43-3 ]
Reference: [1] Patent: US6340759, 2002, B1, . Location in patent: Example 251
  • 10
  • [ 4394-85-8 ]
  • [ 2674-34-2 ]
  • [ 7310-97-6 ]
Reference: [1] Journal of the American Chemical Society, 2003, vol. 125, # 37, p. 11241 - 11248
  • 11
  • [ 4394-85-8 ]
  • [ 78358-11-9 ]
  • [ 824-98-6 ]
YieldReaction ConditionsOperation in experiment
90% With potassium hydroxide In water at 100℃; for 3 h; Green chemistry General procedure: KOH (2.4mmol), H2O (1.0mL), (pseudo)halides 1 (0.8mmol), and formamides 2 (1.6mmol) were successively added into a reaction tube. Then the reaction mixture was stirred under the conditions shown in Tables 1–5. After the reactions were completed, the mixture was extracted by ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography to give products 3.
Reference: [1] Tetrahedron, 2014, vol. 70, # 4, p. 880 - 885
  • 12
  • [ 288-42-6 ]
  • [ 4394-85-8 ]
  • [ 65373-52-6 ]
Reference: [1] Patent: EP1731513, 2006, A1, . Location in patent: Page/Page column 18
[2] Patent: WO2007/37010, 2007, A1, . Location in patent: Page/Page column 32-34
  • 13
  • [ 4394-85-8 ]
  • [ 874-86-2 ]
  • [ 37812-51-4 ]
YieldReaction ConditionsOperation in experiment
98% With NHC-Pd(II)-Im; sodium hydroxide In water at 50℃; for 3 h; Inert atmosphere; Schlenk technique General procedure: Under a N2 atmosphere, NaOH (3.0 equiv), NHC-Pd(II)-Im complex 1 (1.0 molpercent), water (1.0 mL), benzyl chloride 2a (0.8 mmol), and N-formylmorpholine 3a (2.0 equiv) were successively added into a Schlenk reaction tube. The mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. Then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (eluent: PE/EA = 5:1) to give the pure products 4a. 4-Morpholin-4-ylmethyl-benzonitrile (4j):19 Yellow solid, m.p. 78–81 °C; 1H NMR (300 MHz): δ 7.51 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz,2H), 3.61 (t, J = 4.5 Hz, 4H), 3.46 (s, 2H), 2.35 (t, J = 4.5 Hz, 4H); 13C NMR (75 MHz): δ 143.6, 131.8, 129.2, 118.6, 110.6, 66.6, 62.4, 53.3.
92% With potassium hydroxide In water at 50℃; for 3 h; Green chemistry General procedure: KOH (2.4mmol), H2O (1.0mL), (pseudo)halides 1 (0.8mmol), and formamides 2 (1.6mmol) were successively added into a reaction tube. Then the reaction mixture was stirred under the conditions shown in Tables 1–5. After the reactions were completed, the mixture was extracted by ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography to give products 3.
Reference: [1] Journal of Chemical Research, 2013, vol. 37, # 10, p. 611 - 614
[2] Tetrahedron, 2014, vol. 70, # 4, p. 880 - 885
  • 14
  • [ 4394-85-8 ]
  • [ 515-40-2 ]
  • [ 6325-41-3 ]
Reference: [1] Patent: US6369110, 2002, B1, . Location in patent: Page column 65-66
  • 15
  • [ 4394-85-8 ]
  • [ 4111-55-1 ]
  • [ 74-88-4 ]
  • [ 7560-83-0 ]
Reference: [1] Journal of Organic Chemistry, 2000, vol. 65, # 6, p. 1629 - 1635
  • 16
  • [ 4394-85-8 ]
  • [ 452-08-4 ]
  • [ 19415-51-1 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 5955 - 5963
  • 17
  • [ 4394-85-8 ]
  • [ 4175-76-2 ]
  • [ 129880-84-8 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 2, p. 329 - 331
  • 18
  • [ 4394-85-8 ]
  • [ 86847-84-9 ]
  • [ 127446-34-8 ]
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 934 - 939
[2] Organic Process Research and Development, 2009, vol. 13, # 3, p. 555 - 566
  • 19
  • [ 4394-85-8 ]
  • [ 42362-16-3 ]
  • [ 134221-52-6 ]
Reference: [1] Organic Letters, 2006, vol. 8, # 17, p. 3737 - 3740
  • 20
  • [ 4394-85-8 ]
  • [ 89343-06-6 ]
  • [ 163271-80-5 ]
Reference: [1] European Journal of Organic Chemistry, 2001, # 23, p. 4401 - 4409
[2] Synlett, 2000, # 3, p. 315 - 318
[3] European Journal of Inorganic Chemistry, 2011, # 29, p. 4550 - 4557
  • 21
  • [ 4394-85-8 ]
  • [ 4175-77-3 ]
  • [ 167366-05-4 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With TurboGrignard In tetrahydrofuran at -78℃; for 0.25 h; Inert atmosphere
Stage #2: at -78 - 0℃; for 1.66667 h; Inert atmosphere
General procedure: The reaction was carried out in a sealed tube under N2 using THF (4 mL) as the solvent. To the solution of tert-butyl 2-bromothiazole-4-carboxylate 1a (0.397 mmol), iPrMgCl*LiCl (1.3 M, 0.52 mmol) was added dropwise at -78 °C. After 15 min the corresponding aldehyde (0.79-0.99 mmol) or N-formyl-morpholine (in the case of 2-formylthiazoles 3a-b) was added dropwise under stirring and the reaction mixture was stirred at -78 °C for 10 min, then 1.5 h at 0 °C. Saturated aqueous NH4Cl was added and the aqueous layer was extracted with Et2O (3 .x. 10 mL). The combined organic layers were washed with 5percent aqueous HCl (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mixture of EtOAc:P (petroleum ether) as eluent (see below) to give tert-butyl 2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2a-h.
Reference: [1] Tetrahedron Asymmetry, 2012, vol. 23, # 6-7, p. 474 - 481
  • 22
  • [ 4394-85-8 ]
  • [ 220996-80-5 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃;
Stage #2: at -78℃;
20.00 g (54.51 mmol) of 4-bromo-2-(trifluoromethoxy)iodobenzene are dissolved in 200 ml of THF and cooled to -78° C. Then 26.16 ml (65.41 mmol) of a 2.5 M solution of n-butyllithium in hexane are added dropwise.
The mixture is stirred for 30 min and then 14.43 g (125.37 mmol) of N-formylmorpholine are metered in.
After complete conversion is detected (TLC check), solvolysis is carried out at -78° C. with isopropanol.
Warming to room temperature is followed by addition of water and extraction twice with dichloromethane.
The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and the solvent is distilled out under reduced pressure.
The residue is purified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 5:1).
11.43 g (78percent of theory) of the title compound are obtained.
GC-MS (method 7): Rt=4.24 min; MS (EIpos): m/z=270 [M+H]+
1H-NMR (300 MHz, DMSO-d6): δ=7.85-7.92 (m, 3H), 10.20 (s, 1H).
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #3: With isopropyl alcohol In tetrahydrofuran; hexane at -78℃;
a): n-butyllithium, THF, -78° C., then N-formylmorpholine; b): zinc cyanide, tetrakis(triphenylphosphine)palladium(0), DMF, microwave 250° C./5 min; Example 8A
4-Bromo-2-(trifluoromethoxy)benzaldehyde
20.00 g (54.51 mmol) of 4-bromo-2-(trifluoromethoxy)iodobenzene are dissolved in 200 ml of THF and cooled to -78° C. Then 26.16 ml (65.41 mmol) of a 2.5 M solution of n-butyllithium in hexane are added dropwise.
The mixture is stirred for 30 min and then 14.43 g (125.37 mmol) of N-formylmorpholine are metered in.
After complete conversion is detected (TLC check), solvolysis is carried out at -78° C. with isopropanol.
Warming to room temperature is followed by addition of water and extraction twice with dichloromethane.
The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and the solvent is distilled out under reduced pressure.
The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 5:1).
11.43 g (78percent of theory) of the title compound are obtained.
GC-MS (method 7): Rt=4.24 min; MS (EIpos): m/z=270 [M+H]+
1H-NMR (300 MHz, DMSO-d6): δ=7.85-7.92 (m, 3H), 10.20 (s, 1H).
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
4-bromo-2-(trifluoromethoxy)iodobenzene 20.00 g (54.51 mmol) of dissolving the THF 200 ml, the cooled to -78 ° C. Furthermore, 2.5 M 26.16 ml (65.41 mmol) solution of n-butyl lithium in hexane for blended section. 30 minutes obtain a lead line having a mixture, N-formylmorpholine 14.43 g (125.37 mmol) added metering. After confirming the receivable channel been fully converting (TLC can be) in the, -78 ° C it does per minute, performed for all the available using epoxypropanol. Followed by heating at room temperature, water are added, dichloro methane at extracted times 2. Access level 1 plus unencoded sections and washing sodium chloride solution saturation of at organic, and dried by sodium sulfate, solvent the distillation under reduced pressure. Residue column chromatography (silica gel, bed: cyclohexane/ethyl acetate 5:1) was purified by. Title compound (78percent of its theoretical) of 11.43 g are obtained.
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h;
Stage #2: at -78 - 20℃; for 1.58333 h;
Step F:
Synthesis of 4-bromo-2-trifluoromethoxy-benzaldehyde.
A solution of 4-bromo-1-iodo-2-trifluoromethoxy-benzene (1.00 g, 2.72 mmol) in THF (15 mL) was cooled to -78 °C and 2.66 M BuLi in hexane (2.05 mL, 5.44 mmol) was added dropwise.
The reaction mixture was stirred at -78 °C for 1.5 h and N-formylmorpholine (0.57 mL, 5.63 mmol) was added.
The reaction mixture was stirred at -78 °C for 15 min and at ambient temperature for 80 min.
The reaction was quenched with 0.25 M aqueous citric acid (10 mL) and the resulting mixture was extracted with EtOAc (three times).
The combined organic layer was dried over MgSO4, filtrated, concentrated, and purified by flash chromatography (silica gel, 2percent to 5percent EtOAc in hexane) to give 4-bromo-2-trifluoromethoxy-benzaldehyde (560 mg, 77percent) as a pale brown solid.
CI MS m/e 269, M + H+; 1H NMR (300 MHz, CDCl3) δ 7.50-7.67 (m, 2 H), 7.85 (d, J = 8.1 Hz, 1 H), 10.33 (s, 1 H).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 9, p. 1311 - 1316
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 20, p. 5864 - 5868
[3] Patent: US2010/35902, 2010, A1, . Location in patent: Page/Page column 10; 17-18
[4] Patent: US2010/305052, 2010, A1, . Location in patent: Page/Page column 8; 16
[5] Patent: KR101614164, 2016, B1, . Location in patent: Paragraph 0303-0306
[6] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 10, p. 3307 - 3319
[7] Patent: EP1464335, 2004, A2, . Location in patent: Page/Page column 164
[8] Patent: US2010/136142, 2010, A1,
  • 23
  • [ 4394-85-8 ]
  • [ 77-92-9 ]
  • [ 220996-80-5 ]
Reference: [1] Patent: US5968938, 1999, A,
[2] Patent: US6090805, 2000, A,
  • 24
  • [ 4394-85-8 ]
  • [ 109-72-8 ]
  • [ 1435-44-5 ]
  • [ 190011-87-1 ]
Reference: [1] Patent: US5883102, 1999, A,
  • 25
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  • [ 452-08-4 ]
  • [ 426831-32-5 ]
  • [ 1441770-44-0 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 5955 - 5963
  • 26
  • [ 4394-85-8 ]
  • [ 36082-50-5 ]
  • [ 871254-61-4 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With TurboGrignard In tetrahydrofuran at 78℃; for 1 h;
Stage #2: at -78 - -35℃; for 1.5 h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran at -35℃;
Preparation No.1: 2,4-Dichloropyrimidine-5-carbaldehyde; A solution of isopropyl magnesium chloride lithium chloride complex in THF (2M, 184 mL, 368 mmol) was added drop-wise over about 30 min to a 2 L round-bottomed flask charged with a solution of 5-bromo-2,4-dichloropyrimidine (49.6 g, 218 mmol) in THF (1000 mL) at about -78 °C. The reaction was allowed to stir at about -78 °C for about 30 min. Morpholine-4- carbaldehyde (75.0 g, 653 mmol) was then added drop-wise at about -78 °C over about 30 min. The reaction was allowed to stir for about 30 min at about -78 °C then allowed to warm to about - 35 °C and stirred for about 30 min. Aqueous HCl (IN, 250 mL) and Et20 (500 mL) were added and the reaction mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was further extracted with Et20 (200 mL). The combined organic layers were dried over anhydrous MgS04, filtered through a silica gel pad on a fritted funnel, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM (100percent) as the eluent to provide 2,4-dichloropyrimidine-5- carbaldehyde (27.3 g, 71percent ) as a light yellow solid. .H NMR (400 MHz, CDC13 ) δ 10.34 (s, 1H), 9.30 (s, 1H).
Reference: [1] Patent: WO2011/156698, 2011, A2, . Location in patent: Page/Page column 52
  • 27
  • [ 4394-85-8 ]
  • [ 175278-30-5 ]
  • [ 1114808-89-7 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #2: for 1 h;
Method 1 : To a solution of 4-bromo-2-ethyliodobenzene (1 .61 mmol, 0.5 g) dissolved in anhydride THF (6 mL) at -785C was added 2.5 M n-butyllithium solution in hexane (1 .9 mmol, 0.77 mL) dropwise. The mixture was stirred 30 min at -78 5C before /V-formylmorpholine (3.69 mmol, 0.37 mL) was added and the reaction stirred at this temperature for 1 h. The reaction was quenched with aqueous 1 N HCI and extracted with EtAcO. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the crude material by flash chromatography on silica gel using an elution of 3percent ethylacetate in hexanes afforded the title compound (21 1 mg, 62percent). 1 H (400 MHz, CDCI3) δ 10.24 (1 H, s), 7.69 (1 H, d, J = 8.4 Hz), 7.51 (1 H, dd, J = 8.4 & 2 Hz), 7.48 (1 H, d, J = 2 Hz), 3.05 (2H, q, J = 7.6 Hz), 1 .28 (3H, t, J = 7.6 Hz). LC-MS: tR = 3.67 [M+H]+= 213/215 (method 3)
62%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane; benzene at -78℃; Inert atmosphere
Stage #2: at -78℃; for 1 h; Inert atmosphere
full text is not avalable from article
Reference: [1] Patent: WO2013/149997, 2013, A1, . Location in patent: Page/Page column 51
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 7, p. 854 - 881
  • 28
  • [ 4394-85-8 ]
  • [ 3430-18-0 ]
  • [ 885167-81-7 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 3 h;
Stage #2: at 17 - 25℃; for 1 h;
Method 4; Preparation of 6-bromo-5-methylnicotinaldehyde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0° C. The solution was stirred for 2 hours at 0° C. and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10percent ethyl acetate in isohexane, to give the title compound (3.0 g, 74percent); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, 1H), 8.73 (s, 1H), 10.09 (s, 1H).
74%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 3 h;
Stage #2: at 20℃; for 1 h;
Method 3; Preparation of 6-bromo-5-methvmicotmaldehvde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 0C. The solution was stirred for 2 hours at 0 0C and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10 percent ethyl acetate in isohexane, to give the title compound (3.0 g, 74 percent); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, IH), 8.73 (s, IH), 10.09 (s, IH).
Reference: [1] Patent: US2008/119451, 2008, A1, . Location in patent: Page/Page column 35
[2] Patent: WO2007/71956, 2007, A1, . Location in patent: Page/Page column description
[3] Patent: US2012/184520, 2012, A1, . Location in patent: Page/Page column 24
  • 29
  • [ 4394-85-8 ]
  • [ 19745-07-4 ]
  • [ 1357172-39-4 ]
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 7, p. 852 - 853
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