* 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.
With Dess-Martin periodane In dichloromethane at 0 - 23℃; for 12 h;
(B) To a stirred solution of (6-methoxypyridin-3-yl)methanol (9.3 g, 66.906 mmol, 1.0 eq) in DCM (300ml), DMP (42.55 g, 100.35 mmol, 1.5 eq) was added at 0°C. The mixture was allowed to warm to RT andstir for 12 h. Reaction progress was monitored by TLC. The RM was quenched with ice water (150 ml) and extracted with DCM (2x 200 ml). The organic layer was washed with brine solution (100 ml), dried (Na2SO4), filtered and concentrated to afford the crude product, which was purified by CC (silica gel, 25percent EtOAc in PE) to afford 6-methoxynicotinaldehyde (6 g, 61percent).
With sodium bis(2-methoxyethoxy)aluminium dihydride In tert-butyl methyl ether; toluene at 0℃; for 1.63333 h;
Preparation Example 1 Synthesis of (6-methoxypyridin-3-yl)methanol (2) To a solution of methyl-6-methoxynicotinate (1) (650 g, 3.89 mol) in t-butyl methyl ether (hereinafter abbreviated as "MTBE") (6.5 L) cooled in an ice bath was added sodium bis(2-methoxyethoxy)aluminum hydride (65percent solution in toluene, 1.45 kg, 4.67 mol) under a nitrogen atmosphere over a period of 1.3 hours. After stirring for 20 minutes, a 3.5 N aqueous solution of sodium hydroxide (2.6 L) was added to the reaction mixture while keeping the temperature 15° C. or below. The reaction mixture was stirred at 32° C. for 45 minutes and then the organic layer was separated and the aqueous layer was re-extracted with MTBE (2.3 L). The organic layers were combined and concentrated under reduced pressure to dryness, and then toluene (1.3 L) was added to the residue and azeotropic distillation was carried out. Azeotropic distillation with toluene (1.3 L) was repeated three times to give 597 g of the title compound as a pale yellow oil (yield 100percent). 1H-NMR (CDCl3) δ (ppm): 8.11 (1H, d, J=2.4 Hz), 7.62 (1H, dd, J=2.4 Hz, 8.8 Hz), 6.75 (1H, d, J=8.8 Hz), 4.62 (2H, s), 3.93 (3H, s)
94%
at 0 - 25℃; for 72 h;
Sodium borohydride (1 1.30 g, 299 mmol) was added to a solution of the methyl 6- methoxynicotinate (5.00 g, 29.9 mmol) in ethanol (100 ml.) at 0°C. The reaction was allowed to warm to room temperature and stirred for 3 days. The reaction was cooled to 0°C and quenched by slow addition of 1 N HCI until pH 4.0. The reaction mixture was concentrated to remove ethanol. The remaining aqueous solution was washed with ethyl acetate (2x), then neutralized with saturated aqueous sodium bicarbonate, then extracted with ethyl acetate (3X). The organic layers were combined, washed with brine, dried (Na2S04), filtered and concentrated. The crude material was purified by silica chromatography (hexanes / ethyl acetate 1 :1 , 3:7) to give a clear oil. Mass/Yield - 3.9 g / 94percent TLC (hexanes/ethyl acetate = 1 :1 ) Rf = 0.22, UV active. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 4.61 (s, 2 H) 6.68 - 6.77 (m, 1 H) 7.49 - 7.68 (m, 1 H) 8.09 (s, 1 H).
89%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With sodium hydroxide In tetrahydrofuran; water
2 To a stirred suspension of LiAlH4 (11.4 g, 300 mmol) in THF (300 mL) at 0 °C was slowly added a solution of methyl 6-methoxynicotinate (50.0 g, 299 mmol). After stirring for 1 h at 0 °C, 10percent NaOH aq. (25.0 mL) and Na2SO4 were added. The resulting precipitate was removed by filtration through a pad of Celite.(R). and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (41.1 g, 268 mmol, 89percent). 1H NMR (CDCl3, 400 MHz): δ 1.75 (1H, brs), 3.94 (3H, s), 4.62 (2H, s), 6.75 (1H, d, J = 8.0 Hz), 7.62 (1H, dd, J = 8.0, 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz).
86%
With methanol; sodium tetrahydroborate In tetrahydrofuran at 23℃; for 12 h;
(A) To a stirred solution of methyl 6-methoxynicotinate (14 g, 83.83 mmol, 1.0 eq) in THE (300 ml), NaBH4 (47.7 g, 1.257 mol, 15 eq) was added at RT, followed by MeOH (300 ml). The RM was stirred atRT for 12 h. Reaction progress was monitored by TLC. The RM was quenched with sat. NH4CI (100 ml), diluted with water (100 ml) and extracted with EtOAc (3 x 200 ml). The organic layer was washed with brine solution (100 ml), dried (Na2504), filtered and concentrated to afford the crude product, which upon CC (silica gel, 40percent EtOAc in PE afforded (6-methoxypyridin-3-yl)methanol (10 g, 86percent).
83%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere
Under nitrogen, a suspension of lithium aluminium hydride solution in THF (1M, 6.58mL, 6.58mmol) in THF (3.39mL) was stirred at 0°C for 5min. Methyl 6-methoxynicotinate 2b (1.0g, 5.98mmol) was added portionwise and the mixture was stirred for 10m. The suspension was allowed to warm to room temperature and stirred for 2h before the solution was cooled to 0°C. The suspension was carefully quenched with water (0.04mL), 15percent NaOH (0.04mL) followed by water (0.12mL). The resulting precipitate was filtered with Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give product 2c (0.690g, 4.96mmol, 83percent yield) as a yellow oil; (found (ESI): M++H, 140.0711. C7H10NO2 requires M, 140.0706); νmax 3298, 2945, 1608, 1573, 1492cm−1; δH (400MHz, DMSO) 8.07 (1H, s, H3), 7.64 (1H, d, J 8.5, H2), 6.77 (1H, d, J 8.5, H1), 5.11 (1H, t, J 5.6, OH), 4.43 (2H, d, J 5.6, H4), 3.83 (3H, s, CH3); δC (101MHz, DMSO) 162.7, 144.00, 138.3, 130.6, 109.9, 60.2, 52.9; m/z (ESI) 139.8 (M++1).
72%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.66667 h; Stage #2: at 20℃; for 0.333333 h;
Step 1: (6-Methoxy-pyridin-3-yl)-methanol A solution of methyl 6-methoxynicotinate (3.00 g, 17.9 mmol) in tetrahydrofuran (10 mL) was added via an addition funnel over a period of 10 min to a cooled (0° C.) mixture of lithium aluminum hydride (817 mg, 21.5 mmol) in tetrahydrofuran (18 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction mixture was poured into a solution of potassium sodium tartrate (10percent w/v; 100 mL) and the resulting mixture was stirred at room temperature for 20 min. The mixture was filtered through a pad of Celite, washing with ethyl acetate. The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate (2*100 mL). The combined organic layers were dried (magnesium sulfate), filtered and eluted through a silica plug using 40percent ethyl acetate/hexanes to give (6-methoxy-pyridin-3-yl)-methanol (1.8 g, 72percent) as a clear oil.
51%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2 h; Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0 - 20℃; for 0.5 h;
EXAMPLE B (6-Methoxy-pyridin-3-yl)-methanol To lithium aluminium hydride (0.68 g, 18 mmol) suspended in dry THF (10 ml) was added dropwise a solution of methyl 6-methoxynicotinate (1 g, 6 mmol) in dry THF (5 ml). The reaction mixture was stirred for 2 h at r.t. then cooled (ice-bath) and quenched with water (2 ml) followed by the further addition of 1 N NaOH (6 ml) and water (2 ml). The cold-bath was removed and the mixture stirred for 30 min at r.t., filtered and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3*). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:1): colorless oil 0.45 g (51percent); 1H NMR (CDCl3) δ 1.69 (t, 1H), 3.94 (s, 3H), 4.62 (d, 2H), 6.75 (d, 1H), 7.62 (dd, 1H), 8.13 (d, 1H); MS: m/e=139.0(M+)
51%
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2 h;
EXAMPLE B (6-Methoxy-pyridin-3-yl)-methanol To lithium aluminium hydride (0.68 g, 18 mmol) suspended in dry THF (10 ml) was added dropwise a solution of methyl 6-methoxynicotinate (1 g, 6 mmol) in dry THF (5 ml). The reaction mixture was stirred for 2 h at r.t. then cooled (ice-bath) and quenched with water (2 ml) followed by the further addition of 1N NaOH (6 ml) and water (2 ml). The cold-bath was removed and the mixture stirred for 30 min at r.t., filtered and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3*). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:1): colorless oil 0.45 g (51percent); 1H NMR (CDCl3) δ 1.69 (t, 1H), 3.94 (s, 3H), 4.62 (d, 2H), 6.75 (d, 1H), 7.62 (dd, 1H), 8.13 (d, 1H); MS: m/e=139.0 (M+)
35%
With sodium tetrahydroborate In 1,4-dioxane at 0 - 100℃;
A solution of methyl 2-methoxypyridine-5-carboxylate (8.4 g, 50 mmol) in dixoane (70 mL) was treated with sodium borohydride (8.1 g, 244 mmol) at 0 °C. The reaction mixture was warmed to 100 °C and heating continued overnight. After this time, the mixture was cooled, diluted with methanol, filtered through a fritted funnel with methanol washes, and the filtrate was concentrated. The residue was redissolved in water, 0.5 M sodium hydroxide was added dropwise, and the mixture extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (2.9 g, 35percent) as a colorless oil. MW = 139.15. ]H NMR (CD3OD, 300 MHz) δ 8.11-8.05 (m, 1H), 7.67 (dd, Jl = 10.9 Hz, J2 = 2.43 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 4.89 (s, 1H), 4.54 (s, 2H), 3.89 (s, 3H); APCI MS m/z 140 [M + H]+.
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Stage #2: With water; ethyl acetate In toluene
EXAMPLE 25 : 1-(3,4-Difluorobenzyl)-5-(phenoxymethyl)pyridin-2(1H)-one (Final Compound 16-03) ;Step 1 : (6-Methoxypyridin-3-yl)methanol According to Scheme 16 Method A: A solution of 6-methoxynicotinaldehyde (leq, 2.19mmol, 0.30g) and LiAlH4 (0.5eq, 1.05mmol, 0.04g) in THF (10mL) was stirred for 30 min. at 0°C and overnight at room temperature. After the addition of AcOEt, the reaction mixture was diluted with water. The organic layer was washed with saturated NH4Cl solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25g SiO2) using CH2Cl2/AcOEt 80/20 to afford (6-methoxypyridin-3-yl)methanol (1.80mmol, 0.26g, 90percent) as a pale oil. LC (XTerra RP18, 3.5μm, 3.0x50mm Column): RT = 1.86min; MS m/z (CI) [MH]+= 140.
Reference：
[1] Patent: WO2006/30032, 2006, A1, . Location in patent: Page/Page column 104-105
[2] Patent: US4990622, 1991, A,
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
4
[ 50-00-0 ]
[ 163105-89-3 ]
[ 58584-63-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
With bis(η3-allyl-μ-chloropalladium(II)); 1-(2-bromophenyl)-3-(2,6-diisopropylphenyl)-4,5-dihydroimidazolinium chloride In tetrahydrofuran; water at 100℃; for 2 h; Inert atmosphere; Sealed tube
General procedure: [PdCl(η3-allyl)]2 (0.00125-0.005 mmol), imidazolinium salt 1a (0.0025-0.01 mmol), arylboronic acid (0.50 mmol) and an inorganic base (2.0 mmol) were charged in a 10 mL test tube sealed with a rubber septum. The test tube was evacuated and backfilled with argon. This sequence was repeated five times. Then solvent (0.5 mL) and 37 wt percent formaldehyde in H2O (102 mg, formaldehyde 1.25 mmol) were added via the rubber septum with syringe. In anargon flow, the rubber septum was replaced with a Teflon liners crew cap. The test tube was placed in an oil bath preheated at 100 C. The reaction mixture was stirred for 2 h and was cooled to room temperature. Then, operation of (i) or (ii) was performed. (i)The obtained crude was purified by passing it through a silica gel column with a hexane/ethyl acetate eluent (Table 4 entry 2 and Table 5 entries 8-16). (ii) Diphenylmethane (84.1 mg, 0.50 mmol) as an internal standard was added and then an aliquot of the organic layer of the reaction mixture was subjected to the quantitative analysis by 1H NMR (Table 4).
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
[2] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220
6
[ 144-55-8 ]
[ 3099-50-1 ]
[ 7440-05-3 ]
[ 58584-63-7 ]
Reference：
[1] Patent: US4990622, 1991, A,
7
[ 5006-66-6 ]
[ 58584-63-7 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
8
[ 5326-23-8 ]
[ 58584-63-7 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 613 - 615
9
[ 58584-63-7 ]
[ 761-65-9 ]
[ 70258-18-3 ]
Reference：
[1] Patent: US4990622, 1991, A,
10
[ 58584-63-7 ]
[ 101990-70-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 1 h; Inert atmosphere
j0259j To a stirred solution of (6-methoxypyridin-3-yl)methanol (75 mg, 0.54 mmol) in dichloromethane (2 mL) under nitrogen was added triethylamine (0.083 mL, 0.59 mmol) followed by methanesulfonyl chloride (0.044 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichioromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 88 mg (quantitative yield) as a yellow oil.Tr(METCR1278) = 1.63 mm, (ESj (M-J-H) 1581160.
96%
With thionyl chloride In toluene at 20℃; for 1 h; Inert atmosphere
Under nitrogen, thionyl chloride (2.05mL, 3.34g, 28.09mmol) was added to a solution of (6-methoxy-pyridin-3-yl)methanol 2c (3.56g, 25.60mmol) in dry toluene (10.6mL) and the solution was stirred at room temperature for 1h before NaOH (2M, 10mL) was added. The solution was stirred for 10min before extraction with toluene (2×20mL). The organic extracts were washed water and concentrated under reduced pressure to give the product 24 (3.85g, 24.52mmol, 96percent yield) as a yellow oil; δH (400MHz, CDCl3) 8.15 (1H, d, J 2.7, H3), 7.62 (1H, dd, J 8.5, 2.7, H2), 6.75 (1H, d, J 8.5, H1), 4.55 (2H, s, H4), 3.94 (3H, s, CH3); δC (101MHz, CDCl3) 163.6, 146.7, 139.2, 126.1, 111.3, 53.6, 43.3.
91.4%
With thionyl chloride In N,N-dimethyl-formamide at 0℃; for 2.3 h;
Preparation Example 2 Synthesis of 5-chloromethyl-2-methoxypyridine (3) To a solution of (6-methoxypyridin-3-yl)methanol (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23° C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4percent). 1H-NMR (CDCl3) δ (ppm): 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s)
88%
Stage #1: With thionyl chloride In dichloromethane at 20℃; Stage #2: With water; sodium hydrogencarbonate In dichloromethane
Step 2: 5-Chloromethyl-2-methoxy-pyridine Thionyl chloride (9.2 mL, 126 mmol) was added dropwise to a solution of (6-methoxy-pyridin-3-yl)-methanol (1.00 g, 7.2 mmol) in dichloromethane (38 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (this resulted in bubbling). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, and evaporated to give 5-chloromethyl-2-methoxy-pyridine (995 mg, 88percent) as a clear oil.
88%
Stage #1: With thionyl chloride In dichloromethane at 0 - 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Step B: Preparation of 5-(Chloromethyl)-2-methoxypyridine. Thionyl chloride (0.23 ml, 3.23 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.10 g, 8.41 mmol) in DCM at 0° C. and the reaction mixture was stirred for 2 h at room temperature. After completion of reaction, the volatiles were evaporated and the reaction mixture was basified with saturated sodium bicarbonate solution. The compound was extracted with DCM (2.x.30 ml) and washed with brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to afford 1.1 g (88percent) of 5-(chloromethyl)-2-methoxypyridine as a colorless liquid. This compound was directly taken to the next step.
0.58 g
With thionyl chloride In dichloromethane at 0 - 30℃; for 2 h; Inert atmosphere
To a solution of 2-methoxy-5-hydroxymethylpyridine (0.71 g, 0.005mole) in DCM (5 mL) at 0 °C under N2, was added thionyl chloride (0.7 mL, 0.009 mole) drop wise. The reaction mixture was warmed to RT and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and treated with saturated aqueous sodium bicarbonate (10 mL). Organic layer was washed with water (20 mL), brine solution (20 mL), dried over Na2SC>4 and concentrated under vacuum to obtain the title compound. Yield: 0.58 g; lH - NMR (CDC13, 400 MHz) δ ppm: 3.94 (s, 3H), 4.55 (s, 2H), 6.75 - 6.77 (d, J = 8.5 Hz, 1H), 7.61 - 7.64 (dd, J = 2.2, 8.5 Hz, 1H), 8.14 (s, 1H); Mass (m/z): 158.0 - 160.0 (M+H) +.
With phosphorus tribromide In chloroform at 0 - 20℃; for 1 h;
(6-Methoxypyridin-3-yl)methanol (250 mg, 1.797 mmol, commercially available from, forexample, Fluorochem) was dissolved in chloroform (20 mL) in a 50 mL round-bottomed flask, opento the atmosphere and phosphorus tribromide (0.188 mL, 1.989 mmol) was added slowly at 0 °C. The reaction mixture was stirred at rt for 1 h. The aqueous layer was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (30 mL), passed through a hydrophobic frit and evaporated under vacuum. The resulting oil was loaded in DCM and purified byBiotage Isolera SNAP 25 g silica chromatography using a gradient of O-4Opercent cyclohexane/ethyl acetate. The product containing fractions were combined to give the title compound (160 mg, 0.792 mmol, 44.lpercent yield) as a colourless oil.LCMS (2 mm Formic):Rt = 0.93 mi [MH] = 202.
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 613 - 615
[2] Patent: WO2017/37116, 2017, A1, . Location in patent: Page/Page column 76
With Dess-Martin periodane; In dichloromethane; at 0 - 23℃; for 12h;
(B) To a stirred solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (9.3 g, 66.906 mmol, 1.0 eq) in DCM (300ml), DMP (42.55 g, 100.35 mmol, 1.5 eq) was added at 0C. The mixture was allowed to warm to RT andstir for 12 h. Reaction progress was monitored by TLC. The RM was quenched with ice water (150 ml) and extracted with DCM (2x 200 ml). The organic layer was washed with brine solution (100 ml), dried (Na2SO4), filtered and concentrated to afford the crude product, which was purified by CC (silica gel, 25% EtOAc in PE) to afford 6-methoxynicotinaldehyde (6 g, 61%).
With manganese(IV) oxide; In dichloromethane; at 20℃; for 88h;
1) 6-Methoxy-3-pyridinecarboxaldehyde Methyl 6-methoxynicotinate (3.1 g) in tetrahydrofuran (20 mL) was added to a suspension of lithium aluminum hydride (1.4 g) in tetrahydrofuran (30 mL) under cooling on ice, and the mixture was stirred for 1.5 hours. Water, 15% aqueous sodium hydroxide, and water were sequentially added to the reaction mixture, and the resultant mixture was stirred for 1 hour at room temperature, followed by filtration. Ethyl acetate was added to the filtrate for partitioning the mixture, and the organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, to thereby give <strong>[58584-63-7]5-hydroxymethyl-2-methoxypyridine</strong>. The product was dissolved in methylene chloride (100 mL), and manganese dioxide (8 g) was added to the solution in a nitrogen atmosphere at room temperature, followed by stirring for 88 hours. The reaction mixture was filtrated through Celite, and the solvent of the filtrate was removed under reduced pressure. The residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give an aldehyde compound as a solid product (2.4 g, 94%). 1H-NMR(400MHz, CDCl3) delta:4.04(3H, s), 6.85 (1H, dd, J=8.5, 1.8Hz), 8.08 (1H, dd, J=8.5, 2.2Hz), 8.64 (1H, d, J=3.0Hz), 9.96(1H, s).
(6-methoxypyridin-3-yl)methyl methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With triethylamine; In dichloromethane; at 20℃;
A solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (2.9 g, 20.93 mmol) and triethylamine (4.35 mL) in dichloromethane (20 mL) was treated with methanesulfonyl chloride (2.9 g, 25.1 mmol) dropwise and the reaction mixture stirred at rt overnight. After this time, the reaction was diluted with water and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (1.4 g, 49%) as a yellow oil. MW = 217.24. ]H NMR (CDC13, 300 MHz) delta 8.16-8.14 (m, 1H), 7.68-7.59 (m, 1H), 6.76 (d, / = 8.6 Hz, 1H), 4.55 (s, 2H), 3.94 (s, 3H), 3.19 (s, 3H).
With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 2h;
To a stirred solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (0.60 g, 4.316 mmol, 1.0 eq) in DCM (20 mL), was added PBr3 (0.50 mL, 5.179 mmol, 1.2 eq) was added at 0 C. and the reaction was then stirred at RT for 2 h. After completion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction was quenched with sat. NaHCO3 solution (50 mL), extracted with DCM (3×50 mL), dried over Na2SO4 and concentrated to get 5-(bromomethyl)-2-methoxypyridine (0.55 g, 63%).
44.1%
With phosphorus tribromide; In chloroform; at 0 - 20℃; for 1h;
(6-Methoxypyridin-3-yl)methanol (250 mg, 1.797 mmol, commercially available from, forexample, Fluorochem) was dissolved in chloroform (20 mL) in a 50 mL round-bottomed flask, opento the atmosphere and phosphorus tribromide (0.188 mL, 1.989 mmol) was added slowly at 0 C. The reaction mixture was stirred at rt for 1 h. The aqueous layer was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (30 mL), passed through a hydrophobic frit and evaporated under vacuum. The resulting oil was loaded in DCM and purified byBiotage Isolera SNAP 25 g silica chromatography using a gradient of O-4O% cyclohexane/ethyl acetate. The product containing fractions were combined to give the title compound (160 mg, 0.792 mmol, 44.l% yield) as a colourless oil.LCMS (2 mm Formic):Rt = 0.93 mi [MH] = 202.
4-chloro-N-[(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-N-(6-methoxy-pyridin-3-ylmethyl)-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 1h;
a) 4-Chloro-N-[(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-N-(6-methoxy-pyridin-3-ylmethyl)-benzenesulfonamide 4-Chloro-N-[(R)-2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-benzenesulfonamide (0.04 g, 0.07 mmol), <strong>[58584-63-7](6-methoxy-pyridin-3-yl)-methanol</strong> (0.014 g, 0.10 mmol), triphenyl phosphine (0.04 g, 0.13 mmol) were dissolved in dry THF (3 ml) at 0-5 C. (ice-water bath) under an argon atmosphere followed by the dropwise addition of diisopropyl azodicarboxylate (28 mg, 0.13 mmol) in dry THF (0.5 ml). The reaction mixture was further stirred for 1 h at r.t. and then concentrated under reduced pressure. The crude yellow oil was purified over silica gel (ethyl acetate/n-heptane 1:2): colorless gum 23 mg (52%); MS: m/e=610.3 (MH+).
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere;
j0259j To a stirred solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (75 mg, 0.54 mmol) in dichloromethane (2 mL) under nitrogen was added triethylamine (0.083 mL, 0.59 mmol) followed by methanesulfonyl chloride (0.044 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichioromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 88 mg (quantitative yield) as a yellow oil.Tr(METCR1278) = 1.63 mm, (ESj (M-J-H) 1581160.
96%
With thionyl chloride; In toluene; at 20℃; for 1h;Inert atmosphere;
Under nitrogen, thionyl chloride (2.05mL, 3.34g, 28.09mmol) was added to a solution of (6-methoxy-pyridin-3-yl)methanol 2c (3.56g, 25.60mmol) in dry toluene (10.6mL) and the solution was stirred at room temperature for 1h before NaOH (2M, 10mL) was added. The solution was stirred for 10min before extraction with toluene (2×20mL). The organic extracts were washed water and concentrated under reduced pressure to give the product 24 (3.85g, 24.52mmol, 96% yield) as a yellow oil; deltaH (400MHz, CDCl3) 8.15 (1H, d, J 2.7, H3), 7.62 (1H, dd, J 8.5, 2.7, H2), 6.75 (1H, d, J 8.5, H1), 4.55 (2H, s, H4), 3.94 (3H, s, CH3); deltaC (101MHz, CDCl3) 163.6, 146.7, 139.2, 126.1, 111.3, 53.6, 43.3.
91.4%
With thionyl chloride; In N,N-dimethyl-formamide; at 0℃; for 2.3h;
Preparation Example 2 Synthesis of 5-chloromethyl-2-methoxypyridine (3) To a solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23 C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%). 1H-NMR (CDCl3) delta (ppm): 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s)
88%
Step 2: 5-Chloromethyl-2-methoxy-pyridine Thionyl chloride (9.2 mL, 126 mmol) was added dropwise to a solution of <strong>[58584-63-7](6-methoxy-pyridin-3-yl)-methanol</strong> (1.00 g, 7.2 mmol) in dichloromethane (38 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (this resulted in bubbling). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, and evaporated to give 5-chloromethyl-2-methoxy-pyridine (995 mg, 88%) as a clear oil.
88%
Step B: Preparation of 5-(Chloromethyl)-2-methoxypyridine. Thionyl chloride (0.23 ml, 3.23 mmol) was added to a solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (1.10 g, 8.41 mmol) in DCM at 0 C. and the reaction mixture was stirred for 2 h at room temperature. After completion of reaction, the volatiles were evaporated and the reaction mixture was basified with saturated sodium bicarbonate solution. The compound was extracted with DCM (2×30 ml) and washed with brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to afford 1.1 g (88%) of 5-(chloromethyl)-2-methoxypyridine as a colorless liquid. This compound was directly taken to the next step.
With thionyl chloride;N,N-dimethyl-formamide; for 2.3h;Inert atmosphere; Cooling with ice;
Preparation Example 2; Synthesis of 5-chloromethyl-2-methoxypyridine (3) To a solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L), thionyl chloride (310 mL, 4.25 mol) was added dropwise under a nitrogen atmosphere over a period of 1.3 hours while cooling in an ice bath. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2 N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23 C. or below. The reaction mixture was stirred for about 10 minutes. Then, the aqueous layer was separated, and the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness. Toluene (1.0 L) was added to the residue, followed by azeotropic distillation to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%).1H-NMR (CDCl3) delta (ppm): 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s)
With thionyl chloride; In dichloromethane; at 0℃; for 15h;
To a solution of the above compound (1.00 g, 7.19 mrnol) in 25 mL of dichloromethane at 0 C was added thionyl chloride (1.57 mL, 21.6 mmol). After 15 h, the mixture was concentrated in vacuo to provide 5-(chloromethyl)-2-methoxypyridine.
With thionyl chloride; In dichloromethane; at 0℃; for 15h;
To a solution of the above compound (1.00 g, 7,19 mmoi) in 25 mL of dichloromethane at 0 C was added thionyl chloride (1.57 mL, 21.6 mmoi). After 15 h, the mixture was concentrated in vacuo to provide 5-(chloromethyl)-2-methoxypyridine.
With thionyl chloride; In dichloromethane; at 40℃; for 1.5h;
To a solution of the above compound (0.40 g, 2.9 mmol) in 11.5 mL CH2CI2 was added thionyl chloride (0.41 g, 3.5 mmol). The reaction mixture was heated to 40 C for 1.5 h and cool to room temperature. Saturated sodium bicarbonate was added until the reaction mixture was pH basic. The reaction mixture was diluted with CH2CI2, and the layers were separated. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 5- (chloromethyl)-2-methoxypyridine (K3) that gave a mass ion (ES+) of 158.1 for M+H+.
0.58 g
With thionyl chloride; In dichloromethane; at 0 - 30℃; for 2h;Inert atmosphere;
To a solution of <strong>[58584-63-7]2-methoxy-5-hydroxymethylpyridine</strong> (0.71 g, 0.005mole) in DCM (5 mL) at 0 C under N2, was added thionyl chloride (0.7 mL, 0.009 mole) drop wise. The reaction mixture was warmed to RT and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and treated with saturated aqueous sodium bicarbonate (10 mL). Organic layer was washed with water (20 mL), brine solution (20 mL), dried over Na2SC>4 and concentrated under vacuum to obtain the title compound. Yield: 0.58 g; lH - NMR (CDC13, 400 MHz) delta ppm: 3.94 (s, 3H), 4.55 (s, 2H), 6.75 - 6.77 (d, J = 8.5 Hz, 1H), 7.61 - 7.64 (dd, J = 2.2, 8.5 Hz, 1H), 8.14 (s, 1H); Mass (m/z): 158.0 - 160.0 (M+H) +.
2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2-methoxypyridin-5-ylmethyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
With sodium hydroxide; dibromo sulfoxide; tetrabutylammomium bromide; In tetrahydrofuran; dichloromethane;
EXAMPLE 131 Synthesis of 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-1-(5,6-dihydro-6-oxopyridin-3-ylmethyl)-4-isopropyl-1H-imidazole (Compound I-131). In 5 ml of methylene chloride was dissolved 375 mg of <strong>[58584-63-7]2-methoxy-5-hydroxymethylpyridine</strong>, the mixture was cooled to -40 C. on a dry-ice bath, and 209 mul of thionyl bromide was added. The mixture was allowed to warm up, after 10 minutes, stirred at 60 C. After 30 minutes, the mixture was cooled, and the solution was distilled off under reduced pressure. The residue was added to a tetrahydrofuran solution containing 1179 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (101a), 215 mg of powdery sodium hydroxide and 87 mg of tetrabutylammonium bromide under ice-cooling. The temperature was raised up to room temperature, and powdery sodium hydroxide was further added to make alkaline. After 5 hours, the mixture was diluted with water, extracted with diethyl ether, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride:ethyl acetate=4:1)to give 290 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2-methoxypyridin-5-ylmethyl)-1H-imidazole (114a)(yield 19%). 1 H--NMR (CDCl3 --TMS)delta ppm: 1.26 (d, 6H), 3.09 (sept, 1H), 3.83 (s, 3H), 4.58 (s, 2H), 4.70 (s, 2H), 5.08 (s, 2H), 6.46 (d, 1H), 6.54 (d, 2H), 6.99 (m, 1), 7.18~7.40 (m, 6H), 7.88 (d, 1H)
8-(3-chlorophenyl)-pyrido[2,3-d]pyridazin-5-one[ No CAS ]
[ 58584-63-7 ]
[ 2446-83-5 ]
8-(3-chlorophenyl)-6-(6-methoxy-pyridin-3-ylmethyl)pyrido[2,3-d]pyridazin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; In tetrahydrofuran;
Example 51 Preparation of 8-(3-chlorophenyl)-6-(6-methoxy-3-pyridylmethyl)pyrido[2,3-d]pyridazin-5-one Formula I, Where X Is Nitrogen, Y Is Carbon, Z Is Oxygen, R1 is 6-Methoxy-3-pyridylmethyl, R3 Is Chloro, And R2, R4, R5, R6 Are Hydrogen To a suspension of 8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (0.515 g, 2.0 moles), <strong>[58584-63-7]6-methoxy-3-hydroxymethyl pyridine</strong> (0,306g, 2.2 moles) and triphenylphosphine (0.792 g, 3.0 moles) in THF (50 mL) was added diisopropylazodicarboxylate (0.6mL, 3.0 moles). The reaction mixture was stirred for 18 hours at room temperature. The solvent was removed and the product was purified by chromatography (ethyl acetate/hexane 2:3) and crystallized from methanol to yield 0.588g of 8-(3-chlorophenyl)-6-(6-methoxy-3-pyridylmethyl)pyrido[2,3-d]-pyridazin-5-one, mp 145 C.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;
Step 2 : 2-Methoxy-5-(phenoxymethyl)pyridin; According to Scheme 16 Method A: Phenol (1.5eq, 2.80mmol, 0.26g), PPh3 (2eq, 3.70mmol, 1.20g) and DEAD (2eq, 3.70mmol, 1.60g) were added to a solution of (6- methoxypyridin-3-yl)methanol (leq, 1.87mmol, 0.26g) in THF (6mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the reaction mixture was diluted with water. The organic layer was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25g SiO2) using cyclohexane/AcOEt 85/15 to afford 2-methoxy-5- (phenoxymethyl)pyridine (0.93mmol, 0.20g, 49%) as a pale oil. LC (XTerra RP18, 3.5mum, 3.0x50mm Column): RT = 4.46min; MS m/z (CI) [MH]+= 216.
EXAMPLE 25 : 1-(3,4-Difluorobenzyl)-5-(phenoxymethyl)pyridin-2(1H)-one (Final Compound 16-03) ;Step 1 : (6-Methoxypyridin-3-yl)methanol According to Scheme 16 Method A: A solution of 6-methoxynicotinaldehyde (leq, 2.19mmol, 0.30g) and LiAlH4 (0.5eq, 1.05mmol, 0.04g) in THF (10mL) was stirred for 30 min. at 0C and overnight at room temperature. After the addition of AcOEt, the reaction mixture was diluted with water. The organic layer was washed with saturated NH4Cl solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25g SiO2) using CH2Cl2/AcOEt 80/20 to afford (6-methoxypyridin-3-yl)methanol (1.80mmol, 0.26g, 90%) as a pale oil. LC (XTerra RP18, 3.5mum, 3.0x50mm Column): RT = 1.86min; MS m/z (CI) [MH]+= 140.
With hydrogen;aluminum nickel; In ethanol;
STR17 2 g of Raney nickel are added to 10.9 g (0.08 mol) of 6-methoxypyridine-3-aldehyde in 100 ml of ethanol, and the mixture is subsequently hydrogenated at 75 C. and 50 bar hydrogen pressure for 3 hours. For working up, the catalyst is filtered off and the filtrate is concentrated in vacuo. 11.1 g (100% of theory) of 2-methoxy-5-hydroxymethylpyridine are obtained as an oil which can be purified by distillation, of boiling point 85 C. to 88 C. at 0.6 mbar.
With concentrated aqueous hydrochloric acid; sodium methylate; In methanol; water; ethyl acetate;
Step 2+step 3+step 4: (One-pot version) STR19 98.3 g (0.5 mol) of 3-trichloromethylpyridine are added dropwise and with stirring, in the course of 25 minutes at reflux temperature to 344 g (1.6 mol) of a solution of sodium methoxide in methanol; when the addition is complete, the mixture is heated at the boiling point for 5 more hours and then cooled to room temperature, 100 ml of water are added, and a pH of 3 to 4 is established by adding 15 ml of concentrated aqueous hydrochloric acid. The mixture is stirred at room temperature for 14 hours, 10 g of palladium on active carbon (10% of Pd) are then added, 40 ml of water are added, and the mixture is hydrogenated under atmospheric pressure and with vigorous stirring. After 3.5 hours (hydrogen uptake: 10.790 1), the mixture is rendered neutral using saturated aqueous sodium hydrogen carbonate solution and filtered, the filtrate is concentrated, the residue is taken up in ethyl acetate, and the mixture is filtered again, concentrated and distilled. 52.5 g (76.6% of theory) of 2-methoxy-5-hydroxymethylpyridine of boiling point 85 C. to 88 C. at 0.6 mbar are obtained.
With nitrogen; sodium carbonate; In water; toluene;
STR18 6.5 g (0.041 mol) of N,N-dibutylformamide are added to 28.6 g (0.206 mol) of <strong>[58584-63-7]2-methoxy-5-hydroxymethylpyridine</strong> in 100 ml of toluene, the mixture is heated to 80 C., and a stream of phosgene is slowly passed into the solution until the starting material is no longer detectable in the thin-layer chromatogram (silica gel; eluent petroleum ether/ethyl acetate 5:1; about 2.5 hours). For working up, excess phosgene is removed by expelling at 80 C. using nitrogen, the mixture is then cooled to room temperature, water is added, a slightly alkaline pH is established by adding sodium carbonate, the organic phase is separated off, the aqueous phase is extracted using 50 ml of toluene, the combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. High-vacuum distillation gives 27.6 g (88% of theory) of 2-chloro-5-chloromethylpyridine of boiling point 70 C. to 80 C. at 1 mn.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 1h;
b) 3,3,3-Trifluoro-propane-1-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-(6-methoxy-pyridin-3-ylmethyl)-amide 3,3,3-Trifluoro-propane-1-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.15 g, 0.31 mmol), <strong>[58584-63-7](6-methoxy-pyridin-3-yl)-methanol</strong> (0.06 g, 0.38 mmol), triphenyl phosphine (0.17 g, 0.62 mmol) were dissolved in dry THF (15 ml) at 0-5 C. (ice-water bath) under an argon atmosphere followed by the dropwise addition of diisopropyl azodicarboxylate (0.12 ml, 0.62 mmol) in dry THF (1.5 ml). The reaction mixture was further stirred for 1 h at r.t. and then concentrated under reduced pressure. The crude oil was purified over silica gel (first: heptane-ethylacetate, 97:3-0:100; second: dichloromethane-methanol, 98:2-90:10): white solid 214 mg (81%); MS: m/e=654.2 (M+CH3COO-).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 1h;
b) 5-Chloro-thiophene-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-(6-methoxy-pyridin-3-ylmethyl)-amide 5-Chloro-thiophene-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.20 g, 0.40 mmol), <strong>[58584-63-7](6-methoxy-pyridin-3-yl)-methanol</strong> (0.07 g, 0.48 mmol), triphenyl phosphine (0.22 g, 0.80 mmol) were dissolved in dry THF (15 ml) at 0-5 C. (ice-water bath) under an argon atmosphere followed by the dropwise addition of diisopropyl azodicarboxylate (0.16 ml, 0.80 mmol) in dry THF (1.5 ml). The reaction mixture was further stirred for 1 h at r.t. and then concentrated under reduced pressure. The crude oil was purified over silica gel (first: heptane-ethylacetate, 97:3-0:100; second: dichloromethane-methanol, 98:2-90:10): white solid 0.19 g (53%); MS: m/e=674.2 (M+CH3COO-).
With triethylamine; In dichloromethane; at 20℃; for 48h;
The product of the preceding step (31-3 mmol) was dissolved in anhydrous dichloromethane (30 mL) and triethylaimine (6.5 mL), treated dropwise with methanesulfonyl chloride (38.7 mmol) at ambient temperature, and the reaction stirred for 2 d. The reaction was washed with, water, the aqueous layer extracted 3 times with CH2Cl2, combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo giving the title compound as a yellow oil. 1H NMR (CDCl3) 6 8.09 (IH, d, J = 2.3 Hz), 7.65 (IH, dd, J = 8.5 Hz, 2.4 Hz), 6.77 (IH d, J = 8.5 Hz), 4.57 (2H, s), 3.93 (3H, s), 3.41 (3H, s).
ethyl O-(2-mesitylenesulphonyl)acetohydroxamate[ No CAS ]
[ 909717-77-7 ]
Yield
Reaction Conditions
Operation in experiment
<Example 2> 1-Amino-5-hydroxymethyl-2-methoxypyridinium 2,4,6-trimethylbenzenesulfonate [Show Image] [Show Image] Ethyl O-mesitylsulfonylacetohydroxamate (87.8 g) was dissolved in 1,4-dioxane (70 mL). A 70% aqueous perchloric acid solution (31.0 mL) was added to the prepared solution under cooling with ice, and the mixture was stirred. Iced water was added to the mixture, and the precipitated solid was collected by filtration. The collected solid was dissolved in dichloromethane, and the dichloromethane layer was dried over anhydrous magnesium sulfate. The resultant product was added dropwise to a solution of the compound of Example 1 (35.7 g) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure, and the precipitated solid was collected by filtration. The collected solid was washed with diethyl ether to obtain the target product (58.7 g) as a white solid. 1H-NMR (400 MHz, DMSO-d6): delta 2.15 (3H, s), 2.49 (6H, s), 4.24 (3H, s), 4.57 (2H, s), 6.74 (2H, s), 7.70 (1H, d, J = 9.2 Hz), 7.71 (2H, br s), 8.16 (1H, dd, J = 9.2, 1.4 Hz), 8.46 (1H, d, J = 1.4 Hz).
Thionyl chloride (100 mL) was added to a stirred solution of <strong>[58584-63-7](6-methoxy-pyridin-3-yl)-methanol</strong> (31.0 g, 223 mmol) in chloroform (300 mL). After refluxing for 2 hours, the sol- vent and excess thionyl chloride were removed by evaporation in vacuo. The residue wasstripped with toluene, dissolved in dichloromethane (400 mL) and extracted with a saturatedaqueous sodium bicarbonate solution (200 mL). The organic layer was dried over sodiumsulphate, filtered and evaporated in vacuo, yielding a yellow oil. The oil was dissolved in di-methylformamide (750 mL), followed by the addition of potassium cyanide (14.5 g, 223mmol). After stirring overnight at room temperature, the reaction mixture was poured into wa- ter (1.5 L). Ethyl acetate (500 mL) was added and both layers were separated. The waterlayer was extracted with ethyl acetate (4 x 200 mL) and the combined organic layers weredried over sodium sulphate, filtered and evaporated in vacuo. The product was purified byflash column chromatography (SiO2, ethyl acetate/heptane 1/2) yielding (6-methoxy-pyridin-3-yl)-acetonitrile (13.7 g, 42% yield).1H NMR (200 MHz, CDCI3): 6= 3.75 (s, 2H), 4.00 (s, 3H), 6.85 (d, 1H), 7.60 (dd, 1H), 8.15 (br.s,1H);
<Example 2> 1-Amino-5-hydroxymethyl-2-methoxypyridinium 2,4,6-trimethylbenzenesulfonate; [Show Image] Ethyl O-mesitylsulfonylacetohydroxamate (87.8 g) was dissolved in 1,4-dioxane (70 mL). A 70% aqueous perchloric acid solution (31.0 mL) was added to the prepared solution under cooling with ice, and the mixture was stirred. Iced water was added to the mixture, and the precipitated solid was collected by filtration. The collected solid was dissolved in dichloromethane, and the dichloromethane layer was dried over anhydrous magnesium sulfate. The resultant product was added dropwise to a solution of the compound of Example 1 (35.7 g) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure, and the precipitated solid was collected by filtration. The collected solid was washed with diethyl ether to obtain the target product (58.7 g) as a white solid. 1H-NMR (400 MHz, DMSO-d6): delta 2.17 (3H, s), 2.49 (6H, s), 4.24 (3H, s), 4.57 (2H, s), 6.74 (2H, s), 7.70 (1H, d, J = 9.2 Hz), 7.71 (2H, brs), 8.16 (1H, dd, J = 1.4, 9.2 Hz), 8.46 (1H, d, J = 1.4 Hz).
With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 48h;
4-Bromophenol (1.37 g, 7.90 mmol) was added to a solution of (6-methoxypyridin-3- yl)methanol (1.0 g, 7.16 mmol) in THF (100 ml_). Triphenylphosphine (1 .88 g, 7.19 mmol) was added followed by triethylamine (0.727 g, 7.19 mmol). The resulting solution was cooled to 0C and DIAD (1.45 g, 7.19 mmol) was added by drop-wise addition and was maintained at 0C for 30 minutes, then warmed to room temperature and stirred for two days. The reaction was quenched by addition of water and extracted with ether (2x100 ml_). The organic layer was washed with water (2x100 ml.) then brine (1x100 ml_), dried (MgS04), filtered and concentrated to give a yellow oil. The crude material was purified by flash column chromatography on a Biotage SNAP cartridge Kp-sil 100g column (hexanes/ethyl acetate 9: 1 ) to give a white solid. Mass/Yield - 1.78 g / 84% TLC (hexanes/ethyl acetate = 8:2) Rf = 0.12, UV active. LCMS MS ES+294.4/296.4. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.93 (s, 3 H) 4.93 (s, 2 H) 6.72 - 6.78 (m, 1 H) 6.81 - 6.86 (m, 2 H) 7.33 - 7.42 (m, 2 H) 7.58 - 7.65 (m, 1 H) 8.18 (s, 1 H).
With sodium hydride; In tetrahydrofuran; at 0 - 100℃; for 2h;
A mixture of commercially available (6-methoxypyridin-3-yl)-methanol (CAS 58584-63-7, 1 g, 7.19 mmol) and dry THF (9.3 mL) was cooled to 0 C and sodium hydride (0.38 g of a 60% dispersion, 9.58 mmol) was added portionwise. Stirring was continued at 0 C before portionwise addition of 2-amino-4-chloropyrimidine (0.62 g, 4.79 mmol). The mixture was heated at 100 C (bath temperature) for 2 hours. On cooling, the mixture was poured onto ice, extracted with EtOAc (4 x) and the combined organic phase washed with brine, dried and concentrated to give the title compound as a beige solid (1 .33 g, 65% purity) which was used without further purification in the next step.
To a stirred solution of ethyl O-mesitylenesulfonylacetohydroxamate (87.8 g, 308 mmol) in dioxane (70 mL) was added 70% HClO4 (31 mL) at 0 C. After stirring for 0.5 h at the same temperature, ice-water was added to the reaction mixture and the resulting precipitate collected by filtration. The wet filter cake of MSH was dissolved in CH2Cl2; the organic layer was separated and quickly dried over MgSO4. The resulting solution of MSH was slowly added to a stirred solution of <strong>[58584-63-7]5-hydroxymethyl-2-methoxypyridine</strong> (35.7 g, 233 mmol) in CH2Cl2 (20 mL) at 0 C. After stirring for 1 h at room temperature, the reaction mixture was concentrated in vacuo. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration to give the title compound as a white solid (58.7 g, 159 mmol, 68%). 1H NMR (DMSO-d6, 400 MHz): delta 2.17 (3H, s), 2.49 (6H, s), 4.24 (3H, s), 4.57 (2H, s), 6.72 (2H, s), 7.70 (1H, d, J = 9.2 Hz), 8.16 (1H, dd, J = 9.2, 1.4 Hz), 8.46 (1H, d, J = 1.4 Hz).
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