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Chemical Structure| 58584-63-7
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Product Details of [ 58584-63-7 ]

CAS No. :58584-63-7 MDL No. :MFCD06202826
Formula : C7H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :YKTYUHMWNUVAAM-UHFFFAOYSA-N
M.W : 139.15 Pubchem ID :12259941
Synonyms :

Calculated chemistry of [ 58584-63-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.29
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 36.86
TPSA : 42.35 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.87
Log Po/w (XLOGP3) : 0.27
Log Po/w (WLOGP) : 0.43
Log Po/w (MLOGP) : 0.01
Log Po/w (SILICOS-IT) : 1.17
Consensus Log Po/w : 0.75

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.18
Solubility : 9.09 mg/ml ; 0.0653 mol/l
Class : Very soluble
Log S (Ali) : -0.72
Solubility : 26.5 mg/ml ; 0.19 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.95
Solubility : 1.55 mg/ml ; 0.0111 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.62

Safety of [ 58584-63-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 58584-63-7 ]

* 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 [ 58584-63-7 ]
  • Downstream synthetic route of [ 58584-63-7 ]

[ 58584-63-7 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 58584-63-7 ]
  • [ 65873-72-5 ]
YieldReaction ConditionsOperation in experiment
61% 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).
Reference: [1] Tetrahedron, 1992, vol. 48, # 8, p. 1457 - 1464
[2] Patent: WO2015/158427, 2015, A1, . Location in patent: Page/Page column 132
[3] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 35
  • 2
  • [ 26218-80-4 ]
  • [ 58584-63-7 ]
YieldReaction ConditionsOperation in experiment
100% 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]+.

Reference: [1] Patent: US2006/235225, 2006, A1, . Location in patent: Page/Page column 3
[2] Patent: WO2011/73845, 2011, A1, . Location in patent: Page/Page column 123
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 5, p. 1644 - 1658
[4] Patent: WO2015/158427, 2015, A1, . Location in patent: Page/Page column 132
[5] Tetrahedron, 1992, vol. 48, # 8, p. 1457 - 1464
[6] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220
[7] Patent: US2007/49632, 2007, A1, . Location in patent: Page/Page column 38
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 613 - 615
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 304 - 308
[10] Patent: US2007/37789, 2007, A1, . Location in patent: Page/Page column 10
[11] Patent: US2006/14945, 2006, A1, . Location in patent: Page/Page column 39
[12] Patent: WO2014/66659, 2014, A1, . Location in patent: Paragraph 0808
[13] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 91-92
[14] Patent: EP2060572, 2009, A1, . Location in patent: Page/Page column 36-37
[15] Patent: EP2058310, 2009, A1, . Location in patent: Page/Page column 50
[16] Patent: US2010/179321, 2010, A1, . Location in patent: Page/Page column 3-4
[17] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 35
[18] Organic Letters, 2010, vol. 12, # 21, p. 5004 - 5007
[19] Patent: US2011/224225, 2011, A1, . Location in patent: Page/Page column 23
[20] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8336 - 8346
[21] Patent: WO2011/159554, 2011, A1, . Location in patent: Page/Page column 31-32
[22] Patent: WO2011/159553, 2011, A1, . Location in patent: Page/Page column 27-28
[23] Patent: WO2011/84368, 2011, A1, . Location in patent: Page/Page column 54-55
[24] Organic Letters, 2017, vol. 19, # 14, p. 3895 - 3898
  • 3
  • [ 65873-72-5 ]
  • [ 58584-63-7 ]
YieldReaction ConditionsOperation in experiment
90%
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 ]
YieldReaction ConditionsOperation 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] Tetrahedron, 2014, vol. 71, # 1, p. 19 - 26
  • 5
  • [ 66572-55-2 ]
  • [ 58584-63-7 ]
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 ]
YieldReaction ConditionsOperation 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) +.

Reference: [1] Patent: WO2016/33445, 2016, A1, . Location in patent: Paragraph 0259
[2] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220
[3] Patent: US2006/235225, 2006, A1, . Location in patent: Page/Page column 4
[4] Patent: US2007/49632, 2007, A1, . Location in patent: Page/Page column 38
[5] Patent: US2011/224225, 2011, A1, . Location in patent: Page/Page column 23
[6] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
[7] Patent: US2010/179321, 2010, A1, . Location in patent: Page/Page column 4
[8] Organic Letters, 2010, vol. 12, # 21, p. 5004 - 5007
[9] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
[10] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8336 - 8346
[11] Patent: WO2011/159554, 2011, A1, . Location in patent: Page/Page column 31
[12] Patent: WO2011/159553, 2011, A1, . Location in patent: Page/Page column 28
[13] Patent: WO2011/84368, 2011, A1, . Location in patent: Page/Page column 55
[14] Organic Letters, 2017, vol. 19, # 14, p. 3895 - 3898
[15] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 41
  • 11
  • [ 58584-63-7 ]
  • [ 744212-68-8 ]
Reference: [1] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220
  • 12
  • [ 58584-63-7 ]
  • [ 128632-03-1 ]
YieldReaction ConditionsOperation in experiment
44.1% 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
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