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Chemical Structure| 95-01-2
Chemical Structure| 95-01-2
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Product Details of [ 95-01-2 ]

CAS No. :95-01-2 MDL No. :MFCD00011686
Formula : C7H6O3 Boiling Point : -
Linear Structure Formula :- InChI Key :IUNJCFABHJZSKB-UHFFFAOYSA-N
M.W :138.12 Pubchem ID :7213
Synonyms :
2,4-Dihydroxybenzaldehyde

Calculated chemistry of [ 95-01-2 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 35.88
TPSA : 57.53 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 : Yes
Log Kp (skin permeation) : -6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.72
Log Po/w (XLOGP3) : 0.54
Log Po/w (WLOGP) : 0.91
Log Po/w (MLOGP) : 0.18
Log Po/w (SILICOS-IT) : 1.02
Consensus Log Po/w : 0.67

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.41
Solubility : 5.32 mg/ml ; 0.0385 mol/l
Class : Very soluble
Log S (Ali) : -1.32
Solubility : 6.62 mg/ml ; 0.0479 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.17
Solubility : 9.4 mg/ml ; 0.0681 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 95-01-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P273-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335-H412 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 95-01-2 ]

* 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 [ 95-01-2 ]
  • Downstream synthetic route of [ 95-01-2 ]

[ 95-01-2 ] Synthesis Path-Upstream   1~34

  • 1
  • [ 95-01-2 ]
  • [ 531-95-3 ]
Reference: [1] Patent: US2015/57456, 2015, A1,
  • 2
  • [ 543-24-8 ]
  • [ 95-01-2 ]
  • [ 79418-41-0 ]
Reference: [1] Angewandte Chemie, International Edition, 2009, vol. 48, p. 4034 - 4037[2] Angewandte Chemie, 2009, vol. 121, p. 4094 - 4097
[3] Tetrahedron Letters, 2012, vol. 53, # 39, p. 5280 - 5283
[4] Chemical Communications, 2015, vol. 51, # 11, p. 2029 - 2032
[5] Tetrahedron Letters, 2015, vol. 56, # 42, p. 5761 - 5766
[6] Patent: CN105693674, 2016, A, . Location in patent: Paragraph 0024
[7] Chemical Communications, 2017, vol. 53, # 25, p. 3583 - 3586
  • 3
  • [ 95-01-2 ]
  • [ 79418-41-0 ]
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 29, p. 5077 - 5080
[2] Journal of Organic Chemistry, 2011, vol. 76, # 12, p. 4964 - 4972
[3] Chemistry of Heterocyclic Compounds, 2011, vol. 46, # 12, p. 1514 - 1519
[4] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 90, p. 40 - 44
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2779 - 2790
[6] Journal of the American Chemical Society, 2014, vol. 136, # 20, p. 7205 - 7208
[7] Medicinal Chemistry Research, 2014, vol. 23, # 8, p. 3632 - 3643
[8] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 8, p. 2400 - 2402
[9] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5737 - 5742
[10] Tetrahedron, 2016, vol. 72, # 32, p. 4925 - 4930
[11] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5557 - 5561
  • 4
  • [ 105-56-6 ]
  • [ 95-01-2 ]
  • [ 19088-73-4 ]
YieldReaction ConditionsOperation in experiment
80% With [bis(acetoxy)iodo]benzene In ethanol at 35 - 40℃; General procedure: α-substituted ethyl acetate (1.0 mmol)and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant stirring. After 10 minutes benzaldehyde/salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated under reduce pressure. The product was extracted with ethyl acetate, dried over Na2SO4 and solvent was evaporated under reduce pressure. The residue obtained was recrystallized by ethyl acetate and hexane to product 3a-3h and 4a-4r.  
Reference: [1] Synthetic Communications, 2005, vol. 35, # 6, p. 785 - 790
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2002, vol. 177, # 11, p. 2555 - 2559
[3] Tetrahedron Letters, 2017, vol. 58, # 32, p. 3183 - 3187
[4] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 867 - 870
[5] Journal of the Iranian Chemical Society, 2016, vol. 13, # 1, p. 149 - 153
[6] Proceedings - Indian Academy of Sciences, Section A, 1942, # 16, p. 68,77
[7] Journal of Molecular Liquids, 2017, vol. 242, p. 293 - 307
[8] Chemical Papers, 2018, vol. 72, # 6, p. 1461 - 1466
  • 5
  • [ 109-77-3 ]
  • [ 95-01-2 ]
  • [ 19088-73-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 4, p. 799 - 802
[2] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 12, p. 3571 - 3577
[3] Molecular crystals and liquid crystals, 1983, vol. 100, # 3-4, p. 299 - 305
[4] Heterocycles, 1996, vol. 43, # 6, p. 1257 - 1266
  • 6
  • [ 105-53-3 ]
  • [ 95-01-2 ]
  • [ 6093-71-6 ]
YieldReaction ConditionsOperation in experiment
97% at 20℃; for 2 h; To a solution of 2,4-dihydroxybenzaldehyde (3.70 mmol) in diethyl malonate (7.90 mmol) piperidine (10 drops) was added, and the resulting solution was stirred for 2 hours at r.t. The resulting solution was then acidified with an aqueous solution of HCl10percent (5 mL). The precipitate was filtrated and washed with cold water (10 mL). The desired product was purified by flash chromatography using dichloromethane : ethyl acetate (70: 30) as eluent furnishing 3 (0.735g) in 97percent yield. 1H NMR (400 MHz, DMSO-d6) : 1.28 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 6.71 (d, J= 1.8Hz, 1H), 6.83 (dd, J= 1.8, 8.3Hz, 1H), 7.74 (d, J= 8.3Hz, 1H), 8.66 (s, 1H), 11.07 (s, OH). 13C NMR (100 MHz, DMSO-d6): 14.1, 60.8, 101.7, 110.4, 112.0, 113.9, 132.1, 149.4, 156.3, 157.0, 162.9, 164.0.
92% at 20℃; for 1 h; Diethyl malonate (6.6 mL, 43.3 mmol) and 2,4-dihydroxybenzaldehyde (6.0 g, 43.3 mmol) were added to the flask and piperidine (4.4 mL, 44.3 mmol) was slowly added at room temperature.When the reaction mixture turns pale yellow, it is further stirred for 1 hour,HCl 10percent (50 mL) was added. After grinding the green suspension,Filtration and washing with water gave the desired compound as a pink solid (9.32 g, 92percent).
90% With piperidine In ethanol at 90℃; for 6 h; A solution of 2,4-dihydroxybenzaldehyde (0.500 g, 3.60 mmol) and diethyl malonate (0.70 ml, 4.00 mmol) were placed in 100 ml of a vial and dissolved in 95percent Ethanol (20ml), the solution color is reddish brown transparent liquid; then add piperidine (0.40ml, 4.00mmol), the solution surface pan-green light, began to reflux, the reaction after about 6h, the solution becomes dark brown.Cooled to room temperature, concentrated under reduced pressure to a red viscous, ethanol recrystallized, and filtered to give compound 3 (0.758 g, 3.24 mmol) as a pale yellow solid in 90percent yield.ESI-MS m / z 233 (M-1).
88% With amino acid fuctionalized Fe3O4 nanoparticles(Fe3O4-DA-Phe) In neat (no solvent) at 130℃; for 0.116667 h; Microwave irradiation; Green chemistry General procedure: A mixture of o-hydroxy benzaldehyde (2 mmol), 1,3-dicarbonyl compound (2 mmol) and Fe3O4-DA-Phe (30mg)was mixed in a 50 mL flask and irradiated under microwavefor the time indicated in (Table 6.1). The reaction progresswas monitored by TLC. After completion of the reaction, thereaction mixture was cooled to room temperature which thensolidified within an hour. The resulting solidified mixturewas diluted with ethyl acetate (5 mL) and the catalyst wasseparated by using external magnet and dried for reuse. Thereaction mixture was washed twice with water and solventwas evaporated under reduced pressure which yielded thecrude product, which was further purified by recrystallization.The same procedure was used for synthesis of derivatives.All synthesized coumarin derivatives were characterizedusing analytical techniques such as IR and 1H NMR.The identity of these compounds was established by comparisonof IR, 1H NMR spectral data and their melting pointswith those of reported samples (Table 4) [23-33]. Spectraldata for all compounds are listed.
84% With [bis(acetoxy)iodo]benzene In ethanol at 35 - 40℃; General procedure: α-substituted ethyl acetate (1.0 mmol)and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant stirring. After 10 minutes benzaldehyde/salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated under reduce pressure. The product was extracted with ethyl acetate, dried over Na2SO4 and solvent was evaporated under reduce pressure. The residue obtained was recrystallized by ethyl acetate and hexane to product 3a-3h and 4a-4r.  
81% With piperidine In ethanolReflux 2, 4-dihydroxybenzaldehyde (6.9 g, 0.05 mol), diethyl malonate (9.6 g, 0.06 mol) and piperidine(0.2 g, 2.5 mmol) were refluxing in 150 mL ethanol for 10 h. After cooled to room temperature, thecrude products were filtrated and recrystallized from methanol [19].Ethyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate (1e): Light yellow solid; yield 81percent. ESI-HRMS [M +Na]+: (m/z) Calcd. for C12H10O5Na: 257.0420. Found: 257.0434.
70% With piperidine; acetic acid In ethanol for 4.5 h; Heating General procedure: Diethyl malonate (7.5 mL, 49 mmol), 2, 4-dihydroxybenzaldehyde (5.1 g, 37 mmol) or 2, 4-dihydroxy-5-halogenbenzaldehyde, piperidine (0.5 mL, 6 mmol) and 3 drops of acetic acid were dissolved in a 50 mL flask of ethanol (10 mL) to form a mixture. The reaction mixture was heated with stirring for 4.5 h. After cooling, the solid was collected using a vacuum filer. The solid product was filtered and washed with cold ethanol, then dried. The crude product was recrystallized with ethanol to obtain the purified product 1a (6.06g, 25.9 mmol) or 1b-1d. The complex was characterized by1H NMR (Fig. S4).
64.5% With piperidine In ethanol for 12 h; Reflux Compound 1 was synthesized according to the reported papers.37–39 2,4-dihydroxybenzaldehyde 2.76g (20mmol) and diethylmalonate 6.4mL (40mmol) were mixed together in 30mL anhydrous ethanol. 1.5mL piperidine was added to the above solution dropwise after that. The whole mixture was refluxed for 12h after which the solvent was evaporated. The product was extracted with CH2Cl2, washed with brine and purified by column chromatography to give compound 1 as a white yellow solids (4.1g 12.89mmol). 1HNMR (400MHz, DMSO) δ 8.677 (s,1H), 7.768 (d, J=8, 1H) 6.84 (dd, J=4, 1H), 6.73 (d, J=1.2,1H), 4.26 (q, 2 H), 1.29 (t, J=8, 3H) (Fig. S1). 13C NMR δ 164.03, 162.91, 157.07, 156.37, 149.41, 132.08, 113.97, 112.04, 110.39, 101.75, 60.77, 39.47, 14.10 (Fig. S2). HRMS: 257.0422, calcd for: 257.0426 (Fig. S5). Yield: 64.5percent.
64% With piperidine; acetic acid In ethanol at 90℃; for 15 h; To a 250 mL round bottom flask was added 2,4-dihydroxybenzaldehyde(10 g, 72.5 mmol) and 30 mL of absolute ethanol,Stir to make it fully dissolved. diethyl malonate (17.2 mL, 101.9 mmol), hexahydropyridine (0.57 mL, 5.76 mmol)Glacial acetic acid (0.16 mL, 2.88 mmol), heated at 90 °C with stirring, TLC tracks the progress of the reaction. After about 15 h, TLC (EA: PE = 1: 2) was significantThe reaction is basically complete. The reaction solution was allowed to cool to room temperature, 200 mL of ice water was added and allowed to stand overnight at -20 ° C. The filtrate was filtered to give 12.4 g of a yellow solid in 73percent yield. The crude product was recrystallized from 95percent ethanol to give 10.8 g of a pale yellow needle-like solid in a yield of 64percent
63%
Stage #1: With piperidine In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
Example 12; Synthesis of a compound of Formula (I) where R1, R3, R(at), and R8 are OMe, R2, R(at), and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 7-(2- methoxyethyloxy)coumarin-3-ylcarbonylamino (compound 42); Step 1; To a solution of 2,4-dihydroxy-benzaldehyde (5.52 g, 40.0 mmol) in THF (50 mL) were added diethyl malonate (6.7 mL, 44 mmol) and piperidine (11.9 mL, 120 mmol). After 2 hr of stirring at room temperature, the reaction mixture was acidified to pH -1-2 with IN HCl (aq), and extracted with large amount of EtOAc. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. Purification of the crude material by column chromatography provided 7-hydroxy-2-oxo-2H-chromene-3-carboxylic acid ethyl ester as an off-white solid (5.9 g, 63percent).
51.04% With piperidine In ethanol at 20℃; General procedure: The substituted coumarin-3-carboxylic acid ethyl esters (Scheme 2) were prepared by Knoevenagel reaction. To a mixture of diethyl malonate (1 mmol) and the appropriate salicylaldehyde (1 mmol) in ethanol (10 ml) was added piperidine (5 mol percent) and the reaction mixture was stirred at the room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under vacuum and the residue was purified by chromatography. The obtained substituted coumarin-3-carboxylic acid ethyl ester (2 mmol) was dissolved in 10percent NaOH (50 ml), then 3 N HCl (50 ml) was added the mixture. The suspension was filtered and dried under vacuum to provide substituted coumarin-3-carboxylic acid. The coumarin-3-carboxylic acid (2 mmol) was added to thionyl chloride (30 ml), the reaction mixture was refluxed for about 2 h, the thionyl chloride was removed under vacuum. The desired substituted coumarin-3-carbonyl chloride was obtained. To a mixture of substituted coumarin-3-carbonyl chloride (2 mmol) and toluene (20 ml) or ethyl ether (20 ml) was added dropwise appropriate alcohol (2 mmol) and then the reaction mixture was refluxed for about 12 h. The solvent was removed under vacuum and the residue was purified by chromatography.

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[3] Patent: CN106279125, 2017, A, . Location in patent: Paragraph 0039; 0040
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  • 7
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YieldReaction ConditionsOperation in experiment
41% With piperidine In toluene for 6 h; Reflux General procedure: Piperidine (21 mg, 30 molpercent) was added slowly to a stirred solution of salicylaldehyde (1a, 100 mg, 1 equiv) and ethyl 4,4,4-trichloro-3-oxobutanoate(2, 192 mg, 1 equiv) in toluene (2mL) at room temperature. The reaction mixture was refluxed for 4 h. After completion of the reaction (TLC), the crude product was subjected to column chromatography purification using silica gel(60:120) provided coumarin 3a as colorless solid.
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Reference: [1] Patent: WO2012/134724, 2012, A1, . Location in patent: Page/Page column 36-38
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  • 10
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  • [ 95-01-2 ]
  • [ 779-27-1 ]
YieldReaction ConditionsOperation in experiment
99% With tomato juice In water at 20℃; for 0.0833333 h; Sonication; Green chemistry General procedure: 2-Hydroxybenzaldehyde (acetophenone, or benzaldehydes) (1.0 mmol) and Meldrum’s acid (1.01 mmol) were suspended in the aqueous medium (juice or waste water) (2 mL). The resulting mixture was subjected to ultrasound irradiation at room temperature for 5 min (15 min). The precipitate so formed was filtrated under vacuum. Structural assignments (NMR) was made by comparison of the recorded analytical data with those of commercially available sample or those already reported for the same compounds.2-6 The aqueous medium (juice or waste water) was recovered by filtration and re-used as such to perform further processes.
92% at 60℃; for 4 h; Schlenk technique; Green chemistry General procedure: A mixture of Meldrum’s acid (0.5 mmol) and salicylaldehydes (0.55 mmol) was placed in a 10-mL Schlenk tube, then Et3N (0.015 mmol) and 50 μL water were added. The reaction mixture was stirred at the indicated temperature for 4 h. After completion of the reaction, 3 mL aqueous ethanol was added to the mixture and vigorously stirred for a moment. The pH was adjusted to 2–3 with dilute hydrochloric acid. Finally, the precipitate was separated by filtration and washed with aqueous ethanol without further purification to afford the corresponding pure adducts.
90% for 10 h; Reflux General procedure: In a round-bottomed flask the selected salicylaldehyde (1 mmol) and Meldrum's acid (1.2 mmol) in water (2 mL) were heated at reflux under stirring for 10 h; then, the reaction mixture was cooled and filtered on Büchner funnel. The products were purified by recrystallization from methanol.
77% With ammonium acetate In water at 20℃; for 0.1 h; A suspension of 2,4-dihydroxybenzaldehyde (1.30 g, 9.5 mmol) in 21 mL of water was added Meldrum's acid (1.55 g, 10.8 mmol) and ammonium acetate (150 mg, 1.9 mmol). The suspension was stirred at room temperature for about 1 h. The precipitate formed was filtered and washed with cold water (2 x 10 mL) and vacuum drying (1.5 g, yellow-orange solid, 77percent). m.p. 260-264 °C; 1H NMR (DMSO-d6): δ 11.93 (bs, 2H, OH), 8.66 (s, 1H, =CH), 7.73 (d, 1H, Ar-H, J = 8.6 Hz ), 6.83 (dd, 1H, Ar-H, J = 8.6, 2.1 Hz), 6.72 (d, 1H, Ar-H, J = 2.1 Hz)

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[2] Food Chemistry, 2012, vol. 135, # 4, p. 2872 - 2878
[3] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 623 - 630
[4] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 502 - 506
[5] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 40 - 46
[6] Chemical Communications, 2017, vol. 53, # 11, p. 1813 - 1816
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  • 13
  • [ 100-39-0 ]
  • [ 95-01-2 ]
  • [ 52085-14-0 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 0.75 h; Inert atmosphere
Stage #2: Inert atmosphere; Reflux
2,4-Dihydroxybenzaldehyde (3.0g, 1.0equiv) was dissolved in acetonitrile (220ml) and treated with NaHCO3 (2.2equiv) for 45min at rt followed by the addition of benzylbromide (1.1equiv). The reaction mixture was stirred under reflux O.N. and then quenched with H2O (100ml) and extracted with ethyl acetate (3×25ml). The combined organic layers were washed with brine (2×15ml), dried over Na2SO4, filtered and the solvent was eliminated under vacuo to give the title compound 12 as a white solid that was used as it is.
82% With sodium hydrogencarbonate In acetonitrile for 48 h; Reflux; Inert atmosphere Anhydrous NaHCO3 (10.1 g, 120 mmol) was added to a stirred solution of 2,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) in CH3CN (80 mL). BnBr (14.1 mL, 120 mmol) was then added and the reaction mixture refluxed for 48 h. Upon completion (TLC), the reaction mixture was brought to rt followed by addition of H2O (40 mL) and EtOAc (40 mL). The layers were separated and the organic layer was washed with sat. NaHCO3 and brine, dried over anhydrous Na2SO4 and evaporated to give a brown solid which was subjected to crystallization (MeOH) to afford the title compound as an off-white solid (22.5 g, 82percent); mp 82-83 °C (Lit. 80-82 °C1); TLC Rf 0.88 [EtOAc/Hex (1:1)]; 1H NMR (CDCl3) δ 11.47 (s, 1H), 9.72 (s, 1H), 7.35-7.45 (m, 6H), 6.60 (dd, 1H, J = 2.2, 8.8 Hz), 6.51 (d, 1H, J = 2.2 Hz), 5.11 (s, 2H); 13C NMR (CDCl3): δ 194.4, 165.9, 164.4, 135.6, 135.3, 128.7, 128.4, 127.5, 115.3, 108.9, 101.6, 70.4.
80%
Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 1 h;
Stage #2: for 6 h; Reflux
Anhydrous sodium bicarbonate (0.1 g, 1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (0.138 g, 1 mmol) in 10 mL of acetonitrile and the mixture was stirred for 1 hour at RT. Benzylbromide (0.13 mL, 1.1 mmol) was added and the mixture was refluxed for 6 hours.
After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring.
A white solid precipitated and it was recrystallized from methanol (ca. 4 mL) to obtain 0.182 g (80percent) of white powder: mp 78-80° C.; TLC Rf0.88 in toluene:methanol (10:1); 1H NMR (600 MHz, acetone-d6) δ 11.41 (s, 1H, OH), 9.81 (s, 1H, CHO), 7.68-7.67 (d, 1H, J=8.4 Hz, Ar-H6), 7.45-7.35 (m, 5H, C6H5), 6.71-6.69 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar-H5), 6.56 (d, 1H, J=1.8 Hz, Ar-H3), 5.24 (s, 2H, PhCH2); 13C NMR (100 MHz, acetone-d6) 194.61, 166.1, 164.4, 135.9, 128.9, 128.6, 127.8, 115.5, 109.1, 101.8, 70.6; analysis calcd. for C14H12O3: C 73.67, H 5.30, found: C 73.62, H 5.35.
80%
Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 1 h;
Stage #2: for 24 h; Reflux
Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 h. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 percent yield as a white solid. Mp.2 80–81 °C; 1H NMR (600 MHz, CDCl3) δ 11.48 (s, 1H), 9.72 (s, 1H), 7.46 - 7.32 (m, 6H), 6.62 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.11 (s, 2H); 13C NMR (151 MHz, CDCl3) δ 194.6, 166.0, 164.6, 135.8, 135.4, 128.9, 128.6, 127.7, 115.5, 109.1, 101.8, 70.6. Experimental data in agreement with reported data.
80%
Stage #1: With sodium hydrogencarbonate In acetonitrile at 20℃; for 1 h;
Stage #2: for 24 h; Reflux
Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2,4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 percent yield as a white solid. Mp.2 80–81 °C; 1H NMR (600 MHz, CDCl3) δ 11.48 (s, 1H), 9.72 (s, 1H), 7.46 - 7.32 (m, 6H), 6.62 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.11 (s, 2H); 13C NMR (151 MHz, CDCl3) δ 194.6, 166.0, 164.6, 135.8, 135.4, 128.9, 128.6, 127.7, 115.5, 109.1, 101.8, 70.6. Experimental data in agreement with reported data.3
65% With sodium hydrogencarbonate In acetonitrile for 16 h; Inert atmosphere; Reflux 2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) was dissolved in acetonitrile (83 mL). To this solution was added NaHCO3 (9.1 g, 0.10 mol) and stirred for 5 min. Benzyl bromide (12.9 mL, 0.10 mol) was added in under an argon atmosphere. The reaction was heated to reflux for 16 h. After cooling to room temperature, the reaction was quenched by addition of distilled water, and the organic layer extracted into dichloromethane (3 x 50 mL), and organic layers combined, washed with water and brine, dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography (Silica gel, 10percent -20 percent EtOAc in hexane) to give 25 in 65percent yield.
59.9% With sodium hydrogencarbonate In acetonitrile at 85℃; for 20 h; A mixture of sodium bicarbonate (1.216 g, 14.48 mmol), benzyl bromide (2.477 g, 14.48 mmol) and 2,4-dihydroxybenzaldehyde (2 g, 14.48 mmol)) in acetonitrile (50 mL) was stirred at 85 °C for 20 hours. The solvent was removed to give a brown oil The residue was diluted with 80 mL of water, extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over Na2S04, filtered through glass funnel and concentrated to give an orange oil. The crude material was purified by silica gel column chromatography and eluted with 5percent ethyl acetate/heptane. The following fractions were collected and concentrated to give the title compound 4- (benzyloxy)-2-hydroxybenzaldehyde (2.2 g, 8.67 mmol, 59.9 percent yield) as a white solid.LCMS(ESI-MS): m/z: 312.1 [M + H]+; Rt = 2.09 min. (Method A)
49% With sodium hydrogencarbonate; sodium iodide In acetonitrile at 80℃; for 18 h; Inert atmosphere To 2,4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g, 7.2 mmoi), and NaHC03 (1.5g, 17 mmol) in acetonitrile (30 mL, 0.50 M) was added benzyl bromide (1.7 mL, 14 mmol). The reaction mixture was stirred at 80 °C for 18 h under argon, cooled to RT, diluted with EtOAc (100 mL), washed with H20 and brine, and dried over MgS04, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAcihexanes = 1:8) to provided compound 3 as a white solid (49percent). NMR (CDC13, 300 MHz): δ 11.48 (1H, s), 9.72 (1H, s), 7.51 - 7.32 (6H, m), 6.62 (1H, dd, J = 8.7, 2.3 Hz), 6.54 (1H, d, / = 2.3 Hz), 5.11 (2H, s). I3C NMR (CDCI3, 100 MHz): δ 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. LRMS (APCI+): Calc'd for Cl4Hl203 228.1 m/z, measured 229.2 (AfH+).
49% With sodium hydrogencarbonate; sodium iodide In acetonitrile at 80℃; for 18 h; Inert atmosphere To 2,4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g,7.2 mmol), and NaHCO3 (1.5 g, 17 mmol) in acetonitrile (30mE, 0.50 M)was added benzyl bromide (1.7 mE, 14 mmol).The reaction mixture was stirred at 80° C. for 18 h under argon, cooled to RT, diluted with EtOAc (100 mE), washed with H20 and brine, and dried over MgSO4, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAc:hexanes=1 :8) to provided compound 3 aswhite solid (49percent). ‘H NMR (CDC13, 300 MHz): ö 11.48 (1H, s), 9.72 (1H, s), 7.51-7.32 (6H, m), 6.62 (1H, dd, J=8.7, 2.3 Hz), 6.54 (1H, d, J=2.3 Hz), 5.11 (2H, s). ‘3C NMR (CDC13, 100 MHz): ö 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. ERMS (APCI+): Calc’d for C,4H,203 228.1 mlz, measured 229.2 (MH+).
30.77% With potassium carbonate In acetonitrile at 20℃; for 3 h; Intermediate 98: 4-(Benzyloxy)-2-hydroxybenzaldehydeTo a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added 2, 4-dihydroxybenzaldehyde (8.0 g, 57.0 mmol), potassium carbonate (15.77 g, 114.0 mmol). The reaction mixture was brought to 0 °C, was added benzyl bromide (9.905 g, 57.0 mmol) in acetonitrile (100 mL) drop wise and stirred at room temperature for 3 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The product obtained as a white solid (4.0 g, yield: 30.77percent).
40% With potassium carbonate In acetone EXAMPLE I
4-Benzyloxy-2-hydroxybenzaldehyde
13.8 g (0.1 mol) 2,4-dihydroxybenzaldehyde are dissolved in 150 ml acetone, 17.1 g (0.1 mol) benzylbromide and 13.8 g (0.1 mol) potassium carbonate are added, and the mixture is stirred at room temperature for 3 d.
After filtration, the solvent is removed in vacuo and the residual crude product further purified by column chromatography on silica gel using dichloromethane as eluent.
Yield: 9.2 g (40percent); m.p.: 81-82° C. 1H-NMR (CDCl3, 400 MHz): δ=5.11 (s, 2H; CH2): 6.51 (d, 1H, Ar-H); 6.61 (dd, 1H, Ar-H); 7.32-7.45 (m, 6H, Ar-H); 9.82 (s, 1H, CHO); 11.60 (s, 1H, OH) ppm.

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  • 14
  • [ 100-44-7 ]
  • [ 95-01-2 ]
  • [ 52085-14-0 ]
YieldReaction ConditionsOperation in experiment
77.8% With sodium hydrogencarbonate; potassium iodide In acetonitrile at 60 - 65℃; General procedure: A mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 0.01 mol), substituted benzyl chloride (0.011 mol), NaHCO3 (1.26 g, 0.015 mol) and catalytic amount of potassium iodide in 20 mL acetonitrile was heated to 60 °C for 36 h and hot filtered, the filtrate was cooled to 10 °C and filtered, the filtrated cake was collected and recrystallized with EtOH to obtain compounds 10a–g.
67% With sodium hydrogencarbonate; potassium iodide In acetonitrileReflux 2,4-dihydroxybenzaldehyde (100 mg, 0.72 mmol), potassium iodide (179.3 mg, 1.08 mmol) and sodium bicarbonate (90.7 mg, 1.08 mmol) were dissolved in acetonitrile (15 mL), then benzyl chloride (100 uL, 0.87 mmol) were added slowly to the resulted solution. The mixture was stirred at refluxing overnight, and then the reaction was quenched with water and extracted with ethyl acetate (20 mL .x. 3). The combined organic layer was washed with brine (15 mL .x. 3), dried with sodium sulphate anhydrous, concentrated under vacuum, and purified by flash chromatography with eluent (petroleum ether: ethyl acetate = 10:1), to get a colorless solid. Yield 67percent; m.p. 70-72 °C; 1H NMR (300 MHz, CDCl3), δ 5.12 (s, 2H, OCH2Ph), 6.40-6.64 (m, 2H, ArH), 7.41-7.43 (m, 6H, ArH), 9.73 (s, 1H, CHO), 11.44 (brs, 1H, OH); EI-MS m/z: 229.1.
66% With sodium hydrogencarbonate; potassium iodide In acetonitrile for 30 h; Reflux The reaction of 2,4-dihydroxybenzaldehyde with benzyl chloride,To give 2-hydroxy-4-benzyloxybenzaldehyde,As shown in Scheme 5,The specific preparation method is as follows:
A mixture of 2,4-dihydroxybenzaldehyde (50 g, 0.362 mol)Benzyl chloride (59.3 g, 0.471 mol)Sodium bicarbonate (34.7 g, 0.413 mol)Potassium iodide (12 g, 0.0724 mol) was added to 200 mL of acetonitrile,The reaction was refluxed for 30 h.Reaction finished,The reaction solution was poured into water,Precipitation of solids,Filter,Washed cake,dry.Recrystallization from methanol,A white solid of 54 g,Yield 66percent
64% With sodium hydrogencarbonate; potassium iodide In acetonitrileReflux To a solution of2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) and benzylchloride (5.50 g, 43.5 mmol) in CH3CN (50 mL), KI (5.50g, 54 mmol) and NaHCO3 (4.50 g, 54 mmol) were added.The mixture was refluxed overnight and cooled to roomtemperature. The reaction was quenched with water andextracted by ethyl acetate. The combined organic extractswere washed with brine, dried over anhydrous Na2SO4,concentrated and purified over silica gel column (elution:10/1 petroleum ether/ethyl acetate) to give compound 1(5.25 g, 64 percent) as white solid. 1H NMR (CDCl3, 300 MHz):δ = 5.11 (s, 2H, OCH2Ph), 6.51–6.52 (d, 1H, J = 3.0 Hz,ArH), 6.60–6.63 (dd, 1H, J = 1.5 Hz, 7.5 Hz ArH), 7.36–7.46 (m, 6H, ArH), 9.72 (s, 1H, OH), 11.48 (s, 1H, OH).
64% With sodium hydrogencarbonate; potassium iodide In acetonitrile for 12 h; Reflux 2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) was dissolved in acetonitrile (500 mL)Then potassium iodide (9.00 g, 54 mmol) and sodium bicarbonate (4.50 g, 54 mmol) were added,Benzyl chloride (5.50 g, 43.5 mmol) was slowly added dropwise and refluxed for 12 h.After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: : 1)4- (benzyloxy) -2-hydroxybenzaldehyde5.25 g (white solid, yield 64percent).
56% With sodium hydrogencarbonate; potassium iodide In acetonitrile for 24 h; Heating / reflux (Example 197)2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl] -2,3 -dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride (Exemplification compound number 4-136)(a) 4-Benzyloxy-2-hydoxy-benzaldehydeTo a solution of 2,4-dihydroxybenzaldehyde (50.0 g, 362 mmol) in acetonitrile (350 ml) were added sodium hydrogen carbonate (34.6 g, 412 mmol), potassium iodide (6.0 g, 36 mmol), and benzyl chloride (54.0 ml, 470 mmol), and the resulting mixture was refluxed for 24 hours under a nitrogen atmosphere. At the end of the reaction, 1N hydrochloric acid (400 ml) was added, and the resulting mixture was extracted with ethyl acetate (400 ml ? 2). The organic layer was washed successively with 3percent aqueous potassium carbonate solution (300 ml ? 2), water (300 ml ? 1), 1N hydrochloric acid (300 ml ? 1) and saturated aqueous sodium chloride solution (300 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was recrystallized from a mixture of t-butyl methyl ether and hexane to afford the title compound (45.9 g, yield: 56percent) as pale orange crystals. Mp 71-72C.1H NMR (CDCl3, 500MHz) ? ppm : 5.11 (2H,s), 6.51 (1H,d,J=2.0Hz), 6.62 (1H,dd,J=2.0,8.5Hz), 7.35-7.45 (6H,m), 9.72 (1H,s), 11.46 (1H,s).(b) 4-Benzyloxy-2-methoxymethoxy-benzaldehyde o a solution of -benzyloxy-2-hydoxy-benzaldehyd (44.9 g, 197 mmol) synthesized in step (a) of Example 197 in dichloromethane (200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethyl chloride (20.5 ml, 270 mmol) at 0C with stirring, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with dichloromethane (200 ml ? 2). The organic layer was washed successively with water (300 ml ? 1) and saturated aqueous sodium chloride solution (300 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (42.2 g, yield: 79percent) as a colorless oil.1H NMR (CDCl3, 500MHz) ? ppm : 3.51 (3H,s), 5.11(2H,s), 5.26 (2H,s), 6.68 (1H,dd,J=2.0,9.0 Hz), 6.80 (1H,d,J=9.0Hz), 7.34-7.43 (5H,m), 7.81 (1H,d,J=9.0Hz), 9.72 (1H,s), 11.46 (1H,s).(c) Ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate To a suspension of 55percent sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0C with stirring, and the resulting mixture was stirred for 2 hours at 0C under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml ? 2). The organic layer was washed successively with water (100 ml ? 1) and saturated aqueous sodium chloride solution (100 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (9.32 g, yield: 99percent) as a colorless oil.1H NMR (CDCl3, 400MHz) ? ppm : 1.32 (3H,t,J=7.2 Hz), 3.47 (3H,s), 4.24 (2H,q,J=7.2Hz), 5.05 (2H,s), 5.21 (2H,s), 6.39 (1H,d,J=16.0Hz), 6.62 (1H,dd,J=2.0,8.8Hz), 6.81 (1H,d,J=2.0Hz), 7.30-7.43 (5H,m), 7.45 (1H,d,J=8.8Hz), 7.95 (1H,d,J=16.0Hz). (d) Ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate To a solution of (S)-N-benzyl-1-phenylethylamine (4.24 g, 20.1 mmol) in tetrahydrofuran (40 ml) was added 1.6 M solution of n-butyllithium in hexane (12.4 ml, 18.9 mmol) at -78C with stirring, and the resulting mixture was stirred for 20 minutes at -78C under a nitrogen atmosphere. Subsequently, a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate (4.32 g, 12.6 mmol) synthesized in Example 3 in tetrahydrofuran was added dropwise at -78C with stirring, and the resulting mixture was stirred for 30 minutes at -78C under a nitrogen atmosphere. After stirring, a saturated aqueous ammonium chloride solution (40 ml) was added at -78C with stirring, and the resulting mixture was extracted with ethyl acetate (50 ml ? 2). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml ? 1), dried over anhydrous e product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (3.48 g, yield: 82percent) as a colorless oil. [?]D23 +48.0 (c 1.09, CHCl3) .1H NMR (CDCl3, 400MHz) ? ppm : 1.43 (9H,s), 1.94 (2H,dt,J=4.8,6.0Hz), 3.00 (3H,s), 3.08 (3H,s), 3.30 (1H,br s), 3.49 (3H,s), 3.61-3.74 (2H,m), 5.06 (1H,q,J=5.6Hz), 5.23 (2H,dd,J=6.4,10.8Hz), 5.47 (1H,d,J=9.6Hz), 6.74 (1H,dd,J=2.4,8.8Hz), 6.90 (1H,d,J=2.4Hz), 7.19 (1H,d,J=8.8Hz). (h) -[(1R)-Amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxyphenyl dimethylcarbamate To a solution of t-butyl (1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-carbamate (1.63 g, 4.08 mmol) synthesized in step (g) of Example 197, 4-methylthiophenol (660 mg, 4.50 mmol) and triphenylphosphine (1.60 g, 6.12 mmol) in tetrahydrofuran (15 ml), was added dropwise 40 wt percent solution of diethyl azodicarboxylate in toluene (2.66 g, 6.12 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the crude product (2.74 g) containing hydrazine dicarboxylate. Subsequently, to a solution of the crude product (2.74 g) in methanol (18 ml) was added concentrated hydrochloric acid (6 ml), and the resulting mixture was stirred overnight at room temperature. After stirring, the reaction mixture was neutralized with 15percent aqueous sodium hydroxide solution and adjusted to pH 10 with saturated aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate (50 ml ? 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1:0-5:1) as the eluent to afford the title compound (1.05 g, yield: 69percent) as a colorless oil. [?]D23 -66.5 (c 0.77, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 2.12-2.18 (1H,m), 2.21-2.28 (1H,m), 2.44 (3H,s), 2.99 (3H,s), 3.07 (3H,s), 3.89 (1H,dt,J=4.0,10.0Hz), 4.00 (1H,dt,=5.0,10.0Hz), 4.43 (1H,t,J=7.5Hz), 6.51 (1H,dd,J=2.5,8.0Hz), 6.60 (1H,d,J=2.5Hz), 6.82 (2H,d,J=8.5 Hz), 6.86 (1H,d,J=8.0Hz), 7.25 (2H,d,J=8.5Hz). (i) t-Butyl [(1R) - 4-dimethylcarbamoyloxy-2-hydroxy-phenyl) -3-(4-methylthiophenoxy)-propyl]-carbamate To a solution of -[(1R)-amino-3-(4-methylthiophenoxy)-propyl] -3-hydroxy-phenyl dimethylcarbamate (1.05 g, 2.80 mmol) synthesized in step (h) of Example 197 in methanol (10 ml) were added triethylamine (0.83 ml, 6.0 mmol) and di-t-butyl dicarbonate (650 mg, 3.00 mmol), and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (1.34 g, yield: 100percent) as a colorless solid. [?]D23 +14.3 (c 0.52, CHCl3).1H NMR (CDCl3, 400MHz) ? ppm : 1.40 (9H,s), 2.26-2.37 (2H,m), 2.44 (3H,s), 3.00 (3H,s), 3.07 (3H,s), 3.89-3.95 (1H,m), 3.98-4.03 (1H,m), 5.00 (1H,dd,J=8.0,15.2Hz), 5.25 (1H,br s), 6.63 (1H,dd,J=3.2,8.0Hz), 6.66 (1H,d,J=3.2Hz), 6.81 (2H,d,J=8.8Hz), 7.10 (1H,d,J=8.0Hz), 7.24 (2H,d,J=8.8Hz).(j) t-Butyl [(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl] -carbamate To a solution of t-butyl [(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-propyl] -carbamate (1.34 g, 2.80 mmol) synthesized in step (i) of Example 197 in dichloromethane (10 ml) were added pyridine (0.48 ml, 6.0 mmol) and trifluoromethanesulfonic anhydride (0.50 ml, 3.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, water (20 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (20 ml ? 2). The organic layer was washed successively with 0.5N hydrochloric acid (20 ml ? 1) and saturated aqueous sodium chloride solution (20 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude triflate derivative (1.48 g).1H NMR (CDCl3, 500MHz) ? ppm : 1.38 (9H,br s), 2.17-2.34 (2H,m), 2.44 (3H,s), 3.01 (3H,s), 3.09 (3H,s), 3.97 (2H,t,J=6.0Hz), 5.13 (1H,dd,J=8.0,12.5Hz, 5.44 (1H,br s), 6.82 (2H,d,J=8.5Hz), 7.14 (1H,d,J=8.5Hz), 7.15 (1H,s), 7.25 (2H,d,J=8.5Hz), 7.43 (1H d,J=8.5Hz). Subsequently, to a solution of the crude triflate derivative (1.48 g) obtained above in 1,4-dioxane (20 ml) were added tetrakis(triphenylphosphine)palladium (647 mg, 0.560 mmol), 2,6-di-t-butylphenol (5 mg), lithium chloride (356 mg, 8.40 mmol) and tributyl(vinyl)tin (0.88 ml, 3.0 mmol), and the resulting mixture was stirred for 3 hours at 100C under a nitrogen atmosphere. Subsequently, saturated aqueous potassium fluoride solution (10 ml) was added, and the resulting mixture was stirred for 2 hours at room temperature and then filtered and evaporated in vacuo. To the residue obtained was added water (40 ml), and the resulting mixture was extracted with ethyl acetate (50 ml ? 2). The organic layer was washed successively with 1N hydrochloric acid (40 ml ? 1) and saturated aqueous sodium chloride solution (40 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (1.08 g, yield: 79percent) as a colorless oil. [?]D23 -7.7 (c 0.58, CHCl3).1H NMR (CDCl3, 400MHz) ? ppm : 1.40 (9H,s), 2.18 (2H,br m), 2.44 (3H,s), 3.01 (3H,s), 3.09 (3H,s), 3.84-3.96 (2H,m), 5.23 (1H,br s), 5.31 (1H,d,J=10.8Hz), 5.58 (1H,dd,J=1.2,16.8Hz), 6.80 (2H,d,J=8.0Hz), 7.00-7.16 (1H,br m), 7.02 (1H,dd,J=2.8,8.8Hz), 7.19-7.28 (4H,m).(k) t-Butylallyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinylphenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate To a solution of t-butyl [(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl) -3-(4-methylthiophenoxy)-propyl) -carbamate (1.08 g, 2.22 mmol) synthesized in step (j) of Example 197 in dimethylformamide (10 ml) was added sodium hydride (160 mg, 6.66 mmol), being prepared free from mineral oil by washing with hexane, at 0C, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, allyl bromide (0.57 ml, 6.7 mmol) was added at 0C, and the resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added, and the resulting mixture was extracted with ethyl acetate (30 ml ? 2). The organic layer was washed successively with water (30 ml ? 1) and saturated aqueous sodium chloride solution (30 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:1) as the eluent to afford the title compound (932 mg, yield: 80percent) as a colorless oil. [?]D23 +76.1 (c 0.63, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 1.43 (9H,s), 2.29-2.42 (1H,br m), 2.40-2.52 (1H,br m), 2.43 (3H,s), 3.02 (3H,s), 3.11 (3H,s), 3.47 (2H, brs), 3.97 (1H,dt,J=6.0,8.0Hz), 4.06 (1H,br q,J=8.0Hz), 4.82 (1H,d,J=17.0Hz), 4.84 (1H,d,J=9.5Hz), 5.28 (1H,d,J=10.5Hz), 5.48 (1H,br s), 5.58 (1H,d,J=16.5Hz), 5.67 (1H,br s), 6.82 (2H,d,J=8.5Hz), 7.02 (1H,dd,J=10.5,16.5Hz), 7.04-7.06 (1H,m),7.24-7.26 (3H,m), 7.34 (1H,d,J=7.5Hz).(1) t-Butyl 7-dimethylcarbamoyloxy-(1R)-[2(4-methylthiophenoxy)-ethyl] -1, 3-dihydro-benzo[c]azepine-2-carboxylate To a solution of t-butyl allyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate (907 mg, 1.72 mmol) synthesized in step (k) of Example 197 in dichlorometane (100 ml) was added tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium(IV) dichloride (146 mg, 0.172 mmol), and the resulting mixture was stirred for 3 hours at 45C under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:1) as the eluent to afford the title compound (796 mg, yield: 93percent) as a colorless oil. [?]D23 -43.8 (c 0.71, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 1.29 (6H,s), 1.38 (3H,s), 2.27 (1H,br s), 2.36 (1H,br s), 2.44 (3H,s), 3.00 (3H,s), 3.09 (3H,s), 3.77-4.18 (3H,br m), 4.74 (0.34H,d,J=16.0Hz), 4.99 (0.66H,br s), 5.23 (0.66H,br s), 5.35 (0.34H,br s), 5.78 (0.34H,d,J=11.5 Hz), 5.84 (0.66H,d,J=11.5Hz), 6.35 (1H,d,J=11.5Hz), 6.80 (0.68H,d,J=7.5Hz), 6.82 (1.32H,d,J=7.5 Hz), 6.88 (1H,br s), 6.96 (1H,s), 7.08 (1H,br s), 7.20-7.26 (2H,m). (m) -Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride The title compound was obtained as an amorphous solid using t-butyl 7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1,3-dihydro-benzo [c] azepine-2-carboxylate obtained in step (1) of Example 197 by conducting successively reactions similar to those mentioned in step (d) of Example 6 and Example 3. [?]D23 -24.2 (c 0.73, CHCl3).1H NMR (CDCl3, 400MHz) ? ppm : 2.03-2.15 (1H,m), 2.43 (3H,s), 2.53 (3H,s), 2.64-2.76 (1H,m), 3.02 (3H,s), 3.10 (3H,s), 3.76-3.79 (2H,m), 3.92 (1H, quintet,J=5.2Hz), 4.19 (1H,br s), 4.63 (1H,d,J=7.6Hz), 5.84 (1H,d,J=12.4Hz), 6.60 (1H,d,J=12.4Hz), 6.76 (2H,d,J=8.8Hz), 7.00 (1H,dd,J=2.0,8.0Hz), 7.14 (1H,d,J=2.0Hz), 7.15 (1H,d,J=8.0Hz), 7.21 (2H,d,J=8.8Hz).sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (10:1 - 5:1) as the eluent to afford ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) containing a small amount of (S)-N-benzyl-1-phenylethylamine.1H NMR (CDCl3, 500MHz) ? ppm : 0.98 (3H,t,J=7.0Hz), 1.23 (3H,d,J=7.0Hz), 2.60 (1H,dd,J=9.0,13.5Hz), 2.73 (1H,dd,J=7.0,15.0Hz), 3.47 (3H,s), 3.73 (2H,dd,J=14.5,22.5Hz), 3.79-3.92 (2H,m), 4.08 (1H,q,J=7.0Hz), 4.80 (1H,dd,J=6.0,8.0 Hz), 5.03 (2H,s), 5.15 (2H,dd,J=7.0,17.0Hz), 6.61 (1H,dd,J=2.5,8.5 Hz), 6.83 (1H,d,J=2.5Hz), 7.13-7.44 (16H,m).Subsequently, to a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-(benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) obtained above as a yellow oil in a mixture of methanol/water/acetic acid (80 ml/8 ml/4 ml) was added 20percent palladium hydroxide (1.8 g), and the resulting mixture was stirred for 4 hours at room temperature. After stirring, the reaction mixture was filtered through celite and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1 : 0-3 : 1) as the eluent to afford the title compound (2.77 g, yield: 67percent) as an amorphous solid. [?]D23 -8.0 (c 0.82, MeOH) .1H NMR (CD3OD, 400MHz) ? ppm : 1.20 (3H,t,J=7.6Hz), 1.90 (3H,s), 2.93 (1H,dd,J=6.0,16.4Hz), 2.98 (1H,dd,J=8.8,16.4Hz), 3.49 (3H,s), 4.13 (2H,q,J=7.6Hz), 4.71 (1H,t,J=7.4Hz), 5.24 (2H,s), 6.45 (1H,dd,J=2.4,8.8Hz), 6.69 (1H,d,J=2.8Hz), 7.12 (1H,d,J=8.8Hz). (e) Ethyl (3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate To a solution of ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate (4.26 g, 12.9 mmol) obtained in step (d) of Example 197 in methanol (20 ml) were added triethylamine (3.62 ml, 26.0 mmol) and di-t-butyl dicarbonate (3.27 g, 15.0 mmol) with stirring, and the resulting mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the title compound (4.64 g, yield: 97percent) as a colorless solid. The optical purity of the title compound obtained was determined to be 98.8percent ee by chiral liquid chromatography (Dicel Chiral cel OJ, hexane : isopropanol = 95:5, 1 ml/min, R-isomer: 20.48 min and S-isomer: 23.68 min). Mp 82-86C. [?]D23 +42.3 (c 0.86, CHCl3).1H NMR (CDCl3, 500MHz) ? ppm : 1.16 (3H,t,J=7.0Hz), 1.43 (9H,s), 2.79 (1H,dd,J=7.0,14.5Hz), 2.86 (1H,dd,J=6.0,14.5Hz), 3.45 (3H,s), 4.05 (2H,q,J=7. Hz),4.85-5.20 (3H,m), 5.43 (0.2H,br s), 5.81 (0.8H,d,J=8.0Hz), 6.28 (1H,d,J=8.0Hz), 6.50 (1H,br s), 6.57 (1H,br s), 6.98 (1H,d,J=8.0Hz). (f) Ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcaramoyloxy-2-methoxymethoxy-phenyl)-propionate To a solution of ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate (2.35 g, 6.36 mmol) synthesized in step (e) of Example 197 in dimethylformamide (10 ml) were added potassium carbonate (1.80 g, 13.0 mmol) and N,N-dimethylcarbamoyl chloride (0.65 ml, 7.0 mmol) with stirring, and the resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 ml ? 2). The organic layer was washed with saturated aqueous sodium chloride solution (40 ml ? 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the title compound (2.73 g, yield: 97percent) as a colorless oil. [?]D23 +25.3 (c 1.09, CHCl3) .1H NMR (CDCl3, 500MHz) ? ppm : 1.17 (3H,t,J=7.0Hz), 1.41 (9H,s), 2.77-2.89 (2H,m), 2.99 (3H,s), 3.07 (3H,s), 3.49 (3H,s), 4.01-4.10 (2H,m), 5.24 (2H,dd,J=7.0,10.0Hz), 5.30 (1H,br s), 5.74 (1H,br d,J=9.0Hz), 6.73 (1H,dd,J=2.0,9.0Hz), 6.89 (1H,d,J=2.0Hz), 7.23 (1H,d,J=9.0Hz).(g) t-Butyl [(1R) (4-dimethylcarbamoyloxy-2-methoxymethoxyphenyl)-3-hydroxypropyl]-carbamate To a solution of ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-propionate (4.68 g, 10.6 mmol) synthesized in step (f) of Example 197 in tetrahydrofuran (30 ml) was added lithium aluminum hydride (524 mg, 13.8 mmol) at -50C with stirring, and the resulting mixture was stirred successively for 10 minutes at -50C and for 15 minutes at 0C under a nitrogen atmosphere. After stirring, to the reaction mixture were added water (0.5 ml), 15percent aqueous sodium hydroxide solution (0.5 ml) and water (1.5 ml) at 0C in this order, and the resulting mixture was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crud

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YieldReaction ConditionsOperation in experiment
50% With calcium hydroxide In methanol at 20℃; for 48 h; 2,4-Dihydroxybenzaldehyde (15) (3 g/20.17 mmol), calcium hydroxide (1.543 g/20.8 mmol) and 150 mL of methanol were place in a two-necked round-bottom flask. Then, prenal (9.135 g/108.6 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 48 h. The reaction was quenched with HCl 1 M until pH 1–2. The methanol was evaporated and the aqueous phase was extracted with 3 × 150 mL of ethyl acetate. The organic phase was washed with 2 × 100 mL of brine, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate 9:1). Compound 16 was crystallized from n-hexane/ethyl acetate 3:1 as a yellow solid (2.06 g/50percent).
50% With calcium hydroxide In methanol at 20℃; for 48 h; 2,4-Dihydroxybenzaldehyde (42) (3g/20.17mmol), calcium hydroxide (1.543g/20.8mmol) and 150mL of methanol were placed in a round-bottom flask. Then, prenal (9.135g/108.6mmol) was added dropwise. The mixture was stirred at room temperature for 48h. The reaction was quenched with HCl 1M until pH 1–2. The methanol was evaporated and the aqueous phase was extracted with 3×150mL of ethyl acetate. The organic phase was washed with 2×100mL of brine, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by silica gel flash chromatography (n-hexane/ethyl acetate 9:1). Compound 43 was crystallized from n-hexane/ethyl acetate 3:1 as a yellow solid (2.06g/50percent).6-Formyl-5-hydroxy-2,2-dimethyl-2H-benzopyran (43). Mp: 68–69°C. IR νmax (cm−1) (KBr): 3464, 2967, 2922, 2857, 1628, 1484, 1330, 1294, 1247, 1176, 1107, 1081, 748. 1H NMR (300.13MHz, CDCl3) δ (ppm): 11.65 (OH), 9.66 (s, CHO), 7.29 (d, J=8.6), 6.88 (d, J=10.0), 6.44 (d, J=8.6), 5.61 (d, J=10.0), 1.46 (s, 6H). 13C NMR (100.63MHz, CDCl3) δ (ppm): 194.5, 160.6, 158.7, 134.7, 128.6, 115.2, 115.1, 109.4, 108.8, 78.2, 28.4. EIMS m/z (percent): 205 (5, [M+1]+.), 204 (10 [M]+.), 190 (15), 189 (100), 187 (60), 159 (12), 131 (12), 103 (10), 77 (12), 51 (6). HRMS (ESI) m/z calcd for C12H13O3 [M+H]+: 205.08570, found: 205.08592.
0.68 g With calcium hydroxide In methanol at 20℃; for 12 h; A 1 g portion of 2,4-2 hydroxybenzaldehyde (Compound 2 shown in Figure 1)0.514 g Ca (OH) 2, methanol150mL.3.045 g of prenyl aldehyde (compound 1 shown in FIG. 1) was then added dropwise.Stir at room temperature for 12h.Quench with HCl (1 M) until the pH is 1-2.Methanol was evaporated and the aqueous phase was extracted with 3 * 150 mL of ethyl acetate.The organic phase was washed with 2 * 100 mL saturated brine, dried over anhydrous Na2SO4,Vacuum filtration, and spin dry. The crude product was passed through a column of silica gel (petroleum ether: ethyl acetate = 9: 1)Crystallization gave product 3 (0.68 g) as shown in FIG.
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  • [ 95-01-2 ]
  • [ 54287-99-9 ]
YieldReaction ConditionsOperation in experiment
32% With pyridine In acetone at 120℃; for 23.5 h; Heating [0174] Pyridine (0.01 M) solution containing 3-methyl-but-2-enyl (2.0 equivalent) was added to anhydrous acetone solution (0.01 M) containing 2,4-dihydroxyaldehyde (1 equivalent) drop by droop at 120 °C for 5.5 hours, followed by heating for 18 hours. After cooling down at room temperature, the solvent was eliminated under reduced pressure using a rotary evaporator. Pyridine was eliminated by azeotropic distillation along with toluene. The obtained non-purified product was purified by flash column chromatography (EtOAc:n-hexane=1:8) to give the compound 119 as a colorless solid (yield: 32percent, 1.12 g). [0175] 1H-NMR (CDCl3, 300 MHz) δ11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J = 8.6 Hz), 6.39 (d, 1H, J = 8.6 Hz), 5.58 (d, 1H, J = 10.0 Hz), 1.42 (s, 6H).
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  • [ 115-19-5 ]
  • [ 95-01-2 ]
  • [ 54287-99-9 ]
YieldReaction ConditionsOperation in experiment
32% at 120℃; for 23.5 h; Pyridine (0.01 M) solution containing 3-methyl-but-2-enyl (2.0 equivalent) was added to anhydrous acetone solution (0.01 M) containing 2,4-dihydroxyaldehyde (1 equivalent) drop by droop at 120° C. for 5.5 hours, followed by heating for 18 hours. After cooling down at room temperature, the solvent was eliminated under reduced pressure using a rotary evaporator. Pyridine was eliminated by azeotropic distillation along with toluene. The obtained non-purified product was purified by flash column chromatography (EtOAc:n-hexane=1:8) to give the compound 119 as a colorless solid (yield: 32percent, 1.12 g). [0272] 1H-NMR (CDCl3, 300 MHz) δ11.61 (s, 1H), 9.62 (s, 1H), 7.25 (d, 1H, J=8.6 Hz), 6.39 (d, 1H, J=8.6 Hz), 5.58 (d, 1H, J=10.0 Hz), 1.42 (s, 6H).
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  • [ 95-01-2 ]
  • [ 58026-14-5 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 17, p. 5887 - 5894
[2] Patent: WO2012/11125, 2012, A1,
  • 25
  • [ 100-44-7 ]
  • [ 95-01-2 ]
  • [ 74-88-4 ]
  • [ 58026-14-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 1227 - 1236
  • 26
  • [ 90-02-8 ]
  • [ 24677-78-9 ]
  • [ 95-01-2 ]
Reference: [1] Patent: DE155731, , ,
  • 27
  • [ 67-66-3 ]
  • [ 108-46-3 ]
  • [ 387-46-2 ]
  • [ 95-01-2 ]
Reference: [1] Journal of the American Chemical Society, 1983, vol. 105, # 7, p. 2018 - 2021
  • 28
  • [ 75-03-6 ]
  • [ 95-01-2 ]
  • [ 22924-16-9 ]
Reference: [1] Chemische Berichte, 1877, vol. 10, p. 2212
  • 29
  • [ 75-03-6 ]
  • [ 95-01-2 ]
  • [ 22924-16-9 ]
Reference: [1] Journal of the Chemical Society, 1934, p. 1491,1497
[2] Journal of the Chemical Society, 1934, p. 1491,1497
  • 30
  • [ 95-01-2 ]
  • [ 64419-24-5 ]
YieldReaction ConditionsOperation in experiment
70.5% at 20 - 100℃; for 2.25 h; In a double walled reactor 50.0 g (0.362 mol, 1.0 meq) 2,4-dihydroxybenzaldehyde were added to 180 mL formic acid, which resulted in a brown suspension at room temperature.
Then 45.8 g (0.673 mol, 1.8 meq) sodium formate were added over 2 min, and the temperature increased to 33° C.
After the temperature decreased to 30° C., 35.6 g (0.217 mol, 1.2 meq) hydroxyl ammonium sulfate were added during 3 min to give a thick brown suspension which became a brown solution after stirring 10 min at 30-32° C.
While heating the mixture to 100° C., crystallization occurred at 38° C. and stirring was interrupted.
At 70° C. the reaction mixture became a thin suspension, which was easy to stir.
This reaction mixture was stirred for 2 hours at 100° C.
The color turned dark brown. TLC (silica gel 60 F254, acetone:n-hexane:water 20:20:1) showed an almost complete reaction.
Formic acid (170 mL) was evaporated under reduced pressure (60° C., 10 mbar).
The solid dark brown residue was stirred with 400 mL MTBE at 40° C. for 1 hour (incomplete dissolution).
The insoluble residue (62.5 g) was filtered and washed two times each with 50 mL MTBE.
To the mother liquor 10 g activated carbon (Norit CA 5) were added and this mixture was refluxed for 1 hour and filtered at 40° C. by Celite Super Hyflow (washing with 2*50 mL portions of MTBE).
The MTBE-mother liquor was washed three times each with 100 mL water.
After removing the water from this MTBE solution with azeotropic distillation (water separator) it was concentrated under reduced pressure to 20percent of the starting volume and 500 mL toluene were added.
Then the MTBE was distilled off under reduced pressure.
During this process a brown residue began to precipitate, which was filtered.
The toluene mother liquor was concentrated to 150 mL and 2,4-dihydroxybenzonitrile precipitated, which was filtered and washed two times each with 30 mL toluene.
The pale tan product was dried under reduced pressure (45° C., 20 mbar).
The reaction yielded 34.5 g of 2,4-dihydroxybenzonitrile (70.5percent, purity 97percent (HPLC)).
Reference: [1] Tetrahedron, 1999, vol. 55, # 46, p. 13265 - 13268
[2] Patent: US2003/220504, 2003, A1, . Location in patent: Page/Page column 4
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 1, p. 95 - 108
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 10, p. 1000 - 1006
[5] Soft Matter, 2010, vol. 6, # 8, p. 1704 - 1721
[6] Advanced Functional Materials, 2014, vol. 24, # 12, p. 1703 - 1717
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 657 - 667
[8] Chemistry - A European Journal, 2017, vol. 23, # 23, p. 5541 - 5556
  • 31
  • [ 95-01-2 ]
  • [ 131088-02-3 ]
YieldReaction ConditionsOperation in experiment
47% With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 0.5 h; Inert atmosphere To a solution of 2,4-dihydroxybenzaldehyde (3.0 g, 22 mmol) in Et20 (100 mL, 0.22 M) was added dropwise sulfurylchloride (2.1 mL, 26 mmol) at 0 °C under argon. After being stirred at RT for 30 min, the reaction solution was poured into ice-chilled brine, washed with H2O and brine, dried over MgS04, filtered, and concentrated. Purification by flash chromatography (Et20:hexanes = 1:2) provided compound 6 as an ivory solid (47percent). NMR (DMSO-d6, 300 MHz): δ 11.38 (1H, s), 10.87 (1H, s), 9.97 (1H, s), 7.59 (1H, s), 6.58 (1H, s). LRMS (APCI+): Calc'd for C7H5C103 172.0 m/z, measured 173.1 (MH+).
47% With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 0.5 h; Inert atmosphere To a solution of2,4-dihydroxybenzaldehyde (3.0 g, 22 mmol) in Et20 (100 mE, 0.22 M) was added dropwise sulfurylchloride (2.1 mE, 26 mmol) at 00 C. under argon. Afier being stirred at RT for 30 mm, the reaction solution was poured into ice-chilled brine, washed with H20 and brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (Et20:hexanes=1 :2) provided compound 6 as an ivory solid (47percent). ‘H NMR (DMSO-d6, 300 MHz): ö 11.38 (1H, s), 10.87 (1H, s), 9.97 (1H, s), 7.59 (1H, s), 6.58 (1H, s). ERMS (APCI+): Calc’d for C7H5C10C3 172.0 ink, measured 173.1 (MH+).
26% With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 0.5 h; Inert atmosphere To a solution of 2,4-dihydroxybenzaldehyde (20 g, 144.92 mmol) in diethyl ether (500 mL) was added drop wise sulfuryl chloride (14 mL, 171.2 mmol) at 0° C. under argon and stirred at room temperature for 30 min. The reaction mixture was poured into ice-water, the organic layer was separated and washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified on a silica gel column (pet. ether:ethyl acetate=90:10) to get 5-chloro-2,4-dihydroxybenzaldehyde as an off white solid. (6.7 g, 26percent, LC/MS; 97percent). ES−, m/z 170.9 [M−H]; [C7H5ClO3]; NMR (DMSO-d6, 400 MHz): δ 11.39 (1H, s), 10.87 (1H, s), 9.98 (1H, s), 7.0 (1H, s), 6.58 (1H, s).
Reference: [1] Chemical Biology and Drug Design, 2015, vol. 86, # 5, p. 1030 - 1035
[2] Angewandte Chemie - International Edition, 2007, vol. 46, # 19, p. 3505 - 3508
[3] Chemical Communications, 2008, # 10, p. 1217 - 1219
[4] Heterocycles, 1997, vol. 45, # 7, p. 1345 - 1361
[5] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8828 - 8830
[6] Patent: WO2011/94560, 2011, A1, . Location in patent: Page/Page column 54; 56
[7] Patent: US9075014, 2015, B2, . Location in patent: Page/Page column 40; 41
[8] Patent: US2018/65917, 2018, A1, . Location in patent: Paragraph 0379
[9] Canadian Journal of Research, Section B: Chemical Sciences, 1946, vol. 24, p. 208
[10] Patent: EP2857010, 2015, A1, . Location in patent: Paragraph 0102; 0104
  • 32
  • [ 95-01-2 ]
  • [ 131088-02-3 ]
  • [ 131088-00-1 ]
YieldReaction ConditionsOperation in experiment
65% With piperidine; sodium hypochlorite; sulfuric acid In water at 0 - 20℃; for 5 h; Sodium hypochlorite (75 mL, 0.055 mol) and piperidine (4.68 g, 0.055 mol) were cooled to 0° C., combined cautiously and added dropwise over 2 h to a solution of 2,4,-dihydroxybenzaldehyde (6.91 g, 0.05 mol) in 50percent aqueous sulfuric acid (150 mL) while cooling to 0° C.
After three additional hours, the precipitate was collected via filtration in quantitative yield.
1H NMR indicates that it is about 65percent 5-chloro-2,4-dihdroxybenzaldehyde, with the balance being 3-chloro-2,4-dihdroxybenzaldehyde.
The product can be purified via column chromatography and/or repeated recrystallizations from toluene.
However, the 3-chloro-2,4-dihdroxybenzaldehyde does not react in the next reaction, so the product was used without further purification.
32% With sulfuryl dichloride In diethyl ether at 0℃; for 0.5 h; Inert atmosphere In a scintillation vial, 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) was dissolved in ethyl ether (18 ml). The mixture was placed under N2 atmosphere and cooled to 0° C. To the mixture was added sulfuryl chloride (0.91 ml, 11 mmol). The mixture was kept under N2 atmosphere at 0° C. for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate (20 ml). Organic layer was washed with brine, concentrated and chromatographed to yield 5-chloro-2,4-dihydroxybenzaldehyde (0.55 g, 3.2 mmol, 32percent) and 3-chloro-2,4-dihydroxybenzaldehyde (0.233 g, 1.34 mmol, 13.4percent)
Reference: [1] Patent: US8343710, 2013, B1, . Location in patent: Page/Page column 17
[2] Macromolecules, 2010, vol. 43, # 6, p. 2824 - 2831
[3] Patent: US2017/182051, 2017, A1, . Location in patent: Paragraph 0137
  • 33
  • [ 2969-81-5 ]
  • [ 95-01-2 ]
  • [ 152942-06-8 ]
Reference: [1] Journal of the American Chemical Society, 2018, vol. 140, # 44, p. 15114 - 15123
[2] Organic letters, 2000, vol. 2, # 13, p. 1787 - 1790
[3] Patent: US5994378, 1999, A,
  • 34
  • [ 95-01-2 ]
  • [ 189439-24-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 657 - 667
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