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Product Details of [ 139-85-5 ]

CAS No. :139-85-5 MDL No. :MFCD00003370
Formula : C7H6O3 Boiling Point : -
Linear Structure Formula :- InChI Key :IBGBGRVKPALMCQ-UHFFFAOYSA-N
M.W : 138.12 Pubchem ID :8768
Synonyms :
Catechaldehyde;Protocatechuic aldehyde;NSC 22961;3,4-Dihydroxybenzaldehyde;Rancinamycin IV
Chemical Name :3,4-Dihydroxybenzaldehyde

Calculated chemistry of [ 139-85-5 ]

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) : -6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.79
Log Po/w (XLOGP3) : 1.09
Log Po/w (WLOGP) : 0.91
Log Po/w (MLOGP) : 0.18
Log Po/w (SILICOS-IT) : 1.02
Consensus Log Po/w : 0.8

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.76
Solubility : 2.39 mg/ml ; 0.0173 mol/l
Class : Very soluble
Log S (Ali) : -1.89
Solubility : 1.78 mg/ml ; 0.0129 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 : 1.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 139-85-5 ]

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

Application In Synthesis of [ 139-85-5 ]

* 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 [ 139-85-5 ]
  • Downstream synthetic route of [ 139-85-5 ]

[ 139-85-5 ] Synthesis Path-Upstream   1~49

  • 1
  • [ 139-85-5 ]
  • [ 10288-72-9 ]
Reference: [1] Patent: US2011/87027, 2011, A1,
[2] Patent: WO2012/49555, 2012, A1,
[3] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 380 - 396
  • 2
  • [ 106-93-4 ]
  • [ 139-85-5 ]
  • [ 29668-44-8 ]
YieldReaction ConditionsOperation in experiment
97% With caesium carbonate In DMF (N,N-dimethyl-formamide) at 70℃; for 16 h; Example 42; - preparation of 5-f f2,3-dihydro-f .41-benzodioxin)-6-vimethvf)amino}-N- (2-r2-dimethvlamino )ethvll-1 H-benzordelisoguinolin-1,3(2H)-dione; The synthetic route of this compound proceeds in a series of steps schematically shown in attached figure 2 and is described in more details as follows; a); in a first step, 500 mg 3,4-dihydroxybenzaldehyde, 2.6 g cesium carbonate (2 equivalents), 1.4 g 1,2-dibromoethane (2 equivalents) and 5 mL anhy-drous DMF were stirred at 70°C for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue was submitted to a flash chromatography (Si02, eluent : CH2CI2), thus resulting in 575.3 mg (yield : 97 percent) of the intermediate shown as product A in figure 2 ;
86% With potassium carbonate In acetone at 60℃; for 36 h; Inert atmosphere To a solution of 3,4-dihydroxybenzaldehyde (20, 10 g, 72.40 mmol) in acetone (100 mL) was added K2CO3 (20 g, 144.92 mmol), then 1,2-dibromoethane (19 g, 101.44 mmol) was added dropwise under N2 atmosphere. The mixture was stirred for 36 h at 60. The resulting reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/petroleum ether (1:4, v/v) to provide the intermediate (21, 10.5 g, 86percent yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.43 (dd, J = 8.3, 1.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.36-4.34 (m, 2H), 4.31-4.29 (m 2H). 13C NMR (101 MHz, DMSO-d6) δ 191.26 (s), 149.04 (s), 143.73 (s), 130.24 (s), 123.68 (s), 117.78 (s), 117.70 (s), 64.59 (s), 63.89 (s).
74% With potassium carbonate In N,N-dimethyl-formamide at 60 - 90℃; for 8 h; 138 mg of 3,4-dihydroxybenzaldehyde was dissolved in 5 ml of N,N-dimethylformamide.Add 100 mg of 1,2-dibromoethane and 300 mg of potassium carbonate,60-90°C reaction for 8 hours. After the reaction is over, the system is quenched with water.Extract three times with 30 ml of ethyl acetate and wash with saturated saline.Dry over anhydrous magnesium sulfate, filter, and concentrate to obtain intermediate 120 mg1,4-benzodioxane-7-carbaldehyde, yield 74percent, untreated,Used directly for the next reaction.
73% With potassium carbonate In acetone at 50 - 60℃; Industry scale SYNTHETIC PREPARATION 5
Synthesis of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Compound of formula (11)
A 2000 L reactor was charged with acetone (404.5 kg), followed by potassium carbonate (256 kg, 1852 mol) and 1,2-dibromoethane (241.5 kg, 1298 mol).
The mixture was heated at reflux.
A 500 L reactor was charged with acetone (606 kg) and 3,4-dihydroxybenzalhdehyde (128 kg, 926 mol).
The contents of the 500 L reactor were added to the 2000 L reactor at a rate of 150-180 kg/h while the reaction temperature was maintained at 50-60° C.
The reaction mixture was stirred at 54-60° C. for 12 h, was cooled to 20° C. and was filtered through a 500 L Nutsche filter.
The filter cake was washed with acetone (2*202 kg).
The filtrate and acetone washes were combined in a 2000 L reactor and the resultant solution was concentrated to dryness under reduced pressure at a temperature <40° C.
To the residue was added ethyl acetate (683 kg) and the resultant solution was washed with a 5percent by weight aqueous solution of potassium carbonate (256 kg).
The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed.
This washing procedure was repeated three times in total.
The organic phase was temporarily set aside into drums.
A 2000 L reactor was charged with the combined aqueous washes, followed by ethyl acetate (113.9 kg).
The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed.
The organic phase from the drums was added to the reactor followed by a 28percent by weight aqueous solution of sodium chloride (192 kg).
The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed.
The organic phase was concentrated under reduced pressure at a temperature <45° C. until the mixture's ethyl acetate content was below 10percent (as determined by gas chromatography).
Petroleum ether (268.8 kg) was added to the residue at a rate of 80-90 kg/h while the mixture was maintained at a temperature of 35-45° C.
The mixture was cooled to 5° C. over 3 h and held at this temperature for a further 1 h, during which time a precipitate was deposited.
The resultant slurry was filtered through a centrifugal filter and dried to afford 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (111.4 kg, 73percent) as an off-white solid: purity (HPLC-UV at 230 nm) 99.3percent.
67% With potassium carbonate In acetone for 25 h; Reflux Anhydrous potassium carbonate (21 g) was added in portions to a stirred solution of 27.6 g of 3,4-dihydroxy benzaldehyde in 100 ml of dry acetone followed by the dropwise addition of 4.3 ml of ethylene dibromide. Another 21 g of potassium carbonate and 4.3 ml of ethylene dibromide were added similarly and this was repeated twice more using a total of 84 g of potassium carbonate and 17.2 g of ethylene dibromide. Stirring and refluxing was continued for another 25 h. The reaction mixture was then filtered by sintered glass funnel and the solid residue was washed several times with acetone. The combined filtrate was concentrated to about 25 ml and the residue was poured onto crushed ice, asolid was separated which was filtered, dried and crystallized with methanol to give a low melting solid; mp 35-37 °C; 67percent yield; 1H NMR (300 MHz, DMSOd6): δ 4.30 (2H, d, J = 8.7 Hz, CH2-2), 4.33 (2H, d, J = 8.7, CH2-3), 7.03 (1H, d,J = 8.4 Hz, ArH-8), 7.36 (1H, d, J = 2.5 Hz, ArH-5), 7.43 (1H, dd, J = 8.4, 2.5 Hz, ArH-7), 9.79 (1H, s, Ar-CHO).
63% With potassium carbonate In N,N-dimethyl-formamide at 100 - 110℃; General procedure: 43.80 g potassium carbonate (0.32 mol) and 15.1 cm3 1,2-dibromoethane (32.90 g, 0.18 mol) were added to a solutionof 22.00 g 13 (0.16 mol) or 26.70 g 15 (0.16 mol) in250 cm3 DMF. The reaction mixture was stirred at100–110 C for 4–8 h. After cooling to rt, the precipitatedinorganic salts were filtered and the reaction mixture wasevaporated to 80 cm3 in vacuo. The residue was pouredinto 670 cm3 water. The product was isolated as specified.2,3-Dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (16) Theaqueous phase was extracted with ethyl acetate(4 9 200 cm3), and the combined organic layer waswashed with brine and dried over Na2SO4. The crudeproduct was purified by distillation in vacuo to afford 16.Yield: 63percent; white solid; m.p.: 48–49 C (Ref. [63] 49.5–50.5 C); b.p.: 105–108 C (0.3 mbar); 1H NMR(300 MHz, CDCl3): d = 9.82 (s, 1H, CHO), 7.42–7.38 (m,2H, 5-HAr and 7-HAr), 6.98 (d, J = 8.7 Hz, 1H, 8-HAr),4.35–4.28 (m, 4H, OCH2CH2O) ppm; 13C NMR (75 MHz,CDCl3): d = 64.0 (OCH2CH2O), 64.7 (OCH2CH2O), 117.8(5-CAr or 8-CAr), 118.4 (5-CAr or 8-CAr), 124.2 (7-CAr),130.7 (6-CAr), 143.9 (4a-CAr), 149.1 (8a-CAr), 190.7(CHO) ppm; IR (KBr): m = 3001, 2883, 1687, 1581, 1506,1458, 1394, 1291, 1156, 1062, 887, 777 cm-1.
25 g With tetrabutylammomium bromide; sodium hydroxide In water for 5 h; Reflux In this step, 3,4-dihydroxybenzaldehyde was used as a starting material,And 1,2-dibromoethane in the alkaline environment for the reduction reaction, the synthesis of intermediate 2,3-dihydro-1,4-benzodioxane-6-carbaldehyde. The base used in the present reaction includes: potassium hydroxide, The condensing agent is an ammonium bromide compound such as tetrabutylammonium bromide; The molar ratio used was 3,4-dihydroxybenzaldehyde: 1,2-dibromoethane = 1: 5; The use of sodium hydroxide in excess of 5 times, under strong alkaline conditions for testing. The temperature used was the reflux temperature.

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[6] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 380 - 396
[7] Patent: CN108117534, 2018, A, . Location in patent: Paragraph 0844; 0845; 0846
[8] Patent: US2011/87027, 2011, A1, . Location in patent: Page/Page column 11
[9] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 24, p. 7251 - 7254
[10] Monatshefte fur Chemie, 2018, vol. 149, # 12, p. 2265 - 2285
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[12] Farmaco, Edizione Scientifica, 1983, vol. 38, # 4, p. 265 - 273
[13] Yakugaku Zasshi, 1957, vol. 77, p. 478,479[14] Chem. Zentralbl., 1957, vol. 128, p. 14728
[15] Journal of the Chemical Society, 1937, p. 49,52
[16] Patent: WO2010/75469, 2010, A1, . Location in patent: Page/Page column 123
[17] Patent: US2011/9628, 2011, A1, . Location in patent: Page/Page column 43
[18] Patent: WO2012/49555, 2012, A1, . Location in patent: Page/Page column 56
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[24] Patent: CN105801556, 2016, A, . Location in patent: Paragraph 0006; 0011; 0012
[25] Fitoterapia, 2018, vol. 129, p. 25 - 33
  • 3
  • [ 107-06-2 ]
  • [ 139-85-5 ]
  • [ 29668-44-8 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2018,
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 23-24, p. 3634 - 3638
  • 4
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  • [ 656-42-8 ]
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 3, p. 902 - 905
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  • [ 2316-26-9 ]
Reference: [1] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 119
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Reference: [1] Pharmazie, 1994, vol. 49, # 8, p. 573 - 575
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YieldReaction ConditionsOperation in experiment
80.6% With sodium hydrogencarbonate; potassium iodide In acetonitrile at 60 - 80℃; Example 9 N-(2-cvano- 1 -( 1 -hvdroxy-7-isopropoxy- 1.3-dihvdrobenzo [c] [ 1.2"|oxaborol-6-yloxy) propan-2-yl)-4-(trifluoromethoxy)benzamide Into a round-bottom flask equipped with a stir bar are placed 3,4-dihydroxybenzaldehyde (10.0 g, 72.5mmol), sodium bicarbonate (7.91 g, 94.2mmol), KI (2.07 g, 14.5mmol) and MeCN (200mL). The flask is fitted with a refluxing condenser and slowly heated to 60°C. At this time, benzyl bromide (8.5mL, 72.5mmol) is added and the mixture heated to 80°C. After refluxing overnight, the mixture is then cooled to rt and concentrated by rotary evaporation. The residue is quenched with 10percent aq. HCl (50mL) and extracted with EtOAc (3 x lOOmL). The combined organic extracts are washed with brine (lOOmL), dried with Na2S04, filtered, and concentrated. The resulting oil is purified by flash chromatography (Si02, 100percent hexane until removal of benzyl bromide, then PE: EA=6:1) to afford an amorphous yellow solid (13.3 g, yield 80.6percent).
63% With potassium carbonate In acetone for 4 h; Reflux To a solution of 3,4-dihydroxybenzaldehyde (2.03g, 14.7mmol) in acetone (150mL) was added K2CO3 (3.05g, 22.1mmol) and benzyl bromide (1.74mL, 14.7mmol). After stirring at reflux for 4h, the reaction mixture was filtered through Celite®535RVS and concentrated in vacuo. The residue was purified by column chromatography eluted with toluene/EtOAc (13:1) to give 4-(benzyloxy)-3-hydroxybenzaldehyde (2.12g, 63percent) as a colorless prism. 1H NMR (300MHz, CDCl3) δ 5.21 (2H, s), 5.77 (1H, s), 7.05 (1H, d, J=8.2Hz), 7.37–7.43 (7H, m), 9.86 (1H, s); 13C NMR (75MHz) δ 71.2, 111.5 114.4, 124.4, 127.9, 128.8, 128.9, 130.8, 135.2, 146.3, 150.9, 191.0; IR (ATR) 3201, 1671, 1604, 1577, 1511, 1454, 1389, 1343, 1283, 1165, 1151, 1015, 962, 874, 811, 786, 738, 698, 678cm−1; EIMS m/z (relative intensity) 228 [M]+ (40), 91 (100); HR-EIMS m/z: [M]+ calcd for C14H12O3 228.0786; found 228.0789; mp 120.0–122.0°C.
62% With potassium carbonate; potassium iodide In acetone for 5 h; Reflux To a solution of 3,4-dihydroxybenzaldehyde (10.0 g, 72.4 mmol) and benzyl bromide (12.4 mmol, 72.4 mmol, 1.0 eq.) in acetone (400 mL) was added K2C03 (15.0 g, 109 mmol) and KI (1.2 g, 7.14 mmol) and the mixture was heated at reflux for 5 h. The solid was removed by filtration and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (DCM/Pet. Ether, 0-100percent, v/v) to give the product (9.2 g, 62percent) as a white solid. TLC: Rf = 0.65 (silica gel, Pet.ether/EtOAc=4/l,v/v); MR: (400 MHz, CDC13) δ ppm 9.83 (s, 1H), 7.42 (m, 7H), 7.03 (d, J= 8.3 Hz, 1H), 6.00 (s, 1H), 5.20 (s, 2H).
60% With sodium hydrogencarbonate In acetonitrile at 60 - 80℃; 3,4-Dihydroxybenzaldehyde (10 g, 72.5 mmol) was dissolved in acetonitrile (150 mL).Add sodium bicarbonate (8 g, 94.3 mmol), warm to 60 ° C, add benzyl bromide (12.4 g, 72.5 mmol),Then the temperature was raised to 80 ° C and stirred overnight. The acetonitrile was removed by concentration, and 10percent aqueous hydrochloric acid (200 mL) was added to the residue.Extract with ethyl acetate (150 mL * 3), combine and dry.Filtration, concentration, and residue were purified by column chromatography to yield 10 g (yield: 60percent).
51% With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide 0187] Benzyl bromide (9 mL, 0.073 mol, 1.05 eq) was added to a stirred solution of 3,4-dihydroxybenzaldehyde (10 g, 0.07 mol, 1 eq), tetra-n-butylammonium iodide (29.4 g, 0.077 mol, 1.1 eq) and cesium carbonate (24.8 g, 0.073 mol, 1.05 eq) in N,N-dimethylformamide (200 mL). The reaction mixture was stirred overnight, and then concentrated in vacuo. The residual solution was diluted with ethyl acetate (200 mL) and washed with water (2.x.200 mL). The organic solution was then extracted with 0.5M aqueous sodium hydroxide (5.x.200 mL), and the basic extracts combined and washed with ethyl acetate (400 mL), then acidified to pH 1 with concentrated HCl and back extracted with ethyl acetate (2.x.300 mL). The organic extracts were combined, washed with brine (200 mL), dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid, which was recrystallized from ethyl acetate and petroleum ether to give the product as a brown powder (8.4 g, 51percent). 1H NMR (CDCl3) δ 9.84 (s, 1H, OC-H), 5.84 (s, 1H, OH), 5.21 (s, 2H, CH2Ph).
50% With potassium carbonate In acetone at 20℃; for 15 h; Inert atmosphere A mixture of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol), benzyl bromide (1.71 g, 10 mmol), and K2CO3 (1.24 g, 9 mmol) in 20 mL acetone was <n="111"/>stirred at rt for 15 h under Ar atmosphere. Solid was filtered off and the filtrated was diluted with EtOAc (100 mL) and washed with NaH2PO4 (sat. 100 mL), and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford 4-(benzyloxy)-3-hydroxybenzaldehyde as a white solid(1.15 g, 50percent). 1H NMR (400 MHz, CDC13) δ 9.84 (s, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 7.44-7.40 (m, 6 H), 7.04 (d, J = 8.0 Hz, 1 H), 5.80 (s, 1 H), 5.21 (s, 2 H); MS(ESI) m/z 229 (M+H+).
49%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5 h; Inert atmosphere; Cooling with ice
Stage #2: at 20℃; for 18 h; Inert atmosphere; Cooling with ice
An ice cooled, stirred suspension of 60percent sodium hydride/oil (1.76 g, 44 mmol) in anhydrous DMF (40 mL) under nitrogen was treated dropwise with a solution of   3,4-di-hydroxybenzaldehyde (5.525 g, 40 mmol) in anhydrous DMF (40 mL) and the mixture was stirred at room temperature for 30 min and recooled on an ice bath.   Benzyl bromide (5.25 mL, 44 mmol) was then added via syringe and the mixture allowed to reach room temperature and stirred overnight (18 h). The mixture was combined with 1percent aqueous sodium hydroxide (300 mL) and the cloudy solution was extracted with ether (2 × 75 mL) and acidified with concentrated hydrochloric acid. A precipitate soon formed, and the resulting suspension was stirred for a few minutes and filtered. The solid was rinsed with water, partially air dried, dissolved in dichloromethane (100 mL), and dried (Na2SO4). The solution was added directly to a column of silica gel and eluted with dichloromethane to yield a solid, which was triturated from petroleum ethers to afford 4-benzyloxy-3-hydroxybenzaldehyde (4.46 g, 49percent) as a white solid: mp 122–123 °C (lit.38 121–122 °C); LC/MS m/z 229 [M+H]; 1H NMR (CDCl3, 400 MHz) δ 5.20 (s, 2H), 5.92 (s, 1H), 7.03 (d, J = 8.3, 1H), 7.35–7.44 (m, 6H), 7.46 (d, J = 1.9, 1H), 9.82 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 71.5, 111.7, 114.6, 124.4, 128.0, 128.9, 129.0, 131.0, 135.4, 146.5, 151.1, 191.1. Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.91; H, 5.19.

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YieldReaction ConditionsOperation in experiment
60% With sodium hydrogencarbonate; sodium iodide In N,N-dimethyl-formamide at 40℃; for 5 h; To the solution of 3,4-dihydroxybenzaldehyde (27, 285 mg, 2.00 mmol) in DMF (10 mL), NaHCO3 (252 mg, 3.00 mmol), NaI (90 mg, 0.600 mmol), and benzyl chloride (460 μL, 4.00 mmol) were added. The mixture was stirred at 40 °C overnight, acidified with 10percent HCl (20 mL) and the product extracted with ethyl acetate (3 .x. 15 mL). The combined organic phases were washed with brine (2 .x. 10 mL), dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified with flash column chromatography using ethyl acetate/petroleum ether as an eluent. Yield, 60percent (276 mg); white crystals; mp 105-108 °C (lit. [11] 118-120 °C); IR (KBr) ν = 3200, 2931, 2870, 1672, 1605, 1578, 1512, 1454, 1389, 1344, 1284, 1223, 1166, 1116, 1017, 1008, 963, 874, 812, 786, 739, 699, 647 cm-1. 1H NMR (CDCl3) δ 5.23 (s, 2H, CH2), 5.81 (s, 1H, OH), 7.06 (d, 1H, 3J = 8.1 Hz, Ar-H-5), 7.42-7.49 (m, 7H, Ar-H), 9.87 (s, 1H, CHO).
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[8] Organic Letters, 2005, vol. 7, # 23, p. 5325 - 5327
[9] Journal of the American Chemical Society, 2008, vol. 130, # 7, p. 2351 - 2364
[10] ChemMedChem, 2017, vol. 12, # 10, p. 728 - 737
[11] Tetrahedron Asymmetry, 2005, vol. 16, # 9, p. 1645 - 1654
[12] Helvetica Chimica Acta, 1963, vol. 46, p. 2604 - 2612
  • 9
  • [ 100-44-7 ]
  • [ 139-85-5 ]
  • [ 4049-39-2 ]
  • [ 50773-56-3 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 0℃; for 12 h;
To a solution of 3,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol) in DMF (100 mL) at 0°C under N2 was added NaH (60percent dispersion in mineral oil, 2.90 g, 72.4 mmol) and the mixture was stirred at 0°C for 0.5 h. Benzyl chloride (4.12 g, 32.6 mmol) was then added dropwise and stirring was continued at 0°C for 12 h. The mixture was diluted with water (200 mL), extracted with EtOAc and the organic extracts were dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography (EtO Ac/Pet. Ether, 0-25percent, v/v) followed by rinsing with a 25percent EtO Ac/Pet. ether solution to give the product, which contained a small amount of the undesired 4-benzyloxy isomer (G2-a). Further purification by column chromatography (DCM Pet. Ether, 0-100percent, v/v) then enabled separation and gave the desired product G-a (4.5 g, 60percent) and the minor isomer G2-a (0.3 g, 4percent) as white solids. TLC: Rf = 0.70( silica gel, Pet.ether/EtOAc=4/l,v/v); LCMS: m/z 229 1 [M+H]+, 251.0 [M+Naf; 1HNMR: (400 MHz, CDC13) δ ppm 9.77 (s, 1H), 7.50 (d, J= 1.6 Hz, 1H), 7.41 (m, 6H), 7.06 (d, J= 8.0 Hz, 1H), 6.54 (s, 1H), 5.15 (s, 2H).
Reference: [1] Patent: WO2014/56038, 2014, A1, . Location in patent: Paragraph 123-125
  • 10
  • [ 100-39-0 ]
  • [ 139-85-5 ]
  • [ 5447-02-9 ]
  • [ 4049-39-2 ]
  • [ 50773-56-3 ]
Reference: [1] Helvetica Chimica Acta, 2002, vol. 85, # 7, p. 2009 - 2055
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 18, p. 2053 - 2063
  • 11
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  • [ 100-51-6 ]
  • [ 4049-39-2 ]
Reference: [1] Synlett, 2010, # 19, p. 2947 - 2949
  • 12
  • [ 100-39-0 ]
  • [ 139-85-5 ]
  • [ 5447-02-9 ]
  • [ 4049-39-2 ]
Reference: [1] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 2935 - 2938
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 18, p. 2053 - 2063
  • 13
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  • [ 139-85-5 ]
  • [ 5447-02-9 ]
  • [ 4049-39-2 ]
  • [ 50773-56-3 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1985, # 6, p. 311 - 314
  • 14
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Reference: [1] Tetrahedron, 2005, vol. 61, # 34, p. 8101 - 8108
[2] Journal of Organic Chemistry, 2003, vol. 68, # 22, p. 8500 - 8504
[3] Heterocycles, 1996, vol. 43, # 3, p. 665 - 674
[4] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 7, p. 1736 - 1745
[5] European Journal of Organic Chemistry, 2012, # 20, p. 3863 - 3870
[6] Nature Communications, 2017, vol. 8, # 1,
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6563 - 6580
  • 15
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  • [ 139-85-5 ]
  • [ 24677-78-9 ]
Reference: [1] Patent: US6331555, 2001, B1,
[2] Patent: US5990141, 1999, A,
  • 16
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  • [ 120-80-9 ]
  • [ 24677-78-9 ]
  • [ 139-85-5 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1992, vol. 31, # 8, p. 543 - 546
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1992, vol. 31, # 8, p. 543 - 546
  • 17
  • [ 139-85-5 ]
  • [ 4228-66-4 ]
Reference: [1] Asian Journal of Chemistry, 2013, vol. 25, # 13, p. 7158 - 7160
[2] Patent: CN103570546, 2016, B,
[3] Patent: CN103570547, 2016, B,
[4] Advanced Synthesis and Catalysis, 2017, vol. 359, # 21, p. 3773 - 3781
  • 18
  • [ 139-85-5 ]
  • [ 1570-05-4 ]
Reference: [1] Archives of Pharmacal Research, 2011, vol. 34, # 7, p. 1065 - 1070
  • 19
  • [ 109-77-3 ]
  • [ 139-85-5 ]
  • [ 118409-57-7 ]
Reference: [1] Journal of Physical Organic Chemistry, 2012, vol. 25, # 12, p. 1261 - 1268
[2] Tetrahedron Letters, 1999, vol. 40, # 38, p. 7031 - 7033
[3] Journal of Medicinal Chemistry, 1989, vol. 32, # 10, p. 2344 - 2352
[4] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 5, p. 416 - 418
[5] Justus Liebigs Annalen der Chemie, 1924, vol. 437, p. 143
[6] Journal of Medicinal Chemistry, 1991, vol. 34, # 4, p. 1503 - 1505
[7] Journal of Medicinal Chemistry, 2000, vol. 43, # 8, p. 1550 - 1562
[8] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 1, p. 181 - 186
  • 20
  • [ 110-89-4 ]
  • [ 109-77-3 ]
  • [ 139-85-5 ]
  • [ 118409-57-7 ]
Reference: [1] Patent: US5217999, 1993, A,
  • 21
  • [ 1895-39-2 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 2 h;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide
Stage #3: With sodium hydroxide In water; N,N-dimethyl-formamide
[00434] To a solution of 3,4-dihydroxybenzaldehyde (300 mg, 2.2mmol) in DMF (9.0 mL) and H2O (1.0 mL) was added sodium chlorodifluoroacetate (1.33 g) and K2CO3 (729 mg). The mixture was heated up to 100°C for 2 h before cooling down to rt. Concentrated HCl (1.54 mL) and H2O (2.0 mL) were added and the reaction was stirred overnight. The mixture was neutralized with IN NaOH to pH > 9, extracted with EtOAc, washed with brine, dried over MgS O4 and concentrated. The crude product was purified by silica gel chromatography to give 132 A (470 mg, 90percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.29 - 6.89 (m, 2 H) 7.42 (d, J=8.35 Hz, 1 H) 7.66 - 7.90 (m, 2 H) 9.95 (s, 1 H).
65% With potassium carbonate In water; N,N-dimethyl-formamide at 80℃; for 16 h; Sodium chlorodifluoroacetate (88 g, 58mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (20 g, 14 mmol), potassiumcarbonate (80 g, 58 mmol) and water (10 mL, 58 mmol) in DMF (200 mL). Thesuspension was heated to 80 °C for 16h and then cooled to rt and diluted with water. The aqueous phase was extractedwith EtOAc and the combined organic fractions were washed with water, brine,dried and concentrated. The residue was partially purified by columnchromatography, eluting with 5-10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde(22.5 g, 65percent) as a colourless oil; δH (400 MHz, CDCl3)6.60 (t, J = 72 Hz, 1H, OCHF2), 6.64 (t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6= 8.0 Hz, 1H, H5), 7.76–7.78 (m,2H, H2, H6), 9.96 (s, 1H, CHO); δC(125 MHz, CDCl3) 115.2 (t, J= 259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.The 3,4-bis(difluoromethoxy)benzaldehyde coeluted with approximately 10-20percentunidentified colourless oil: δH (400 MHz, CDCl3) 7.13 (s,1H), 7.19 (d, J = 8.0 Hz, 1H), 7.30(s, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.61(dd, J = 1.5 Hz, 8.0 Hz, 1H), 9.91(s, 1H).
Reference: [1] Patent: WO2006/76246, 2006, A2, . Location in patent: Page/Page column 220
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
[3] Patent: WO2009/20642, 2009, A1, . Location in patent: Page/Page column 69
[4] Patent: US2010/35931, 2010, A1, . Location in patent: Page/Page column 17
  • 22
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
YieldReaction ConditionsOperation in experiment
39.5% With potassium carbonate In hexane; ethyl acetate; N,N-dimethyl-formamide Step 1
3,4-Bis(difluoromethoxy)benzaldehyde
A suspension of 3,4-dihydroxybenzaldehyde (6.9 g, 50 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) in N,N-dimethylformamide (400 mL) was cooled to -45~C. Chlorodifluoromethane was bubbled into the mixture until 19 g had been dissolved (219 mmol).
A dry ice condenser was installed and the temperature was raised gradually to 85.infin. C., and kept at that temperature for 16 hours.
After cooling to room temperature, the mixture was carefully diluted with water (600 mL) and extracted 4 times with ether, the extracts were washed 3 times with brine, dried and evaporated.
The residue was chromatographed on silica gel, eluding with a 1:3 mixture of ethyl acetate and hexane, to afford the desired product as a colorless liquid (4.7 g, 39.5percent).
1 H NMR (400 MHz, acetone-d6) d 7.13 (t, large J, 1H); 7.20 (t, large J, 1H); 7.58 (d, 1H); 7.87 (s, 1H); 7.93 (d, 1H); 10.04 (s, 1H).
38% With potassium carbonate In <i>N</i>-methyl-acetamide 2a.
3,4-Bisdifluoromethoxybenzaldehyde
A vigorously stirred mixture of 3,4-dihydroxybenzaldehyde (40 g, 290 mmol) and powdered potassium carbonate (120 g, 870 mol) in dimethylformamide (500 mL) was heated under an atmosphere of chlorodifluoromethane at 80° C. for 7 h and then was stirred at room temperature overnight.
The mixture was diluted with ether and was filtered.
The filtrate was concentrated under reduced pressure, the residue was partitioned between ether and aqueous potassium carbonate and was extracted five times with ether.
The organic extract was washed with aqueous potassium carbonate and dried (potassium carbonate).
The solvent was removed in vacuo and the residue was purified by flash chromatography, eluding with 4;1 hexanes/ether, to provide an oil (26.2 g, 38percent).
38% With potassium carbonate In <i>N</i>-methyl-acetamide 2a.
3,4-Bisdifluoromethoxybenzaldehyde
A vigorously stirred mixture of 3,4-dihydroxybenzaldehyde (40 g, 290 mmol) and potassium carbonate (120 g, 870 mol) in dimethylformamide (500 mL) was heated under an atmosphere of chlorodifluoromethane at 80° C. for 7 h and then was stirred at room temperature overnight.
The mixture was diluted with ether and was filtered.
The filtrate was concentrated under reduced pressure, the residue was partitioned between ether and aqueous potassium carbonate and was extracted five times with ether.
The organic extract was washed with aqueous potassium carbonate and dried (potassium carbonate).
The solvent was removed in vacuo and the residue was purified by flash chromatography, eluding with 4:1 hexanes/ether to provide an oil (26.2 g, 38percent).
Reference: [1] Patent: US5710170, 1998, A,
[2] Patent: US5449686, 1995, A,
[3] Patent: US5605923, 1997, A,
[4] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 16, p. 2149 - 2152
[5] Patent: WO2005/123748, 2005, A1, . Location in patent: Page/Page column 75
  • 23
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 percent) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); δH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1.
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10percent EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH(400 MHz, CDCl3) 6.60 (t, J= 72 Hz, 1H, OCHF2), 6.64(t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1H, H5), 7.76–7.78 (m, 2H, H2, H6),9.96 (s, 1H, CHO); δC (125MHz, CDCl3) 115.2 (t, J =259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21percent)as a colourless crystalline solid; mp 94–95 °C (recrystallized from EtOAc); δH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); δC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm–1.
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7673 - 7688
[2] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 35
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
  • 24
  • [ 75-45-6 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
  • [ 151103-08-1 ]
Reference: [1] Patent: WO2005/21515, 2005, A2, . Location in patent: Page/Page column 64-65
  • 25
  • [ 75-45-6 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1989, vol. 25, # 11.2, p. 2134 - 2138[2] Zhurnal Organicheskoi Khimii, 1989, vol. 25, # 11, p. 2367 - 2372
  • 26
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
Reference: [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
  • 27
  • [ 621-03-4 ]
  • [ 139-85-5 ]
  • [ 133550-35-3 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1896 - 1907
[2] Patent: US5217999, 1993, A,
  • 28
  • [ 10412-93-8 ]
  • [ 139-85-5 ]
  • [ 133550-30-8 ]
YieldReaction ConditionsOperation in experiment
36% for 3 h; Heating / reflux EXAMPLE 1; General Methodfor Synthesis of Compounds; N- (Phenylalkyl) cinnamides were prepared by the following general procedure. Benzylamine (3. 0g, 28 mmol) and ethyl cyanoacetate (4. 7 g, 42 mmol) in acetonitrile (20 mL) was stirred and reflux for 4 hr. Benzylamine in this general procedure can be replaced by any other substituents depicted as R3 above. The solvent was removed in vacuo to give an oil which solidified upon standing. Precipitation (EtOAc) resulted in 3.28g (68percent) of an off-white powder corresponding to N-benzylcyanoacetamide as an intermediate. A mixture of N- benzylcyanomethylamide (1.3, 7.5 mmol), 3,4-dihydroxybenzaldehyde (1.1 g, 8.2 mmol), and piperidine (catalytic, 5 drops) was stirred at reflux for 3 hr. Flash chromatography (EtOAc) followed by two recrystalizations (H20/EtOH) yielded product as a white powder 0.8g (36percent).
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1896 - 1907
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 17, p. 3412 - 3420
[3] Patent: WO2005/58829, 2005, A1, . Location in patent: Page/Page column 22
  • 29
  • [ 139-85-5 ]
  • [ 848598-50-5 ]
  • [ 104594-70-9 ]
YieldReaction ConditionsOperation in experiment
270 g With piperidine In pyridine; toluene at 95℃; for 15 h; Add 1L of toluene to the 3L reaction flask,SM1 (cyclopropane (isopropyl) isopropyl ester, 240 g, commercially available) was added in succession under mechanical stirringAnd SM2 (phenylethanol, 202 g, commercially available),After the addition,Warm up to 100°C to start timingStop the reaction after 8 hoursCool naturally to cool down to room temperatureSM3 (3,4-dihydroxybenzaldehyde, 160 g, commercially available) was added while stirring was continued.Then add pyridine 166ml and piperidine 17ml,Then it warms up to an internal temperature of 95°C.The reaction was stopped after 15 hours of reaction.Cool down to room temperatureAfter adding 1 L of ethyl acetate, the organic phase was washed successively with 1 L of 1M hydrochloric acid solution and 1 L of saturated saline, and the organic phase was dried over anhydrous sodium sulfate for 30 minutes, filtered, and the organic solvent was evaporated in vacuo to obtain a crude product. 2L n-hexane was filtered after beatingThe cake was vacuum dried in a box at 40°C for 24 hours to give 270 g of a product of caffeic acid phenylethyl ester.
Reference: [1] Journal of Chemical Research, 2005, # 5, p. 332 - 334
[2] Journal of Chemical Research, 2006, # 9, p. 586 - 588
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
[5] Patent: CN107337604, 2017, A, . Location in patent: Paragraph 0071; 0072; 0073; 0074
  • 30
  • [ 627-42-9 ]
  • [ 139-85-5 ]
  • [ 80407-64-3 ]
YieldReaction ConditionsOperation in experiment
96.4% With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 105 - 110℃; Inert atmosphere the 121g (leq) ELTA 1200ml and dimethylformamide (DMF) was stirred clear solution; sequentially added 323g (4eq) 2- chloroethyl methyl ether, 944g (8eq) of anhydrous potassium carbonate and 23.6gTetrabutylammonium bromide; purged with nitrogen three times,Under nitrogen, the reaction was heated to 105~110 ° C 13~14h; the filter cake was rinsed DCM until the filtrate was colorless; the combined filtrate was concentrated under reduced pressure to a fraction distilled off; the residue was added DCM, cooled to room temperature , washed with 3Ν K0H, the DCM phase was separated, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to 45 ° C to give 210g oil ELTB, yield 96.4percent
70% With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 14 h; To a solution of 3,4-dihydroxybenzaldehyde (10 g, 72.5 mmol) (Aldrich) in DMF (200 mL) was added 2-chloroethyl methyl ether (16.5 mL, 181.2 mmol) (Aldrich), potassium carbonate (50 g, 362.3 mmol) and a catalytic amount of potassium iodide (Aldrich).
The reaction mixture was heated at 85° C. for 14 hours.
The reaction mixture was cooled down, diluted with EtOAc and washed with brine.
The organic phase was dried over anhydrous sodium sulfate, evaporated to afford 3,4-bis-(2-methoxy-ethoxy)-benzaldehyde as an oil and was used in the next step without further purification. (Yield 11 g, 70percent).
Reference: [1] Patent: CN105566233, 2016, A, . Location in patent: Paragraph 0015; 0052
[2] Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 435 - 440
[3] Patent: US2012/184548, 2012, A1, . Location in patent: Page/Page column 23; 24
  • 31
  • [ 6482-24-2 ]
  • [ 139-85-5 ]
  • [ 80407-64-3 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dimethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. ^Evaporation yielded 3,4-bis (2-methoxyethoxy) benzaldehyde of formula III (45g, 98percent).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(s, 1 H), 7.45(d, 1 H) and 9.83(s, 1 H).
98% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dmethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. Evaporation yielded 3,4-bis (2- methoxyethoxy) benzaldehyde of formula III (45g, 98percent).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(S1 1H)1 7.45(d, 1 H) and 9.83(s, 1 H).
Reference: [1] Heterocycles, 2007, vol. 71, # 1, p. 39 - 48
[2] Patent: WO2007/138612, 2007, A2, . Location in patent: Page/Page column 9
[3] Patent: WO2007/138613, 2007, A2, . Location in patent: Page/Page column 10
[4] Organic Letters, 2017, vol. 19, # 11, p. 3005 - 3008
  • 32
  • [ 4296-15-5 ]
  • [ 139-85-5 ]
  • [ 80407-64-3 ]
Reference: [1] Patent: US2010/298351, 2010, A1, . Location in patent: Page/Page column 35
  • 33
  • [ 36865-41-5 ]
  • [ 139-85-5 ]
  • [ 80407-64-3 ]
Reference: [1] Patent: WO2007/71348, 2007, A1, . Location in patent: Page/Page column 83-84
  • 34
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
79.4% at 60 - 65℃; for 3 h; The 138.1g (1mol) 3,4- dihydroxybenzaldehyde was added to a concentration of 1L 7mol / L sodium hydroxide solution was added phase transfer catalyst tetrabutylammonium 16.6 g Ammonium, chloro-difluoro-acetic acid methyl ester 180.5g (1.3mol), stirred, solution was reacted at 60 -65 3 hours the reaction is complete, diluted with 1L of water and twice with 500mL ethyl acetate, the aqueous layer was collected, concentrated hydrochloric add was adjusted to pH 2 with 1.5L extracted three times with ethyl acetate, ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to dryness and the residue with petroleum ether - ethyl acetate (3: l) recrystallization, white crystals 149.4g, yield 79.4percent, 99.45percent purity.,
57% With caesium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 0.5 h; Microwave irradiation; Green chemistry Method (a): A suspension of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in an. DMF (15 mL) was stirred under nitrogen atmosphere for 10 min.
Then, Cs2CO3 (3.26 g, 10 mmol) and methyl chlorodifluoroacetate (1.73 g, 12 mmol) were added.
The mixture was stirred at 60-70 °C for 6 h.
After cooling to room temperature, the solution was poured into water (30 mL) and extracted with ethylacetate (3 * 20 mL), washed with brine (3 * 10 mL), dried (MgSO4) and concentrated under reduced pressure.
The obtained oil was purified by Silicagel (100-200 mesh) column chromatography using a mixture of ethylacetate/exane (15:85) as the eluent.
The pure product was obtained as a white solid. Yield: 39percent (lit.:15-30percent).
27
Mp: 86-88 °C.
Method (b):
The 4-(difluoromethoxy)-3-hydroxybenzaldehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaldehyde (0.415 g, 3 mmol)in an. DMF (5 mL), Cs2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate(0.520 g, 3.6 mmol) were added; then the mixturewas irradiated with microwaves, under pressure, increasing theemitted power until 300W in 2 min and at the same time coolingby compressed air to avoid the temperature increasing over 90 C; the irradiation was carried on for further 3 min and then the mixturewas cooled to room temperature, with compressed air, in1 min. The cycle was repeated five times for a total reaction timeof 30 min. The mixture was poured into water (100 mL) andextracted with ethyl acetate (3 20 mL); the organic phase waswashed with water (20 mL), brine (20 mL), dried (MgSO4) and concentratedunder reduced pressure, yielding a brown oil which waspurified by Silicagel (100–200 mesh) column chromatographyeluting with an ethylacetate/exane mixture (15:85). The pureproduct was obtained as a light gray solid. Yield: 57percent (lit. 15–30percent).27 Mp: 86–88 C. 1H NMR (CDCl3): d 6.05 (br s, 1H, OH, 1H disappearswith D2O), 6.65 (t, 1H, J = 72.6 Hz, OCHF2), 7.26 (d, 1H,J = 8.2 Hz, H-5 Ar), 7.45 (dd, 1H, J = 8.2 Hz, 2.0 Hz, H-6 Ar), 7.12(d, 1H, J = 2.0 Hz, H-2 Ar), 9.90 (s, 1H, CHN). IR (KBr) cm1:1687 (CO), 3305 (OH). Anal. C8H6F2O3 (C, H, N).
57% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 0.5 h; Microwave irradiation The 4-(difiuoromethoxy)-3-hydroxybenzaidehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaIdehyde (0.415 g, 3 mmol) in an. DMF (5 mL), CS2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate (0.520 g, 3.6 mmol) were added; then the mixture was irradiated with microwaves, under pressure, increasing the potency until 300 W in 2 minutes and cooling by compressed air to avoid the temperature increasing over 90 °C; the irradiation was carried on for further 3 minutes and then the mixture was cooled to room temperature, with compressed air, in 1 minute. The cycle was repeated five time for a total reaction time of 30 minutes, The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL); the organic phase was washed with water (20 mL), brine (20 mL), dried (MgS04) and concentrated under reduced pressure, yielding a brown oil which was purified by silicagel (100-200 mesh) column chromatography eluting with an ethylacetate /exane mixture (15:85). The pure product was obtained as a light grey solid. (0324) Yield; 57percent (lit.: 15-30percent). Mp: 86-88 °C. -NMR (CDC13): δ 6.05 (br s, IH, OH, 1H disappears with D20), 6.65 (t, J = 72.6 Hz, OCHF2)f 7.26 (d, J = 8.2 Hz, IH, H-5 Ar), 7.45 (dd, J = 8.2, 2.0 Hz, 1H( H-6 Ar), 7.12 (d, J = 2.0 Hz, H-2 Ar), 9.90 (s, IH, CH=N). IR (KBr) (cm's): 1687 (OO), 3305 (OH). Anal. (C8H6F203) C, H. (percent calculated/found) C: 51.07/ 50.96; H: 3.21/ 331.
38% With potassium carbonate In N,N-dimethyl-formamide EXAMPLE 10
Preparation of 4-difluoromethoxy-3-hydroxybenzaldehyde
3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol, Aldrich), methyl chlorodifluoroacetate (0.52 g, 3.62 mmol, Aldrich) and potassium carbonate (0.50 g, 3.62 mmol) were combined in DMF (5.0 mL) under an argon atmosphere.
After stirring at 60°-65° C. for 3 h, DMF was removed in vacuo and the residue was partioned between aqueous 3N HCl and ether.
The aqueous layer was extracted three times with ether.
The combined organic extracts were washed with water, with brine, were dried (MgSO4), filtered and evaporated.
The residue was purified by flash chromatography (silica gel, 25percent ethyl acetate/hexanes) to provide the title compound as a white solid (0.20 g, 38percent).
mp 83°-85° C.
33% With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 3 h; To a solution of 3,4-hydroxybenzaldehyde [1 (Figure2), 1.38 g, 10 mmol] in dimethylformamide (DMF) (20 mL)were added methyl chlorodifluoroacetate (1.39 mL, 13 mmol)and cesium carbonate (4.23 g, 13 mmol). After the mixturerhad been stirred at 70 °C for 3 h under an air atmosphere,DMF was removed in vacuo. The residue was portionedbetween aqueous 3 N HCl and ethyl acetate. Layers wereseparated, and the aqueous layer was extracted with ethylacetate (3 × 30 mL). Combined organic layers were washedwith brine, dried over Na2SO4, and concentrated in vacuo. Thecrude product was purified by flash chromatography (5:1hexane/EtOAc) to afford compound 2 (0.61 g, 33percent) as awhite solid: 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.45 (dd, J = 4.0, 8.4 Hz, 1H), 7.28 (d, J =8.4 Hz, 1H), 6.67 (t, J = 72.8 Hz, 1H), 6.17 (br s, 1H).

Reference: [1] Patent: CN105254559, 2016, A, . Location in patent: Paragraph 0035; 0036
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3426 - 3435
[3] Patent: WO2015/121212, 2015, A1, . Location in patent: Paragraph 46-47
[4] Patent: US5731477, 1998, A,
[5] Biochemistry, 2018, vol. 57, # 30, p. 4518 - 4525
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
[7] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 16, p. 2149 - 2152
  • 35
  • [ 1895-39-2 ]
  • [ 139-85-5 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
57.5% With sodium carbonate In water; N,N-dimethyl-formamide at 80℃; for 6 h; In a 100 ml round bottom flask, 3,4-dihydroxybenzaldehyde (5.1 g, 36.9 mmol, 1.0 eq), Na2CO3(11.73 g, 110.7 mmol, 3.0 eq) was suspended in 250 mL of DMF, 8.57 g of sodium chlorodifluoroacetate, (56.1 mmol, 1.5 eq) in 20 ml of water was added and the temperature was raised to 80 ° C for 6 hours. The reaction solution was adjusted to pH 5-6 with 1.0 M / L hydrochloric acid and extracted with ethyl acetate 20 mL x 3. The organic phase was collected and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography. Stripping Ethyl Acetate: Petroleum Ether (1:20) to give A3.99 g of monosubstituted compound, 57.5percent yield, 0.26 g of disubstituted product, yield 3.75percent
46% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 3,4-dihydroxybenzaldehyde (1.66 g, 12 mmol)and sodium chlorodifluoroacetate (1.83 g, 12 mmol) in DMF (15 mL) and water (0.3 mL) was added sodium hydroxide (0.48 g,12 mmol). Then, the mixture was heated at 120° C and stirred at this temperature for 2 h. The solvent was removed by vacuum distillation, and to the residue was added aqueous HCl (2 mL). The mixture was extracted with Et2O and washed with brine.The solvent was removed under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/EtOAc = 80:20) to afford 12 as a white solid (1.05 g,5.28 mmol, 46percent). ESI-MS (m/z): 187.4 ([MH]).
44%
Stage #1: With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h;
Stage #2: With hydrogenchloride In water
A solution of 3,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and sodium chlorodifluoroacetate (18.3 g, 120 mmol) in dimethylformamide (150 ml) and water (3 ml) was added with sodium hydroxide (4.8 g, 120 mmol), heated to 120° C. and stirred at this temperature for 2 hrs.
The solvent was removed by vacuum distillation and the residue added with aqueous hydrochloric acid (20 ml).
The mixture was extracted with diethyl ether (2*50 ml), the combined organic layers were washed with water and brine and the solvent removed under reduced pressure.
The crude product was purified by chromatography on silica gel (hexane/ethyl acetate 8:2) to furnish 4-difluoromethoxy-3-hydroxybenzaldehyde as a colourless solid (10 g, 52.8 mmol, 44percent yield).
39% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; Production Example 19-1
4-(Difluoromethoxy)-3-hydroxybenzaldehyde
Commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and commercially available sodium chlorodifluoroacetate (5.57 g, 36.5 mmol) were dissolved in N,N-dimethylformamide (45 mL) and water (905 μL), and then sodium hydroxide (1.48 g, 37.0 mmol) was added at room temperature, and the mixture was heated and stirred at 120° C. for 2 hours.
The solvent was evaporated under vacuum, the residue was cooled to 0° C., and 5 M hydrochloric acid and diethyl ether were added for partition.
The organic layer was washed with water and a saturated saline solution, and then the solvent was evaporated.
The residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate 9:1-7:3), and then the target fraction was concentrated under vacuum to obtain the title compound (2.66 g, 39percent).
1H-NMR Spectrum (CDCl3) δ (ppm): 5.69-5.74 (1H, m), 6.65 (1H, t, J=72.5 Hz), 7.23-7.31 (1H, m), 7.46 (1H, dd, J=8.4, 1.8 Hz), 7.54 (1H, d, J=1.8 Hz), 9.92 (1H, s).
37% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 3,4-dihydroxybenzaldehyde (41.52 g, 0.3 mol, 1.0 eq) and sodium chloro(difluoro)acetate (45.75 g, 0.3 mol, 1.0 eq) in DMF (375 ml) and water (7.5 ml) was added NaOH (12 g, 0.3 mol, 1.0 eq) and the resulting mixture was heated at 120 °C for 2 h. The solvent was removed by vacuum distillation and aqueous HCl was added to the residue. The mixture was extracted with EA (500 ml x 2) and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EA from 10/1 to 8/1) to afford 4-(difluoromethoxy)-3-hydroxybenzaldehyde (20.86 g, 37percent yield, 99.8percent purity) as a white solid.
36.9% With sodium hydroxide In water; N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 3,4-dihydroxybenzaldehyde (41.52 g, 0.3 mol, 1.0 eq) and sodium chloro(difluoro)acetate (45.75 g, 0.3 mol, 1.0 eq) in DMF (375 ml) and water (7.5 ml) was added NaOH (12 g, 0.3 mol, 1.0 eq) and the resulting mixture was heated at 120 °C for 2 h. The solvent was removed by vacuum distillation and HCl and water were added to the residue. The mixture was extracted with EA (500 ml x 2) and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EA from 10/1 to 8/1) to furnish Intermediate 1 (20.86 g, 36.9percent yield, 99.8percent purity) as a white solid.
24%
Stage #1: With sodium hydroxide In DMF (N,N-dimethyl-formamide) at 55℃; for 16 h;
Stage #2: With hydrogenchloride In DMF (N,N-dimethyl-formamide); water
3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55°C under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10 percent aqueous HC1 followed by extraction with ethyl acetate (3x 500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difluoromethoxy-3- hydroxybenzaldehyde was isolated in 24percent yield (6.62 G). IH NMR (CDC13,400 MHz) 8 6.1 (br s, 1H), 6.48-6. 85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).
24% With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 16 h; Intermediate E Synthesis of 4-difluoromethoxy-3-hydroxybenzaldehyde 3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55° C. under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10percent aqueous HCl followed by extraction with ethyl acetate (3.x.500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difluoromethoxy-3-hydroxybenzaldehyde was isolated in 24percent yield (6.62 g). 1H NMR (CDCl3, 400 MHz) δ 6.1 (br s, 1H), 6.48-6.85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).

Reference: [1] Patent: CN105732348, 2016, A, . Location in patent: Paragraph 0034; 0039; 0040
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[3] Patent: US2008/15226, 2008, A1, . Location in patent: Page/Page column 10
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[5] Patent: US2014/235614, 2014, A1, . Location in patent: Paragraph 0470; 0471; 0472
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4594 - 4597
[7] Patent: WO2013/21021, 2013, A1, . Location in patent: Page/Page column 39; 40
[8] Patent: WO2004/94411, 2004, A1, . Location in patent: Page 111
[9] Patent: US2007/254913, 2007, A1, . Location in patent: Page/Page column 36
[10] Patent: EP2070913, 2009, A1, . Location in patent: Page/Page column 21-22
[11] Patent: CN102964297, 2018, B, . Location in patent: Paragraph 0020-0021; 0277-0278
  • 36
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YieldReaction ConditionsOperation in experiment
37% With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In N,N-dimethyl-formamide for 0.166667 h; Example 1; Preparation of 3-hydroxy-4-difluoromethoxybenzaldehydeBenzyltriethyl ammonium chloride (4.12 g, 0.0182 mol) was added to a solution of 3,4-dihydroxy benzaldehyde (5 g, 0.0362 mol) in dimethylformamide (35 mL). Sodium hydroxide solution (0.0905 mol of 30percent solution) was added dropwise to the resulting reaction mixture for about 10 minutes with a continuous flow of chloro-difluoro methane. The reaction mixture was acidified with dilute hydrochloric acid and then diluted with water. It was extracted with ethyl acetate, washed with saturated solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 10percent ethyl acetate in hexane to furmish the title compound. Yield: 2.5 g (37percent).
25% With potassium carbonate In N,N-dimethyl-formamide at 80 - 85℃; for 4.5 h; To a well stirred suspension of 3,4-dihydroxy benzaldehyde (100 gm) and anhydrous potassium carbonate (120 gm) in dry N,N-dimethyl formamide (1.0 lit) was passed chlorodifluoromethane gas for about 30 minutes at about 80-850C. After an hour another lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The third lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The reaction mixture was then stirred for about 5-6 hours at an ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified through silica gel column to give 4-difluoromethoxy-3 -hydroxy benzaldehyde. Yield: 25-30 percent.
25.3% With potassium carbonate In N,N-dimethyl-formamide at 75 - 80℃; Example 47: Synthesis of ethyl 2-(4-(difluoromethoxy)-8-nitrodibenzo[b,d]furan- l-yl)-l,3-oxazoIe-4-carboxylate; Step 1: Synthesis of 4-(difluoromethoxy)-3-hydroxy benzaldehyde; To a stirred solution of 3,4-dihydroxybenzaldehyde (25 g, 0.181 mol) in DMF (75 mL), potassium carbonate (70 g, 0.507 mol) was added. It was refluxed to 75-80 0C. Chlorodifluoro methane gas was purged into the reaction mixture until 95percent of the starting material was consumed. The reaction mixture was poured into the crushed ice and kept aside. After sometime the aqueous layer was extracted with ethyl acetate (3x500 mL). The organics were dried over sodium sulphate and filtered. The filtrate was evaporated under reduced pressure to give the crude product. The product was purified by column chromatography by using gradient (0-1)percent of ethyl acetate in hexane. The solid obtained was washed with hexane and dried. Yield - 25.3percent. R/ -.0.41 (Ethyl acetate: Hexane (3:7).
Reference: [1] Patent: US2010/29728, 2010, A1, . Location in patent: Page/Page column 9
[2] Patent: WO2008/142542, 2008, A2, . Location in patent: Page/Page column 19
[3] Patent: WO2010/84402, 2010, A2, . Location in patent: Page/Page column 31
[4] Patent: US2014/275551, 2014, A1, . Location in patent: Paragraph 0051
  • 37
  • [ 683-98-7 ]
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  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
90.3% With hydroxylamine In water; acetonitrile at 45℃; 1) hydroxylamine (50wtpercent aqueous solution) (16.5g),3,4-hydroxybenzaldehyde (60.8g, 500mmol),Difluoro methyl bromoacetate (106.6g, 525mmol)Acetonitrile was added to 45 Contacting the reaction is carried out,After completion of the reaction,The reaction solution was added water,Extracted with dichloromethane,concentrate,Recrystallized from petroleum ether to give 3-hydroxy-4-fluoro-methoxybenzaldehyde84.9g,Yield 90.3percent,Purity of 98.66percent.
Reference: [1] Patent: CN105523922, 2016, A, . Location in patent: Paragraph 0023; 0031
  • 38
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 percent) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); δH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1.
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10percent EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH(400 MHz, CDCl3) 6.60 (t, J= 72 Hz, 1H, OCHF2), 6.64(t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1H, H5), 7.76–7.78 (m, 2H, H2, H6),9.96 (s, 1H, CHO); δC (125MHz, CDCl3) 115.2 (t, J =259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21percent)as a colourless crystalline solid; mp 94–95 °C (recrystallized from EtOAc); δH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); δC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm–1.
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7673 - 7688
[2] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 35
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
  • 39
  • [ 139-85-5 ]
  • [ 76-04-0 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
24%
Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 16 h;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide
3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 550C under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10 percent aqueous HCl followed by extraction with ethyl acetate (3x 500 mL).The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difiuoromethoxy-3- hydroxybenzaldehyde was isolated in 24percent yield (6.62 g). 1H NMR (CDCl3, 400 MHz) δ 6.1 (br s, IH), 6.48-6.85 (t, IH OCHF2), 7.26 (d, IH), 7.44 (d, IH), 7.55 (s, IH), 9.91 (s,IH).
Reference: [1] Patent: WO2006/44528, 2006, A1, . Location in patent: Page/Page column 111
  • 40
  • [ 7732-18-5 ]
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  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
19% With hydrogenchloride; sodium hydroxide In 1,4-dioxane PREPARATION 19
4-(Difluoromethoxy)-3-hydroxybenzaldehyde
Dissolved (5.00 g, 36.2 mmol, 1.0 eq) of 3,4-dihydroxybenzaldehyde in 60 ml of 1,4-dioxane, then added 24 ml of H2 O and 36.2 ml (72.4 mmol, 2.0 eq) of 2N NaOH to the above solution at room temperature.
After heating to 70° C. external, chlorodi-fluoromethane was bubbled into the reaction mixture for 50 minutes, maintaining a temperature of 60°-70° C.
The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with 1 L H2 O and the pH adjusted to 5 using 1N HCl.
The aqueous layer was then transferred to a separatory funnel, extracted four times with 300 ml each of ethyl acetate.
The ethyl acetate layers were combined and washed once with brine and dried over anhydrous Na2 SO4.
The crude product was chromatographed over silica gel eluding with 25percent ethyl acetate-hexane.
Yield was 1.30 g, 19percent, as a white solid.
Elemental Analysis:
Calc'd for C8 H6 O3 F2: Calc'd: C, 51.08; H, 3.22. Found: C, 51.10; H, 3.14. NMR (300 MHz, CDCl3): δ6.65 (1H, t), δ9.91 (1H, s). M.P.: 82°-83° C.
Reference: [1] Patent: US5814651, 1998, A,
  • 41
  • [ 75-45-6 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
  • [ 151103-08-1 ]
Reference: [1] Patent: WO2005/21515, 2005, A2, . Location in patent: Page/Page column 64-65
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  • [ 139-85-5 ]
  • [ 151103-08-1 ]
Reference: [1] Patent: US5449686, 1995, A,
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  • [ 139-85-5 ]
  • [ 151103-08-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6900 - 6908
  • 44
  • [ 667-27-6 ]
  • [ 139-85-5 ]
  • [ 151103-08-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6900 - 6908
  • 45
  • [ 139-85-5 ]
  • [ 151103-09-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[2] Patent: US2014/275551, 2014, A1,
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[4] Patent: CN105254559, 2016, A,
[5] Patent: CN105523922, 2016, A,
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