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[ CAS No. 100-51-6 ]

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Chemical Structure| 100-51-6
Chemical Structure| 100-51-6
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CAS No. :100-51-6 MDL No. :MFCD00004599
Formula : C7H8O Boiling Point : 203-205°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :108.14 g/mol Pubchem ID :244
Synonyms :

1. Benzyl Alcohol

Safety of [ 100-51-6 ]

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

Application In Synthesis of [ 100-51-6 ]

  • Upstream synthesis route of [ 100-51-6 ]
  • Downstream synthetic route of [ 100-51-6 ]

[ 100-51-6 ] Synthesis Path-Upstream   1~39

  • 1
  • [ 612-62-4 ]
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  • [ 116249-87-7 ]
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1649 - 1655
  • 2
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  • [ 10315-06-7 ]
Reference: [1] ChemSusChem, 2016, vol. 9, # 1, p. 67 - 74
[2] ChemSusChem, 2016, vol. 9, # 1, p. 67 - 74
  • 3
  • [ 6825-20-3 ]
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  • [ 118599-27-2 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 12, p. 2187 - 2190
  • 4
  • [ 3934-20-1 ]
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  • [ 108381-28-8 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.5 h; Reflux
Stage #2: at -78℃; for 1 h;
Step 1. A mixture formed by 2.26 g (20.1 mmol, 1 equiv.) of potass tert-butoxide and 4.3 g (40.2 mmol, 2 equiv.) of compound phenylmethanol in 10 ml of THF was heated under reflux temperature for half an hour. The reaction mixture was cooled down to 0 0C and slowly added drop-wise to 3 g (20.1 mmol, 1 equiv.) of 2,4-dichloropyrimidine dissolved in 15 ml of N,N- dimethyl formamide, maintaining the temperature below -78 0C. After stirring for one hour, it was left to reach room temperature. The mixture was added drop-wise to 100 ml of cold water, obtaining white solid 4-(benzyloxy)-2-chloropyrimidine (3.3 g, 75percent). The compound was determination by LC-MS (LC-MS (m/z) =222.0 [M+H]+)
24%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 1 - 2℃; for 0.5 h;
Stage #2: at 1 - 2℃; for 3.5 h;
To a cooled (1-2° C.) suspension of sodium hydride (60percent in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N2.
This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2° C. (internal thermometer).
The resulting mixture (0.06 M) was stirred at temp <2° C. for 2.5 hrs, then quenched with NH4Cl(sat.) and extracted with EtOAc.
Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24percent). LC/MS=221.0 (M+H), LC=3.93 min.
Reference: [1] Organic Letters, 2017, vol. 19, # 7, p. 1854 - 1857
[2] Chemistry - A European Journal, 2017, vol. 23, # 58, p. 14563 - 14575
[3] Patent: WO2011/19405, 2011, A1, . Location in patent: Page/Page column 107
[4] Patent: US2011/195980, 2011, A1, . Location in patent: Page/Page column 28
[5] Patent: EP1564212, 2005, A1, . Location in patent: Page 13
  • 5
  • [ 100-52-7 ]
  • [ 1073-06-9 ]
  • [ 65-85-0 ]
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Reference: [1] Dalton Transactions, 2018, vol. 47, # 11, p. 3705 - 3716
  • 6
  • [ 100-02-7 ]
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  • [ 103-14-0 ]
  • [ 588-53-4 ]
YieldReaction ConditionsOperation in experiment
82% at 24.84℃; for 8 h; Irradiation General procedure: A quantity of 20 mg of catalyst was placed in a 20 mL Schrunkglass bottle (1) which was filled with N2 at a pressure of 1 bar. Benzylalcohols (5 mmol) and nitroarenes (0.5 mmol) were mixed fullyin a Schrunk glass bottle (2) and nitrogen was bubbled to removedissolved oxygen molecules. The mixed solution was transferredto bottle (1) under 1 atm N2 and stirred to make the catalyst blendevenly in the solution. The suspensions were irradiated by a 300WXe arc lamp (PLS-SXE300, Beijing Perfect Light Co.), and an IR-cutfilter was used to remove all wavelengths longer than 800 nm.After the reaction, the mixture was centrifuged to completelyremove the catalyst particles. The remaining solution was determinedby an Agilent online gas chromatograph (GC 6890, FID) withan HP-5973 mass spectrometer. An HP-5 column (length 30 m;inner diameter 320 mm; film thickness 0.25 mm) was applied forseparation of product. Helium (purity 99.999percent) was used as thecarrier gas at a constant flow rate of 20 mL min-1. The temperaturesof the injector and detector were maintained at 280 and300 °C, respectively. The pressure of injection was set at 8.363psi. The column temperature was programmed from 40 to 180 °Cat 15 °C/min, and then up to 280 °C at 15 °C/min, and held 5 min.The injection volume was 5 μl. Conversion of nitroarenes andselectivity for secondary amines were as follows:
Reference: [1] Journal of Catalysis, 2018, vol. 361, p. 105 - 115
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  • [ 2050-16-0 ]
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Reference: [1] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2856 - 2860
  • 8
  • [ 100-02-7 ]
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  • [ 103-14-0 ]
Reference: [1] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2467 - 2473
  • 9
  • [ 123-30-8 ]
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  • [ 103-14-0 ]
  • [ 588-53-4 ]
Reference: [1] Green Chemistry, 2010, vol. 12, # 7, p. 1281 - 1287
  • 10
  • [ 107-15-3 ]
  • [ 100-51-6 ]
  • [ 104-71-2 ]
Reference: [1] European Journal of Organic Chemistry, 2013, # 23, p. 5160 - 5164
  • 11
  • [ 106-48-9 ]
  • [ 100-51-6 ]
  • [ 120-32-1 ]
Reference: [1] Synthetic Communications, 2008, vol. 38, # 15, p. 2684 - 2691
[2] Journal of the American Chemical Society, 1933, vol. 55, p. 4639,4640
  • 12
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  • [ 1234-35-1 ]
Reference: [1] Chemische Berichte, 1932, vol. 65, p. 1192,1198
  • 13
  • [ 96-48-0 ]
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  • [ 10385-30-5 ]
Reference: [1] Journal of Organic Chemistry, 1967, vol. 32, p. 1844 - 1846
  • 14
  • [ 108-30-5 ]
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  • [ 103-40-2 ]
YieldReaction ConditionsOperation in experiment
93.8% With dmap; triethylamine In dichloromethane at 20℃; a)
Succinic acid monobenzyl ester
To the ice-cooled solution of benzyl alcohol (12.96 g, 120 mmol) in methylene chloride (300 mL) was added triethylamine (25 mL, 180 mmol), 4-dimethylaminopyridine (610 mg, 5 mmol) followed by dropwise addition of succinic anhydride (10 g, 100 mmol).
The reaction mixture was stirred at room temperature overnight and washed with 1N HCl (2*100 mL) and brine (100 mL).
The organic layer was dried (Na2SO4) and concentrated.
The residue was dissolved in ethyl acetate (150 mL) and extracted with saturated aqueous NaHCO3 (3*150 mL).
The combined aqueous layers were acidified with concentrated HCl to pH=1-2, and extracted with methylene chloride (4*250 mL).
The combined organic layers were dried (Na2SO4) and concentrated to give the title acid (19.5 g, 93.8percent).
1H NMR (400 MHz, CDCl3) δ: 11.80-10.50 (br, 1H), 7.35 (m, 5H), 5.15 (s, 2H), 2.70 (m, 4H).
89% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; General procedure: To a solution of succinic anhydride (1.0g, 10mmol) in DMF (4mL) was added benzyl alcohol (0.94mL, 9.09mmol) and DIEA (1.93mL, 11mmol) at 0°C. The reaction mixture was stirred at room temperature overnight and was evaporated in Speed-vac. The residue was dissolved in ethyl acetate (50mL) and washed with saturated NaCl (10mL×2). The organic solution was extracted with aqueous NaHCO3 (5M, 5mL×3) and the aqueous extractions were combined, acidified to pH 4 by adding citric acid (5M), extracted with ethyl acetate (30mL×3). The EtOAc extractions were combined, washed with saturated NaCl, and dried over Na2SO4. Solvent was removed by evaporation in vacuo to give a white solid (1.66g, 89percent); 1H NMR (200MHz, CDCl3) δ 7.38 (s, 5H), 5.18 (s, 2H), 2.73–2.71 (m, 4H); LC–MS (ESI−) 207.0 (100percent).
88% With dmap In tetrahydrofuran for 18 h; Reflux A solution of succinic anhydride (1.0 g, 10 mmol), benzyl alcohol (1.14 g,11 mmol), and DMAP (54 mg, 0.44 mmol) in THF (5 mL) was refluxed for 18 h. The mixture was bacified with sat. NaHCO3, and washed with AcOEt. The aqueous layer was then acidified, and the precipiated solid was extracted with AcOEt. The solid was recrystalized to afford succinic acid monobenzyl ester as colorless needles, 1.85 g, 88percent. 1H NMR (400 MHz, CDCl3) d. 2.65–2.73 (m, 4H,CH2CH2), 5.15 (s, 2H, PhCH2), and 7.31–7.38 ppm(s, 5H, aromatic).
85% With dmap; triethylamine In dichloromethane at 20℃; for 18 h; Method B: Succinic anhydride (5 g, 50.0 mmol) was dissolved in anhydrous DCM (40 mL). Benzyl alcohol (5.69 mL, 55.0 mmol), triethylamine (7.50 mL, 55.0 mmol), and a catalytic amount of DMAP were added to this solution. The resulting clear solution was stirred at room temperature for 18h, after which the, all the volatiles were removed under vacuum. The crude residue was taken up in diethyl ether (200 mL) and was extracted with 2N NaOH (2 χ 75 mL). The aqueous extracts were carefully acidified to pH 2 with concentrated HC1 and then extracted with diethyl ether (2 χ 100 mL). The organic layer was dried (Na2S04), filtered and concentrated to give the title compound as a white solid (8.84 g, 85 percent). M.p. 52-54 °C, lit. 56-57 °C; 1H NMR (300 MHz, acetone-tfc): δ 2.68-2.71 (m, 4H, 2 χ CH2), 5.14 (s, 2H, CHiAr), 7.34-7.36 (m, 5H, ArH).
77% With pyridine; dmap In dichloromethane 3-Hydroxyflavone-3-hemisuccinate (15) was produced according to the reaction outlined in Figure 3. Reaction of succinic anhydride (11) and benzyl alcohol (12) in the presence of 4-dimethylaminopyridine (DMAP) and pyridine in dichloromethane produced the succinic acid monobenzyl esteT (13) as white crystalline flakes in 77percent yield. This protected succinic acid derivative was coupled to 3-hydroxyflavone (1) in the presence of DCC and DMAP, forming flavone-3-hemisuccinate monobenzyi ester(14) as yellow or brown oil that solidified upon standing, with yields of up to 96percent produced.The deprotection of the monobenzyl ester to form the corresponding hemisuccinate using a Pd(OAc)2 in the THF:EtOH;acetic acid solvent system, a larger scale reaction was undertaken to yield the requiτed 3-hydrosyflavone-3-hernisuccinate (15).
71% With dmap In dichloromethane at 0 - 25℃; for 96 h; Example 14; 1-(((4-(benzyloxy)-4-oxobutanoyl)oxy)methyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium iodide (Compound 14)Synthesis of 4-(benzyloxy)-4-oxobutanoic acidSuccinic anhydride (7 g, 70.0 mmol) and benzyl alcohol (8.7 mL, 83.9 mmol) were combined in dichloromethane (350 mL) at 0° C. and DMAP (0.85 g, 7.0 mmol) was added portion-wise. The reaction was allowed to gradually warm to 25° C. and stirred for 4 days. The reaction mixture was washed with 1M HCl (3.x.200 mL) then water (300 mL). The organic phases were then extracted with aq saturated NaHCO3 (3.x.300 mL). This was then acidified with conc HCl until pH 1 resulting in a solid precipitating which was filtered then dissolved in dichloromethane. The dichloromethane was dried (MgSO4) and concentrated in vacuo to give 4-(benzyloxy)-4-oxobutanoic acid (10.36 g, 71percent).1H-NMR (300 MHz, CDCl3) δ 7.41-7.29 (5H, m), 5.15 (2H, s), 2.74-2.63 (4H, m).
70.47% at 100℃; for 2 h; A mixture of 5.0 g (0.05 mol) of succinic acid anhydride, 5.4 g (0.05 mol) of benzyl alcohol, 16.25 g (0.05 mol) of cesium carbonate, and 50 ml of N,N-dimethylforamide was stirred at 100° C. for 2 hours.
The reaction mixture was cooled to room temperature, and then poured into 200 ml of ethyl acetate.
The mixture was washed with saturated aqueous NaCl containing 0.35 N HCl (3*100 mL).
The ethyl acetate phase, which contains the product, was collected and dried over anhydrous MgSO4.
The MgSO4 was removed via filtration, and the ethyl acetate was removed under reduced pressure.
The crude product was purified by crystallization in diethyl ether and hexane to provide 7.34 g of succinic acid monobenzyl ester, 70.47percent.
63.29% With dmap In tetrahydrofuran at 50℃; for 5 h; Succinic anhydride 1 (5.00 g, 49.96 mmol), benzyl alcohol (5.94 g, 54.96 mmol)And 4-dimethylaminopyridine (DMAP, 61 mg, 0.50 mmol) was added to 50 mL of tetrahydrofuran, and the mixture was heated to 50 ° C and stirred under heating for 5 hours.The solvent was removed under reduced pressure, 100 mL of ethyl acetate was added to the residue, washed with saturated sodium bicarbonate (100 mL) with,Discard the organic layer, adjust the water layer to pH=2 with dilute hydrochloric acid (1 mol/L), and filter.The filter cake was dried to obtain a white solid of 6.58 g, and the yield was 63.29percent.
57%
Stage #1: at 100℃; for 0.5 h; Microwave irradiation
Stage #2: With water In ethyl acetate at 20℃; for 2 h;
Succinic acid anhydride (0.66 g, 6.6 mmol) and benzyl alcohol (0.65 g, 6.0 mmol) were dissolved in CH2Cl2 (5 mL) and the mixture was kept under stirring in a microwave reactor (Biotage Initiator 8) at 100 °C (pressure: ca 7 bar) for 30 min. The solvent was removed under reduced pressure and the residue was taken up in EtOAc (80 mL) and water (10 mL). The mixture was stirred at rt for 2 h, washed with 5percent KHSO4 (2 * 20 mL) and brine (20 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the colorless oil was subjected to column chromatography (eluent: CH2Cl2/EtOAc 10:1 to CH2Cl2/EtOAc 2:1). The volatiles were removed from the eluate under reduced pressure, CH2Cl2 (20 mL) was added, the solvent was evaporated, and the process repeated. Product 10 was obtained as colourless oil, which crystallized during drying in vacuo to give a white compact solid (0.71 g, 57percent) mp 55-56 °C (lit.;31 mp 56-57 °C). Rf = 0.3 (CH2Cl2/EtOAc 5:1). 1H NMR (300 MHz, [D4]MeOH): δ (ppm) 2.57-2.68 (m, 4H), 5.13 (s, 2H), 7.26-7.38 (m, 5H). C11H12O4 (208.21).
57.7% With dmap In tetrahydrofuran at 50℃; for 5 h; The succinic anhydride (10g, 0.1mol), benzyl alcohol (11.88g, 0.11mol), 4- dimethylaminopyridine (DMAP) (120mg) was added to a 100ml flask, THF (50ml) as solvent, the outside temperature 50 ° C reaction 5h. The reaction solution was concentrated, ethyl acetate was added, the organic layer was successively washed with water, saturated NaHCO3 solution, saturated brine, dried over anhydrous Na2SO4, and concentrated to a solid with isopropyl ether / acetone and recrystallized to give a white solid 12g, yield 57.7percent,
48% for 4 h; Reflux Benzyl succinic acid was synthesized by following a known procedure.33 Here, succinic anhydride (30 g, 300 mmol) was dissolved in benzyl alcohol (31.6 mL, 33 g, 300 mmol), and the resulting solutionwas heated at reflux for 4 h. The reaction mixture was dissolvedin ether (100 mL), and the insoluble succinic acid wasremoved by filtration. The filtrate was extracted with saturatedaqueous Na2CO3 (3 100 mL), and the combined aqueous extractswere acidified with 2 M HCl (2.0 L). The precipitate was collectedby filtration and dried under vacuum to give 2 (30 g, 48percent). 1HNMR (CDCl3, 300 MHz) d 7.35 (m, 5H), 5.15 (s, 2H), 2.70 (m, 4H).13C NMR (CDCl3, 75 MHz) d 177.7, 172.1, 135.7, 128.8, 128.5,128.4, 66.9, 29.1, 29.0.
250 g With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene for 5 h; Reflux A solution of Succinic anhydride (184 grams, 1.84 mol), Benzyl alcohol (200 grams, 1.849 mol) and PTSA (1 gram, 5.25 mmol) in Xylene (1200 ml) was stirred at reflux temperature for 5 hours. The reaction mixture was cooled to room temperature, poured onto 10percent Sodium bicarbonate solution (2500 ml), aqueous layer washed with Ethyl acetate (500 ml), pH made acidic with dil HCl, extracted with Chloroform, dried over Sodium sulphate, distilled under reduced pressure, precipitated the residue by using Hexane to give pure Succinic acid mono benzyl ester (250 grams) as white powder with a melting point of 61-63° C. The product was characterized by IH NMR (CDCl3) δ 2.70 (m, 4H, CH2X2), 5.20 (s, 2H, CH2), 7.35 (m, 5H, Ar), 10.25 (bs, 1H, COOH).
18.5 g With pyridine In tetrahydrofuran at 20℃; for 120 h; 10.0 g (100 mmol) of succinic anhydride, 10 ml of THF (tetrahydrofuran), 10.8 g (100 mmol) of benzyl alcohol and 4 ml of pyridine were combined and stirred for 5 days at ambient temperature. The solution was diluted with toluene. The mixture was extracted with a saturated solution of sodium hydrogen carbonate. The water phase was separated, and acidified with hydrochloric acid. The product was extracted with toluene to yield 18.5 g of succinic acid monobenzyl ester.

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YieldReaction ConditionsOperation in experiment
75.3% With triethylamine In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere; Cooling with ice Take compound 3-9, 42g (207.92mmo1) was placed in a 500mL round bottomed flask, was added 300mL of anhydrous tetrahydrofuran, 66mL (455.44mmol, 46g) of anhydrous triethylamine were dissolved with stirring. When the flask was placed in an ice-salt bath until the system temperature was lowered to 0 the right, under nitrogen was added dropwise over anhydrous benzyl alcohol 45mL (416.67mmol, 45g), was added dropwise maintaining temperature of the system is always near 0 , IH complete after the suspension was added dropwise to give a white solid containing the ice bath was removed to room temperature, stirring was continued at room temperature for 3h stirring was stopped to stand 10min, filtered off with suction, washed solid was tetrahydrofuran, the filtrate was collected, rotary evaporated to give tetrahydrofuran was no liquid column liquid chromatography to give an oil 54.0g, a yield of 75.3percent.
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  • [ 100-51-6 ]
  • [ 110223-15-9 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With sodium hydride In 1-methyl-pyrrolidin-2-one for 0.5 h;
Stage #2: at 80℃; for 24 h;
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80percent) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82percent). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
82%
Stage #1: With sodium hydride In 1-methyl-pyrrolidin-2-one for 0.5 h;
Stage #2: at 80℃; for 24 h;
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80percent) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82percent). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
53.76%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: at 100℃; for 15 h;
Sodium hydride (188.6 mg, 4.72 mmol) in N, N- dimethylformamide (3 mL) was slowly added dropwise at room temperature and benzyl alcohol was dissolved in it and it was stirred at room temperature for 1 hour. It was added dropwise slowly to a mixture of 2-amino-3-chloro-pyrazine and heating at 100 °C refluxed for 15 hours. After cooling the reaction to room temperature and the solvent was evaporated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filter and concentrate under reduced pressure . By separation and purification of the residue by column chromatography (ethyl acetate / n-hexane = 1/4) to obtain the objective compound 300 mg at a yield of 53.76percent.
53.8%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h; Inert atmosphere; Schlenk technique
Stage #2: at 100℃; for 15 h; Inert atmosphere; Schlenk technique
General procedure: Sodium hydride (60percent in mineral oil, 0.04 g, 1 mmol) was addedto a stirred solution of benzyl alcohol derivative (1 mmol) inanhydrous N,N-dimethylformamide (3 mL of DMF) at room temperatureand stirring was continued for 1 h. 2-Amino-3-chloropyrazine (8b, 0.13 g, 1 mmol) was added to the reactionmixture and the reaction mixture was stirred at 100 °C for 15 h.After cooling, the solvent was evaporated and the residue waspartitioned betweenwater and dichloromethane. The organic layer was dried over sodium sulfate anhydrous, filtered, and concentrated.The residue was purified by column chromatography (SiO2,EA/n-Hex 1/5). 4.1.2.1 3-(Benzyloxy)pyrazin-2-amine (9g) Yellow solid, yield: 53.8percent, 1H NMR (400 MHz, CDCl3) δ = 5.45 (2H, s, OCH2Ph), 6.20 (2H, br, NH2), 7.38-7.48 (7H, m, ArH). Reported [ 48,49].

Reference: [1] Patent: WO2005/34837, 2005, A2, . Location in patent: Page/Page column 43-44
[2] Patent: WO2005/34837, 2005, A2, . Location in patent: Page/Page column 43-44
[3] Patent: KR101481952, 2015, B1, . Location in patent: Paragraph 0797; 0798
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 529 - 543
[5] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1639 - 1643
[6] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[7] MedChemComm, 2014, vol. 5, # 3, p. 333 - 337
[8] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 268 - 278
  • 29
  • [ 6863-73-6 ]
  • [ 100-51-6 ]
  • [ 110223-15-9 ]
  • [ 132972-99-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1639 - 1643
  • 30
  • [ 100-51-6 ]
  • [ 113400-36-5 ]
Reference: [1] Patent: US2014/248242, 2014, A1,
  • 31
  • [ 100-51-6 ]
  • [ 105891-54-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 44, p. 8537 - 8545
  • 32
  • [ 927-58-2 ]
  • [ 100-51-6 ]
  • [ 126430-46-4 ]
YieldReaction ConditionsOperation in experiment
83% With potassium carbonate In dichloromethane for 2 h; To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83percent yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H).
82% With dmap In dichloromethane at 20℃; for 2 h; [00140] Benzyl alcohol (3.1 ml_, 30 mmol) was added to a solution of Compound 1 (3.47 ml_, 30 mmol) and 4-dimethylaminopyridine (732 mg, 6 mmol) in dichloromethane (100 ml_). The reaction was stirred for 2 hours at room temperature then quenched with 1 M HCI (100 ml_). The organic phase was washed once more with 1 M HCI (100 ml_), dried over MgS04, filtered, dried by rotary evaporation and was dried under vacuum to yield Compound 2 as a colorless oil (6.29 g, 24.5 mmol, 82percent).
Reference: [1] Patent: US2006/189603, 2006, A1, . Location in patent: Page/Page column 57
[2] Patent: WO2016/86026, 2016, A1, . Location in patent: Paragraph 00140
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 26, p. 5176 - 5182
[4] Synthesis, 2010, # 6, p. 953 - 958
[5] Patent: EP1724278, 2006, A1, . Location in patent: Page/Page column 44-45
  • 33
  • [ 2623-87-2 ]
  • [ 100-51-6 ]
  • [ 126430-46-4 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With S-phenyl benzenethiosulfinate; diisopropyl-carbodiimide In dichloromethane at 20℃; for 2 h;
General procedure: General Procedure for Benzyl Protection of the Bromo-Acid (1c, 1d) [0103] Diisopropylcarbodiimide (DIC) (3.59 mmol, 1.3 eq) was added to a mixture of the bromo-acid (4-bromobutyric acid or 5-bromovaleric acid) (2.76 mmol, 1 eq) and DPTS (3.04 mmol, 1.1 eq) in dry DCM (30 mL) and was allowed to react for 2 hours at room temperature. Benzyl alcohol (4.14 mmol, 1.5 eq) was added and allowed to react overnight. The reaction was washed water and brine, and the DCM was removed by evaporation. Hexanes was added and the resulting white precipitate was removed by filtration. The hexanes was removed from the filtrate by evaporation resulting in an oil which was purified by silica gel chromatography (Hexanes/Ethyl Acetate 3.5/1). Benzyl 4-bromobutyrate (1c) [0104] 70percent yield [0105] 1H NMR (500 MHz, CDCl3) 2.22 (p 2H), 2.58 (t, 2H), 3.48 (t, 2H), 5.16 (s, 2H), 7.40 (m, 5H) [0106] 13C NMR (125 MHz, CDCl3): 28.0, 32.7, 33.0, 66.7, 128.5, 128.6, 128.9, 136.1, 172.6
Reference: [1] European Journal of Organic Chemistry, 2008, # 15, p. 2592 - 2600
[2] Advanced Synthesis and Catalysis, 2007, vol. 349, # 3, p. 432 - 440
[3] Journal of Organic Chemistry, 2001, vol. 66, # 12, p. 4115 - 4121
[4] Journal of the American Chemical Society, 2011, vol. 133, # 41, p. 16346 - 16349
[5] Patent: US2013/302258, 2013, A1, . Location in patent: Paragraph 0102; 0103; 0104; 0105; 0106
[6] Chemistry - A European Journal, 2016, vol. 22, # 4, p. 1270 - 1276
[7] Patent: EP1544208, 2005, A1, . Location in patent: Page/Page column 58
  • 34
  • [ 348-61-8 ]
  • [ 100-51-6 ]
  • [ 1036724-54-5 ]
  • [ 133057-82-6 ]
Reference: [1] Tetrahedron Letters, 2008, vol. 49, # 31, p. 4588 - 4590
  • 35
  • [ 100-51-6 ]
  • [ 1000896-40-1 ]
YieldReaction ConditionsOperation in experiment
6%
Stage #1: With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 10 - 15℃; for 0.666667 h;
Stage #2: at 5 - 25℃; for 61 h;
5-benzyloxy-1H-pyrazol-3-amine, used as starting material, was obtained as follows: i) A solution of 5-amino-2H-pyrazol-3-ol (6.0 g, 60.6 mmol) was stirred in dichloromethane (75 ml). Triphenylphosphine (19.06 g, 72.7 mmol) was added and the mixture was then cooled to 5-10mC. Di-iso-propylazodicarboxylate (14.31 ml, 72.7 mmol) was added dropwise over a period of 20 minutes, maintaining the internal temperature <15° C. The mixture was then held at 10° C. for a further 20 minutes. Benzyl alcohol (7.52 ml, 72.7 mmol) was added dropwise and the mixture stirred at 5-10C for 1 hour and then allowed to warm to room temperature and stirred under nitrogen for 60 hours. The mixture was filtered and the filtrate was then extracted with 1 M hydrochloric acid (3.x.) and the combined extracts washed with dichloromethane (1 5 ml). The aqueous phase was basified with sodium bicarbonate (6.7 g) and the mixture was then extracted with dichloromethane (2.x.40 ml). The combined organic extracts were evaporated to leave a brown oil which was purified by chromatography on silica eluting with a mixture of 0-3percent methanol in dichloromethane. The fractions containing product were combined and then evaporated to leave 5-benzyloxy-1H-pyrazol-3-amine (0.67 g, 6percent yield). 1H NMR (300 MHz, CDCl3): 5.05 (s, 1H), 5.12 (s, 2H), 7.25-7.45 (m, 5H).MS: m/z 190 (MH+).; 5-Phenylmethoxy-2H-pyrazol-3-amine (also named as 5-benzyloxy-1H-pyrazol-3-amine), used as starting material was prepared as in Example 72.
Reference: [1] Patent: US2008/4302, 2008, A1, . Location in patent: Page/Page column 96; 105
  • 36
  • [ 100-51-6 ]
  • [ 477889-91-1 ]
  • [ 1083329-33-2 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[2] Organic and Biomolecular Chemistry, 2009, vol. 7, # 24, p. 5103 - 5112
  • 37
  • [ 100-51-6 ]
  • [ 1229006-21-6 ]
Reference: [1] Patent: EP2602260, 2013, A1,
  • 38
  • [ 100-51-6 ]
  • [ 1246616-66-9 ]
Reference: [1] Patent: US2012/22251, 2012, A1,
[2] Patent: EP2602260, 2013, A1,
[3] Patent: CN108101838, 2018, A,
  • 39
  • [ 26452-80-2 ]
  • [ 100-51-6 ]
  • [ 1006052-55-6 ]
YieldReaction ConditionsOperation in experiment
87%
Stage #1: With potassium hydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 18 h; Inert atmosphere
A suspension of KH (1.08 g, 27 mmol) in dry THF (80 mL) at 0 °C under N2, was treated with benzyl alcohol (1.7 mL, 16.2 mmol) and stirred for 1 h. Then, a solution of 2,4-dichloropyridine 5 (1.5 mL, 13.5 mmol) in THF (5 mL) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NH4Cl (20 mL) and the organic solvent was removed in vacuo. The product was extracted from the residual aqueous layer with CH2Cl2 (3 x 50 mL), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (light petroleum/Et2O 8:2) to yield compound 7 as a pale yellow oil (2.58 g, 87percent); Rf = 0.56 (light petroleum/Et2O 8:2). 1H NMR (300 MHz, CDCl3) δ 5.46 (s, 2H), 6.87-6.89 (m, 2H), 7.33-7.52 (m, 5H), 8.09 (dd, 1H, J = 4.7, 1.8 Hz).
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 64, p. 23 - 34
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