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USD 80+
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Structure of 79-14-1 * Storage: {[proInfo.prStorage]}
* 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.
(5-Methyl-1H-benzimidazole-2-yl)-methanol 25 was prepared using the Phillips procedure [1], 4-Methyl-1,2-phenylenediamine (12.22 g; 0.1 mol) and glycolic acid (11.40 g; 0.15 mmol) in hydrochloric acid (50 ml, 5.5 M) were heated under reflux with for 3 h. The reaction mixture was cooled to room temperature and ammonia solution was added and the mixture cooled in ice until a bright brown precipitate formed. The resulting solid was recrystallised from aqueous ethanol to give (5-methyl-1H-benzimidazole-2-yl)-methanol as a pale creamy powdery solid Yield 100percent.
72%
at 130℃; for 3 h;
General procedure: To a mixture of 1a–1c (10 mmol) with glycolic acid (2.28 g, 30 mmol) was added concentrated H3PO4(20 mL). The reaction mixture was refluxed at 130°C for 3 h, then quenched with 20percent NaOH. The respective solid product was collected by filtration.
70%
at 150℃; for 3 h;
Step 1 The mixture of 4-methyl-benzene-1,2-diamine (500 mg, 4.10 mmol) and hydroxy-acetic acid (374 mg, 4.92 mmol) was heated to 150° C. with stirring for 3 hrs. After cooled to room temperature, the reactant was purified by silica gel column (DCM/MeOH=30/1) to afford (5-methyl-1H-benzoimidazol-2-yl)-methanol (400 mg, yield: 70percent) as a yellow solid.
Reference：
[1] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[2] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1272 - 1274
[3] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 3006 - 3016
[4] Patent: US2018/44324, 2018, A1, . Location in patent: Paragraph 0614
[5] Chemische Berichte, 1912, vol. 45, p. 3495
[6] Journal of the American Chemical Society, 1957, vol. 79, p. 4391,4393
[7] Journal of the Chemical Society, 1950, p. 1600,1602
[8] Biochemische Zeitschrift, 1955, vol. 327, p. 422,447
[9] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 933 - 936
[10] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 584 - 600
2
[ 79-14-1 ]
[ 95-83-0 ]
[ 6953-65-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 150℃; for 4 h;
21 a)A mixture of 4-chlorobenzene-1,2-diamine (105 g, 736 mmoles, 1 eq.) andhydroxyacetic acid (112 g, 2 eq.) in xylene (1500 mL) was stirred at 150 °C for 4 hours. The mixture was then cooled to 60 °C and treated with 3N HC1 (480 ml), then basified to pH=7-8 by the addition of aqueous ammonia. The mixture was filtered and the solid was collected, washed with H20 and tert-butyl methyl ether to give 123 g (82percent yield) of (5 -chloro- 1 H-benzo [d]imidazo l-2-yl)methano 1 21 a.
82%
at 150℃; for 4 h;
A mixture of 4-chlorobenzene-1,2-diamine (105 g, 736 mmoles, 1 eq.) and hydroxyacetic acid (112 g, 2 eq.) in xylene (1500 mL) was stirred at 150°C for 4 hours. The mixture was then cooled to 60°C and treated with 3N HC1 (480 ml), then basified to pH = 7-8 by the addition of aqueous ammonia. The mixture was filtered and the solid was collected, washed with H20 and tert-butyl methyl ether to give 123 g (82percent yield) of (5 -chloro- 1 H-benzo [d]imidazol-2-yl)methanol (7a).
Reference：
[1] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[2] Patent: WO2014/60411, 2014, A1, . Location in patent: Page/Page column 58
[3] Patent: WO2015/158653, 2015, A1, . Location in patent: Page/Page column 37; 38
[4] Annales Pharmaceutiques Francaises, 2003, vol. 61, # 1, p. 57 - 61
[5] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1272 - 1274
[6] Chemische Berichte, 1951, vol. 84, p. 719,727
[7] Journal of the Chemical Society, 1949, p. 1260,1268
[8] Journal of the Chemical Society, 1950, p. 1515,1516
[9] Patent: WO2004/22060, 2004, A2, . Location in patent: Page/Page column 24
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 933 - 936
[11] MedChemComm, 2018, vol. 9, # 7, p. 1194 - 1205
3
[ 79-14-1 ]
[ 99-56-9 ]
[ 20034-00-8 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 130℃; for 3 h;
General procedure: To a mixture of 1a–1c (10 mmol) with glycolic acid (2.28 g, 30 mmol) was added concentrated H3PO4(20 mL). The reaction mixture was refluxed at 130°C for 3 h, then quenched with 20percent NaOH. The respective solid product was collected by filtration.
Reference：
[1] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 3006 - 3016
[2] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1272 - 1274
[3] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[4] Journal of the American Chemical Society, 1952, vol. 74, p. 3689
[5] Journal of the American Chemical Society, 1957, vol. 79, p. 4391,4393
[6] Patent: US2004/209865, 2004, A1,
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 933 - 936
4
[ 94740-40-6 ]
[ 79-14-1 ]
[ 68060-69-5 ]
[ 68-95-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1991, # 10, p. 1595 - 1600
This compound was prepared based on a known methodwith some modification [19, 20]. Mixture of o-phenylenediamine (27 g, 0.25 mol) in 500 mL 4M HCl and glycolic acid (34.2 g, 0.45 mol) in 250 mL 4 M HCl stirred and heated under refluxfor 2 h. Then slowly cooled and resultant mixture was basified with aqueous sodium hydroxidesolution. The solid obtained, filtered, dried and re-crystallized with hot water (Scheme 1). (I:white to light brown powder, m.p. 171-174 oC, 89.1percent yield).
85%
With hydrogenchloride In water at 100℃; for 4 h;
At room temperature,10.0 g (92.6 mmol) of o-phenylenediamine and 20.0 g (263.0 mmol) of glycolic acid were placed in a 250 mL flask,Add 80 mL of 4 mol 1 / L hydrochloric acid and reflux at 100 ° C for 4 h.After completion of the reaction, the reaction solution was cooled to room temperature,Adjusted to pH 8.0 with potassium hydroxide and precipitated in a large amount. The solid was collected by filtration and recrystallized from water. Yield: 85.0percent.
85%
With hydrogenchloride In water; N,N-dimethyl-formamide at 100℃; for 4 h;
The o-phenylenediamine (10.0 g, 92.6 mmol)And glycolic acid (20.0 g, 263.0 mmol) were placed in 250 mL of eggplantFlask, add 80mL 4mol / L hydrochloric acid, 100 reflux 4h. After completion of the reaction, the reaction solution was cooled to room temperature and treated with hydrogenPotassium adjusted to pH 8.0, precipitate a large amount of solid, filter the solid, and recrystallize with water. The yield was 85percent.
81%
at 130℃; for 3 h;
General procedure: To a mixture of 1a–1c (10 mmol) with glycolic acid (2.28 g, 30 mmol) was added concentrated H3PO4(20 mL). The reaction mixture was refluxed at 130°C for 3 h, then quenched with 20percent NaOH. The respective solid product was collected by filtration. (1H-Benzoimidazole-2-yl)methanol (2a). White solid, yield 81percent, mp 169–171°C (177–179°C [18]). 1H NMR spectrum, δ, ppm: 4.69 s (2H, CH2), 5.69 s (1H, OH), 7.12–7.52 m (4H, ArH), 12.31 s (1H, NH).
73%
With hydrogenchloride In water at 100℃; for 3 h;
Step 1: ( lH-Benzo[d]imidazoI-2-yl)methanoiTo a stirred solution of O-phenylenediamine (5 g, 0.046 mol) in 4N HCI (50 mL) was added 2-hydroxyacetic acid (4.2 g, 0.0555 mol) and stirring was continued for 3 h at 100°C. The reaction mixture was cooled to room temperature, neutralized with satu rated sodium bicarbonate solution and the solid obtained was collected by filtration and dried to afford the title compound (3.5 g, 73percent).lNMR (400 MHz, DMSO-d6) : δ 12.28 (brs, 1H), 7.52-7.44 (m, 2H), 7.12 (d, J = 4.80 Hz, 2H), 5.66 (t, J = 6.0 Hz, 1H), 4.68 (d, J=5.2 Hz, 2H) .
73%
With hydrogenchloride In water at 95℃; for 2 h;
(1H-Benzimidazol-2-yl)methanol To a mixture of benzene-1,2-diamine (5.0 g, 46.3 mmol) and glycolic acid (10.5 g, 138.0 mmol) was added 4N HCl (30 mL). The reaction mixture was heated under reflux at 95° C. for 2 h, then cooled to 0° C. and neutralized with saturated aqueous NaOH. The precipitated solid was isolated by filtration and dried in vacuo to afford the title compound (5 g, 73percent) as an off-white solid. δH (d6-DMSO) 12.20 (br s, 1H), 7.49-7.47 (dd, J 5.8, 3.2 Hz, 2H), 7.13-7.11 (dd, J 5.8, 3.2 Hz, 2H), 4.68 (s, 2H). LCMS (ES+) 149 (M+H)+.
65%
With hydrogenchloride In water for 16 h; Reflux
To a well stirred mixture of 1,2-phenylenediamine 17 (1 g, 9.25 mmol) in 6 M HCl (10 ml) was added 67percent w/v glycolic acid (6.30 ml, 55.48 mmol) dropwise, till the suspension was clear. After stirring for 10 min at room temperature, the reaction flask was plugged to a condenser and refluxed overnight. Reaction mixture was cooled and concentrated under overnight ventilation affording the HCl salt of the title compound as needle crystals. The crystals were washed with least amount of cold EtOH on a filter paper and dried in oven at 45 °C overnight. The dried crystals were dissolven in water and then precipitated with 1 M K2CO3 (20 ml) furnishing the title compound as a free base in crude mixture. After the effervescence was settled, the crude residue was extracted with EtOAc (2x), washed with brine and the organic solvent was removed in-vacuo. The pure free base was obtained as white crystals (4.45 g). Yield: 65percent; mp: 165-167 °C; IR (KBr): 3257, 3061, 2931, 1617, 1485, 1440, 1347, 1270, 1048, 876, 746, 681; 1H NMR (300 MHz, DMSO-d6): δ 4.68 (d, J = 5.74 Hz, 2H), 5.63 (t, J = 5.74 Hz, 1H), 7.05-7.22 (m, 2H), 7.48 (dd, J = 3.42, 5.86 Hz, 2H), 12.26 (br s, 1H); MS (EI+) m/z: 148 [M+].
47%
With hydrogenchloride In waterReflux
General procedure: The mixture of appropriate 1,2-diaminobenzene derivatives (0.1 mol) and appropriate carboxylic acid derivatives (0.15 mol) in 100 ml 5N HCl were heated to reflux and stirred for 3-5 hours. After the reaction mixture was cooled to the room temperature and neutralized with sodium bicarbonate. The precipitate formed was filtered by suction filtration, washed with water and dried.
38%
With hydrogenchloride In water for 4 h; Reflux
General procedure: (1H-benzo[d]imidazol-2-yl)methanol was prepared by stirring o-phenylenediamine (1.3 g, 12mmol), and 85percent glycolic acid (2.74 g, 36 mmol, 300 molpercent), in 4 N HCl (40 mL), under reflux for 4 hours. Aftercooling to room temperature, the pH was adjusted to 7, with NaOH. The resulting crystals were filtered, washedwith water and dried in vacuo (0.67 g, 4.4 mmol, 38percent yield).
Reference：
[1] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[2] Bulletin of the Chemical Society of Ethiopia, 2014, vol. 28, # 3, p. 451 - 456
[3] Monatshefte fur Chemie, 2016, vol. 147, # 12, p. 2209 - 2220
[4] Patent: CN106905241, 2017, A, . Location in patent: Paragraph 0127-0129
[5] Patent: CN107118249, 2017, A, . Location in patent: Paragraph 0117; 0118; 0119
[6] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 3006 - 3016
[7] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1272 - 1274
[8] Patent: WO2014/169167, 2014, A1, . Location in patent: Page/Page column 60
[9] Patent: US2015/152065, 2015, A1, . Location in patent: Paragraph 0483
[10] CrystEngComm, 2011, vol. 13, # 3, p. 883 - 888
[11] Journal of Fluorescence, 2011, vol. 21, # 5, p. 2005 - 2013
[12] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 157 - 172
[13] Journal of Pharmacy and Pharmacology, 2014, vol. 66, # 11, p. 1593 - 1605
[14] Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4713 - 4726
[15] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2458 - 2464
[16] Synthesis, 2005, # 7, p. 1069 - 1076
[17] Revue Roumaine de Chimie, 2016, vol. 61, # 1, p. 15 - 22
[18] Annales Pharmaceutiques Francaises, 2003, vol. 61, # 1, p. 57 - 61
[19] Journal of Medicinal Chemistry, 1997, vol. 40, # 26, p. 4199 - 4207
[20] Synthesis (Germany), 2015, vol. 47, # 13, p. 1913 - 1921
[21] Chemische Berichte, 1912, vol. 45, p. 3495
[22] Journal of the Chemical Society, 1928, p. 2395
[23] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1986, vol. 25, # 12, p. 1092 - 1096
[24] Journal of Medicinal Chemistry, 2009, vol. 52, # 5, p. 1345 - 1357
[25] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 933 - 936
[26] Phosphorus, Sulfur and Silicon and the Related Elements, 2013, vol. 188, # 11, p. 1564 - 1575
[27] Patent: WO2015/76801, 2015, A1, . Location in patent: Page/Page column 140
[28] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 584 - 600
[29] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 608 - 621
[30] Molecules, 2016, vol. 21, # 11,
[31] Patent: CN107698577, 2018, A, . Location in patent: Paragraph 0111; 0112; 0113; 0114
[32] MedChemComm, 2018, vol. 9, # 7, p. 1194 - 1205
7
[ 79-14-1 ]
[ 108-45-2 ]
[ 4856-97-7 ]
Reference：
[1] Journal de Chimie Physique et de Physico-Chimie Biologique, 1988, vol. 85, # 2, p. 309 - 314
8
[ 79-14-1 ]
[ 98-86-2 ]
[ 2166-31-6 ]
Yield
Reaction Conditions
Operation in experiment
17.9%
Stage #1: at 110℃; for 2 h; Stage #2: With ammonia In water at 40℃; Stage #3: With hydrazine hydrate In water at 100℃; for 2 h;
Preparation of 6-Phenylpyridazin-3(2H)-one 5-3: (1197) (1198) A mixture of Cpd-5-1(1 g, 13.5 mmol) and 5-2 (4.88 g, 40.5 mmol) was heated at 110°C for 2h, cooled down to 40°C followed by addition of water (4.5 ml) and concentrated aqueous ammonia (1 ml). The reaction mixture was thereafter extracted with DCM, organic part was separated and the ammoniacal aqueous layer was treated with hydrazine hydrate (676 mg, 13.5mmol) followed by heating at 100°C for 2h, reaction mass cooled down to room temperature, precipitate formed was collected by filtration, residue dried under vaccum to afford 6-phenylpyridazin-3(2H)-one 5-3 (417 mg, 2.42 mmol, 17.9 percent) as an off-white solid. LC MS: ES+ 173.3
4-chloro-N1-methylbenzene-1,2-diamine (15.0 g, 96 mmol) and glycolic acid (8.1 g, 106 mmol) were mixed together in a sealed tube. The mixture was heated at 150 C for 5 hours before it was cooled down to room temperature. The residue was purified by flash column chromatography (0-5percent MeOH in CH2CI2) to give the product (8.5 g, 45percent YIELD). H NMR (300 MHz, CDC13) 5 : 3.80 (s, 3 H), 4.86 (s, 2 H), 7.13-7. 22 (m, 2 H), 7.62-7. 64 (m, 1 H).
Reference：
[1] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 131
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1724 - 1730
11
[ 79-14-1 ]
[ 2439-85-2 ]
[ 13831-31-7 ]
[ 5493-24-3 ]
Yield
Reaction Conditions
Operation in experiment
80.6%
With di(rhodium)tetracarbonyl dichloride; triphenylphosphine copper; toluene-4-sulfonic acid In 1,4-dioxane; acetonitrile at 100℃; for 8 h;
At room temperature, 100 mmol of the compound of formula (I)150 mmol of the compound of formula (II)14 mmol of a catalyst (a mixture of 7 mmol of ruthenium tetracarbonyl diboride and 7 mmol of triphenylphosphine copper (Cu (PPh3) Br)160 mmol of acetoxyacetyl chloride and 25 mmol of acidic compound p-toluenesulfonic acid were added to an appropriate organic solvent (a mixture of acetonitrile and 1,4-dioxane in a volume ratio of 2: 1) and then heated to 100 ° C The reaction was stirred at this temperature for 8 hours;After completion of the reaction, the reaction system was filtered and the pH of the filtrate was adjusted to pH with a base, and then distilled under reduced pressure The silica gel column was eluted with an equal volume of a mixture of chloroform and ethyl acetate and distilled again under reduced pressure to give The compound of the above formula (III) having a melting point of 109 to 110 ° C has a yield of 80.6percent.
Reference：
[1] Patent: CN106432049, 2017, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052
Reference：
[1] Synthetic Communications, 1998, vol. 28, # 5, p. 903 - 912
[2] Journal of the American Chemical Society, 2014, vol. 136, # 16, p. 5900 - 5903
[3] Biomacromolecules, 2010, vol. 11, # 8, p. 1930 - 1939
[4] Zeitschrift fuer Physikalische Chemie, Stoechiometrie und Verwandtschaftslehre, 1925, vol. 118, p. 102
[5] Monatshefte fuer Chemie, 1936, vol. 68, p. 372
15
[ 79-14-1 ]
[ 187737-37-7 ]
[ 623-61-0 ]
Reference：
[1] Patent: US2265946, 1939, ,
16
[ 77287-34-4 ]
[ 79-14-1 ]
[ 849585-22-4 ]
[ 2491-15-8 ]
[ 144-62-7 ]
[ 127-17-3 ]
[ 57-13-6 ]
Yield
Reaction Conditions
Operation in experiment
0.002 mg
at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
To a thermometer, condenser,1L four-neck flask trap successively added glycolic acid (70percent) 200 g580 g of n-butanol and acidic ion exchange resin pretreated 10 g (pH = 2.0), heated to 120 ,Adjust the system vacuum, so that the system to maintain a certain amount of return.Use the water separator to separate the water produced by the reaction.After tracking the amount of water to the theoretical amount, stop the reaction, cool to room temperature, filter, with a small amount of n-butanol washing acid resin.The resulting filtrate was recovered by decompression of n-butanol,Distillation gave 224 g of n-butylhydroxyacetate,Purity 99.5percent, yield 92percent.
Reference：
[1] Patent: CN105130801, 2017, B, . Location in patent: Paragraph 0031; 0032; 0033; 0034; 0035; 0036; 0037-0049
[2] Journal of the Chemical Society of Pakistan, 2014, vol. 36, # 6, p. 1109 - 1113
[3] Journal of the American Pharmaceutical Association (1912-1977), 1941, vol. 30, p. 133[4] Chem.Abstr., 1941, p. 6235
[5] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 259
19
[ 79-14-1 ]
[ 71-36-3 ]
[ 502-97-6 ]
[ 7397-62-8 ]
Reference：
[1] Asian Journal of Chemistry, 2013, vol. 25, # 15, p. 8447 - 8450
20
[ 109-65-9 ]
[ 79-14-1 ]
[ 7397-62-8 ]
Reference：
[1] Turkish Journal of Chemistry, 2010, vol. 34, # 2, p. 187 - 191
21
[ 79-14-1 ]
[ 25561-30-2 ]
[ 354-38-1 ]
[ 33581-77-0 ]
[ 55982-15-5 ]
Reference：
[1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
22
[ 67-56-1 ]
[ 131543-46-9 ]
[ 79-14-1 ]
[ 2517-44-4 ]
[ 96-35-5 ]
[ 51673-84-8 ]
Yield
Reaction Conditions
Operation in experiment
11%
for 4 h;
[0041] A 40percent aqueous glyoxal solution was metered at a rate of 0.17 mol/h into the top of a heatable 1 m column (diameter 29 mm) filled with spheres of diameter 5 mm of the catalyst KA-3 (Sud-Chemie). At the same time, gaseous methanol was metered in at the bottom of the column. During the entire reaction, the apparatus was operated under nitrogen as a protective gas. The column was heated. A mixture of water and methanol was collected at the top of the column. The bottom effluent of the column consisted of a mixture of 1,1,2,2-tetramethoxyethane, 2,2-dimethoxyacetaldehyde, methyl 2-hydroxyacetate, 2-hydroxyacetic acid and methanol. The apparatus was operated for 4 hours, and the bottom effluent was analyzed by gas chromatography. According to the analysis, there were 11 g (0.07 mol, 11percent) of 1,1,2,2-tetramethoxyethane.
Stage #1: With caesium carbonate In methanol; water at 20℃; for 0.5 h; Stage #2: at 20℃; for 24 h;
A suspension 2-hydoxyaceticacid 47 (70percent in H2O) (889 mg, 12.0 mmol) and Cs2CO3 (1955 mg, 6.00 mmol) in MeOH (22 mL)/H2O (4 mL) was stirred for 30 min at rt. After that the solvent was removed and the residue was dissolved in DMF (18 mL) cooled at 0°C and after 10 min benzylbromide (2155 mg, 12.6 mmol) was added and the reaction mixture was stirred at rt for 24 h. The reaction mixture was quenched with brine (20 mL) and the organic layer was extracted with ethyl acetate (3x 25 mL), washed with H2O (25 mL), brine (20 mL), dried over MgSO4 and concentrated in vacuo to give 1877 mg (97percent) of Benzyl 2-hydroxyacetate 48 as a colorless liquid.HPLC: 2.68 min (70percent).
94%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0℃;
10127] Glycolic acid (7.60 g, 0.10 mol) was dissolved in10 ml of acetonitrile, into which benzyl bromide (13.60 g,0.08 mol) was added and uniformly stirred. DBU (12.16 g,0.08 mol) was slowly added dropwise into the reaction liquid at 00 C. Afier that, the reaction liquid was stirred overnight at room temperature. The reaction liquid was poured into ice water, extracted with ethyl acetate, the combined resultant organic phase was washed with 1 M hydrochloric acid solution and saturated salt water successively, dried with anhydrous sodium sulfate and concentrated by rotary evaporation to give the compound as a yellow oil (12.50 g, 94percent).
94%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃;
a. Preparation of benzyl glycolate (0150) Glycolic acid (7.60 g, 0.10 mol) was dissolved in 10 ml of acetonitrile, into which benzyl bromide (13.60 g, 0.08 mol) was added and uniformly stirred. DBU (12.16 g, 0.08 mol) was slowly added dropwise into the reaction liquid at 0° C. After that, the reaction liquid was stirred overnight at room temperature. The reaction liquid was poured into the ice water, extracted with ethyl acetate, the combined resultant organic phase was washed with 1M hydrochloric acid solution and saturated salt water successively, dried with anhydrous sodium sulfate and concentrated by rotary evaporation to give the compound as a yellow oil (12.50 g, 94percent).
69%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 100℃; for 24 h;
NaH (6.31 g, 158 mmol) was suspended in dry THF (500 ml) and cooled to 0° C. 2-hydroxyacetic acid (12 g, 158 mmol) was added portion wise, and the mixture was stirred at RT for 1 hour. The solvent was removed, and the residue was suspended in DMF (500 ml); KI (2.488 g, 14.99 mmol) and benzyl bromide (18.77 ml, 158 mmol) were added; and the mixture was heated to 100° C. for 24 hours. The solvent was removed, and the crude was portioned between EtOAc (600 ml) and water (200 ml). The organic phase was washed with brine and dried over Na2SO4. The solvent was removed and the crude was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80/20). Benzyl 2-hydroxyacetate was obtained (18.089 g, 69percent yield).
63%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tolueneReflux
A mixture of 2-hydroxyacetic acid (5.0 g, 65.7 mmol), l,8-diazabicyclo[5.4.0]undec-7- ene (9.9 g, 65.7 mmol) and benzyl bromide (13.0 g, 78.9.mmol) in toluene (150 mL) was refluxed overnight. The reaction mixture was worked up and the crude product was purified by silica gel flash column chromatography (eluent 20-50percent ethyl acetate in hexane) to give tert- butyl benzyl 2-hydroxyacetate (6.9g, yield 63percent) as a colorless oil. *H NMR (400 MHz, CDC13): δ 2.60 (t, / = 5.6 Hz, 1H), 4.19 (d, / =5.6 Hz, 2H), 5.21 (s, 2H), 7.35-7.37 (m, 5H).
59%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 100℃; for 24 h;
NaH (6.31 g, 158 mmol) was suspended in dry THF (500 ml) and cooled to 0°C. 2-hydroxyacetic acid (12 g, 158 mmol) was added portion wise and the mixture was stirred at RT for lh. The solvent was removed and the residue was suspended in DMF (500 ml); KI (2.488 g, 14.99 mmol) and benzyl bromide (18.77 ml, 158 mmol) were added and the mixture was heated to 100°C for 24h. The solvent was removed and the crude was portioned between EtOAc (600 ml) and water (200 ml). The organic phase was washed with brine and dried over Na2S04. The solvent was removed and the crude was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80/20). Benzyl 2-hydroxyacetate was obtained (18.089 g, 69percent yield).
54%
With Ki; NaH In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil
B. Alternatively, to a cold (0° C.) suspension of NaH (3.8 g of a 60percent weight dispersion in mineral oil, 95.0 mmol) in THF (50 mL) was added a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 mL) dropwise via cannula. The resulting solution was warmed to 25° C. and concentrated in vacuo. The resulting salt was suspended in DMF (100 mL) and treated with KI (1.57 g, 0.1 eq) and benzyl bromide (12.3 mL, 1.1 eq). The mixture was heated at 100° C. for 23 hours under argon and the DMF was evaporated. The residue was dissolved in ether and washed with water, saturated Na2 S2 O3, and brine, and dried over MgSO4. Distillation afforded benzyl glycolate (8.5 g, 54percent) as a colorless oil, b.p. 85-87° C. (0.5 Torr).
54%
With Ki; NaH In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil
B. Alternatively, to a cold (0° C.) suspension of NaH (3.8 g of a 60percent weight dispersion in mineral oil, 95.0 mmol) in THF (50 mL) was added a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 mL) dropwise via cannula. The resulting solution was warmed to 25° C. and concentrated in vacuo. The resulting salt was suspended in DMF (100 mL) and treated with KI (1.57 g, 0.1 eq) and benzyl bromide (12.3 mL, 1.1 eq). The mixture was heated at 100° C. for 23 hours under argon and the DMF was evaporated. The residue was dissolved in ether and washed with water, saturated Na2 S2 O3, and brine, and dried over MgSO4. Distillation afforded benzyl glycolate (8.5 g, 54percent) as a colorless oil, b.p. 85°-87° C. (0.5 Torr).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 16, p. 4903 - 4909
[2] Journal of Organic Chemistry, 2000, vol. 65, # 22, p. 7667 - 7675
[3] Patent: US2016/340365, 2016, A1, . Location in patent: Paragraph 0126; 0127
[4] Patent: US2016/297784, 2016, A1, . Location in patent: Paragraph 0150; 0151
[5] Journal of the American Chemical Society, 2010, vol. 132, # 31, p. 10920 - 10934
[6] Journal of the American Chemical Society, 1993, vol. 115, # 21, p. 9774 - 9788
[7] Journal of Organic Chemistry, 1988, vol. 53, # 18, p. 4282 - 4295
[8] Patent: US2013/79313, 2013, A1, . Location in patent: Paragraph 0714
[9] Journal of Medicinal Chemistry, 2009, vol. 52, # 10, p. 3348 - 3353
[10] Chemical Biology and Drug Design, 2016, p. 542 - 555
[11] Patent: WO2017/30814, 2017, A1, . Location in patent: Paragraph 00286
[12] Patent: WO2013/45280, 2013, A1, . Location in patent: Page/Page column 134
[13] Patent: US6013792, 2000, A,
[14] Patent: US5773428, 1998, A,
[15] Journal of the American Chemical Society, 2010, vol. 132, # 6, p. 1766 - 1767
[16] Journal of Medicinal Chemistry, 1992, vol. 35, # 10, p. 1828 - 1839
[17] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[18] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3217 - 3220
[19] Journal of Chemical Research, 2010, # 10, p. 562 - 564
[20] Journal of Materials Chemistry, 2011, vol. 21, # 39, p. 15305 - 15315
24
[ 79-14-1 ]
[ 100-51-6 ]
[ 30379-58-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With toluene-4-sulfonic acid In benzene for 0.5 h; Reflux Stage #2: Reflux
General procedure: Benzyl alcohol (1.2 equiv) and p-toluenesulfonic acid (0.1 equiv) were taken in benzene and refluxed for 0.5 h, then compounds 10(A-G) (1 equiv) was added, and continuously reflexed until the completion of the reaction (monitored by TLC: petroleum ether/ethyl acetate, 8:1; typically 4 h). The reaction mixture was washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Purification by flash column chromatography gave the desired compounds 11(A-G) as colorless oil.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 482 - 484
[2] Synthesis, 2005, # 20, p. 3555 - 3564
25
[ 79-14-1 ]
[ 100-44-7 ]
[ 30379-58-9 ]
Reference：
[1] Angewandte Chemie, 1986, vol. 98, # 3, p. 264 - 265
[2] Bulletin de la Societe Chimique de France, 1970, p. 4018 - 4023
26
[ 79-14-1 ]
[ 908094-04-2 ]
[ 30379-58-9 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 19, p. 2691 - 2698
27
[ 79-14-1 ]
[ 824-94-2 ]
[ 88920-24-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 17, p. 3472 - 3485
28
[ 79-14-1 ]
[ 58479-61-1 ]
[ 76271-74-4 ]
Yield
Reaction Conditions
Operation in experiment
90.3%
at 20℃;
0.8 mol of glycolic acid (Compound 5) was dissolved in 1 L of pyridine.One mole of tert-butyldiphenylchlorosilane (TBDPSCl) was added and allowed to react at room temperature overnight. Vacuum removal of pyridine,600 mL of distilled water was added and the mixture was extracted three times with 600 mL each of ethyl acetate.The organic layer was neutralized with 5percent aqueous HCl, washed with 500 ml of brine, dried over Na2SO4, filtered and concentrated.The residue was purified on a silica gel column using a gradient of ethyl acetate/petroleum ether (1/2) to give a colorless oil, yielding 227 g of compound 5-1.The yield was 90.3percent.
Reference：
[1] Patent: CN107854694, 2018, A, . Location in patent: Paragraph 0032; 0035-0037
[2] Journal of the American Chemical Society, 2004, vol. 126, # 32, p. 10162 - 10173
[3] Organic and Biomolecular Chemistry, 2012, vol. 10, # 17, p. 3472 - 3485
29
[ 79-14-1 ]
[ 2582-30-1 ]
[ 63870-39-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 25 - 108℃; for 22.1 h;
[439] A mixture of glycolic acid (26.2 g, 345 mmol) and water (10 mL) was treated with aminoguanidine bicarbonate (23.5 g, 172 mmol) in small portions over a period of 0.1 hr. The resultant mixture was gently heated to maintain an internal temp of 25 °C during the addition. The mixture was then treated with slow addition of cone, nitric acid (1.0 mL), followed by heating to an internal temperature of 104-108 °C over 22 hr. The heating was then discontinued and the solution allowed to cool with stirring. The resultant slurry was cooled down 10 °C, stirred over 2 hr, filtered, and rinsed with EtOH. The solids were dried overnight in a vacuum to provide the product 88a as a glycolic acid salt (29.5 g, 85percent). MS calcd: (M+H)+ = 115. MS found: (M+H)+ = 115.
75%
Stage #1: at 20 - 25℃; for 0.166667 h; Stage #2: With nitric acid In water at 104 - 108℃; for 22 h;
Glycolic acid (1 L, 70percent in water, 11.51 mol) was added to a 5 L flask. To the solution was slowly added aminoguanidine bicarbonate (783.33 g, 5.755 mol) in portions to control significant bubbling. As solids are added, the solution cools due to endothermic dissolution. EPO <DP n="56"/>The solution was gently heated to maintain an internal temp of 25 °C during addition. Ten minutes after complete addition of aminoguanidine bicarbonate, cone. Nitric acid (6.8 ml_) was carefully added. The solution was heated to an internal temperature of 104-108 0C (mild reflux) for 22 h. The heating was discontinued and the solution allowed to cool, with stirring. At an internal temp of aboutδi °C, solids began to crystallize. After the internal temperature was just below 80 0C, ethanol (absolute, 375 mL) was slowly added to the mixture. After the internal temp had cooled to aboutδδ 0C1 the cooling was sped up by the use of an ice/water bath. After cooling below rt, the solution became very thick but remained stirrable at all times. The slurry was stirred for 2h at T<10 0C, then filtered and the solids rinsed with ethanol (900 mL cold, then 250 mL rt). The solids were dried overnight in a vacuum oven (about25 mmHg, 45-50 0C) to provide 815.80 g (75percent) of (5-amino-1H-1 ,2,4-triazol-3-yl)methanol as the glycolate salt. 1H (300 MHz, de-DMSO): 3.90 (s, 2), 4.24 (s, 2).
70.5%
Stage #1: With octanol In water Stage #2: With nitric acid In water at 5℃; for 40.7 h; Heating / reflux
The title compound was prepared by a slight modification of a reported procedure (Allen, C. F. H. J. ORG. CHEM, 1959, 24,793) : A 5-L 3-necked flask was charged with aminoguanidine bicarbonate (275.6 g, 2.025 mol) and octyl alcohol (5.5 mL, to control foaming). To the mixture was added 70percent aqueous glycolic acid (440 g, 4.05 mol, 2 equiv) gradually, during which time evolution of CO2 was observed. When foaming and gas evolution had ceased, concentrated nitric acid (2.2 mL) was added so that it wet the sides of the flask above the liquid. The reaction mixture was refluxed for 40 h, then cooled to 5 C and maintained at this temperature for 40 min. The resulting slurry was filtered, and the solid washed with EtOH and dried in vacuo at 30 C to give the crude product as a white solid (313 g). The mother liquor was stirred at 0 C (ice bath) for 1 h and filtered, affording a second batch of material (51 g). These two batches were combined and recrystallized from hot ETOH, affording 271.5 g, (70.5 percent). 'H NMR (300 MHz, DMSO-d6) 5 3.89 (2H), 4.24 (2H), 5.58 (2H). LC-MS (APCI) calcd for C3H6N40 : 114.05 ; found (M+H+) : 115.1 m/z
70.5%
Stage #1: With octanol In water Stage #2: With nitric acid In water at 5℃; for 40.6667 h; Heating / reflux
The title compound was prepared by a slight modification of a reported procedure (Allen, C. F. H. J. Org. Chem, 1959, 24, 793): A 5-L 3-necked flask was charged with aminoguanidine bicarbonate (275.6 g, 2.025 mol) and octyl alcohol (5.5 mL, to control foaming). To the mixture was added 70percent aqueous glycolic acid (440 g, 4.05 mol, 2 equiv) gradually, during which time evolution of CO2 was observed. When foaming and gas evolution had ceased, concentrated nitric acid (2.2 mL) was added so that it wet the sides of the flask above the liquid. The reaction mixture was refluxed for 40 h, then cooled to 5° C. and maintained at this temperature for 40 min. The resulting slurry was filtered, and the solid washed with EtOH and dried in vacuo at 30° C. to give the crude product as a white solid (313 g). The mother liquor was stirred at 0° C. (ice bath) for 1 h and filtered, affording a second batch of material (51 g). These two batches were combined and recrystallized from hot EtOH, affording 271.5 g, (70.5percent). 1H NMR (300 MHz, DMSO-d6) δ 3.89 (2H), 4.24 (2H), 5.58 (2H). LC-MS (APCI) calcd for C3H6N4O: 114.05; found (M+H+): 115.1 m/z.
With sodium chlorite; dimethyl sulfoxide; In aq. phosphate buffer; at 0 - 20℃;pH 4.0;
General procedure: Aldehyde (70-350 mM), an internal standard (DSS or 20) and the specified additive (none, NH4Cl, H2O2, DMS, DMSO, sulfamic acid or L-methinone) were dissolved in phosphate buffer (60 mM, D2O, pH 4-7). Sodium chlorite (5 M, 1.4 equiv.) was added in five portions over 1 h at 0 C, then the solution was warmed to ambient temperature and NMR spectra were acquired. The carboxylic acid product was confirmed by sample spiking, and the yield (Table 1 and Supplementary Table 1) was quantified with respect to the internal standard.
(5-Methyl-1H-benzimidazole-2-yl)-methanol 25 was prepared using the Phillips procedure [1], 4-Methyl-1,2-phenylenediamine (12.22 g; 0.1 mol) and glycolic acid (11.40 g; 0.15 mmol) in hydrochloric acid (50 ml, 5.5 M) were heated under reflux with for 3 h. The reaction mixture was cooled to room temperature and ammonia solution was added and the mixture cooled in ice until a bright brown precipitate formed. The resulting solid was recrystallised from aqueous ethanol to give (5-methyl-1H-benzimidazole-2-yl)-methanol as a pale creamy powdery solid Yield 100%.
72%
With phosphoric acid; at 130℃; for 3h;
General procedure: To a mixture of 1a-1c (10 mmol) with glycolic acid (2.28 g, 30 mmol) was added concentrated H3PO4(20 mL). The reaction mixture was refluxed at 130C for 3 h, then quenched with 20% NaOH. The respective solid product was collected by filtration.
70%
at 150℃; for 3h;
Step 1 The mixture of 4-methyl-benzene-1,2-diamine (500 mg, 4.10 mmol) and hydroxy-acetic acid (374 mg, 4.92 mmol) was heated to 150 C. with stirring for 3 hrs. After cooled to room temperature, the reactant was purified by silica gel column (DCM/MeOH=30/1) to afford (5-methyl-1H-benzoimidazol-2-yl)-methanol (400 mg, yield: 70%) as a yellow solid.
O-phenylenediamine and glycolic acid were placed in a round bottom flask at a ratio of 1:3, and hydrochloric acid (4N) was added to reflux at 100 C (second condensation reaction) for 6 hours.After the reaction was completed, it was cooled to room temperature, and NaHCO 3 was added to neutralize hydrochloric acid.An off-white precipitate was precipitated, suction filtered, and the filter cake was washed several times with water.Purification by silica gel column gave Compound 1a in a yield of 85% to 92%.
89.1%
With hydrogenchloride; In water; for 2h;Reflux;
This compound was prepared based on a known methodwith some modification [19, 20]. Mixture of o-phenylenediamine (27 g, 0.25 mol) in 500 mL 4M HCl and glycolic acid (34.2 g, 0.45 mol) in 250 mL 4 M HCl stirred and heated under refluxfor 2 h. Then slowly cooled and resultant mixture was basified with aqueous sodium hydroxidesolution. The solid obtained, filtered, dried and re-crystallized with hot water (Scheme 1). (I:white to light brown powder, m.p. 171-174 oC, 89.1% yield).
88%
With hydrogenchloride; for 18h;Reflux;
To 5.0 g (0.046 mol) of o-phenylenediamine dissolved in 100 mL of a solution of hydrochloric acid (4 N), 3 equiv. (10.48 g, 0.138 mol) of glycolic acid were added, and the mixture was refluxed for 18 h. After completion of the reaction (TLC), the mixture was allowed to cool to room temperature, and alkalinization with NH4OH (10%) was achieved (pH = 9). The resulting precipitate was isolated by filtration, washed with water (3 × 5 mL), and dried on air. White solid; Yield: 6.02 g (88%); M.p. 114-116 C.
88%
With hydrogenchloride; In water; at 100℃; for 4h;
To a solution of 1,2-diaminobenzene (10.0 g, 92.6 mmol),in 4 N HCl (80 mL), glycolic acid (20.0 g, 263 mmol) was added and stirred for 4 h at 100 C andmonitored by TLC. After complete conversion of starting material, cooled the solution to roomtemperature, the pH of the solution was adjusted to 8 with a 2 mol/L aqueous sodium hydroxidesolution, the precipitate was filtered and dried to afford 1 as white solid in 88.0% yield. LC-MS m/z:149.2 [M + H]+.
85%
With hydrogenchloride; In water; at 100℃; for 4h;
At room temperature,10.0 g (92.6 mmol) of o-phenylenediamine and 20.0 g (263.0 mmol) of glycolic acid were placed in a 250 mL flask,Add 80 mL of 4 mol 1 / L hydrochloric acid and reflux at 100 C for 4 h.After completion of the reaction, the reaction solution was cooled to room temperature,Adjusted to pH 8.0 with potassium hydroxide and precipitated in a large amount. The solid was collected by filtration and recrystallized from water. Yield: 85.0%.
85%
With hydrogenchloride; In water; N,N-dimethyl-formamide; at 100℃; for 4h;
The o-phenylenediamine (10.0 g, 92.6 mmol)And glycolic acid (20.0 g, 263.0 mmol) were placed in 250 mL of eggplantFlask, add 80mL 4mol / L hydrochloric acid, 100 reflux 4h. After completion of the reaction, the reaction solution was cooled to room temperature and treated with hydrogenPotassium adjusted to pH 8.0, precipitate a large amount of solid, filter the solid, and recrystallize with water. The yield was 85%.
81%
With phosphoric acid; at 130℃; for 3h;
General procedure: To a mixture of 1a-1c (10 mmol) with glycolic acid (2.28 g, 30 mmol) was added concentrated H3PO4(20 mL). The reaction mixture was refluxed at 130C for 3 h, then quenched with 20% NaOH. The respective solid product was collected by filtration. (1H-Benzoimidazole-2-yl)methanol (2a). White solid, yield 81%, mp 169-171C (177-179C [18]). 1H NMR spectrum, delta, ppm: 4.69 s (2H, CH2), 5.69 s (1H, OH), 7.12-7.52 m (4H, ArH), 12.31 s (1H, NH).
80%
With hydrogenchloride; In water; at 100℃; for 8h;
o-phenylenediamine (2 g, 18.3 mmol) and glycolic acid (4.2 g, 55 mmol) were dissolved in 100 ml of 4N HCl and refluxed at 100 C for 8 h.TLC detection. Cool to room temperature, adjust the pH to 7, precipitate a brown solid, and dry to give the product.About: 2.2g. Yield: 80%.
74%
With hydrogenchloride; for 6h;Reflux;
General procedure: Mixture of phenylenediamine 10 g (92.6 mmol), glycolic/lactic acid (166.7 mmol), 135 ml4M HCl was refluxed for 6 hours. Then reaction mixture was alkalinized to pH 7 with aqueoussolution of KOH. Precipitate was filtered and crystallized from water.(Benzimidazol-2-yl)methanol (3a) [5] was obtained as beige solid in 74% yield. M.p. 159-161C from H2O. 1H NMR (500 MHz, (CD3)2CO) delta 4.86 (s, 2H), 7.23 - 7.11 (m, 2Harom.), 7.64 -7.46 (m, 2Harom.), 11.47 (brs, 1H). 13C NMR (125 MHz, (CD3)2CO) delta 59.2, 122.4, 155.8. HRMS,m/z calculated for C8H8N2NaO [M+Na]: 171.0534. Found: 171.0537.
73%
With hydrogenchloride; In water; at 100℃; for 3h;
Step 1: ( lH-Benzo[d]imidazoI-2-yl)methanoiTo a stirred solution of O-phenylenediamine (5 g, 0.046 mol) in 4N HCI (50 mL) was added 2-hydroxyacetic acid (4.2 g, 0.0555 mol) and stirring was continued for 3 h at 100C. The reaction mixture was cooled to room temperature, neutralized with satu rated sodium bicarbonate solution and the solid obtained was collected by filtration and dried to afford the title compound (3.5 g, 73%).lNMR (400 MHz, DMSO-d6) : delta 12.28 (brs, 1H), 7.52-7.44 (m, 2H), 7.12 (d, J = 4.80 Hz, 2H), 5.66 (t, J = 6.0 Hz, 1H), 4.68 (d, J=5.2 Hz, 2H) .
73%
With hydrogenchloride; In water; at 95℃; for 2h;
(1H-Benzimidazol-2-yl)methanol To a mixture of benzene-1,2-diamine (5.0 g, 46.3 mmol) and glycolic acid (10.5 g, 138.0 mmol) was added 4N HCl (30 mL). The reaction mixture was heated under reflux at 95 C. for 2 h, then cooled to 0 C. and neutralized with saturated aqueous NaOH. The precipitated solid was isolated by filtration and dried in vacuo to afford the title compound (5 g, 73%) as an off-white solid. deltaH (d6-DMSO) 12.20 (br s, 1H), 7.49-7.47 (dd, J 5.8, 3.2 Hz, 2H), 7.13-7.11 (dd, J 5.8, 3.2 Hz, 2H), 4.68 (s, 2H). LCMS (ES+) 149 (M+H)+.
65%
With hydrogenchloride; In water; for 16h;Reflux;
To a well stirred mixture of 1,2-phenylenediamine 17 (1 g, 9.25 mmol) in 6 M HCl (10 ml) was added 67% w/v glycolic acid (6.30 ml, 55.48 mmol) dropwise, till the suspension was clear. After stirring for 10 min at room temperature, the reaction flask was plugged to a condenser and refluxed overnight. Reaction mixture was cooled and concentrated under overnight ventilation affording the HCl salt of the title compound as needle crystals. The crystals were washed with least amount of cold EtOH on a filter paper and dried in oven at 45 C overnight. The dried crystals were dissolven in water and then precipitated with 1 M K2CO3 (20 ml) furnishing the title compound as a free base in crude mixture. After the effervescence was settled, the crude residue was extracted with EtOAc (2x), washed with brine and the organic solvent was removed in-vacuo. The pure free base was obtained as white crystals (4.45 g). Yield: 65%; mp: 165-167 C; IR (KBr): 3257, 3061, 2931, 1617, 1485, 1440, 1347, 1270, 1048, 876, 746, 681; 1H NMR (300 MHz, DMSO-d6): delta 4.68 (d, J = 5.74 Hz, 2H), 5.63 (t, J = 5.74 Hz, 1H), 7.05-7.22 (m, 2H), 7.48 (dd, J = 3.42, 5.86 Hz, 2H), 12.26 (br s, 1H); MS (EI+) m/z: 148 [M+].
47%
With hydrogenchloride; In water;Reflux;
General procedure: The mixture of appropriate 1,2-diaminobenzene derivatives (0.1 mol) and appropriate carboxylic acid derivatives (0.15 mol) in 100 ml 5N HCl were heated to reflux and stirred for 3-5 hours. After the reaction mixture was cooled to the room temperature and neutralized with sodium bicarbonate. The precipitate formed was filtered by suction filtration, washed with water and dried.
38%
With hydrogenchloride; In water; for 4h;Reflux;
General procedure: (1H-benzo[d]imidazol-2-yl)methanol was prepared by stirring o-phenylenediamine (1.3 g, 12mmol), and 85% glycolic acid (2.74 g, 36 mmol, 300 mol%), in 4 N HCl (40 mL), under reflux for 4 hours. Aftercooling to room temperature, the pH was adjusted to 7, with NaOH. The resulting crystals were filtered, washedwith water and dried in vacuo (0.67 g, 4.4 mmol, 38% yield).
at 180℃; for 1.16667h;Microwave irradiation;
A microwave tube containing 2-hydroxyacetic acid (6 g, 78.9 mmol) was pre-heated, then benzene- 1,2-diamine (1.27 g, 11.75 mmol) was added. The mixture was placed in a microwave oven and heated at 180C for 70 min. The mixture was partitioned between 5% methanol in ethyl acetate and saturated NaHCC>3 solution. The organic phase was washed with brine, dried over Mg2S04, filtered and evaporated. The residual material was triturated with ethyl ether to afford the product (2.6 g, 95%) as a brown solid.
With hydrogenchloride; In water; at 65 - 100℃; for 5h;
General procedure: The procedures were conducted according to the literature [16]. Glycolic acid (15.24 g, 0.2 mol)was dissolved in 40 mL HCl (20% aqueous) in the flask. When the temperature reached 65 C,compound 1a-1d (16.27 g, 0.15 mol) was added at three times, then refluxed at 100 C for 5 h. After cooling to room temperature, the solution was basified with NaOH (15%, aqueous) until itreached pH 9.0 to precipitate the desired compounds 2a-2d (in 75%-85% yield).
With hydrogenchloride; In water; at 100℃; for 6h;
General procedure: The molar ratio is 1:1.5O-phthalamide or its derivatives and glycolic acid were catalyzed by 4N hydrochloric acid and reacted at 100C for 6 h. The reaction was cooled to room temperature. The pH was adjusted to 8 with sodium bicarbonate solution. Solids precipitated, which were filtered and dried in the infrared.
With hydrogenchloride; In water;Reflux;
Starting from the o-phenylenediamine compound (1.0equiv) and glycolic acid (2.0equiv), the reaction was refluxed in the presence of a 4.0 mol/L aqueous hydrochloric acid solution, and the TLC was traced until the reaction of the starting material was complete, and the reaction solution was cooled. To room temperature,Adjusting the pH to 7 with 20% NaOH, standing to precipitate a solid, suction filtration, and drying to obtain compound 5; transferring compound 5 to a round bottom flask,Add NaOH aqueous solution,KMnO4 (2.5 equiv) was added in portions at 80 C with stirring, and the reaction was continued after the addition.After all the raw materials were completely reacted, the reaction solution was cooled to room temperature, and the filtrate was filtered by suction.Adjust the pH to neutral with 20% aqueous HCl solution to precipitate a solid.Drying by suction filtration to obtain compound 6;Compound 6 with DMF(1.0equiv) dissolved, then added 1-hydroxybenzotriazole (HOBt, 1.1equiv)And 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 equiv),The reaction was stirred at room temperature for 30 min, and then compound 4 (1.1 equiv) was added to the reaction solution.Continue to stir the reaction,The TLC traces to the completion of the reaction of the starting material, and the reaction solution is poured into ice water.It was then extracted with ethyl acetate and the organic layer was evaporated.The crude product was purified by column chromatography to give the allyl intermediates Sb.
With hydrogenchloride; In water; at 100℃;
o-phenylenediamine (1 g, 1 eq) and glycolic acid (1.5, 3 eq) were added to 20 mL of dilute hydrochloric acid solution, and refluxed at 100 C until the reaction was completed.Cool to room temperature, adjust the pH to neutral with concentrated ammonia, precipitate a brown solid, dry, and directly into the next step. Yield: 67%.
General procedure: To a mixture of 1a-1c (10 mmol) with glycolic acid (2.28 g, 30 mmol) was added concentrated H3PO4(20 mL). The reaction mixture was refluxed at 130C for 3 h, then quenched with 20% NaOH. The respective solid product was collected by filtration.
With sodium hydroxide; In hydrogenchloride; water;
3.40a (5-nitro-1H-benzimidazol-2-yl)-methanol 6.2 g (81.5 mmol) glycolic acid is added to a solution of 6.24 g (40.8 mmol) 4-nitro-o-phenylenediamine in 80 mL semiconcentrated HCl. The reaction solution is refluxed for 4 h and the solvent is eliminated i.vac. The residue is taken up in water and made basic with 2 N NaOH. The product precipitates out and is stirred for another 1 hour in the ice bath. The precipitate is suction filtered and washed successively with water and PE. The product is dried at 40 C. This still contains 40% 4-nitro-o-phenylenediamine. It is again taken up in semiconcentrated HCl and after the addition of 6.5 mL glycolic acid (57% in water) it is refluxed for 3 h and heated for a further 12 h at 80 C. The solvent is eliminated i.vac. and the residue is dissolved in water and made alkaline with 6 N NaOH, during which time the product is precipitated. The precipitate is suction filtered and washed successively with water and PE. The product is dried in the circulating air dryer at 50 C. Yield: 6.40 g (81.3% of theory). C8H7N3O3 (M=193.163).
With dihydrogen peroxide; zinc(II) oxide; In water; for 3h;UV-irradiation;
First, 3 g of glycerin was placed in a disc-shaped glass vessel containing 30 ml of water,The vessel was then placed in a water bath. Then, 15 mL of 30% hydrogen peroxide and 1.5 g of zinc oxide were added,The magnetic stirrer was operated at a rotational speed of 200 rpm and the container was irradiated with ultraviolet light,The irradiation degradation time was 3 hours.After completion of the reaction, the undissolved solid was removed by filtration,The yield of the filtrate glycolic acid was 77%.
16.0%
With dihydrogen peroxide; yttrium(III) trifluoromethanesulfonate; In acetonitrile; at 70℃; for 12h;
General procedure: GLY oxidation reaction was carried out in a glass reactor (25mL) containing 47 mg (0.10 mmol) Al(OTf)3, 4.54 g (40 mmol,30 wt%) H2O2, 0.37 g (4 mmol) GLY, and 2.37 g acetonitrile.The reaction mixture was stirred and heated at 70 C for 12 h.Similar procedure was employed for all the other metal saltsand biomass platform molecules. Unless otherwise specified,the reaction was carried out at 70 C for 12 h at a GLY/catalystmolar ratio of 40. The reaction was quenched by placing thebottle into an ice cool water bath. The liquid products alongwith the unreacted substrate were collected and quantitativelyanalyzed on an Agilent 1260 high-performance liquid chromatographequipped with a refractive index and ultraviolet(210 nm) detectors in series using a Bio-Rad Aminex HPX-87Hcolumn for product separation and diluted H2SO4 (0.5 Mm) as the eluent at 55 C and a flow rate of 0.5 mL/min. Prior to theanalysis, the reaction mixture was filtered using a 0.22-mmmembrane filter. For catalyst recycling, the aqueous mixturewas extracted thrice with dichloromethane, followed by dryingunder vacuum. All the experiments were carried out in duplicateand the average data were recorded.The GLY conversion and product yields of the catalysts werecalculated as follows:Conversion = GLY converted (mole)/total GLY in the feed(mole) 100%, Yield = (a product (mole)/total GLY converted(mole)) (number of carbon atoms in the products/3) 100%,Carbon balance yield in liquid products = Carbon atoms found inthe liquid products/Carbon atoms of GLY 100%.
With niobium(V) oxide; dihydrogen peroxide; In water; at 59.84℃; under 4560.31 Torr; for 5h;
General procedure: The glycerol oxidation experiments were performed in a 300 cm3batch reactor from Parr. The oxidation reactions were carried outwith hydrogen peroxide (0.2 and 0.6 M) or oxygen (under pressure6 atm) at 333 K; 0.2 g of catalyst were added to a 1 M aqueous solutionof glycerol (with NaOH/glycerol molar ratio = 2). The quantitativeanalyses of the reaction mixtures were conducted by highperformance liquid chromatography (HPLC). The analysis was carriedout using a HPLC chromatograph (Waters) equipped with ultraviolet(UV) and refractive index (RI) detectors. The samples were taken atthe end of the reactions, 1 cm3 of the sample was diluted in 10 cm3 ofwater and 5 mul of this solution was analyzed.
To a thermometer, condenser,1L four-neck flask trap successively added glycolic acid (70%) 200 g580 g of n-butanol and acidic ion exchange resin pretreated 10 g (pH = 2.0), heated to 120 ,Adjust the system vacuum, so that the system to maintain a certain amount of return.Use the water separator to separate the water produced by the reaction.After tracking the amount of water to the theoretical amount, stop the reaction, cool to room temperature, filter, with a small amount of n-butanol washing acid resin.The resulting filtrate was recovered by decompression of n-butanol,Distillation gave 224 g of n-butylhydroxyacetate,Purity 99.5%, yield 92%.
132.45 g
In toluene; at 90℃;
To a 500 mL four-necked flask, 76.82 g of 99% glycolic acid (1 mol), 101.10 g of 99% n-butanol, and 38.0 g of toluene were added, and the mixture was heated to 90 C to react and dehydrate. After the reaction, the unreacted alcohol and toluene were distilled off under reduced pressure.The remaining material was n-butyl glycolate and weighed 132.45 g.
In benzene;Dean-Stark;
General procedure: Esters were synthesized via esterification ofhydroxycarboxylic acids with the appropriate alcohols.With monobasic hydroxycarboxylic acids (glycolicand lactic), the reaction was conducted without a catalyst.Amberlist 36 DRY cation exchanger was used asa heterogeneous catalyst in the esterification of dibasichydroxycarboxylic acids (malic and tartaric).When the esterification reaction was conductedwith methyl and ethyl (C1C2) alcohol, the acid :alcohol molar ratio was 1 : 5. The water that formedwas removed from the reaction mass via distillation.When the acids were esterified with heavy alcohols(C3C8), the acid : alcohol molar ratio was 1 : 3. Anazeotropic agent, benzene, and a Dean-Stark apparatuswere used to remove the reaction water. The resulting compounds were purified via fractionaldistillation under vacuum. The reaction massand obtained hydroxycarboxylic acid esters were analyzedvia GLC using the Khromatek-Analytic softwareand a hardware complex based on a Kristall-2000Mgas chromatograph equipped with a flame ionizationdetector and a 100 m × 0.2 mm × 0.5 mum capillary columnwith the grafted liquid stationary phase (LSP)dimethylpolysiloxane or DB-1. The temperature ofthe injector was 250C, the temperature of the detectorwas 280C, the carrier gas was helium, the splitratio was 1/80, and the volume of each sample was0.2 muL. The following column temperature conditionswere used for our analysis: the initial temperature wasmaintained for 20 min (100 or 150C for the analysis oflactic acid esters of C3C5 alcohols), and the thermostatwas then heated to 260C at a rate of 5 K/min. Thepurity of the obtained samples was 9899 wt %.
A suspension 2-hydoxyaceticacid 47 (70% in H2O) (889 mg, 12.0 mmol) and Cs2CO3 (1955 mg, 6.00 mmol) in MeOH (22 mL)/H2O (4 mL) was stirred for 30 min at rt. After that the solvent was removed and the residue was dissolved in DMF (18 mL) cooled at 0C and after 10 min benzylbromide (2155 mg, 12.6 mmol) was added and the reaction mixture was stirred at rt for 24 h. The reaction mixture was quenched with brine (20 mL) and the organic layer was extracted with ethyl acetate (3x 25 mL), washed with H2O (25 mL), brine (20 mL), dried over MgSO4 and concentrated in vacuo to give 1877 mg (97%) of Benzyl 2-hydroxyacetate 48 as a colorless liquid.HPLC: 2.68 min (70%).
94%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0℃;
10127] Glycolic acid (7.60 g, 0.10 mol) was dissolved in10 ml of acetonitrile, into which benzyl bromide (13.60 g,0.08 mol) was added and uniformly stirred. DBU (12.16 g,0.08 mol) was slowly added dropwise into the reaction liquid at 00 C. Afier that, the reaction liquid was stirred overnight at room temperature. The reaction liquid was poured into ice water, extracted with ethyl acetate, the combined resultant organic phase was washed with 1 M hydrochloric acid solution and saturated salt water successively, dried with anhydrous sodium sulfate and concentrated by rotary evaporation to give the compound as a yellow oil (12.50 g, 94%).
94%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃;
a. Preparation of benzyl glycolate (0150) Glycolic acid (7.60 g, 0.10 mol) was dissolved in 10 ml of acetonitrile, into which benzyl bromide (13.60 g, 0.08 mol) was added and uniformly stirred. DBU (12.16 g, 0.08 mol) was slowly added dropwise into the reaction liquid at 0 C. After that, the reaction liquid was stirred overnight at room temperature. The reaction liquid was poured into the ice water, extracted with ethyl acetate, the combined resultant organic phase was washed with 1M hydrochloric acid solution and saturated salt water successively, dried with anhydrous sodium sulfate and concentrated by rotary evaporation to give the compound as a yellow oil (12.50 g, 94%).
69%
NaH (6.31 g, 158 mmol) was suspended in dry THF (500 ml) and cooled to 0 C. 2-hydroxyacetic acid (12 g, 158 mmol) was added portion wise, and the mixture was stirred at RT for 1 hour. The solvent was removed, and the residue was suspended in DMF (500 ml); KI (2.488 g, 14.99 mmol) and benzyl bromide (18.77 ml, 158 mmol) were added; and the mixture was heated to 100 C. for 24 hours. The solvent was removed, and the crude was portioned between EtOAc (600 ml) and water (200 ml). The organic phase was washed with brine and dried over Na2SO4. The solvent was removed and the crude was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80/20). Benzyl 2-hydroxyacetate was obtained (18.089 g, 69% yield).
63%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene;Reflux;
A mixture of 2-hydroxyacetic acid (5.0 g, 65.7 mmol), l,8-diazabicyclo[5.4.0]undec-7- ene (9.9 g, 65.7 mmol) and benzyl bromide (13.0 g, 78.9.mmol) in toluene (150 mL) was refluxed overnight. The reaction mixture was worked up and the crude product was purified by silica gel flash column chromatography (eluent 20-50% ethyl acetate in hexane) to give tert- butyl benzyl 2-hydroxyacetate (6.9g, yield 63%) as a colorless oil. *H NMR (400 MHz, CDC13): delta 2.60 (t, / = 5.6 Hz, 1H), 4.19 (d, / =5.6 Hz, 2H), 5.21 (s, 2H), 7.35-7.37 (m, 5H).
59%
NaH (6.31 g, 158 mmol) was suspended in dry THF (500 ml) and cooled to 0C. 2-hydroxyacetic acid (12 g, 158 mmol) was added portion wise and the mixture was stirred at RT for lh. The solvent was removed and the residue was suspended in DMF (500 ml); KI (2.488 g, 14.99 mmol) and benzyl bromide (18.77 ml, 158 mmol) were added and the mixture was heated to 100C for 24h. The solvent was removed and the crude was portioned between EtOAc (600 ml) and water (200 ml). The organic phase was washed with brine and dried over Na2S04. The solvent was removed and the crude was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80/20). Benzyl 2-hydroxyacetate was obtained (18.089 g, 69% yield).
54%
With Ki; NaH; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil;
B. Alternatively, to a cold (0 C.) suspension of NaH (3.8 g of a 60% weight dispersion in mineral oil, 95.0 mmol) in THF (50 mL) was added a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 mL) dropwise via cannula. The resulting solution was warmed to 25 C. and concentrated in vacuo. The resulting salt was suspended in DMF (100 mL) and treated with KI (1.57 g, 0.1 eq) and benzyl bromide (12.3 mL, 1.1 eq). The mixture was heated at 100 C. for 23 hours under argon and the DMF was evaporated. The residue was dissolved in ether and washed with water, saturated Na2 S2 O3, and brine, and dried over MgSO4. Distillation afforded benzyl glycolate (8.5 g, 54%) as a colorless oil, b.p. 85-87 C. (0.5 Torr).
54%
With Ki; NaH; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil;
B. Alternatively, to a cold (0 C.) suspension of NaH (3.8 g of a 60% weight dispersion in mineral oil, 95.0 mmol) in THF (50 mL) was added a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 mL) dropwise via cannula. The resulting solution was warmed to 25 C. and concentrated in vacuo. The resulting salt was suspended in DMF (100 mL) and treated with KI (1.57 g, 0.1 eq) and benzyl bromide (12.3 mL, 1.1 eq). The mixture was heated at 100 C. for 23 hours under argon and the DMF was evaporated. The residue was dissolved in ether and washed with water, saturated Na2 S2 O3, and brine, and dried over MgSO4. Distillation afforded benzyl glycolate (8.5 g, 54%) as a colorless oil, b.p. 85-87 C. (0.5 Torr).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃;
Glycolic acid (7.60 g, 0.10 mol) was dissolved in 10 mL of acetonitrile.Benzyl bromide (13.60 g, 0.08 mol) was added to the solution.After being uniformly stirred, DBU (12.16 g, 0.08 mol) was slowly added dropwise to the reaction mixture at 0 C. After the dropwise addition was completed, the reaction mixture was stirred at room temperature overnight.The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phases were combined.Wash with 1M hydrochloric acid solution, saturated brine and dry over anhydrous magnesium sulfate.Concentration by rotary evaporation gave Compound 1 as a yellow oil.
With phosphovanadomolybdic acid; oxygen; In water; at 150℃; under 15001.5 Torr; for 3h;
General procedure: The oxidative conversions of cellulose by various HPA catalysts were carried out in a 75 mL Teflon-lined stainless autoclave at 453 K for 3 h under 0.4-2 MPa O2 with a stirring rate of 600 rpm. Typically, the reaction mixture comprised 20 mL of H2O, 0.2 g of alpha-cellulose powder (containing 1.23 mmol glucose units), and 0.1 mmol of HPA catalyst. In the reactions with other substrates, a fixed amount of reactant (200 mg) and the typical reaction conditions were used unless otherwise specified.
63.1%
With aluminium(III) triflate; dihydrogen peroxide; In acetonitrile; at 70℃; for 12h;
General procedure: GLY oxidation reaction was carried out in a glass reactor (25mL) containing 47 mg (0.10 mmol) Al(OTf)3, 4.54 g (40 mmol,30 wt%) H2O2, 0.37 g (4 mmol) GLY, and 2.37 g acetonitrile.The reaction mixture was stirred and heated at 70 C for 12 h.Similar procedure was employed for all the other metal saltsand biomass platform molecules. Unless otherwise specified,the reaction was carried out at 70 C for 12 h at a GLY/catalystmolar ratio of 40. The reaction was quenched by placing thebottle into an ice cool water bath. The liquid products alongwith the unreacted substrate were collected and quantitativelyanalyzed on an Agilent 1260 high-performance liquid chromatographequipped with a refractive index and ultraviolet(210 nm) detectors in series using a Bio-Rad Aminex HPX-87Hcolumn for product separation and diluted H2SO4 (0.5 Mm) as the eluent at 55 C and a flow rate of 0.5 mL/min. Prior to theanalysis, the reaction mixture was filtered using a 0.22-mmmembrane filter. For catalyst recycling, the aqueous mixturewas extracted thrice with dichloromethane, followed by dryingunder vacuum. All the experiments were carried out in duplicateand the average data were recorded.The GLY conversion and product yields of the catalysts werecalculated as follows:Conversion = GLY converted (mole)/total GLY in the feed(mole) 100%, Yield = (a product (mole)/total GLY converted(mole)) (number of carbon atoms in the products/3) 100%,Carbon balance yield in liquid products = Carbon atoms found inthe liquid products/Carbon atoms of GLY 100%.
(+/-)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With triphenylphosphine hydrobromide; In dichloromethane; at 20℃; for 3h;
Part D: Synthesis of (+/-) 5,6-Dimethoxy-5,6-dimethyl-[l, 41dioxane-2-oneTriphenylphosphine hydrobromide (165 mg, 0.48 mmol) was added to a stirred solution of hydroxy-acetic acid (270 mg, 3.55 mmol) and 2,3 -dimethoxy- 1,3 -butadiene (490 mg, 2.29 mmol) in CH2Cl2 (10 ml) at room temperature. After 3 h, the reaction mixture was diluted with CH2Cl2 (20 ml). The organic phase was washed with saturated aqueous NaHCO3 (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane-EtOAc 4:1) to give the lactone as a white solid (559 mg, 83 %). 1H-NMR (CDCl3, 400 MHz): delta[ppm] = 1.38 (3H, s), 1.49 (3H, s), 3.30 (3H, s), 3.43 (3H, s), 4.14 (IH, d, J = 17.6 Hz), 4.28 (IH, d, J = 17.6)
83%
With triphenylphosphine hydrobromide; In dichloromethane; at 20℃; for 3h;
Part i: Synthesis of (+/-) 5,6-Dimethoxy-5,6-dimethyl-[l, 41dioxane-2-one Triphenylphosphine hydrobromide (165 mg, 0.48 mmol) was added to a stirred solution of hydroxy-acetic acid (270 mg, 3.55 mmol) and 2,3-dimethoxy-l, 3 -butadiene (490 mg, 2.29 <n="51"/>mmol) in CH2Cl2 (10 ml) at room temperature. After 3 h, the reaction mixture was diluted with CH2Cl2 (20 ml). The organic phase was washed with saturated aqueous NaHCO3 (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane-EtOAc 4:1) to give the lactone as a white solid (559 mg, 83 %). 1H-NMR (CDCl3, 400 MHz): delta[ppm] = 1.38 (3H, s), 1.49 (3H, s), 3.30 (3H, s), 3.43 (3H, s), 4.14 (IH, d, J = 17.6 Hz), 4.28 (IH, d, J = 17.6)
0.8 mol of glycolic acid (Compound 5) was dissolved in 1 L of pyridine.One mole of tert-butyldiphenylchlorosilane (TBDPSCl) was added and allowed to react at room temperature overnight. Vacuum removal of pyridine,600 mL of distilled water was added and the mixture was extracted three times with 600 mL each of ethyl acetate.The organic layer was neutralized with 5% aqueous HCl, washed with 500 ml of brine, dried over Na2SO4, filtered and concentrated.The residue was purified on a silica gel column using a gradient of ethyl acetate/petroleum ether (1/2) to give a colorless oil, yielding 227 g of compound 5-1.The yield was 90.3%.
To a solution of 42 mL of 6N HCI and 63 mL of water, 5-bromo-N1-methylbenzene- 1 ,2-diamine (9.1 g, 45.4 mmol) and glycolic acid (17.2 g, 227.2 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was neutralized to PH 9 by ammonium hydroxide. Precipitate formed, filtered, rinsed by water and dried by vacuum to yield (6-bromo-1-methyl-1H- benzo[d]imidazol-2-yl)methanol (8.5 g). 400 MHz 1H NMR (CDCI3) delta 7.5 (d, 1 H), 7.46 (m, 1H), 7.35 (dd, 1 H), 4.92 (s, 2H), 4.74(b, 1 H), 3.8 (s, 3H); MS (M+1) 241 , 243
To a solution of 42 ml 6N HCI and 63 ml water, 5-bromo-N1-methylbenzene-1 ,2-diamine (9.1 g, 45.4 mmol) and glycolic acid (17.2 g, 227.2 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was neutralized to PH 9 by ammonium hydroxide. Precipitate formed, filtered, rinsed by water and dried by vacuum to yield (6-bromo-1-methyl-1 H-benzo[d]imidazol-2-yl)methanol (8.5 g). 400 MHz 1H NMR (CDCI3) delta 7.5 (d, 1 H), 7.46 (m, 1 H), 7.35 (dd, 1 H), 4.92 (s, 2H), 4.74(b, 1H), 3.8 (s, 3H); MS (M+1 ) 241 , 243.
With water; at 95 - 97℃; under 760.051 Torr; for 2h;Reactive distillation;
As a reactive distillation apparatus, an apparatus obtained by connecting a 3-stage packed column to a flask and further providing a refluxing device at the top of the packed column was used. A mixed liquid obtained by mixing 150 g of water with 50 g of the distillate containing more than 98 wt % of methyl glycolate obtained in (3) above was put into the flask. Next, reactive distillation was carried out for 2 hours at normal pressure, maintaining the temperature at the base of the column of the reactive distillation apparatus (i.e. the liquid temperature) at 95 to 97 C. At this time, distillate containing methanol was distilled off. The temperature at the top of the column was 65 C. at the start of the reactive distillation, but had reached 100 C. by the end. [0322] After the reactive distillation had been completed, 114 g of an aqueous solution containing 36.1 wt % of glycolic acid was recovered from the flask. The yield of glycolic acid relative to the methyl glycolate was 100%. Regarding impurities, formaldehyde and chlorine compounds were not detected, and 20 ppm of oxalic acid and 76 ppm of ethylene glycol were detected.
With water; In methanol; at 100℃;
The distilled mixture was pooled. 150 ml of deionized water was added to the ester hydrolysis kettle. The ester hydrolysis was carried out at 100C with stirring. Methanol was distilled off and then steamed part of the water (for recycling). An aqueous solution of glycolic acid having a commercial mass concentration of 70% was obtained. Yield 88%.
4-chloro-N1-methylbenzene-1,2-diamine (15.0 g, 96 mmol) and glycolic acid (8.1 g, 106 mmol) were mixed together in a sealed tube. The mixture was heated at 150 C for 5 hours before it was cooled down to room temperature. The residue was purified by flash column chromatography (0-5% MeOH in CH2CI2) to give the product (8.5 g, 45% YIELD). H NMR (300 MHz, CDC13) 5 : 3.80 (s, 3 H), 4.86 (s, 2 H), 7.13-7. 22 (m, 2 H), 7.62-7. 64 (m, 1 H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 20h;
(1) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (742 mg) and 1-hydroxybenzotriazole (523 mg) are added to a solution of <strong>[61367-07-5]methyl trans-4-aminocyclohexanecarboxylate hydrochloride</strong> (500 mg) obtained in Reference Example 2(1), triethylamine (540 mul) and glycolic acid (295 mg) in N,N-dimethylformamide (10 ml) under ice-cooling.
Intermediate 49; Preparation of (6-Amino-3H-imidazo[4,5-b]pyridin-2-yl)-methanol; (6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)-methanol Solid <strong>[3537-14-2]2,3-Diamino-5-nitropyridine</strong> (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145 C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH4OH solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
at 145℃; for 0.5 - 0.75h;
Intermediate 12 Preparation of (6-Amino-3H-imidazo[4,5-b]pyridin-2-yl)-methanol (6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)-methanol; Solid <strong>[3537-14-2]2,3-Diamino-5-nitropyridine</strong> (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145 C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH3 solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]octane[ No CAS ]
1-[3-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2-hydroxy-ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With citric acid; In pyridine; N-methyl-acetamide; hydrogenchloride; methanol; dichloromethane;
EXAMPLE 84 To a solution of glycolic acid (0.157 g, 2.07 mmol), dimethylamino pyridine (catalytic), and pyridine (0.327g, 4.14 mmol), in dichloromethane (6 ml) is added dropwise chloro trimethylsilane (0.526 ml, 4.14 mmol). The reaction mixture is stirred at ambient temperature for 4 hours, and then catalytic dimethylformamide and oxalyl chloride (2 M in dichloromethane, 1.0 ml, 2.0 mmol) are added. The resulting reaction mixture is stirred at 0 C. for 1 hour, warmed to ambient temperature for 30 minutes, and then cooled to 0 C. To the mixture is added (4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]octane (0.500 g, 2.2 mmol) in pyridine (0.474 g, 6.1 mmol). The reaction mixture is then slowly warmed to ambient temperature over 2 hours. Citric acid (0.422 g, 2.2 mmol) in methanol (6.0 ml) is added to the resulting reaction mixture, which is then stirred for 30 minutes at ambient temperature. The reaction mixture is diluted with ethyl acetate, washed with IN aqueous hydrochloric acid, then saturated aqueous sodium hydrogen carbonate and brine. The organics are dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-[3-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2-hydroxy-ethanone (0.480 g, 84%).
Example IV Preparation of 4-hydroxy-2-hydroxymethylbenzimidazole STR117 To a solution of 40 ml 4M CHl 1.1 g (0.0087 mol) of <strong>[59649-56-8]2,3-diaminophenol</strong> and 2 g (0.026 mol) of glycolic acid were added and the solution was heated under reflux for 20 h. Upon cooling the reaction mixture was alkalized with 10M NaOH to pH 8.5. The volatiles were removed under reduced pressure and the residual oil was suspended in methanol. The suspension was filtered and evaporated to dryness in vacuo. Chromatography on silica gel and elution with methylene chloride:methanol (10:2) gave 0.78 g of the title compound.
2-hydroxy-N-[4-(4-pyridinyl)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 5 2-Hydroxy-N-[4-(4-pyridinyl)phenyl]acetamide--A mixture containing 15 g. of <strong>[13296-04-3]4-(4-pyridinyl)benzeneamine</strong>, 28.25 g. of 70% glycolic acid and 250 ml. of xylene was refluxed for over 4 hours with stirring in a flask equipped with a condenser and water separator. The reaction mixture was concentrated in vacuo; the residue was stirred with 250 ml. of water; and, the aqueous mixture was made alkaline with potassium carbonate solution. The solid was collected, recrystallized from isopropyl alcohol (final volume of 250 ml.) and dried at 90 C. in a vacuum oven for 18 hours to yield 13.8 g. of 2-hydroxy-N-[4-(4-pyridinyl)phenyl]acetamide, m.p. 231-234 C. A second crop of 1.39 g. of product was obtained. Combined crops were recrystallized from acetonitrile (final volume 1500 ml.) and the product dried at 180 C. in vacuo over 16 hours.
With potassium hydroxide; In dimethyl sulfoxide; at 170℃; for 2.5h;
2-hydroxyacetic acid (5.00 g, 65 mmol) and KOH (6.00 g,90 mmol) were mixed and heated to 170 C. <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (5.00 g, 26 mmol) dissolved in DMSO (20 mL)was added dropwise. The reaction mixture was stirred at 170 C for2.5 h. After cooled to room temperature, the solutionwas poured to50 mL ice water. Saturated aqueous sodium carbonate solutionwasadded to adjust the PH to 7-8. The mixture was filtered and driedin vacuo to give 3.70 g of 4 as brown solid: 62% yield. m.p.:223-225 C; HRMS (ESI+) m/z 234.0763 (234.0761 calcd forC12H12NO4+, [M+H]+).
51.6%
With potassium hydroxide; In dimethyl sulfoxide; at 170℃; for 3h;
Add 5g (65.74mmol) of glycolic acid to a 250mL single-necked flask andPotassium hydroxide 6g (106.93mmol), heated to 170 CAdd Y-1 5g (25.82mmol) in DMSO solution, reflux reaction at 170 C for 3h,The reaction was completely detected by TLC, and the reaction solution was poured into a 250 mL beaker containing 100 mL of water after standing at room temperature, and the pH was adjusted to 3 with concentrated hydrochloric acid, and a yellow solid was precipitated and suction filtered.The filter cake is washed with water and dried under vacuum.It has a pale yellow solid of 6.02g.The yield was 51.6%.
36%
A 250-mL, 3-neck, rb flask equipped with a magnetic stirbar, a reflux condenser and a powder funnel was charged with potassium hydroxide (6.0 g, 90 mmol) then 2-hydroxyacetic acid (5.0 g, 65 mmol) with stirring. The solid reactants gradually reacted and liquified as significant heat was generated. Upon dissolution of all the reagents, flask containing the hot syrupy liquid was immersed in a 170 0C oil bath, then a solution of <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (5.0 g, 26 mmol) in anhydrous DMSO (20 mL, 4 vol wrt quinoline) was added dropwise over 20-30 min via addition funnel. The resulting brown solution was maintained in the oil bath with stirring. After 2.5 h, the flask was removed from the oil bath, then quenched by the addition of water <n="53"/>(100 mL, 5 vol wrt DMSO). The resulting brown solution was immersed in an ice bath, and the mixture was neutralized by the dropwise addition of 6 N HCl (15 mL, 1 equiv to KOH), which resulted in the formation of a thick yellow ppt and brought the mixture to pH 3. The mixture was filtered and washed with water and ACN. The solid products were dried under vacuum to yield 2-(7-methoxyquinolin-4-yloxy)acetic acid (2.16 g, 36% yield) as a yellow solid. (ESI, pos. ion) m/z: 234.1 (M+H).
In tetrahydrofuran;Product distribution / selectivity;
176 mg of <strong>[71125-38-7]meloxicam</strong> was ground with 38 mg of glycolic acid and 400 muL of THF was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 25℃;
Step A: Preparation of l-(6-Bromo-3,4-dihydroisoquinolin-2(li/)-yl)-2- hydroxyethanone.A 4 L jacketed reactor equipped with mechanical stirrer, thermocouple, gas inlet, heating/cooling and condenser was charged with 6-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (150 g, 603 mmol), followed by dichloromethane (2.8 L), and the resulting slurry was mechanically stirred. Glycolic acid (55.07 g, 724 mmol) was added, followed by 1- hydroxybenzotriazole hydrate (101.66 g, 672 mmol) and N-(dimethylaminopropyl),N- ethylcarbodiimide hydrochloride (173.5 g, 905 mmol), followed by additional dichloromethane (0.2 L). With efficient stirring, 4-methylmorpholine (134.29 g, 1.327 mol) was slowly added in portions, while cooling to maintain a temperature at or below 25 0C, and then the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was then treated with 1 nu HCl (2 L), resulting in formation of solids, which were removed by filtration. The aqueous layer was then removed, and the organic layer was washed with water (150 mL). The organic extract was dried over MgSO4 filtered, and the solvent was removed from the filtrate to provide a golden yellow oil (190.6 g). The oil was then suspended in 1 nu NaOH (1 L), and stirred until fine colorless solids separated out. The solids were collected by filtration and rinsed with water (2 x 200 mL). A second batch of the same scale was prepared under identical conditions, and the solids were consolidated at this stage. After filtering and rinsing with additional water (4 x 500 mL), the combined solid was dried in a vacuum oven at 45 0C for 48 h <n="93"/>to provide the title compound (292 g). LCMS m/z = 270.1 [M+H]+; 1H NMR (400 MHz, CDCl3) delta 2.48 (bs, IH), 2.91 (m, 2H), 3.55 (t, J = 5.9 Hz, 1.2H), 3.89 (t, J= 6.1 Hz, 0.8H), 4.26 (m, 2H), 4.40 (s, 0.8H), 4.75 (s, 1.2H), 7.00 (d, J = 8.3 Hz, 0.4H), 7.07 (d, J= 8.3 Hz, 0.6H), 7.37 (m, 2H).
1.05 g (4 mmol) of desvenlafaxine was suspended in 15 ml of water and 0.30 g (4 mmol) of glycolic acid was added. After the addition of acid the solution was formed. This solution was filtered and filtrate was evaporated. The residue was further processed by adding and evaporating isopropanol. 1.2 g of desvenlafaxine glycolate as semi solid was isolated. IR: 2935, 1600, 1516, 1270, 1135, 1109, 952, 842, 746, 700
With trifluorormethanesulfonic acid; acetic acid; at 140℃; under 13689.1 - 52476.2 Torr; for 4h;Autoclave;Catalytic behavior;
A 100 mL zirconium high pressure autoclave was fitted with an impeller, gas inlet tube, sample tube, and thermowell. The autoclave was heated with a heating block, with temperature control provided by feedback via a thermocouple in the autoclave thermowell. Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure regulator. Triflic acid (0.562 g, 3.7 mmol), acetic acid (30.03 g, 0.5 mol) and paraformaldehyde (3.94 g, 0.125 mol) were added to the autoclave and sealed. The autoclave was secured to the stand and the system was purged with carbon monoxide and pressurized to 250 psig carbon monoxide. The temperature in the autoclave was increased to 140 C. while stirring at 1000 rpm. Upon reaching 140 C., the pressure in the autoclave was increased to 1,000 psig carbon monoxide. Once temperature and pressure were reached, a sample was taken, ?time 0.? The pressure and temperature were maintained for 4 hours. Subsequent samples of the reaction were taken at approximately 15, 30, 45, 60, 90, 120, 180 and 240 minutes and analyzed by HPLC. Results are given in Table 4, in terms of yield of glycolic acid and selectivity.
99.9%
With trifluorormethanesulfonic acid; acetic acid; at 140℃; under 13689.1 - 52476.2 Torr; for 4h;Autoclave;Catalytic behavior;
A 100 mL zirconium high pressure autoclave was fitted with an impeller, gas inlet tube, sample tube, and thermowell. The autoclave was heated with a heating block, with temperature control provided by feedback via a thermocouple in the autoclave thermowell. Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure regulator. Triflic acid (0.562 g, 3.7 mmol), acetic acid (30.03 g, 0.5 mol) and paraformaldehyde (3.94 g, 0.125 mol) were added to the autoclave and sealed. The autoclave was secured to the stand and the system was purged with carbon monoxide and pressurized to 250 psig carbon monoxide. The temperature in the autoclave was increased to 140 C. while stirring at 1000 rpm. Upon reaching 140 C., the pressure in the autoclave was increased to 1,000 psig carbon monoxide. Once temperature and pressure were reached, a sample was taken, ?time 0.? The pressure and temperature were maintained for 4 hours. Subsequent samples of the reaction were taken at approximately 15, 30, 45, 60, 90, 120, 180 and 240 minutes and analyzed by HPLC. Results are given in Table 4, in terms of yield of glycolic acid and selectivity.
99.9%
With trifluorormethanesulfonic acid; acetic acid; at 140℃; under 13689.1 - 52476.2 Torr; for 4h;Autoclave;Catalytic behavior;
A 100 mL zirconium high pressure autoclave was fitted with an impeller, gas inlet tube, sample tube, and thermowell. The autoclave was heated with a heating block, with temperature control provided by feedback via a thermocouple in the autoclave thermowell. Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure regulator. Triflic acid (0.562 g, 3.7 mmol), acetic acid (30.03 g, 0.5 mol) and paraformaldehyde (3.94 g, 0.125 mol) were added to the autoclave and sealed. The autoclave was secured to the stand and the system was purged with carbon monoxide and pressurized to 250 psig carbon monoxide. The temperature in the autoclave was increased to 140 C. while stirring at 1000 rpm. Upon reaching 140 C., the pressure in the autoclave was increased to 1,000 psig carbon monoxide. Once temperature and pressure were reached, a sample was taken, ?time 0.? The pressure and temperature were maintained for 4 hours. Subsequent samples of the reaction were taken at approximately 15, 30, 45, 60, 90, 120, 180 and 240 minutes and analyzed by HPLC. Results are given in Table 4, in terms of yield of glycolic acid and selectivity.
75.6%
With sulfolane; In water; at 120℃; under 30003 - 40504.1 Torr; for 4h;Autoclave;Product distribution / selectivity;
Cs2.5H0.5PW12O40 was prepared in an identical way to that of Example 1, except that 15 mL of 0.2M Cs2CO3 and 30 mL of 0.08M phosphotungstic acid hydrate were used and, after being left to age overnight, the sample was stirred in its supernatant solution for a second period of 3 hours before evaporation and calcination.Before use, catalysts were dried in a glass tube reactor at 300 C. under vacuum for 6 hours. They were then allowed to cool and were held in dry nitrogen until required.Catalysts were tested in a batch reaction, in which 0.2 g paraformaldehyde, 25 g (20 mL) sulfolane, 0.12 g water and 1 g catalyst was added to a 100 mL stainless steel autoclave fitted with a Teflon liner. The autoclave was purged with CO three times, before finally being filled with CO to a pressure of 4.0 MPa (40 bara) and heated slowly to reaction temperature of 120 C. Reaction was continued for 4 hours. The pressure in the autoclave at the reaction temperature is estimated as 5.4 MPa (54 bara).The resulting suspension was filtered to remove catalyst, and the reaction product filtrate was treated with 2 g methanol at 70 C. for 2 hours to convert any glycolic acid to the corresponding methyl ester before the filtrate was analysed by gas chromatography (GC). This is required, as glycolic acid can decompose under GC conditions.Table 1 lists physical data for different caesium salts of phosphotungstic acid, and compares this with catalytic activity. Table 2 lists surface acid concentrations of caesium salts of phosphotungstic acid.Hammett Acidity (H0) values were calculated using eight indicators with known pKa values, ranging from -3.3 to -14.52. The indicators used and their pKa values were: 2,4-dinitrofluorobenzene (-14.52), 2,4-dinitrotoluene (-13.7), m-nitrochlorobenzene (-13.16), p-nitrochlorobenzene (-12.7), p-nitrotoluene (-11.35), anthraquinone (-8.2), benzalacetophenone (-5.6), dicinnamalacetone (-3.0). The H0 values quoted in Table 1 correspond to the pKa value of the indicator with lowest pKa value (i.e. most negative) that could be protonated by the sample. Protonation of the indicator was detectable by a colour change of the indicator.From Tables 1 and 2, it can be seen that Example 1 (x=2.5) has a remarkably high surface area, external surface area and external surface acid site concentration. These properties correlate with a very high acidity (low H0 value), and high catalytic activity in terms of glycolic acid yield. TABLE 1 Physical data and catalytic activities of CsxH3-xPW12O40. Acid Surface Area (m2/g) Strength Glycolic Acid x Example Micropore External Total(H0) Yield (%) 0.485a - - 2 -12.7 25.6 1.04a - - 2 -12.7 36.5 1.483a - - 3 -11.35 1.952a 27 37 64 -11.35 40 2.491 13 120 133 -14.52 73.5 2.5014a 117 17 134 -11.35 2.976a 15 139 152 -3.0 1.2 aComparative Example TABLE 2 Proton Concentrations of CsxH3-xPW12O40 Total Proton External Proton x Example Concentration (mumol/g) Concentration (mumol/g) 0 - 1041.6 20.6 0.55a 856.1 6.9 1.04a 664.0 5.5 2.02a 318.1 53.3 2.51 159.0 84.0 3.06a 9.2 5.7 aComparative ExampleComparing Comparative Example 14 with Example 1 (both having x=2.5), the samples have very different activities and Hammett acidities. It is apparent that the synthetic procedure has created differences in the proportion of surface area existing within micropores, which has surprising consequences inter alia on the Hammett Acidity and the catalytic activity.In the Figures, labels 1 to 14 correspond to Examples and Comparative Examples 1 to 14 respectively.FIG. 1 shows plots of the yield of methyl glycolate in the presence of CsxH3-xPW12O40 at various x values, 20, and also methyl glycolate yields for the corresponding compounds supported on the silica SBA-15, 21. The results demonstrate that activity of the catalysts follows the same trend when caesium salts of phosphptungstic acid (CsxH3-xPW12O40) are supported, in this case on a mesoporous silica SBA-15. Supporting the catalyst on a support improves dispersion of the active catalyst, which can improve the catalytic activity per polyoxometalate unit. FIG. 1 additionally highlights the sharp increase in activity where x is between 2 and 3.FIG. 2 shows the glycolic acid yield, 20, and the Hammett Acidity value (H0), 22, as a function of x (i.e. caesium content) for the unsupported caesium salts of phosphotunstic acid (CsxH3-xPW12O40). Phosphotungstic acid is identified as 15 These results also highlight the sharp increase in activity where x is between 2 and 3, which also correlates with a sharp decrease in the Hammett Acidity value.FIGS. 3 and 4 show the X-ray diffraction (XRD) patterns of phosphotungstic acid, 15, some caesium salts of phosphotungstic acid, 1, 2, 4, 5 and 6, and an SBA-15-supported caesium salt, 7. It can be seen that the overall structure for the materials is generally the same, except that the peaks are broader when caesium is present, indicating lower long-range order, and are also shifted to higher 2theta values, indicating th...
29.4%
With water;phosphotungstic acid in partially dealuminatid zeolite Y; In sulfolane; at 120℃; under 30003 - 40504.1 Torr;Autoclave;Product distribution / selectivity;
Carbonylation experiments were carried out using a 10OmL stainless steel autoclave, which was lined with a Teflon liner. 1.Og of catalyst was added to the autoclave, along with 0.2g paraformaldehyde, 0.12g water and 2OmL sulfolane solvent. The autoclave was purged with carbon monoxide (CO) three times, before finally being filled with CO to a pressure of 4.0 MPa (40 bara) and heating slowly to a reaction temperature of 12O0C. The autoclave pressure at reaction temperature was estimated to be 5.4 MPa (54 bara). Reaction was continued for 4 hours.
With water;cesium 12-tungstophosphate; In sulfolane; at 120℃; under 30003 - 40504.1 Torr; for 4h;Product distribution / selectivity;
Catalysts were tested in a batch reaction, in which 0.2g paraformaldehyde, 25g (2OmL) sulfolane, 0.12g water and Ig catalyst was added to a 10OmL stainless steel autoclave fitted with a Teflon liner. The autoclave was purged with CO three times, before finally being filled with CO to a pressure of 4.0 MPa (40 bara) and heated slowly to reaction temperature of 12O0C. Reaction was continued for 4 hours. The pressure in the autoclave at the reaction temperature is estimated as 5.4 MPa (54 bara). The resulting suspension was filtered to remove catalyst, and the reaction product filtrate was treated with 2g methanol at 7O0C for 2 hours to convert any glycolic acid to the <n="10"/>corresponding methyl ester before the filtrate was analysed by gas chromatography (GC). This is required, as glycolic acid can decompose under GC conditions.
73.5%Chromat.
With water;cesium 12-tungstophosphate; In sulfolane; at 120℃; under 30003 - 40504.1 Torr; for 4h;Product distribution / selectivity;
Catalysts were tested in a batch reaction, in which 0.2g paraformaldehyde, 25g(2OmL) sulfolane, 0.12g water and Ig catalyst was added to a 10OmL stainless steel autoclave fitted with a Teflon liner. The autoclave was purged with CO three times, before finally being filled with CO to a pressure of 4.0 MPa (40 bara) and heated slowly to reaction temperature of 12O0C. Reaction was continued for 4 hours. The pressure in the autoclave at the reaction temperature is estimated as 5.4 MPa (54 bara).
With water;PW(NE)-USY; In sulfolane; at 120℃; under 30003 - 40504.1 Torr; for 4h;Autoclave;Product distribution / selectivity;
COMPARATIVE EXAMPLE 4The procedure of Comparative Example 3 was followed, except that the support was USY. This is different from Examples 1 and 2, in that the phsophotungstic acid is supported on the external zeolite surface, and is not encapsulated within the pore and cage structure of the zeolite The phosphotungstic acid loading was 20 wt %. The non-encapsulated catalyst so prepared is represented henceforth as PW(NE)-USY.Carbonylation experiments were carried out using a 100 mL stainless steel autoclave, which was lined with a Teflon liner. 1.0 g of catalyst was added to the autoclave, along with 0.2 g paraformaldehyde, 0.12 g water and 20 mL sulfolane solvent. The autoclave was purged with carbon monoxide (CO) three times, before finally being filled with CO to a pressure of 4.0 MPa (40 bara) and heating slowly to a reaction temperature of 120 C. The autoclave pressure at reaction temperature was estimated to be 5.4 MPa (54 bara). Reaction was continued for 4 hours.The catalyst was reused, and was separated, washed with water and dried between experiments.The reaction mixture filtrate was analysed using gas chromatography (GC). As glycolic acid is unstable under GC conditions, it was converted to the methyl ester before the GC analysis was conducted by adding 2.0 g methanol to the reaction mixture filtrate, and maintaining a temperature of 70 C. for 2 hours. After the esterification step, dimethylsulphoxide (DMSO) was added to product mixture as an internal standardTable 1 shows the results of glycolic acid yield (based on the quantity of methyl glycolate identified in the GC-analysis) for each use of the catalyst. It is clear that the encapsulated PW-USY catalysts show little or no signs of deactivation, even after several reaction cycles, whereas the SBA-15 and non-encapsulated PW-USY catalysts show deactivation with each re-use, indicating that the phosphotungstic acid is leaching from the support. No methyl glycolate was observed when polyoxometalate-free USY was used as a catalyst. The yields of methyl glycolate quoted in Table 1 are equivalent to glycolic acid yields.The results are illustrated in FIG. 1, which show the maintenance of catalytic activity with re-use for the encapsulated polyoxometalate catalysts, as opposed to a decline in activity with reuse for the non-encapsulated polyoxometalate catalyst. In FIG. 1, the labels relate to samples prepared according to the corresponding Examples and Comparative Examples. TABLE 1 Methyl Glycolate Yield. Methyl Glycolate Yield (%) for successive catalyst re-use. Catalyst 1 2 3 4 5 6 7 8 9 10 10% PW-USY 16.7 16.2 16.3 16.1 16.0 16.1 16.0 15.9 16.0 15.8 25% PW-USY 29.4 27.9 28.7 28.5 28.1 29.2 29.0 28.8 27.8 28.6 PW(NE)-USY 79.8 21.7 8.6 2.7 1.2 0 - - - - PW(NE)-SBA-15 23.4 20.0 15.7 11.5 7.9 3.5 1 0 - - (57)
99.9%Chromat.
With trifluorormethanesulfonic acid; acetic acid; at 140℃; under 13689.1 - 52476.2 Torr; for 4h;Autoclave;Catalytic behavior;
A 100 mL zirconium high pressure autoclave was fitted with an impeller, gas inlet tube, sample tube, and thermowell. The autoclave was heated with a heating block, with temperature control provided by feedback via a thermocouple in the autoclave thermowell. Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure regulator. Triflic acid (0.562 g, 3.7 mmol), acetic acid (30.03 g, 0.5 mol) and paraformaldehyde (3.94 g, 0.125 mol) were added to the autoclave and sealed. The autoclave was secured to the stand and the system was purged with carbon monoxide and pressurized to 250 psig carbon monoxide. The temperature in the autoclave was increased to 140 C. while stirring at 1000 rpm. Upon reaching 140 C., the pressure in the autoclave was increased to 1,000 psig carbon monoxide. Once temperature and pressure were reached, a sample was taken, ?time 0.? The pressure and temperature were maintained for 4 hours. Subsequent samples of the reaction were taken at approximately 15, 30, 45, 60, 90, 120, 180 and 240 minutes and analyzed by HPLC. Results are given in Table 4, in terms of yield of glycolic acid and selectivity.
With silica-gel-supported sulfuric acid; In water; at 160℃; under 127513 Torr;
Example 1 Comparative Example 1 was repeated except that the catalyst was replaced with a catalyst system comprising an unfunctionalised porous silica support and a sulfuric acid catalyst. Typical physical properties of the material include 0.98 cm3/g pore volume, 2.1 to 2.7 nm pore size and a surface area of 500 to 1000 m2/g (BET). As illustrated in Figure 3, whilst the catalyst activity did vary with the sulfuric acid concentration, the combination of the porous support and the liquid catalyst resulted in a catalyst activity significantly higher than was achieved in either Comparative.Examples 1 or 2.
With dihydrogen peroxide;methyltrioxorhenium(VII); In dichloromethane; water; acetonitrile; at 20℃;
Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below.
With dihydrogen peroxide;methyltrioxorhenium(VII); In ethanol; water; at 20℃;
Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below.
500 mg (2.920 mmol) of <strong>[136236-51-6]rasagiline</strong> base are dissolved in 1.5 ml of methanol, whereupon 220 mg (2.920 mmol) of hydroxyacetic acid are added. The solution is stirred at room temperature for an hour. The solvent is removed in vacuo and the residue is crystallized from a mixture of isopropyl alcohol and diisopropyl ether. The crystals are filtered, washed with cold diisopropyl ether and air-dried at room temperature.Yield: 452 mg (62 %), off-white crystalsMelting point: 78.0-79.5 CElementary analysis for the Formula C14Hj7N03 (247.30):Calculated [%] C: 68.00 H: 6.93 N: 5.66 O: 19.41 Found [%] C: 67.82 H: 6.86 N: 5.55IR (KBr): 3333, 3276, 2916, 1630, 1550, 1460, 1400, 1314,1082 cm"1. '1H-NMR (DMSO- , 400 MHz): delta 7.35 (m, 1H), 7.22 (m, 1H), 7.18 (m, 1H), 7.16 (m, 1H), 4.30 (m, 1H), 3.87 (m, 2H), 3.43 (s, 2H), 3.11 (m, 1H), 2.93 (m, 1H), 2.74 (m, 1H), 2.22 (m, 1H), 1.79 (m, 1H) ppm. HPLC purity: >99.8 %[a] 22D = +20,0 (c=l; EtOH)
2-Hydroxymethyl- and 2-ethyl-5-trifluoromethoxybenzimidazole. The procedure of Philips, M. A. was used. A mixture of 2-amino-4-trifluoromethoxyaniline (0.7 g, 0.0036 Mol) and corresponding carboxylic acid (0.00546 Mol) in HCl (3.5 ml, 4N) was refluxed for 6 h. Water (5 mL), and 0.5 g of charcoal were added, and the mixture was refluxed 10-15 min. After cooling, the mixture was filtered and resulted clear filtrate was washed with ether (2×10 mL). The water layer was neutralized with excess of diluted NH4OH, the precipitate was filtered, washed with water, and dried.2-Hydroxymethyl-5-trifluoromethoxybenzimidazole. Glycolic acid was used, R(HO)CH2. Yield 0.65 g (75 wt. %). M.p. 192-194 C. 1H NMR (DMSO-d6): 4.68 (d, 5.5 Hz, 2H), 5.67 (t, 5.5 Hz, 2H), 7.05 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.49 (br s, 1H), 12.48 (br s, 1H). 13C NMR (DMSO-d6): 57.62, 104.44, 110.79, 111.98, 114.70, 118.20, 120.08 (q, J=254.8 Hz), 143.21, 157.22. 19F NMR (DMSO-d6): -57.76. [M+1]+ 233.
[Pd(2,2'-bipyridine)(glycolate dianion)]*3H2O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
[Pd(bpy)Cl2] (0.20 g, 0.60 mmol) was suspended in water (25 mL). Silver nitrate (0.20 g, 1.19 mmol) in water (5 mL) was added and the reaction mixture was stirred for 6 h at 60 C and then at room temperature, always in absence of light. The resulting solution was centrifuged and filtered to remove AgCl. A few drops of water, glycolic acid (0.05 g, 0.66 mmol) and 1 M NaOH (1.20 mL) were added to the filtrate. The resulting solution was stirred for 5 days and concentrated at 60 C to 5 mL on a rotary evaporator. The mixture was cooled to room temperature and the yellow powder was filtered off and dissolved from water and again concentrated to 5 mL. Yellow single crystals suitable for X-ray diffraction were obtained from the resulting solution by slow evaporation at room temperature. Yield: 41%, m.p.: 212 C. Elemental Anal. Calc. for C12H16N2O6Pd (390.67): C, 36.9; H, 4.1; N, 7.2. Found: C, 36.7; H, 4.0; N, 7.1%. MS (FAB+): m/z [assignment(relative intensity)]: 337(35) [M+], 262(94), 157(100). IR (KBr, numax/cm-1): 3376 m,br, 3207 m,br, nu(OH); 1626 s, nu(CC), nuasym(CO2); 1497 w, 1451 m, nu(CC,CN); 1370 m, nusim(CO2); 415 m. Far-IR (Nujol, numax/cm-1): 385 s, nu(Pd-O); 252 m, nu(Pd-N). 1H NMR (CD3OD, delta/ppm): 4.35 (s, 2H, b), 7.71 (m, 2H, 5,5?), 8.28 (m, 2H, 4,4?), 8.39 (d, 2H, 3,3?), 8.49 (d, 2H, 6,6?). 13C NMR (CD3OD, delta/ppm): 72.71 (1C, b), 124.93 (2C, 3,3?), 128.64, 129.04 (2C, 5,5?), 142.44, 142.78 (2C, 4,4?), 150.10, 151.44 (2C, 6,6?). UV-Vis (numax/cm-1): 36101, 30120, 26525 (Reflectance).
With trifluorormethanesulfonic acid; water; acetic acid; at 190℃; under 34375.6 Torr; for 1.16667h;Autoclave;
Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure flow controller. The gas entered the body of the autoclave via groves in the impeller bearings. The off gas flow rate was monitored by a dry bubble-type flow meter. The flow rates of the two liquid feeds were controlled to a precision of 0.001 ml/min with double-barreled 500 ml high-precision syringe pumps connected to stirred feed vessels. Reactor effluent passed through heated Hastelloy tubing, an automatic pressure control valve (research control valve), and into a 1.0 L heatable Hastelloy collection vessel. The effluent collection vessel was fitted with a chilled coiled condenser. The gas outlet from the effluent tank was connected to a manual back pressure regulator to maintain vessel pressure at 40-100 psig. Temperatures, pressures, and other relevant system parameters were recorded automatically by a distributed control system. Feed 1 (0.4 g/min) and Feed 2 (0.39 g/min), having the composition given in Table 15 were fed to the reactor. Carbon monoxide was fed at a rate of 998 SCCM as noted in Table 16. The reaction was run at a pressure of 1500 psig and a temperature of 170 C. with a residence time of 85 minutes. Table 16 also gives feed molar ratios and the source of formaldehyde. For Example 107 the source was trioxane. Samples of the hydrocarboxylation reaction were analyzed by HPLC. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 17. Any glycolic acid fed was subtracted out for conversion and yield calculations. Methanol was present as free methanol, methyl glycolate, and methyl valerate, and was converted to free methanol, glycolic acid, and valeric acid by the analytical method. Example 97 was repeated but with MDA as the source of formaldehyde and at the feed rates and compositions noted in Table 19. In these experiments moles of MDA represent the formaldehyde equivalent, while acetic acid equivalents are calculated as the sum of free acetic acid fed and two times the MDA molar flow rate. The feed molar ratios, temperature, pressure, and hold-up time are given in Table 20. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 21. All methanol was present as methyl acetate, and was also converted to free methanol and acetic acid by the analytical method.
With trifluorormethanesulfonic acid; water; acetic acid; at 190℃; under 34375.6 Torr; for 1.16667h;Autoclave;
Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure flow controller. The gas entered the body of the autoclave via groves in the impeller bearings. The off gas flow rate was monitored by a dry bubble-type flow meter. The flow rates of the two liquid feeds were controlled to a precision of 0.001 ml/min with double-barreled 500 ml high-precision syringe pumps connected to stirred feed vessels. Reactor effluent passed through heated Hastelloy tubing, an automatic pressure control valve (research control valve), and into a 1.0 L heatable Hastelloy collection vessel. The effluent collection vessel was fitted with a chilled coiled condenser. The gas outlet from the effluent tank was connected to a manual back pressure regulator to maintain vessel pressure at 40-100 psig. Temperatures, pressures, and other relevant system parameters were recorded automatically by a distributed control system. Feed 1 (0.4 g/min) and Feed 2 (0.39 g/min), having the composition given in Table 15 were fed to the reactor. Carbon monoxide was fed at a rate of 998 SCCM as noted in Table 16. The reaction was run at a pressure of 1500 psig and a temperature of 170 C. with a residence time of 85 minutes. Table 16 also gives feed molar ratios and the source of formaldehyde. For Example 107 the source was trioxane. Samples of the hydrocarboxylation reaction were analyzed by HPLC. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 17. Any glycolic acid fed was subtracted out for conversion and yield calculations. Methanol was present as free methanol, methyl glycolate, and methyl valerate, and was converted to free methanol, glycolic acid, and valeric acid by the analytical method. Example 97 was repeated but with MDA as the source of formaldehyde and at the feed rates and compositions noted in Table 19. In these experiments moles of MDA represent the formaldehyde equivalent, while acetic acid equivalents are calculated as the sum of free acetic acid fed and two times the MDA molar flow rate. The feed molar ratios, temperature, pressure, and hold-up time are given in Table 20. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 21. All methanol was present as methyl acetate, and was also converted to free methanol and acetic acid by the analytical method.
With trifluorormethanesulfonic acid; water; acetic acid; at 190℃; under 34375.6 Torr; for 1.16667h;Autoclave;
Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure flow controller. The gas entered the body of the autoclave via groves in the impeller bearings. The off gas flow rate was monitored by a dry bubble-type flow meter. The flow rates of the two liquid feeds were controlled to a precision of 0.001 ml/min with double-barreled 500 ml high-precision syringe pumps connected to stirred feed vessels. Reactor effluent passed through heated Hastelloy tubing, an automatic pressure control valve (research control valve), and into a 1.0 L heatable Hastelloy collection vessel. The effluent collection vessel was fitted with a chilled coiled condenser. The gas outlet from the effluent tank was connected to a manual back pressure regulator to maintain vessel pressure at 40-100 psig. Temperatures, pressures, and other relevant system parameters were recorded automatically by a distributed control system. Feed 1 (0.4 g/min) and Feed 2 (0.39 g/min), having the composition given in Table 15 were fed to the reactor. Carbon monoxide was fed at a rate of 998 SCCM as noted in Table 16. The reaction was run at a pressure of 1500 psig and a temperature of 170 C. with a residence time of 85 minutes. Table 16 also gives feed molar ratios and the source of formaldehyde. For Example 107 the source was trioxane. Samples of the hydrocarboxylation reaction were analyzed by HPLC. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 17. Any glycolic acid fed was subtracted out for conversion and yield calculations. Methanol was present as free methanol, methyl glycolate, and methyl valerate, and was converted to free methanol, glycolic acid, and valeric acid by the analytical method. Example 97 was repeated but with MDA as the source of formaldehyde and at the feed rates and compositions noted in Table 19. In these experiments moles of MDA represent the formaldehyde equivalent, while acetic acid equivalents are calculated as the sum of free acetic acid fed and two times the MDA molar flow rate. The feed molar ratios, temperature, pressure, and hold-up time are given in Table 20. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 21. All methanol was present as methyl acetate, and was also converted to free methanol and acetic acid by the analytical method.
With trifluorormethanesulfonic acid; water; acetic acid; at 190℃; under 34375.6 Torr; for 1.16667h;Autoclave;
Pure carbon monoxide gas (>99.9%) was fed to the autoclave via a high pressure flow controller. The gas entered the body of the autoclave via groves in the impeller bearings. The off gas flow rate was monitored by a dry bubble-type flow meter. The flow rates of the two liquid feeds were controlled to a precision of 0.001 ml/min with double-barreled 500 ml high-precision syringe pumps connected to stirred feed vessels. Reactor effluent passed through heated Hastelloy tubing, an automatic pressure control valve (research control valve), and into a 1.0 L heatable Hastelloy collection vessel. The effluent collection vessel was fitted with a chilled coiled condenser. The gas outlet from the effluent tank was connected to a manual back pressure regulator to maintain vessel pressure at 40-100 psig. Temperatures, pressures, and other relevant system parameters were recorded automatically by a distributed control system. Feed 1 (0.4 g/min) and Feed 2 (0.39 g/min), having the composition given in Table 15 were fed to the reactor. Carbon monoxide was fed at a rate of 998 SCCM as noted in Table 16. The reaction was run at a pressure of 1500 psig and a temperature of 170 C. with a residence time of 85 minutes. Table 16 also gives feed molar ratios and the source of formaldehyde. For Example 107 the source was trioxane. Samples of the hydrocarboxylation reaction were analyzed by HPLC. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 17. Any glycolic acid fed was subtracted out for conversion and yield calculations. Methanol was present as free methanol, methyl glycolate, and methyl valerate, and was converted to free methanol, glycolic acid, and valeric acid by the analytical method. Example 97 was repeated but with MDA as the source of formaldehyde and at the feed rates and compositions noted in Table 19. In these experiments moles of MDA represent the formaldehyde equivalent, while acetic acid equivalents are calculated as the sum of free acetic acid fed and two times the MDA molar flow rate. The feed molar ratios, temperature, pressure, and hold-up time are given in Table 20. Conversion, space-time yield, and selectivity of reacted formaldehyde to end products are summarized in Table 21. All methanol was present as methyl acetate, and was also converted to free methanol and acetic acid by the analytical method.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 18h;
General procedure: Glycine benzyl ester monotosylate (8) (19.3g, 57.3mmol), 1-hydroxybenzotriazole monohydrate (HOBt·H2O) (7.75g, 57.3mmol) and N-methylmorpholine (NMM) (6.59g, 65.1mmol) were dissolved in CH2Cl2 (150mL). This solution was cooled to 0C. To this solution were added the hydroxy acid 7a (3.98g, 38.3mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (11.0g, 57.3mmol), successively. After stirring at room temperature for 18h, the reaction mixture was concentrated in vacuo to remove CH2Cl2. Ethyl acetate (250mL) was added to the residue, and the resultant mixture was washed successively with 1N HCl, sat. NaHCO3 and sat. NaCl, and was dried over anhydrous Na2SO4. After removal of solvent in vacuo, the residue was purified by flash column chromatography (40-60% ethyl acetate in hexane) to afford 9a as a pale yellow oil (4.93g, 51%).
Part A: Phenyl methylcarbamate (300 g, 1.95 mol) was charged to a 2 L vessel with cooling jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. IPA (390 mL) was added at 23 C. Hydrazine hydrate (119 g, 2.33 mol) was added and the slurry heated to 75 C for 6 h. Part B: On complete reaction (>99% conversion by HPLC), IPA (810 mL) and glycolic acid (222 g, 2.92 mol) were added and the mixture stirred at 83-85 C for 10-12 h. The reaction mixture is initially a clear colorless solution. The mixture is seeded with product (0.5 g) after 4h at 83-85 C. The slurry was slowly cooled to 20 C over 2h and aged for lh. The slurry was filtered and washed with IPA (600 mL). The cake was dried under 2 sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: XH NMR (D20, 500 MHz): delta 4.11 (s, 2H), 2.60 (s, 3H).
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With pretreated aluminium vanadium phosphate; In water; at 280℃; under 760.051 Torr;Catalytic behavior; Activation energy;
The glycerol transformation was carried out in a continuous-flow fixed-bed reactor under atmospheric pressure, as previouslydescribed [23]. The reactor was made of stainless-steel tubing(7 mm internal diameter and 190 mm long), placed in a tubularelectric furnace. The temperature was monitored by a thermocou-ple located in the catalyst bed. The analysis of the feed and reactionproducts was carried out on-line using a multicolumn gas chro-matograph (GC) equipped with both flame ionization (FID) andthermal conductivity (TCD) detectors in parallel. The compoundswere separated in a capillary column, DB-1 (100percent methylpolysilox-ane, 60 m x 0,25 mm x 0,25 m).The catalyst (100 mg) was pretreated at the reaction tempera-ture during 2 h in a N2flow (75 mL/min). A 36 wtpercent glycerol (99.5percent,Sigma-Aldrich) aqueous solution was fed at 0.6 mL/h (0.69 mol/sof glycerol). In general, each catalytic test was conducted at least for3 h at different temperatures (220C, 250C and 280C). The reac-tion products were identified by chromatographic patterns and/or agas chromatograph-mass spectrometer (GC?MS) (VARIAN CP 3800,QUADRUPOLE MS 1200) also equipped with a capillary column DB-1. A blank test showed the absence of homogeneous reactions andthe reactor inactivity in the absence of a catalyst.
2-hydroxymethylimidazo[4,5-f]phenanthroline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.82 g
With hydrogenchloride; In water; at 100℃; for 2h;
0.456 g of glycolic acid (6 mmol) was added to 20 mL of 4 mol / L HCl, placed in a 100 mL three-necked flask and then 0.84 g of <strong>[168646-54-6]1,10-phenanthroline-5,6-diamine</strong> (4 mmol) was added and heated to 100 ° C for 2 h. Filter, add Na2CO3 tune solution pH = 5, then add 20percent NaOH solution pH = 7, after standing to precipitate white flaky solid 2-hydroxymethylimidazo [4,5-f] phenanthroline 0.82g.
199.0 mg of compound I freebase powder was added into 10.0 mL of acetone/water (v/v=19/1), and 34.0 mg of glycolic acid was added to the solution, then stirred at room temperature, the solid was obtained. The H?NMR spectrum is displayed in FIG. 24.?H NMR data of glycollate Form A produced inthis example is shown as following:?H NMR (400 MHz, DM50) oe 9.09 (d, J=10.7 Hz,1H), 8.53 (s, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.78 (d, J=2.9 Hz,1H), 7.21 (dd, J=9.1, 2.9 Hz, 1H), 6.37 (s, 1H), 4.55-4.45 (m,1H), 3.54 (s, 2H), 2.95-2.87 (m, 4H), 2.83 (s, 6H), 2.79-2.74(m, 4H), 2.24-2.17 (m, 2H), 1.75 (s, 4H), 1.41 (d, J=5.0 Hz,2H).The result shows the solid is glycollate Form A.The XRPD data of the glycollate Form A is listed in Table11. The XRPD pattern is displayed in FIG. 19, the DSCcurve is displayed in FIG. 20, the TGA curve is displayed inFIG. 21
Weigh 42.1 grams of LAE hydrochloride,Add 80 g of butyl acetate,Heated to 60 dissolved,9.5 g of pyridine was added,The reaction was stirred for 1 hour,To the reaction solution was added 20 g of water,After standing stratified to remove the water layer,The resulting organic layer was added 9.1 g of glycolic acid,The reaction was continued at 60 C for 3 hours with stirring,Cold to -5 2 hours crystallization,The resulting powder was filtered,dry,43.9 grams of product was obtained,Yield 95.2%.
3-[1-(2-hydroxyacetyl)-piperidin-4-yl]-3,4-dihydro-1H-quinazolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
212 mg (1.6 mmol) of 1-hydroxybenzotriazole and 307 mg (1.6 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a solution of 100 mg (1.3 mmol) of hydroxyacetic acid in 10 ml of dimethylformamide. The reaction mixture is stirred for 5 minutes at room temperature and 304 mg (1.6 mmol) of <strong>[79098-75-2]3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one</strong> (prepared as described in example 1.5) is added. After stirring for two hours at room temperature, the reaction mixture is hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and diluted with ethyl acetate. The product is extracted twice with ethyl acetate and once with n-butanol. The organic phases are combined, washed once with water and once with a saturated aqueous solution of sodium chloride. They are dried over magnesium sulphate, filtered and concentrated under vacuum. The crude residue is chromatographed on silica gel eluted with a dichloromethane/methanol 97/3 mixture. 140 mg (35%) of 3-[1-(2-hydroxyacetyl)-piperidin-4-yl]-3,4-dihydro-1H-quinazolin-2-one is obtained in the form of a white solid.
Weigh 5 g of 4-amino-5-chloro-2,1,3-benzothiadiazole and 5.26 g of <strong>[64205-92-1]imidazoline-2-sulfonic acid</strong>, add 75 ml of n-butanol, and add 7.17 g of glycolic acid.The temperature was raised to 110 to 115°C and the reaction was stirred for 13 hours. Add 30 mg of activated carbon, stir for about 30 minutes, and filter while still hot.The filtrate was cooled to 10-15°C and stirred for 1 hour. The mixture was filtered, the cake was added to 60 ml of saturated ethanolic hydrogen chloride solution, stirred for 3 hours, and filtered. The filter cake was washed with anhydrous ethanol and dried. The filter cake was added to 65 ml of 95percent ethanol, refluxed until completely dissolved, naturally cooled, crystallized, filtered, and the filter cake was washed with dry ethanol and dried to give 6.47 g of tizanidine hydrochloride in a yield of 89.2percent with a purity of 99.99percent. .
General procedure: (1) 4-aminophenol derivative, alpha-hydroxy acid inAcetonitrile is the solvent,DCC is dehydrated to synthesize amide under the condition of a condensing agent, The excess DCC was removed by filtration and concentrated under reduced pressure.Removing unreacted 4-aminophenol derivative with dilute hydrochloric acid,After concentration, it is separated and purified by silica gel column chromatography.get2-hydroxy-N-(4-hydroxyphenyl)acetamides
General procedure: Mixture of phenylenediamine 10 g (92.6 mmol), glycolic/lactic acid (166.7 mmol), 135 ml4M HCl was refluxed for 6 hours. Then reaction mixture was alkalinized to pH 7 with aqueoussolution of KOH. Precipitate was filtered and crystallized from water.
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