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Structure of 27871-49-4 * 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.
The stainless steel pressure vessel (40 cc, Swagelok) is filled in with the methanol (15.0 g: Sigma-Aldrich, 003e99.8percent) solution of the metal salt (metal ion supply source), and sucroses (0.450 g: Fluka, 003e99.0percent) and catalyst (0.150 g). The reactor is closed and it heats up under the mixing (700 rpm) with 160. In 160 reaction, it makes maintained for 16 hours and the container reaction rapidly is cooled in the cold water after this period as the dipping. Sample from the reaction container was filtered and it analyzed with the HPLC (the Agilent 1200, the Biorad Aminex HPX-87H column, 65, 0.05 M H2SO4, 0.6 ml min-1) and it was the art exhibition ring hexose and dihydroxy acetone (DHA), the methyllactate (ML) using the fixed quantity: and GC (the Agilent 7890 in which the Phenomenex Solgelwax column is comprehended) the glyceraldehyde (GLA), and methyl vinyl glycol rate (MVG, and the methyl 2- hydroxy -3- butenoate) and glycol aldehyde dimethylacetal (GADMA) the fixed quantity.
Reference：
[1] Patent: KR2016/45675, 2016, A, . Location in patent: Paragraph 0054; 0055; 0056; 0057; 0058
2
[ 547-64-8 ]
[ 117-34-0 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
[ 1208982-48-2 ]
Yield
Reaction Conditions
Operation in experiment
68 % ee
With 2,2-dimethylpropanoic anhydride; N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; for 12 h;
Test Example 5Production of Optically Active 2-Hydroxy Ester Using Various Types of Racemic 2-Hydroxy Ester (3) As shown in the above reaction scheme, to diethyl ether (0.2 M) containing 0.6 equivalents of pivalic acid anhydride and 0.5 equivalents of diphenylacetic acid were added 1.2 equivalents of diisopropyl ethylamine, 5percent by mole of (+)-benzotetramisole (BTM), and a solution containing 1 equivalent of a racemic 2-hydroxy ester in diethyl ether at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. After the organic layers were admixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and unreacted optically active 2-hydroxy ester. The results are shown in Table 5. TABLE 5 Yield [percent] [a] cc [percent] No.R5 R6 5a; 5b 5a; 5b s 29 Et n-Pr 47; 47 97; 89 217 30 Me Me 47; 23 97; 68 119 [a] Isolation yieldAs is seen from Table 5, prominently high enantiomeric excess ee and reaction velocity ratio s were exhibited also when a material other than the benzyl ester was used (Entries 29 and 30).The physical properties of the optically active hydroxy esters and the diesters in Table 5 are shown below.(Entry 29)Ethyl (S)-2-hydroxypentanoate1H NMR (CDCl3): δ4.19 (dq, J=14.0, 7.0 Hz, 1H, Eta), 4.18 (dq, J=14.0, 7.5 Hz, 1H, Eta), 2.96 (br d, J=3.5 Hz, 1H, OH), 1.75-1.65 (m, 1H, 3-H), 1.62-1.52 (m, 1H, 3-H), 1.48-1.30 (m, 2H, 4-H), 1.24 (dd, J=7.5, 7.0 Hz, 3H, Eta), 0.89 (t, J=7.3 Hz, 3H, 5-H);13C NMR (CDCl3): δ175.3, 70.2, 61.4, 36.4, 17.9, 14.1, 13.6.Ethyl (R)-2-(diphenylacetyloxy)pentanoateHPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=15.0 min (1.4percent), tR=17.5 min (98.6percent);IR (neat): 1745, 1496, 1454, 745, 701 cm-1;1H NMR (CDCl3): δ7.33-7.17 (m, 10H, Ph), 5.08 (s, 1H, 2'-H), 4.98 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 4.12 (dq, J=14.0, 7.5 Hz, 3H, Eta), 4.11 (dq, J=14.0, 7.0 Hz, 3H, Eta), 1.78-1.71 (m, 2H, 3-H), 1.32-1.28 (m, 2H, 4-H), 1.16 (dd, J=7.5, 7.0 Hz, 3H, Eta), 0.81 (t, J=7.5 Hz, 3H, 5-H);13C NMR (CDCl3): δ172.1, 170.1, 138.4, 138.3, 128.7, 128.6, 128.4, 127.3, 127.2, 120.4, 72.9, 61.2, 56.8, 33.0, 18.3, 14.0, 13.5;HR MS: calcd for C21H24O4Na (M+Na+) 363.1567. found 363.1569.(Entry 30)Methyl (S)-lactate1H NMR (CDCl3): δ4.24 (q, J=7.0 Hz, 1H, 2-H), 3.72 (s, 3H, MeO), 3.16 (br s, 1H, OH), 1.36 (d, J=7.0 Hz, 3H, 3-H);13C NMR (CDCl3): δ176.0, 66.6, 52.3, 20.2.Methyl (R)-2-(diphenylacetyloxy)propanoateHPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=0.75 mL/min): tR=16.4 min (98.3percent), tR=19.7 min (1.7percent);IR (neat): 1744, 1496, 1454, 748, 699 cm-1;1H NMR (CDCl3): δ7.28-7.20 (m, 8H, Ph), 7.19-7.13 (m, 2H, Ph), 5.07 (q, J=7.0 Hz, 1H, 2-H), 5.03 (s, 1H, 2'-H), 3.60 (s, 3H, MeO), 1.37 (d, J=7.0 Hz, 3H, 3-H);13C NMR (CDCl3): δ171.9, 170.9, 138.3, 138.2, 128.7, 128.63, 128.55, 128.4, 127.3, 127.2, 69.2, 56.6, 52.2, 16.8;HR MS: calcd for C18H18O4Na (M+Na+) 321.1097. found 321.1091.
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 1, p. 167 - 172
[2] Patent: US2011/319650, 2011, A1, . Location in patent: Page/Page column 11
3
[ 600-22-6 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Yield
Reaction Conditions
Operation in experiment
33 % ee
With hydrogen In methanol at 50℃; for 15 h;
The hydrogenation reaction of methyl pyruvate was performed by the same method as in Example 38 except that the sulfonate catalyst was changed to Ru(OTf)[(S,S)-Tsdpen](p-cymene). As a result, (S)-methyl lactate with 33percent ee was produced in a yield of only 25percent.
76 % ee
With hydrogen In methanol at 50℃; for 15 h;
In a stainless steel autoclave, Cp*Ir(OTf)[(S,S)-Tsdpen] (1.7 mg, 2.0 μmol) was charged, followed by purging with argon. Then, 1 ml of methanol and methyl pyruvate (0.18 ml, 2.0 mmol) were charged, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 30 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1HNMR and GC analysis of the product showed that (S)-methyl lactate with 76percent ee was quantitatively produced. The spectral data of the resultant alcohol compound was as follows:1HNMR (400 MHz, CDCl3) δ 1.42 (d, J=7 Hz, 3H, CH3), 3.10 (br, 1H, OH), 3.79 (s, 3H, OCH3), 4.30 (q, J=7 Hz, 1H, CHOH); GC (Chirasil-DEX CB; column temperature, 80° C.; injection temperature, 250° C.; detection temperature, 275° C.; helium pressure, 100 kPa); tR of (R)-methyl lactate, 3.11 minutes; tR of (S)-methyl lactate, 3.49 minutes.
53 % ee
With hydrogen In methanol at 50℃; for 2 h; Autoclave
General procedure: All catalytic reactions were carried out at 50 C in 25 mL ofmethanol solvent in a stainless steel autoclave reactorequipped with a gas inlet and outlet, pressure gauge, mechanicalstirrer and temperature controller thermocouple. The systemwas controlled by computerized software and an electronicmotherboard unit. For each reaction, 70 mg (0.1 mmol ofcatalytically active Pt metal) of solid catalyst and 100 mmol ofsubstrate were used. The catalytic hydrogenation reaction wascarried out under 5 MPa of hydrogen and the reaction time wasfixed at 2 h. At the end of the catalytic runs, the reaction mixturewas analyzed by GC and the conversion was calculated onthe basis of the areas of the starting material and product usingcalibration curve calculations.
56 % ee
With bis(acetylacetonato)palladium(II); hydrogen; Cinchonidin In methanol; tolueneAutoclave
General procedure: Hydrogenation reaction was performed in a Picoclave GlassUster cyclone 075 BUCHI autoclave. A solution of the precursor and the modifier: 0.0304 g (1×10–4 mol) of palladium acetylacetonate, ~10–4 mol of the modifier, 3 mL of toluene, and 19 mL of methanol was transferred to a 100 mL vessel being bubbled with hydrogen. The pale-yellow solution was stirred under hydrogen pressure of 5 atm during 30 min, then 0.5 mL of the substrate in 8 mL of methanol was added, and the “zero sample” was withdrawn. The mixture of hydrogenation products was then analyzed each 30 or 60 min using the chromato–mass spectrometer. Configuration of the prevailing enantiomer was determined by comparison with the reference data [43].
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1992, # 23, p. 1738 - 1740
[2] Journal of the Chemical Society, Chemical Communications, 1994, # 21, p. 2431 - 2432
[3] Recueil des Travaux Chimiques des Pays-Bas, 1994, vol. 113, # 10, p. 465 - 474
[4] Journal of Catalysis, 1994, vol. 150, # 2, p. 321 - 328
[5] Synthesis, 1998, # 1, p. 45 - 55
[6] Tetrahedron Letters, 1998, vol. 39, # 14, p. 1941 - 1944
[7] Chemical Communications, 1998, # 14, p. 1451 - 1452
[8] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1231 - 1238
[9] Journal of Organic Chemistry, 1985, vol. 50, # 9, p. 1384 - 1394
[10] Journal of the American Chemical Society, 1984, vol. 106, # 5, p. 1531 - 1533
[11] Journal of Organic Chemistry, 1994, vol. 59, # 11, p. 3064 - 3076
[12] Journal of the Chemical Society, Chemical Communications, 1995, # 6, p. 685 - 686
[13] Journal of Organic Chemistry, 1996, vol. 61, # 18, p. 6244 - 6251
[14] Chemical Communications, 1998, # 14, p. 1451 - 1452
[15] Journal of Organic Chemistry, 1990, vol. 55, # 26, p. 6328 - 6333
[16] Journal of the American Chemical Society, 1988, vol. 110, # 2, p. 629 - 631
[17] Journal of Organic Chemistry, 1994, vol. 59, # 11, p. 3064 - 3076
[18] Chemical Communications, 1998, # 14, p. 1451 - 1452
[19] Tetrahedron, 1999, vol. 55, # 25, p. 7787 - 7804
[20] Journal of the American Chemical Society, 1999, vol. 121, # 20, p. 4920 - 4921
[21] Journal of the American Chemical Society, 1999, vol. 121, # 20, p. 4920 - 4921
[22] Journal of Organic Chemistry, 1999, vol. 64, # 18, p. 6603 - 6608
[23] Tetrahedron Letters, 2000, vol. 41, # 16, p. 2867 - 2870
[24] Tetrahedron Letters, 2000, vol. 41, # 16, p. 2867 - 2870
[25] Journal of Catalysis, 2004, vol. 221, # 2, p. 653 - 656
[26] Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1872 - 1880
[27] Journal of the American Chemical Society, 2006, vol. 128, # 17, p. 5955 - 5965
[28] Canadian Journal of Chemistry, 2005, vol. 83, # 6-7, p. 903 - 908
[29] Synlett, 2006, # 8, p. 1169 - 1172
[30] Chemistry Letters, 1987, p. 855 - 858
[31] Chemistry Letters, 1987, p. 855 - 858
[32] Chemical Communications, 2003, # 15, p. 1926 - 1927
[33] Organic Letters, 2002, vol. 4, # 14, p. 2421 - 2424
[34] Tetrahedron Asymmetry, 2007, vol. 18, # 19, p. 2305 - 2312
[35] Patent: WO2004/78686, 2004, A1, . Location in patent: Page 20
[36] Patent: US2008/234525, 2008, A1, . Location in patent: Page/Page column 10
[37] Patent: US2008/234525, 2008, A1, . Location in patent: Page/Page column 10
[38] Patent: US2008/234525, 2008, A1, . Location in patent: Page/Page column 10
[39] Angewandte Chemie - International Edition, 2011, vol. 50, # 21, p. 4913 - 4917
[40] Dalton Transactions, 2011, vol. 40, # 13, p. 3325 - 3335
[41] Advanced Synthesis and Catalysis, 2014, vol. 356, # 9, p. 1943 - 1948
[42] Advanced Synthesis and Catalysis, 2014, vol. 356, # 9, p. 1943 - 1948
[43] Chinese Journal of Catalysis, 2015, vol. 36, # 4, p. 634 - 638
[44] RSC Advances, 2015, vol. 5, # 124, p. 102481 - 102487
[45] Advanced Synthesis and Catalysis, 2015, vol. 357, # 16-17, p. 3513 - 3520
[46] Russian Journal of General Chemistry, 2018, vol. 88, # 2, p. 199 - 207[47] Zh. Obshch. Khim., 2018, vol. 88, # 2, p. 219 - 227,9
4
[ 547-64-8 ]
[ 79-33-4 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Yield
Reaction Conditions
Operation in experiment
84 % ee
With marine microbial esterase In aq. phosphate buffer at 37℃; for 1 h; Resolution of racemate; Enzymatic reaction
A standard 500‐μL hydrolytic reaction system containing140 μg purified esterase PHE14, 50 mmol/L substrate (racemicmethyl lactate) and 50 mmol/L phosphate buffer (pH 7.5) wasincubated at 37 °C for 1 h. After the completion of the enzymaticreaction, reaction samples were extracted with an equalvolume of ethyl acetate and the organic phase was further analyzedto evaluate the enzymatic resolution of (±)‐methyl lactate.
Reference：
[1] Chinese Journal of Catalysis, 2016, vol. 37, # 8, p. 1396 - 1402
5
[ 547-64-8 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Reference：
[1] Patent: US2008/234525, 2008, A1, . Location in patent: Page/Page column 10
[2] ChemPlusChem, 2013, vol. 78, # 12, p. 1466 - 1474
[3] Chemical Communications, 2015, vol. 51, # 13, p. 2565 - 2568
[4] Chemical Communications, 2015, vol. 51, # 13, p. 2565 - 2568
[5] Chemistry - A European Journal, 2015, vol. 21, # 28, p. 10236 - 10240
[6] Chemistry - A European Journal, 2015, vol. 21, # 28, p. 10236 - 10240
6
[ 617-35-6 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1503 - 1511
7
[ 67-56-1 ]
[ 616-09-1 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 10, p. 2817 - 2824
8
[ 27871-49-4 ]
[ 73246-45-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 12, p. 1715 - 1720
[2] Russian Chemical Bulletin, 1998, vol. 47, # 7, p. 1359 - 1364
9
[ 27871-49-4 ]
[ 5445-17-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 8, p. 1519 - 1528
10
[ 27871-49-4 ]
[ 74-88-4 ]
[ 4324-37-2 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃;
50 g sodium hydride (60 percent in mineral oil) are dissolved in 600 ml tetrahydrofurane and cooled to 00C. 98 g methyl-(S)-(-)-lactate in 150 ml tetrahydrofurane are added dropwise and stirring is continued for 20 minutes. Then 76 ml methyliodide in 100 ml tetrahydrofurane are added dropwise and the mixture is stirred for further 12 hours, while warming to room temperature. After cooling to 5°C 400 ml of a 10 N solution of sodium hydroxide in water are added and the mixture is stirred for 2 hours. Then concentrated hydrochloric acid until pH of <n="140"/>1 is reached is added. The tetrahydrofurane is evaporated in vacuo and the aquous phase is extracted three times with dichloromethane. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The crude product, which is obtained as a racemate under the reaction conditions, is used directly in the next step. Yield: 65,6 g (67 percent of theory) Mass spectrometry (ESI"): m/z = 103 [M-H]"
-20C Coming nextL-methyl lactate(1.04 g, 0.01 mol)Was dissolved in 20 ml of THF,Then slowly add 60%Sodium hydride (0.508 g, 0.0127 mol)After stirring for 20min,Benzyl bromide (2.48 g, 0.0145 mol) was added dropwise,After the addition is completed,Tetrabutylammonium iodide (0.0044 g, 0.12 mmol) was added.Return to room temperature,Stir overnight (12-14 hours, the same below).TLC (Thin Layer Chromatography) tracking monitoring.After the reaction is completed, the reaction solvent is spun dry,Washed with ether,dry,Spin dry,Crude product.Column chromatography on silica eluted with petroleum ether and ethyl acetate gave a pale yellow solid.
72%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
Example 24 (Compound 248); Synthesis of (S)-2-methyl-2-(4-((l-(l-(4-methylbenzyl)-5-oxo-4-propyl-4,5-dihydro-lH-1 ,2,4-triazol-3-yl)ethoxy)carbonyl)phenylthio)propanoic acid; Preparation of CSVmethyl 2-(benzyloxy)propanoate; Sodium hydride (60% dispersion in mineral oil, 10.6 g, 0.264 mol) was added portionwise to (-)-methyl-Z-lactate (25 g, 0.240 mol)) and benzyl bromide (28.5 mL, 0.240 mol) in dimethylformamide (125 mL) at 0 0C. The mixture was stirred at 0 0C for 30 minutes, allowed to warm to room temperature and then stirred overnight. The reaction was cooled, diluted with 10% hydrochloric acid and extracted with ether. The ether extract was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (5% ethyl acetate/hexanes) to give product as an oil (33.6 g, 72%).
With sodium hydride; In tetrahydrofuran; at -15 - 20℃;
2 gr of methyl lactate was reacted with excess of benzyl bromide to get 880 mg of (S)-benzyloxymethyl lactate. The reaction was performed by slurring sodium hydride in THF and cooling down to approximately -15C. The reaction mixture was then allowed to warm slowly to room temperature and stirred for approximately 1 to 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with MTBE twice followed by the removal of solvent on a rotary evaporator to get a crude oil. The crude product was purified by column chromatography to get pure (S)-2-benzyloxymethyl lactate. (R)-2- benzyloxymethyl lactate isomer was present at 0.93% only. According to some embodiments, the yield of this step may be increased by avoiding the presence of moisture in the reaction solution (i.e. THF).
With <polystyrene-CH2-cinchonine(1+)>2<Pt15(CO)30>; hydrogen In methanol at 25℃; for 4h; other keto esters; var. polystyrene-supported platinum and ruthenium catalysts; enantioselective hydrogenation;
With hydrogen In dichloromethane at 24.9℃; enantioselectivity, rate enhancement, var. of alkaloid, solvent, further with butane-2,3-dione;
With hydrogen at 19.9℃; further alkaloid-modified platinum;
With hydrogen In ethanol at 24.9℃; activation energy; enantioselective hydrogenation; var. alkaloid-modified or non-modified var. prepared iridium catalysts, var. temp. and solvents;
With hydrogen In methanol; toluene at 25℃; for 19h; various dimenthylphosphanyl substituted ligands and time;
With hydrogen; Cinchonidin In ethanol at 25℃; for 0.5h; influence of Pt particle size and solvents on e.e.;
With hydrogen In ethanol at 25℃; for 1h; other solvents, catalysts, pressure; initial rate; also for ethyl pyruvate;
With potassium 9-O-(1,2:5,6-di-O-isopropylidene-α-D-glucofuranosyl)-9-boratabicyclo<3.3.1>nonane In tetrahydrofuran at -78℃; for 6h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With 3-pinanyl-9-borabicyclo[3.3.1]nonane at 25℃; for 2h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With 3-pinanyl-9-borabicyclo[3.3.1]nonane at 25℃; for 4h; Yield given. Yields of byproduct given;
With hydrogen In methanol at 30℃; for 95h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In methanol at 25℃; for 100h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With <(-)-2,2'-bis(diphenylphosphino)-4,4',6,6'-tetramethyl-3,3'-bibenzo<b>thiophene>RuCl2; hydrogen In methanol at 25℃; for 100h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In ethanol at 25℃; for 1h; Title compound not separated from byproducts;
With Eapine-Borane at 25℃; for 4h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In methanol for 46h; Ambient temperature; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In methanol at 30℃; for 90h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In ethanol at 25℃; for 1h; Title compound not separated from byproducts;
With hydrogen; butan-1-ol In acetic acid at 24.85℃; for 1h; enantioselectivity under different reaction conditions, various reactants and catalysts;
With hydrogen In acetic acid at 17℃; Yield given; Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In acetic acid at 17℃; Yield given; Yields of byproduct given. Title compound not separated from byproducts;
With baker's yeast; Sucrose In water at 20℃; for 24h; Title compound not separated from byproducts;
With hydrogen In toluene at 20℃; for 3h;
With hydrogen In toluene at 20℃; for 3h;
With hydrogen; Cinchonidin In dichloromethane at 20℃; Title compound not separated from byproducts;
With (R)-N-dicyclohexylphosphino-N-methyl-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine; hydrogen In tetrahydrofuran at 25℃; for 6h; Title compound not separated from byproducts;
With hydrogen In methanol at 20℃; for 48h;
With hydrogen In methanol at 20℃; for 20h; Title compound not separated from byproducts;
With hydrogen In methanol at 20℃; for 20h; Title compound not separated from byproducts;
With hydrogen In tetrahydrofuran at 20℃; for 24h; Yield given;
With hydrogen In tetrahydrofuran at 20℃; for 24h; different catalysts, optical yield;
With hydrogen In toluene at 25℃; Title compound not separated from byproducts.;
With hydrogen In tetrahydrofuran at 20℃; for 6h; Title compound not separated from byproducts.;
With hydrogen In methanol at 50℃; for 24h; Title compound not separated from byproducts.;
93.5 % ee
78 % ee
With hydrogen
39 Synthesis of (S)-methyl Lactate by Hydrogenation Reaction of Methyl Pyruvate
Example 39 Synthesis of (S)-methyl Lactate by Hydrogenation Reaction of Methyl Pyruvate The hydrogenation reaction of methyl pyruvate was performed by the same method as in Example 10 except that Cp*Ir(OTf)[(S,S)-Msdpen] (1.5 mg, 2.0 μmol) was used. As a result, (S)-methyl lactate with 78% ee was quantitatively produced.
33 % ee
With hydrogen In methanol at 50℃; for 15h;
38
The hydrogenation reaction of methyl pyruvate was performed by the same method as in Example 38 except that the sulfonate catalyst was changed to Ru(OTf)[(S,S)-Tsdpen](p-cymene). As a result, (S)-methyl lactate with 33% ee was produced in a yield of only 25%.
76 % ee
With hydrogen In methanol at 50℃; for 15h;
38
In a stainless steel autoclave, Cp*Ir(OTf)[(S,S)-Tsdpen] (1.7 mg, 2.0 μmol) was charged, followed by purging with argon. Then, 1 ml of methanol and methyl pyruvate (0.18 ml, 2.0 mmol) were charged, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 30 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1HNMR and GC analysis of the product showed that (S)-methyl lactate with 76% ee was quantitatively produced. The spectral data of the resultant alcohol compound was as follows:1HNMR (400 MHz, CDCl3) δ 1.42 (d, J=7 Hz, 3H, CH3), 3.10 (br, 1H, OH), 3.79 (s, 3H, OCH3), 4.30 (q, J=7 Hz, 1H, CHOH); GC (Chirasil-DEX CB; column temperature, 80° C.; injection temperature, 250° C.; detection temperature, 275° C.; helium pressure, 100 kPa); tR of (R)-methyl lactate, 3.11 minutes; tR of (S)-methyl lactate, 3.49 minutes.
With hydrogen; cinchonidine In acetic acid at 19.84℃; optical yield given as %ee; enantioselective reaction;
With hydrogen; toluene-4-sulfonic acid In methanol; dichloromethane at 80℃; for 1h; Autoclave; optical yield given as %ee; enantioselective reaction;
11 % ee
With D-glucose; Candida glabrata keto ester reductase1-mutate3; lyophilized powders of BmGDH at 25℃; Enzymatic reaction;
81 % ee
With D-glucose; Candida glabrata keto ester reductase1-wide-type; lyophilized powders of BmGDH; sodium carbonate In aq. phosphate buffer at 25℃; Enzymatic reaction; stereoselective reaction;
53 % ee
With hydrogen In methanol at 50℃; for 2h; Autoclave; enantioselective reaction;
2.6. Catalytic experiments with activated catalysts (1) and (2)
General procedure: All catalytic reactions were carried out at 50 C in 25 mL ofmethanol solvent in a stainless steel autoclave reactorequipped with a gas inlet and outlet, pressure gauge, mechanicalstirrer and temperature controller thermocouple. The systemwas controlled by computerized software and an electronicmotherboard unit. For each reaction, 70 mg (0.1 mmol ofcatalytically active Pt metal) of solid catalyst and 100 mmol ofsubstrate were used. The catalytic hydrogenation reaction wascarried out under 5 MPa of hydrogen and the reaction time wasfixed at 2 h. At the end of the catalytic runs, the reaction mixturewas analyzed by GC and the conversion was calculated onthe basis of the areas of the starting material and product usingcalibration curve calculations.
31 % ee
With hydrogen; acetic acid; (+)-cinchonine at 20℃; for 4h; Autoclave; enantioselective reaction;
34 % ee
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; [2,2-bis((4R)-benzyl-4,5-dihydro-1,3-oxazol-2-yl)propane]copper(II) bistriflate at 60℃; Flow reactor; Inert atmosphere; enantioselective reaction;
56 % ee
With bis(acetylacetonato)palladium(II); hydrogen; Cinchonidin In methanol; toluene Autoclave; enantioselective reaction;
Hydrogenation procedure.
General procedure: Hydrogenation reaction was performed in a Picoclave GlassUster cyclone 075 BUCHI autoclave. A solution of the precursor and the modifier: 0.0304 g (1×10-4 mol) of palladium acetylacetonate, ~10-4 mol of the modifier, 3 mL of toluene, and 19 mL of methanol was transferred to a 100 mL vessel being bubbled with hydrogen. The pale-yellow solution was stirred under hydrogen pressure of 5 atm during 30 min, then 0.5 mL of the substrate in 8 mL of methanol was added, and the “zero sample” was withdrawn. The mixture of hydrogenation products was then analyzed each 30 or 60 min using the chromato-mass spectrometer. Configuration of the prevailing enantiomer was determined by comparison with the reference data [43].
10 % ee
With hydrogen In 1,4-dioxane Autoclave;
5 % ee
With hydrogen In 1,4-dioxane Autoclave;
30.4 % ee
With hydrogen; 1-butyl-3-methylimidazolium trifluoromethanesulfonimide In tetrahydrofuran at 0℃; for 10h; Autoclave; Schlenk technique; enantioselective reaction;
87.6 % ee
With SmADH31 Enzymatic reaction; stereoselective reaction;
82 % ee
With hydrogen; cinchonidine; acetic acid at 24.84℃; Autoclave; enantioselective reaction;
With triethylamine; In dichloromethane; at 0 - 15℃; for 2h;Inert atmosphere;
To a solution of methyl (2S)-2-hydroxypropanoate (69.7 ml, 730 mmol) and triethylamine (122 ml, 877 mmol) in dichloromethane (500 ml) was added trifluoromethanesulfonic anhydride (132 ml, 803 mmo) at 0 C under nitrogen and the mixture was stirred at 15 C for 2 h. The reaction mixture was poured into water (800 ml) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with brine (500 ml), dried over sodium sulfate, filtered and concentrated under vacuum to deliver 188 g (quantitative) of the title compound which was used without further purification.
With 2,6-dimethylpyridine; In dichloromethane; at 0℃; for 0.25h;Inert atmosphere;
General procedure: A solution of (S)-alpha-hydroxyester 2 (1.0 equiv, 30 mmol) and 2,6-lutidine (2.3 equiv, 69 mmol) in CH2Cl2 (40 mL) at 0 C, under an atmosphere of nitrogen, was treated with triflic anhydride (1.1 equiv, 33 mmol). After 15 min, a solution of BocNHNHR' 1 (1.0 equiv, 30 mmol) in CH2Cl2 (30 mL) was added dropwise for 30 min and the mixture was stirred for 4-6 h at 0 C until completion (monitored by TLC). After evaporation of the solvent, Et2O (50 mL) was added and 2,6-lutidinium triflate was precipitated by storing the reaction mixture overnight in the refrigerator. The 2,6-lutidinium triflate was filtered and the filtrate was diluted in Et2O (100 mL) and washed with water (20 mL), dried over MgSO4, filtered, and evaporated in vacuo. The resulting crude material was purified and characterized as reported below.
1.538 g
With 2,6-dimethylpyridine; In n-heptane; dichloromethane; at -10℃; for 0.666667h;Inert atmosphere;
Step 1 : (S)-Methyl 2-(trifluoromethylsulfonyloxy)propanoate 2,6-Lutidine (1.2 ml_, 10 mmol) and methyl (Sj-lactate (1 .041 g, 10.0 mmol) were dissolved in a mixture of heptanes:dichloromethane (4:1 , 10 ml.) under nitrogen. The solution was cooled to -10C using an ice-brine bath. Trifluoromethanesulfonic anhydride (2.0 ml_, 12 mmol) was added dropwise over 10 min while stirring the cooled solution. After the addition was completed, the reaction mixture was stirred at -10C for 30 min, then quenched with aqueous hydrochloric acid (0.5 M, 15 ml.) and stirred at - 10C for another 30 min. The resulting mixture was transferred to a separatory funnel and the phases were separated. Silica gel (2g) was added to the funnel containing the organic layer and the mixture was shaken, and then filtered through a 2 g silica gel plug (eluting with 40 ml. of a 3% ethyl acetate in heptanes solution). The filtrate was concentrated at room temperature to afford (S)-methyl 2- (trifluoromethylsulfonyloxy)propanoate as a clear oil (1.538g). 1H NMR (500 MHz, CDCI3) delta 1.72 (d, 3H), 3.87 (s, 3H), 5.24 (q, 1 H).
With dmap; triethylamine; at 0 - 20℃; for 24h;Inert atmosphere;
Under an Ar atmosphere, to a solution of methyl L-lactate (10.0 g, 96.1 mmol) in THF (100.0 mL) were added NEt3 (33.5 mL 240.2 mmol), DMAP (1.17 g, 9.6 mmol) and TBSCl (19.3 g, 128.1 mmol) at 0C, and the mixture was stirred for 24 h at r.t. The reaction mixture was diluted with Et2O, successively washed with 10% HCl aq. and sat. NaHCO3 aq., dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel (hexane:AcOEt = 5:1) to afford the TBS ether (S-1) (20.9 g, 95.5 mmol, 99%) as a colorless oil.
97%
Imidazole (3.39 mmol, 0.23 g) was added to the solution of (-)-methyl-L-lactate (2.16 mmol, 0.20 mL) in anhydrous CH2Cl2 (6.5 mL) at 0C. After 10 min of stirring at 0C, tert-butyldimethylsilyl chloride (2.59 mmol, 0.40 g) was added and reaction mixture was stirred at room temperature for 6 h. Then cold water (25 mL) was added and the mixture was extracted with CH2Cl2 (3x20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated to afford (S)-methyl 2-(tert-butyldimethylsilyloxy)propanoate 1a (0.46 g, 97%) as clear oil; [alpha]D23 = -27 (c 1, CHCl3); 1H NMR (CDCl3): delta = 0.07 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.40 (d, J = 6.8 Hz, 3H), 3.72 (s, 3H), 4.33 (q, J = 6.8 Hz, 1H); 13C NMR (CDCl3): delta = -5.3, -5.0, 18.3, 21.3, 25.7, 51.8, 68.4, 174.5.
95%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 24h;
To a cooled mixture of S-(+) Methyl lactate (7) (30.0 g, 0.288 mole), Imidazole (64.29 g, 0.865 mole) in DCM (240 mL) was added TBDMSCl (52.16 g, 0.346 mole) at 0 to 5 C. Stirred for 24 h at rt, upon completion of reaction, solution was poured in ice cold water (240 mL), organic layer separated was evaporated under vacuum and crude product was purified by fractional distillation to afford S-isomer of O-TBS ether (9), output: 59.7 g, Yield: 95%. Similarly R-isomer of O-TBS ether (10) was synthesized by using above procedure from antipode (8), output: 61 g, Yield: 97%. Colorless oil; S-Isomer: [alpha]D25 = -25.54 (c 1.0, CHCl3) and R-Isomer: [alpha]D25 = + 23.80 (c 1.0, CHCl3); IR (Neat): 2953, 2936, 2893, 2859, 1756, 1255, 838, 780 cm-1; 1H NMR (400 MHz, CDCl3): delta 4.30 (q, J = 6.9 Hz, 1H), 3.71 (S, 3H), 1.38 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3): delta -5.05, -5.34, 18.24, 21.28, 25.65, 51.76, 68.33, 174.47; HRMS Calcd. for C10H23O3Si+H: 219.1416 found: 219.1426.
82%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 3h;
Example 17: (2R, 75R)-2-[(l-Aminoisoquinolin-6-yl)amino]-8-fluoro-7-[(25)-2- hydroxypropoxy]-4,15,20-trimethyl-13-oxa-4,l l-diazatricyclo[14.2.2.16' 10]henicosa- l(18),6,8,10(21),16,19-hexaene-3, 12-dione; trifluoroacetic acid 17A: (5)-Methyl 2-((tert-butyldimethylsilyl)oxy)propanoate OTBS o [00276] To a solution of (5)-methyl 2-hydroxypropanoate (1.00 g, 9.61 mmol) in DMF (10 mL) at rt, were added imidazole (0.981 g, 14.41 mmol) and TBS-C1 (1.737 g, 11.53 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was diluted with hexanes. The organic phase was washed with water (2X) and brine, dried ( a2S04) and concentrated. The crude product was purified by flash chromatography (0 to 10% ethyl acetate/hexanes) to give 17A (1.73 g, 7.92 mmol, 82% yield) as a colorless oil. lR NMR (400 MHz, chloroform-d) delta ppm 4.34 (q, J=6.7 Hz, 1 H) 3.72 (s, 3 H) 1.40 (d, J=6.8 Hz, 3 H) 0.90 (s, 8 H) 0.09 (d, J=10.8 Hz, 6 H). 17B: (5)-2-((tert-Butyldimethylsilyl)oxy)propan-l-ol OTBS [00277] To a solution of 17A (1.33 g, 6.09 mmol) in THF (20 mL) at 0 C, was added lithium borohydride (0.531 g, 24.36 mmol). The resultant suspension was stirred at rt for 7 h. The reaction was cooled to 0 C, then was quenched with sat. NH4C1 (5 mL). The mixture was diluted with H2O and hexanes. The reaction mixture was acidified with 1 N HC1, then was extracted with hexanes (3X). The combined organic phase was washed with brine, dried ( a2S04), and concentrated. The crude product was purified by flash chromatography (0 to 60% ethyl acetate/hexanes) to give 17B (980 mg, 5.15 mmol, 85% yield) as a colorless oil. MS (ESI) m/z: 191.2 [M+l]+. NMR (400 MHz, chloroform-d) delta ppm 3.87 - 3.96 (m, J=6.3, 6.3, 6.3, 6.3, 3.6 Hz, 1 H) 3.51 (ddd, J=l 1.0, 7.7, 3.6 Hz, 1 H) 3.37 (ddd, J=l l . l, 6.3, 5.1 Hz, 1 H) 1.93 (dd, J=7.8, 5.3 Hz, 1 H) 1.12 (d, J=6.3 Hz, 3 H) 0.90 (s, 9 H) 0.09 (s, 6 H). -Fluoro-2-hydroxy-5-nitrobenzaldehyde [00278] To a flask with 3-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol) in acetic acid (10 mL, 175 mmol), was added nitric acid (cone, 10 mL, 244 mmol) at 0 C. The mixture was stirred 0 C for 30 min, quenched with ice, extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried ( a2S04) and concentrated to give 17C (5.457 g, 29.5 mmol, 83% yield) as a yellow solid. -Butyl 3 -fluoro-2-hydroxy-5 -nitrobenzyl(methyl)carbamate [00279] To a solution of 17C (5.965 g, 32.2 mmol) in MeOH (150 mL), methylamine (33% in EtOH) (5.21 mL, 41.9 mmol) was added dropwise and stirred rt for 1 h. The reaction mixture was cooled to 0 C, sodium borohydride (1.463 g, 38.7 mmol) was added portionwise and the mixture was stirred at rt for lh. The reaction mixture was diluted by water (50 mL) and THF (50 mL), then di-tert-butyl dicarbonate (8.44 g, 38.7 mmol) and sodium bicarbonate (8.12 g, 97 mmol) was added. The mixture was stirred rt for 1 h. Most of THF and MeOH were removed under reduced pressure. The pH was adjusted to ~5.0 with 1 M HC1. The mixture was extracted with EtOAc (3x20 mL), washed with water, brine, dried ( a2S04). [00280] EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-60% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 17D (5.992 g, 19.95 mmol, 61.9% yield) as an off-white solid. MS (ESI) m/z: 245.0 [M+l]+ - ?Bu. lR NMR: (400 MHz, CDC13) delta ppm 7.97 (1 H, dd, J=10.16, 2.64 Hz), 7.86 - 7.92 (1 H, m), 4.38 (2 H, s), 2.94 (3 H, s), 1.50 (9 H, s). 17E: tert-Butyl 2-(benzyloxy)-3 -fluoro-5-nitrobenzyl(methyl)carbamate [00281] 17D (2.500 g, 8.33 mmol) and (bromomethyl)benzene (1.483 mL, 12.49 mmol) were dissolved in acetone (40 mL). Cesium carbonate (5.43 g, 16.65 mmol) was added, and the reaction mixture was stirred at 50 C for 4 h. The reaction mixture was filtered, the filter cake was washed with acetone (3x25 mL). Organic fractions were combined, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-50% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 17E (2.789 g, 7.14 mmol, 86% yield) as a white solid. MS (ESI) m/z: 391.0 [M+l]+. lH NMR: (400 MHz, CDC13) delta ppm 7.94 (1 H, d, J=11.54 Hz), 7.77 - 7.90 (1 H, m), 7.39 (5 H, s), 5.31 (2 H, br. s.), 4.25 - 4.50 (2 H, m), 2.78 (3 H, s), 1.35 - 1.55 (9 H, m). -2-(benzyloxy)-3-fluorobenzyl(methyl)carbamate [00282] To a solution of 17E (2.789 g, 7.14 mmol) in methanol (40 mL) and THF (10 mL) was added zinc (dust) (4.67 g, 71.4 mmol) and ammonium chloride (7.64 g, 143 mmol). The resulting solution was stirred at rt for 30 min, then at 40 C overnight. MeOH was removed under reduced pressure, a2C03 (aq, 100 mL) and EtOAc (150 mL) were added, and the suspension was stirred vigorously for 10 min. The mixture was filtered though glass frit, solid residue was washed with EtOAc (3x150 mL). Combined EtOAc fractions were washed with sat. a2C03 (aq, 2x50 mL), water (2x50 mL), br...
78%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 20h;
To a stirred solution of methyl (S)-2-hydroxypropanoate (0.3g, 2.88mmol,1.0 eq) and imidazole (0.39 g, 5.76 mmol, 2 eq) in dichloromethane (10 mL) at 0 C, tertButyldimethylsilyl chloride (0.65 g, 4.32 mmol, 1.5 eq) was added. The reaction mixture was stirred for 20 hours at room temperature. After confirming the reaction by TLC, the solvent was evaporated under vacuum. The crude residue obtained was purified by flashcolumn chromatography to afford methyl (S)-2-((tert-butyldimethylsilyl) oxy)propanoate as a colorless liquid (0.6g, 78 %). 1H NMR (400 MHz, DMSO-d6) delta : 4.37 (d, J = 8.80 Hz, 1H), 3.64 (s, 3H), 1.28-1.30 (m, 3H), 0.86-0.93 (m, 9H), 0.05-0.05 (m, 6H).
76%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
a solution of methyl (2S)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and 1H-imidazole (4.9 g, 71.98mmol, 1.50 eq.) in dichloromethane (100 mL) was placed into a 250-mL round-bottom flask. This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.69 g, 57.66 mmol, 1.20 eq.) in dichloromethane (50 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 80 mL of water/ice and extracted with dichloromethane (3x50 mL). The resultingmixture was washed with brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8 g (76%) of methyl (2S)-2-[(tert- butyldimethylsilyl)oxy]propanoate as a colorless liquid.
76%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
Step 1: methyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate: a solution of methyl (2S)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and l H-imidazole (4.9 g, 71.98 mmol, 1.50 eq.) in dichloromethane (100 mL) was placed into a 250-mL round-bottom flask. This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.69 g, 57.66 mmol, 1.20 eq.) in dichloromethane (50 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 80 mL of water/ice and extracted with dichloromethane (3x50 mL). The resulting mixture was washed with brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8 g (76%) of methyl (2S)-2-[(tert- butyldimethylsilyl)oxy]propanoate as a colorless liquid.
76%
With 1H-imidazole; In dichloromethane; at 0 - 20℃;
a solution of methyl (2S)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and IH-imidazole (4.9 g, 71.98 mmol, 1.50 eq.) in dichloromethane (100 mL) was placed into a 250-mL round-bottom flask. This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.69 g, 57.66 mmol, 1.20 eq.) in dichloromethane (50 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 80 mL of water/ice and extracted with dichloromethane (3x50 mL). The resulting mixture was washed with brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8 g (76%) of methyl (2S)-2-[(tert- butyldimethylsilyl)oxy]propanoate as a colorless liquid.
76%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
a solution of methyl (2S)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and IH-imidazole (4.9 g, 71.98 mmol, 1.50 eq.) in dichloromethane (100 mL) was placed into a 250-mL round-bottom flask. This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.69 g, 57.66 mmol, 1.20 eq.) in dichloromethane (50 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 80 mL of water/ice and extracted with dichloromethane (3x50 mL). The resulting mixture was washed with brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8 g (76%) of methyl (2S)-2-[(tert- butyldimethylsilyl)oxy]propanoate as a colorless liquid.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 4.5h;
Example 4(a) - (S)-Methyl 2-(tert-butyldimethylsilyloxy)propanoate:; <strong>[27871-49-4](S)-Methyl lactate</strong> (5.45g, 52.4mmol) was mixed with of te/Y-butyldimethylsilyl chloride (9.47g, 1.2eq. 62.8mmol) in 35mL of anhydrous lambda/,lambda/-dimethylformamide at RT under N2-atm. Imidazole (4.39g, 1.25eq. 65.4mmol) was added and the reaction mixture was stirred for 4.5 h at RT. Diisopropyl ether (15OmL) was added and the mixture was extracted with 15OmL of 1 M aqueous HCI, 15OmL water, 15OmL brine, dried with MgSO4, filtered through a paper filter and after solvent evaporation 12.33g of 4(a) was obtained as a colorless oil.1H NMR (400 MHz, DMSOd6) delta 4.33 (q, 1 H), 3.60 (s, 3H), 1.25 (d, J=6.64Hz, 3H), 0.82 (s, 9H), 0.01 (s, 6H).
With 1H-imidazole; In dichloromethane; at 20℃;Inert atmosphere; Cooling;
1.2.3.2. Illustrative synthesis of Intermediate Gen-15-b: (S)-2-(tert-Butyl-dimethyl-silanyloxy)- propionic acid methyl ester To a solution of Intermediate Gen-14-b (694 g, 6.67 mol, 1 eq.) in DCM (7 L) under stirring and nitrogen, are added lH-imidazole (500 g, 7.34 mol, 1.1 eq.) and Intermediate Gen-9-b (1055 g, 7.00 mol, 1.05 eq.). The reaction mixture is cooled during the addition, then stirred at room temperature overnight under nitrogen. The reaction mixture is diluted in IPE (5.5 L), the organic layer is washed once with an aqueous 1 M HCl solution (2.8 L), once with a mixture of an aqueous 1 M HCl solution and brine (1/1) (1.4 L/1.4 L) and once with brine (2.8 L), dried over Na2S04, filtered and evaporated to dryness to give Intermediate Gen-15-b. 'H NMR (300 MHz, CDCl3-i ) delta ppm 4.34 (1 H, q), 3.73 (3 H, s), 1.40 (3 H, d), 0.91 (9 H, s), 0.90 (6 H, d).
With 1H-imidazole; In dichloromethane; at 20℃;Inert atmosphere;
To a solution of Intermediate Gen-14-b (694 g, 6.67 mol, 1 eq.) in DCM (7 L) under stirring and nitrogen, are added 1H-imidazole (500 g, 7.34 mol, 1.1 eq.) and Intermediate Gen-9-b (1055 g, 7.00 mol, 1.05 eq.). The reaction mixture is cooled during the addition, then stirred at room temperature overnight under nitrogen. The reaction mixture is diluted in IPE (5.5 L), the organic layer is washed once with an aqueous 1 M HCl solution (2.8 L), once with a mixture of an aqueous 1 M HCl solution and brine (1/1) (1.4 L/1.4 L) and once with brine (2.8 L), dried over Na2SO4, filtered and evaporated to dryness to give Intermediate Gen-15-b. 1H NMR (300 MHz, CDCl3-d) delta ppm 4.34 (1H, q), 3.73 (3H, s), 1.40 (3H, d), 0.91 (9H, s), 0.90 (6H, d)
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Inert atmosphere;
A solution of (S)-methyl 2-hydroxypropanoate (12.379 g, 119 mol) and TEA (17.4 mL, 125 mol) in DCM (100 mL) was chilled to 0 C and methanesulfonyl chloride (12.4 mL, 125 mol) was added dropwise at 0 C over 1 h. The mixture was stirred at 20 C for 1.5 h. The resulting mixture was quenched with ice-water (100 mL). The organic layer was separated, washed with water (2 x 50 mL) and brine, dried over Na2S04and concentrated to afford the crude product (S)-methyl 2-(methylsulfonyloxy)propanoate (20.940 g, 97%) as brown oil which was used without purification.
(Example 10) methyl (S)-2-methanesulfonyloxypropionate triethylamine (40.5 g, 0. 40 mol) was added over 30 minutes to a solution prepared by mixing 20.8 g (0.20 mol) of methyl L-lactate (optical purity 100% ee) with 200 ml of toluene at an inside temperature of 10C. After 30 minutes of stirring at 10C, 34.4 g (0.30 mol) ofmethanesulfonyl chloride was added in succession at 10C over 4 hours.. After 2 hours of stirring at 5C, 100 ml of pure water was added and, further, 36 g of concentrated hydrochloric acid was added to adjust the PH to 5 to 6 and, after 30 minutes of stirring at 20C, the organic layer was separated (extract).. This extract was washed with 100 ml of pure water and further concentrated under reduced pressure to give 36.2 g of oily methyl (S)-2-methanesulfonyloxypropionate.
48.2 g
With triethylamine; In dichloromethane; at -10℃; for 3h;
Example: 2 Preparation of Methyl 2-(S)-methylsul?onyloxypropionate (IX) Triethylamine (107 ml) was added to a cold, stirred solution of methyl (S)- lactate (40 g) in dichloromethane (400 ml) -10C. Methanesulfonyl chloride (38.8 ml) was added to the reaction mixture drop by drop over a period of 1 h at this temperature, and the reaction mixture was stirred at this temperature for about 2 h when the reaction was complete, as indicated by TLC. The reaction mixture was poured on cold water (400 ml) and stirred for 10 minutes. The separated organic layer was washed with 5 % dilute hydrochloric acid (1 X 80 ml), saturated sodium bicarbonate solution (1 X 100 ml), brine (1 X 100 ml), dried over sodium sulfate and concentrated at 50C to furnish the desired product; 48.2 g.
With trifluorormethanesulfonic acid; In dichloromethane; cyclohexane; at 0 - 26℃; for 6.25h;
To a cooled (0 C) solution of (S)-methyl lactate (2.0 g, 19.21 mmol) in a mixture of cyclohexane (20 mL) and dichloromethane (10 mL) were added benzyl 2,2,2-trichloroacetimidate (4.3 mL, 23.05 mmol) followed by trifluoromethane sulfonic acid (140 pL, 1.53 mmol) and the resultant mixture was stirred at 0 C for 15 mm. The mixture was warmed up to RT and stirred for 6 h. The reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 1.78 g of titled product. ‘H NMR (300 MHz, CDC13) ö 1.44 (d, J= 6.9 Hz, 3H), 3.75 (s, 3H), 4.07 (q, J= 6.9 Hz, 1H), 4.45 (d, J= 11.7 Hz, 1H), 4.69 (d, J= 11.7 Hz, 1H), 7.27-7.37 (m, 5H).
With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; for 2.25h;
With lithium aluminium tetrahydride In tetrahydrofuran at 25℃; for 1h;
77 % Spectr.
With hydrogen In methanol at 25℃;
92.3 - 95.9 % ee
With hydrogen In Dimethyl ether at 110℃; for 1.2 - 6.33333h;
4; 6
Hydrogenation of methyl lactate Experiments 4-7:; Table : List of performed experiments Samples are taken at regular intervals after the substrate feed is started. Substrate feed rate = 100P1/MIN Results :
92.5 % ee
With hydrogen In tetrahydrofuran at 80℃; for 17h; Autoclave;
35
Methyl (S)-lactate (5.0 mmol, optical purity 99.6% ee), Complex 16 (0.05 mmol) obtained in Synthesis Example 2 and tetrahydrofuran (2 mL) were placed in a 100-ml autoclave equipped with a stirrer-bar, and the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 80°C for 17 hours. The hydrogenated gave (S)-1,2-propanediol at a conversion rate of 62.0% and a selectivity of 96.8%. The optical purity of the alcohol obtained was found to be 92.5% ee, and an alcohol obtained retains an optical purity of 90% or more of that of the ester in optical purity. The optical purity was measured after carbonation of the alcohol obtained. Optical purity analysis condition: Column: β-DEX 225Injection temperature: 250°CDetection temperature: 250°COven temperature: 170°C constant
40.1 %Chromat.
With RuH(η1-BH4)(dppp)((S,S)-dpen); hydrogen In tetrahydrofuran at 80℃; for 16h; Autoclave;
With {OsH(CO)[PyCH2N(CH2)2PiPr2]2; hydrogen In tetrahydrofuran at 100℃; for 9h; Autoclave;
With ruthenium(bis[2‐(ethylsulfanyl)ethyl]amine)(dichloro)(triphenylphosphine); potassium methanolate; hydrogen In toluene at 100℃; for 1h; Glovebox; Inert atmosphere;
2; 1
Pyrrolidine (39.25 g, 0.48 mole) was added dropwise to methyl-(S)-(-)-lactate (25.0 g, 0.24 mol) at 0° C. and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and purified with distillation to afford (2S)-2-hydroxy-1-(pyrrolidin-1-yl)propan-1-one 2 (29.0 g, 84%) at 150° C.-160° C. as light yellow oil.
82%
for 72h; Ambient temperature;
at 20℃; for 72h;
at 20℃;
In methanol Heating / reflux;
I; a
In order to assign the absolute configurations at the stereogenic centers of the oxazolidinone rings, a new synthetic route was designed which employed an enantiomerically pure substrate derived from the chiral pool. Commercially available (S)-(+)-methyl lactate was converted into its pyrrolidine amide according to the method of Martin et al (Martin, R.; Pascual, O.; Romea, P.; Rovira, R.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1997, 38, 1633). Following the protection of the hydroxy group of (2S)-1-oxo-1-(1-pyrrolidinyl)-2-propanol to a TBDMS group, treatment of tert-butyl(dimethyl)silyl(1S)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl ether with 3,4-difluorophenyllithium yielded (2S)-2-[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-propanone as the sole product, which was then converted to (2S)-2-[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-propanone oxime. Reduction of the (2S)-2-[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-propanone oxime with LiAlH4, N-acylation, and base induced cyclization provided oxazolidinone diastereomers, which were separated by flash column chromatography. The enantiomeric purity of these isomers was confirmed by chiral HPLC analysis and their relative configurations were assigned by comparison of their 1H NMR spectra with those of the racemic isomers. As the absolute configuration at C-5 of the lactic acid derived oxazolidinone described above is (S), the C-4 center in trans compounds also has the (S) configuration. Accordingly, the absolute configurations for the stereogenic centers in the cis compounds are assigned accordingly (4R,5S). [00483] 4-NITROPHENYL(4S,5R)-4-(3,4-DIFLUOROPHENYL)-5-METHYL-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, 2H, J=8.8 Hz), 7.30-6.99 (m, 5H), 5.35 (d, 1H, J=7.7 Hz), 5.07 (apparent quintet, 1H), 1.17 (d, 3H, J=6.5 Hz); Anal. Calc. for C17H12F2N2O6+0.5H2O: C, 52.72; H, 3.38; N, 7.23. Found: C, 53.09; H, 3.19; N, 7.50.
at 80 - 85℃; for 3.5h; Large scale;
1 Process for preparation of (2S)-l-Oxo-l-pyrrolidin-l-ylpropan-2-ol:
S-Methyl lactate (1 kg) was added to the flask at room temperature followed by the slow addition of N-Pyrrolidine (1 kg) for 30 min. The reaction mixture was slowly heated to 80-85 C and maintained for 3 hrs. After completion of the reaction N- Pyrrolidine was completely distilled out under vacuum at 85°C .Crude: 1.3 kg; G.C: 92%
at 45℃; for 24h; Large scale;
1; 2 BP004a01
Add 15.5kg of S-lactate methyl ester and 11.2kg of tetrahydropyrrole to the pre-dried three-necked flask, and incubated at 45 °C for 24h. The GC monitors the raw material ≤ 2%, the temperature control T ≤ 50 ° C, and concentrates under reduced pressure to no fraction. Add 60 kg of dichloromethane, 60 kg of water,The layers were extracted, the aqueous phase was back-extracted with 60 kg of dichloromethane, and the organic phases were combined.Dry, concentrate to dryness under reduced pressure, and directly in the next step.
at 45℃; for 24h; Large scale;
1; 2 BP004a01
Add 15.5 kg of methyl S-lactate to the pre-dried three-necked bottle. 11.2kg of tetrahydropyrrole, incubated at 45 ° C for 24 h, GC monitoring raw materials ≤ 2%, temperature control T ≤ 50 ° C, concentrated under reduced pressure to no fraction, add 60kg of dichloromethane, 60kg of water, extract layering, The aqueous phase was back-extracted with 60 kg of dichloromethane, and the organic phases were combined. Dry, concentrate to dryness under reduced pressure, and directly in the next step.
at 45℃; for 24h;
1; 2 BP004a01
Add 15.5 kg of S-lactate methyl ester and 11.2 kg of tetrahydropyrrole to the pre-dried three-necked bottle.The reaction was incubated at 45 ° C for 24 h.GC monitoring raw materials ≤ 2%, temperature control T ≤ 50 ° C,Concentrated under reduced pressure to no fraction.Add 60 kg of dichloromethane, 60 kg of water,The layers were extracted and the aqueous phase was back-extracted with 60 kg of dichloromethane. The organic phases were combined and dried.Concentrate to dryness under reduced pressure and directly to the next step.
With trifluorormethanesulfonic acid; In dichloromethane; cyclohexane; at 0 - 25℃; for 21.25h;
A solution of PMBOH (109 mmol) in Et2O (44 mL) was added to a solution of NaH (60% in oil, 32.6 mmol, 0.3 equiv) in Et2O(65 mL). The solution was stirred at room temperature for 45 min. After cooling to 0 C, Cl3CCN (109 mmol, 1 equiv) was addedand the solution was stirred at 0 C for 1 h, then at room temperature for 4 h. The solution was filtered through a pad of celite anda saturated aqueous solution of NaHCO3 (40 mL) was added. The product was extracted with Et2O (3 30 mL). The combinedorganic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the desired imidate (28.5 g, 93%)as an orange oil which was used without further purification.TfOH (0.202 mmol, 0.003 equiv) was added dropwise to a solution of imidate (101 mmol, 1.5 equiv) and methyl (L)-lactate (67.2mmol) in a mixture CH2Cl2/cyclohexane (6:4, 152 mL) cooled at 0 C. The solution was stirred at 0 C for 15 min, then at roomtemperature for 21 h. The solution was filtered through a pad of celite and concentrated under reduced pressure. A saturatedaqueous solution of NaHCO3 (30 mL) was added and the product was extracted with CH2Cl2 (3 30 mL). The combined organiclayer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography (EtOAc/cyclohexane, 5:95 to 10:90) to afford ester (14.7 g, 92%) as a yellow oil.
N, O-dimethylhydroxylamine hydrochloride (500 mmoL) was dissolved in CH2Cl2 (500 mL), FeCl3 (500 mmoL) was added at -30C, and the mixture was stirred at room temperature for 30 min.The temperature was adjusted to -30 & lt; 0 &The reaction was quenched by the addition of saturated ammonium chloride, adjusted to pH 6, extracted with CH2Cl2 and concentrated in vacuo to give (<strong>[27871-49-4]L-lactic acid methyl ester</strong>) (S) -2-hydroxy-N-methoxy-N-methylpropanamide, purity 97% The yield was 96%, and the recovery rate of the solvent was 90%.
Stage #1: (S)-Methyl lactate; Merrifield resin coupled silyl chloride With dmap; triethylamine In dichloromethane at 20℃; for 0.333333h;
Stage #2: phenylmagnesium bromide In tetrahydrofuran at 0 - 20℃;
Stage #3: With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃;
A solution of the aminophenol (37.3 g, 198 mmol), S-lactic acid methyl ester (20 ml) and triphenylphosphine (58 g, 220 mmol) in THF (2000 ml) was cooled in ice/salt (temperature <10C). Then a solution of azodicarboxic acid ester (DIAD, 43 ml , 218 mmol) in THF (400 ml) was added slowly. After stirring at room temperature for 18 hours the reaction mixture was concentrated in vacuo and ethanol (500 ml) and 36% HCl (125 ml) were added to the residue. The mixture was heated to 100C (development of gas). After cooling the compound was isolated by filtration and washed with 96% ethanol (about 100 ml). Yield 42 g (87%).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
The construction to the (R)-isomer of this tether (T33a) was accomplished from 2-iodophenol (33-0) and (5)-methyl lactate (33-A). Mitsunobu reaction of 33-0 and 33-A proceeded with inversion of configuration in excellent yield to give 33-1. Reduction of the ester to the corresponding alcohol (33-2) also occurred in high yield and was followed by Sonagashira reaction with Ddz-propargylamine. The alkyne in the resulting coupling product, 33-3, was reduced with catalytic hydrogenation. Workup with scavenger resin provided the desired product, Ddz-T33a.
With hydrogen;ruthenium on silica; In Dimethyl ether; at 150℃; for 0.666667h;Product distribution / selectivity;
Hydrogenation of methyl lactate Experiments 4-7:; Table : List of performed experiments Samples are taken at regular intervals after the substrate feed is started. Substrate feed rate = 100P1/MIN Results :
With hydrogen;Ru/C; In Dimethyl ether; at 150℃; for 0.833333h;Product distribution / selectivity;
Hydrogenation of methyl lactate Experiments 4-7:; Table : List of performed experiments Samples are taken at regular intervals after the substrate feed is started. Substrate feed rate = 100P1/MIN Results :
Synthetic example 1(R)-Methyl-2-fluoropropionateTo 10.4 g (0.1 mol) (S)-(-)-methyl lactate 21.75 g (0.15 mol) tertafluoroethyldimethylamine were slowly added dropwise to keep the temperature below 30 0C. The reaction mixture was then stirred at room temperature for 12 hours. It was then poured on ice and the product extracted using dichloromethane. The product was further cleaned by distillation over a Vigreux distilling column. Three fractions were obtained.Fraction 1 b.p. 45-50C/15 mbar, 8.3 g (83 %) R-methyl-2-fluoropropionate, 98% content and 96 % ee (determined by Chirale GC). 98 % Enantiomer R, 2 % Enantiomer S.1H NMR: 1.5 (3H, dqw ), 3.8 (3H, s), 5.1 (dqw, IH) ppm.Fraction 2 b.p. 60-650C/ 15 mbar, I g lactic acid methyl ester (Educt).Fraction 3 b.p. 70-80C/15 mbar, 1 1.3 g difluoroacetic acid diethylamide
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
This tether required a five (5) step procedure in order to prepare Ddz-T109 in an overall yield of 34% starting from 2-fluorophenol (109-1, 11.2 g, 100 mmol). The corresponding (S)-isomer, Boc-T109b, can be constructed analogously, but using (R)-methyl lactate in place of (S)-methyl lactate (109-3) in the second step.TLC: Rf: 0.25 [Et2O:hexane, (1:1)]Boc-T109 was synthesized similarly in an overall yield of 15-25%.1H NMR (CDCl3, 300 MHz): delta 6.94 (m, 3H), 4.45 (m, 1H), 3.85 (dd, J=12, 3.2, 1H), 3.72 (m, 1H), 3.05 (m, 2H), 2.72 (m, 2H), 2.52 (s, br, 1H), 1.76 (m, 2H), 1.45 (s, 9H), 1.24 (dd, J=6.5, 1.1, 3H).13C NMR (CDCl3, 75 MHz): delta 136.97, 125.26, 125.22, 123.81, 123.70, 122.78, 114.62, 114.36, 79.82, 79.75, 66.31, 39.55, 30.58, 28.41, 26.66, 16.08.
50 g sodium hydride (60 % in mineral oil) are dissolved in 600 ml tetrahydrofurane and cooled to 00C. 98 g methyl-(S)-(-)-lactate in 150 ml tetrahydrofurane are added dropwise and stirring is continued for 20 minutes. Then 76 ml methyliodide in 100 ml tetrahydrofurane are added dropwise and the mixture is stirred for further 12 hours, while warming to room temperature. After cooling to 5C 400 ml of a 10 N solution of sodium hydroxide in water are added and the mixture is stirred for 2 hours. Then concentrated hydrochloric acid until pH of <n="140"/>1 is reached is added. The tetrahydrofurane is evaporated in vacuo and the aquous phase is extracted three times with dichloromethane. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The crude product, which is obtained as a racemate under the reaction conditions, is used directly in the next step. Yield: 65,6 g (67 % of theory) Mass spectrometry (ESI"): m/z = 103 [M-H]"
With (R)-(+)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole; 2,2-dimethylpropanoic anhydride; N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; for 12h; Inert atmosphere; Resolution of racemate; optical yield given as %ee; enantioselective reaction;
1: 68 % ee
2: 47%
With 2,2-dimethylpropanoic anhydride; N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; for 12h;
5
Test Example 5Production of Optically Active 2-Hydroxy Ester Using Various Types of Racemic 2-Hydroxy Ester (3) As shown in the above reaction scheme, to diethyl ether (0.2 M) containing 0.6 equivalents of pivalic acid anhydride and 0.5 equivalents of diphenylacetic acid were added 1.2 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole (BTM), and a solution containing 1 equivalent of a racemic 2-hydroxy ester in diethyl ether at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. After the organic layers were admixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and unreacted optically active 2-hydroxy ester. The results are shown in Table 5. TABLE 5 Yield [%] [a] cc [%] No.R5 R6 5a; 5b 5a; 5b s 29 Et n-Pr 47; 47 97; 89 217 30 Me Me 47; 23 97; 68 119 [a] Isolation yieldAs is seen from Table 5, prominently high enantiomeric excess ee and reaction velocity ratio s were exhibited also when a material other than the benzyl ester was used (Entries 29 and 30).The physical properties of the optically active hydroxy esters and the diesters in Table 5 are shown below.(Entry 29)Ethyl (S)-2-hydroxypentanoate1H NMR (CDCl3): δ4.19 (dq, J=14.0, 7.0 Hz, 1H, Eta), 4.18 (dq, J=14.0, 7.5 Hz, 1H, Eta), 2.96 (br d, J=3.5 Hz, 1H, OH), 1.75-1.65 (m, 1H, 3-H), 1.62-1.52 (m, 1H, 3-H), 1.48-1.30 (m, 2H, 4-H), 1.24 (dd, J=7.5, 7.0 Hz, 3H, Eta), 0.89 (t, J=7.3 Hz, 3H, 5-H);13C NMR (CDCl3): δ175.3, 70.2, 61.4, 36.4, 17.9, 14.1, 13.6.Ethyl (R)-2-(diphenylacetyloxy)pentanoateHPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=15.0 min (1.4%), tR=17.5 min (98.6%);IR (neat): 1745, 1496, 1454, 745, 701 cm-1;1H NMR (CDCl3): δ7.33-7.17 (m, 10H, Ph), 5.08 (s, 1H, 2'-H), 4.98 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 4.12 (dq, J=14.0, 7.5 Hz, 3H, Eta), 4.11 (dq, J=14.0, 7.0 Hz, 3H, Eta), 1.78-1.71 (m, 2H, 3-H), 1.32-1.28 (m, 2H, 4-H), 1.16 (dd, J=7.5, 7.0 Hz, 3H, Eta), 0.81 (t, J=7.5 Hz, 3H, 5-H);13C NMR (CDCl3): δ172.1, 170.1, 138.4, 138.3, 128.7, 128.6, 128.4, 127.3, 127.2, 120.4, 72.9, 61.2, 56.8, 33.0, 18.3, 14.0, 13.5;HR MS: calcd for C21H24O4Na (M+Na+) 363.1567. found 363.1569.(Entry 30)Methyl (S)-lactate1H NMR (CDCl3): δ4.24 (q, J=7.0 Hz, 1H, 2-H), 3.72 (s, 3H, MeO), 3.16 (br s, 1H, OH), 1.36 (d, J=7.0 Hz, 3H, 3-H);13C NMR (CDCl3): δ176.0, 66.6, 52.3, 20.2.Methyl (R)-2-(diphenylacetyloxy)propanoateHPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=0.75 mL/min): tR=16.4 min (98.3%), tR=19.7 min (1.7%);IR (neat): 1744, 1496, 1454, 748, 699 cm-1;1H NMR (CDCl3): δ7.28-7.20 (m, 8H, Ph), 7.19-7.13 (m, 2H, Ph), 5.07 (q, J=7.0 Hz, 1H, 2-H), 5.03 (s, 1H, 2'-H), 3.60 (s, 3H, MeO), 1.37 (d, J=7.0 Hz, 3H, 3-H);13C NMR (CDCl3): δ171.9, 170.9, 138.3, 138.2, 128.7, 128.63, 128.55, 128.4, 127.3, 127.2, 69.2, 56.6, 52.2, 16.8;HR MS: calcd for C18H18O4Na (M+Na+) 321.1097. found 321.1091.
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at -20 - 50℃;Inert atmosphere;
A. Preparation of methyl (2S>2-(blphenyl-4-ylmethoxy)propanoate (C4). A mixture of 4«(bromomethyl)blphenyl (49.9 g, 202 mmol), and sodium hydride (60% dispersion in mineral oil, 8.45 g, 211 mmol) in dimethylformamide/tetrahydrofupsilonran (400 ml/600 mL) was held at -2OC and treated drop-wise with methyl (S)-2-hydroxypropanoate (20.0 g, 192 mmol) The mixture was stirred at -20C for 30 minutes, then 25"C for 30 minutes, then 50C for 1 hour The mixture was then carefully quenched with a mixture of water (1000 mL) and hexanes (500 mL) The organic layer was collected, and the aqueous layer was re-extracted with 1 1 hexanes diethyl ether. The combined organic fractions were washed with water (2X) and saturated aqueous sodium chloride solution, and then dned over sodium sulfate The crude material was then concentrated, and purified by chromatography on silica gel (gradient 95 5 hexanes ethyl acetate to 80 20 hexanes ethyl acetate) to provide C4 as a clear oil Yield 44.4 g, 85% 1H NMR (400 MHz, CDCI3) 6 1.43 (3H, d, 7=7.0 Hz), 3.74 (3H, S), 4.07 (1H, q,7«6 8 Hz), 4 46 (1H, d, 7*11 5 Hz)1 4 70 (1H, d, 7«11 7 Hz), 7 32 (1 H, t, 7*7 3 Hz), 7 40 (4H, m), 7.55 (4H. m).
85%
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at -20 - 50℃; for 2h;Inert atmosphere;
A mixture of 4-(bromomethyl)biphenyl (49.9 g, 202 mmol), and sodium hydride (60% dispersion in mineral oil, 8.45 g, 211 mmol) in dimethylformamide/tetrahydrofuran (400 mL/600 mL) was held at 20oC and treated drop-wise with methyl (S)-2-hydroxypropanoate (20.0 g, 192 mmol). The mixture was stirred at -20oC for 30 minutes, then 25C for 30 minutes, then 50oC for 1 hour. The mixture was then carefully quenched with a mixture of water (1000 mL) and hexanes (500 mL). The organic layer was collected, and the aqueous layer was re-extracted with 1:1 hexanes:diethyl ether. The combined organic fractions were washed with water (2X) and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The crude material was then concentrated, and purified by chromatography on silica gel (gradient: 95:5 hexanes:ethyl acetate to 80:20 hexanes:ethyl acetate) to provide 16 as a clear oil. Yield: 44.4 g, 85%. 1H NMR (400 MHz, CDCl3) d 1.43 (3H, d, J=7.0 Hz), 3.74 (3H, s), 4.07 (1H, q, J=6.8 Hz), 4.46 (1H, d, J=11.5 Hz), 4.70 (1H, d, J=11.7 Hz), 7.32 (1H, t, J=7.3 Hz), 7.40 (4H, m), 7.55 (4H, m).
Scheme A6; Preparation of key-intermediate (/?)-A-18 A-15 (R)-A-16 Intermediate (R)-A-IG: (R)-methy 2-{5-bromo-2-nitrophenoxy)propanoate -step a11Triphenylphosphine (624.0 mg, 2.38 mrnol) was added at room temperature to a solution of 5-bromo-2-nitrophenoI A-15 (400.0 mg, 1.83 mmol) and methyl (-)-(S)-lactate (0.149 mL, 1.56 mmol) in anhydrous methylene chloride (18.3 mL) under an atmosphere of argon. After 10 mins of stirring, the reaction mixture was cooled to 0 0C and diisopropyl azodicarboxylate (0.360 mL, 1.83 mmol) was added dropwise. The orange solution was warmed to room temperature, stirred for 12 h, then concentrated to ca. 1.0 mL, diluted with pentane (7 mL) and diethyl ether (8 mL), filtered and rinsed with diethyl ether-pentane (15 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give (R)- methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-IQ as a yellow solid (525.0 mg; Yield=94%). MS (ESI) [M+1]+ 304, 306.
With carbon dioxide; at 165℃; under 21110.9 - 39353.1 Torr; for 1h;Industry scale;Product distribution / selectivity;
EXAMPLE- 7; DIRECT ESTERIFICATION OF SODIUM LACTATE SOLUTION IN METHANOL WITH CARBON DIOXIDE AT 165C AT HIGH PRESSURE (FIGURE-1); 1100 g (40% by wt) of water free sodium lactate solution (1) in methanol (2) prepared as explained in Example-6 was charged in mild steel high pressure reactor vessel (4) having capacity of 5 L and continuously stirred at 750 RPM using agitator. Carbon dioxide gas from cylinder (3) was used to pressurize the reactor so as to get initial pressure of 28.7 Kg/cm2. Reaction material was then allowed to heat till 165C and was maintained at this temperature for 1 hour. During operation the pressure inside reactor rose up to 53.5 Kg/cm2. Reaction mass was then allowed to cool till 25C and was filtered on the basket centrifuge (5) at 3000 RPM. Wet cake (6) containing sodium carbonate was allowed to dry in oven (7) at 110C and stored (8). Filtrate collected (9) from centrifuge (5) was analyzed for methyl ester, methanol contents using Shimadzu made GC-MS Model-QP5000 where as the moisture was measured by Automatic Karl- Fischer, Lab India made instrument. The concentration of methyl ester in filtrate was found to be 20.3 % by wt where as methanol concentration was 76.9 % by wt. and moisture content by Karl-Fischer method was 0.5 % by wt. After desired operation time, pressure inside reactor (4) was released through vent (10), vapors were passed to separator (11) where carbon dioxide gas (13) was separated, which can be recycled at (4), from other volatile reaction liquid mixture (12) which was recycled at (4), unconverted methanol, methyl ester, moisture if any obtained at (4), was sent for recovery having Reboiler-packed tower fractional distillation assembly (14). 1% by wt of methyl ester sodium-bicarbonate was added in reboiler as stabilizer. Pure methyl ester (15) was separated and stored separately from methanol (16) with or without using vacuum in fractional distillation assembly (11). Pure methanol obtained can be recycled at (4).
With sodium methansulfinate; potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h;
L-methyl lactate 0.46g (0.005 mol) and 2-Chloro-4,6-dimethoxy-pyrimidine 0.88g (0.005 mol) were dissolved in DMF 20 ml, K2CO3 0.52g (0.75 eq) was added thereto, and sodium methane sulfinate 0.1g was added thereto, followed by stirring at 120C for 5 hours. The reacted solution was cooled to room temperature, and distilled under reduced pressure to obtain residue. The residue was extracted with cold water and ethylacetate (EA) three times, and washed with brine twice, the organic layer was dried with MgSO4, and the solvent was removed under reduced-pressure. Through purification with silica gel column chromatography, a target material 0.66g (54%) was obtained.: 1H NMR (300MHz, CDCl3) delta: 1.63(d, 3H), 3.73(s, 3H), 3.89(s, 6H), 5.22(q, 1H), 5.72(s, 1H).
With 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II); Novozym 435 In toluene at 80℃; for 82h; Schlenk technique; Enzymatic reaction; stereoselective reaction;
General procedure A for inversion of L-alkyl lactates:
General procedure: A Schlenk tube was charged with Shvo's catalyst 2 (27 mg, 0.045 mmol), alkyl lactate (0.5 mmol), Novozym 435 (10 mg, 100 units), p-chlorophenyl acetate (0.21 mL, 1.5 mmol), and abs. degassed toluene (5 mL) at rt. The mixture was stirred for 82 h at 80 °C. The composition of the reaction mixture was analyzed by gas chromatography.
(S)-methyl 6-((1-methoxy-1-oxopropan-2-yl)oxy)-5-nitronicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 0 - 20℃; for 1.5h;Inert atmosphere;
Part I- Synthesis of (S)-methyl6-((1-methoxy-1-oxopropan-2-yl)oxy)-5-nitronicotinate [0248] To methyl (S)-lactate (0.56 g, 5.4 mmol) and methyl 6-chloro-5-nitro-pyridine-3- carboxylate (0.8 g, 3.7 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen at 0°C was added l,8-diazabicyclo[5.4.0]undec-7-ene (0.88 mL, 5.9 mmol). The solution quickly turned dark. The reaction mixture was stirred at 0°C for 30 minutes, then allowed to stir at ambient temperature for one hour. A solid precipitated out of solution. Next, the reaction mixture was diluted with ethyl acetate (15 mL), solids were removed by filtration, and the filtrate was concentrated in the presence of silica to provide a crude product, which was purified by column chromatography eluting with a gradient of 10-50percent ethyl acetate in hexanes to provide the title compound (0.68 g, 64percent yield); HPLC retention time Method A: 5.46 minutes (98.9percent pure).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 0 - 20℃; for 1.5h;Inert atmosphere; Molecular sieve;
Part I - Synthesis of (S)-methyl -((l-methoxy-l-oxopropan-2-yl)oxy)-5-nitronicotinate [0362] To methyl (S)-lactate (5.8 g, 55.4 mmol) and methyl 6-chloro-5-nitropyridine-3- carboxylate (10 g, 46 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen with activated molecular sieves at 0 °C was added l ,8-diazabicyclo[5.4.0]undec-7-ene (9 mL, 60 mmol). The solution quickly turned dark, was stirred at 0 °C for thirty minutes, then was allowed to stir at ambient temperature for an hour. A solid precipitated out of solution. The solution was diluted with ethyl acetate, solids were filtered off, and then the filtrates were concentrated. The residue was purified by column chromatography eluting with a gradient of 10-50percent ethyl acetate in hexanes to yield the title compound.
6-[1-hydroxyethyl]-1-tetrahydropyran-4-yl-5H-pyrazolo-[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.7%
With sodium ethanolate; In ethanol; at 80℃;
To a solution of intermediate I-45a (5.0 g, 23.86 mmol) in anhydrous EtOH (100 mL) was added R-16, (S)-methyl 2-hydroxypropanoate, (7.28 g, 70 mmol) and EtONa (25 mL, 2.7M), the reaction mixture was stirred at 80C for overnight. Then the reaction mixture was concentrated under vacuo and purified by column (PE: EA=10:1 to 0:1)to give intermediate I-48a as aracemic mixture (3.0 g, 47.7%). ESI-MS (Mi-i): 265 calc. for C12H16N403:264.1.
(1-methoxy-1-oxopropane-2-yl)-2-hydroxypropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%Spectr.; 91%Spectr.
With dibutylmagnesium; In hexane; dichloromethane; at 20℃; for 0.0166667h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: The monomer, i.e., l-LA(0.72 g, 5 mmol), in CH2Cl2 (10 mL) and MeOH (0.81 mL, 20mmol) were placed in a Schlenk flask and stirred for 10 min, and then MgBu2(0.1 mL of 1.0 M solution in hexane, 0.1 mmol) was added dropwise. Standard molar ratios of reagents: [MgBu2]/[l-LA]/[ROH]= 1/50/200. The reaction mixture was vigorously stirred at room temperature and at certain time intervals aliquots of about 1 mL were taken, quenched with one drop of acetic acid, dried under vacuum, and analyzed using 1H NMR spectroscopy and mass spectrometry.
With dibutylmagnesium; In hexane; dichloromethane; at 20℃; for 0.5h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: The monomer, i.e., l-LA(0.72 g, 5 mmol), in CH2Cl2 (10 mL) and MeOH (0.81 mL, 20mmol) were placed in a Schlenk flask and stirred for 10 min, and then MgBu2(0.1 mL of 1.0 M solution in hexane, 0.1 mmol) was added dropwise. Standard molar ratios of reagents: [MgBu2]/[l-LA]/[ROH]= 1/50/200. The reaction mixture was vigorously stirred at room temperature and at certain time intervals aliquots of about 1 mL were taken, quenched with one drop of acetic acid, dried under vacuum, and analyzed using 1H NMR spectroscopy and mass spectrometry.
Stage #1: (S)-Methyl lactate With C35H52N4O4; scandium tris(trifluoromethanesulfonate) In tetrahydrofuran at 35℃; for 0.5h; Molecular sieve;
Stage #2: acetic anhydride In tetrahydrofuran at 30℃; for 0.15h; Molecular sieve;
(S)-2-[4-(4-hydroxybenzyl)phenoxy]propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran;Cooling with ice; Inert atmosphere;
General procedure: To an ice-bath cooled mixture of (R)-or (S)-methyl lactate(4.8 mmol), bis(4-hydroxyphenyl)methane (4.8 mmol), and triphenylphosphine(4.8 mmol) in anhydrous THF (30 mL), a solutionof diisopropyl azodicarboxylate (DIAD, 4.8 mmol) in anhydrous THF(20 mL) was added dropwise under nitrogen atmosphere. Themixture was allowed to warm to room temperature and stirred forovernight. The solvent was evaporated affording an oil which waschromatographed on a silica gel column (n-hexane/ethyl acetate9:1 as eluent) to give the target methyl esters as white solids.
(R)-methyl 2-[(6-bromo-2-nitropyridin-3-yl)oxy]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; for 0.166667h;Inert atmosphere;
Under a nitrogen atmosphere, DIAD (19.2 mL, 98 mmol) was added dropwise to a solution of <strong>[443956-08-9]6-bromo-2-nitropyridin-3-ol</strong> (21.5 g, 98 mmol), (5)-methyl 2-hydroxy- propanoate (10.2 g, 98 mmol) and triphenylphosphine (25.8 g, 98 mmol) in THF (dry, 300 mL) at 0C. After 10 minutes, the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SC"4) and evaporated in vacuo. The residue was triturated from diethyl ether (250 mL) for 30 minutes, then filtered and washed with diethyl ether (50 mL). The combined filtrates were evaporated in vacuo, then the residue was purified by column chromatography (silica; eluent: DCM), to afford the title compound (29.5 g, 98%). 5H (300 MHz, CDCls) 7.64 (d, J 8.7 Hz, IH), 7.33 (d, J 8.7 Hz, IH), 4.85 (q, J 6.8 Hz, IH), 3.78 (s, 3H), 1.69 (d, J 6.8 Hz, 3H)
With potassium carbonate; at 160℃; for 16h;Flow reactor;
The stainless steel pressure vessel (40 cc, Swagelok) is filled in with the methanol (15.0 g: Sigma-Aldrich, 003e99.8percent) solution of the metal salt (metal ion supply source), and sucroses (0.450 g: Fluka, 003e99.0percent) and catalyst (0.150 g). The reactor is closed and it heats up under the mixing (700 rpm) with 160. In 160 reaction, it makes maintained for 16 hours and the container reaction rapidly is cooled in the cold water after this period as the dipping. Sample from the reaction container was filtered and it analyzed with the HPLC (the Agilent 1200, the Biorad Aminex HPX-87H column, 65, 0.05 M H2SO4, 0.6 ml min-1) and it was the art exhibition ring hexose and dihydroxy acetone (DHA), the methyllactate (ML) using the fixed quantity: and GC (the Agilent 7890 in which the Phenomenex Solgelwax column is comprehended) the glyceraldehyde (GLA), and methyl vinyl glycol rate (MVG, and the methyl 2- hydroxy -3- butenoate) and glycol aldehyde dimethylacetal (GADMA) the fixed quantity.
cyclohex-3-en-1-ylmethyl (2S)-2-hydroxypropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.7%
With toluene-4-sulfonic acid In n-heptane at 125℃; for 3h; Dean-Stark;
5 EXAMPLE 5: Preparation of cyclohex-3-en-l-ylmethyl (2S)-2-hydroxypropanoate ((S)-isomer version)
1 1 1.5 g (993.7 mmol) of 3 -cyclohexene-1 -methanol, 218.0 g (2.094 mol) of methyl L-(-)-lactate, 2.1 10 g of p-toluenesulfonic acid, and 1 1 1 mL of heptane were added to a 500 mL four-neck flask equipped with a thermometer, Dean-Stark apparatus, and Dimroth condenser, and heat under reflux was performed. The methanol formed during this period was removed by the Dean-Stark apparatus, and 3 -cyclohexene-1 - methanol as a raw material disappeared 3 hours later. The thus obtained reaction solution was washed with 1 1 1 mL of saturated sodium hydrogen carbonate aqueous solution and 1 1 1 mL of saturated brine in this order and then heptane was evaporated to carry out distillation under a reduced pressure (93.7-95.3°C/230 Pa), thereby obtaining 131.3 g of the intended cyclohex-3-en-l-ylmethyl (2,S)-2-hydroxypropanoate as a colorless oil (theoretical yield based on 3 -cyclohexene-1 -methanol, 71.7%). The odor was herbal, green, violet, and mushroom.
(R)-Methyl 2-(2-Bromo-6-Nitrophenoxy)Propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 15h; Inert atmosphere;
115.1 Step 1:
To a solution of 2-bromo-6-nitrophenol (2.0 g,9.17 mmol),(S)-methyl 2-hydroxypropanoate (1.15 g,11.01 mmol)and triphenylphosphine (3.61 g,13.76 mmol)in DCM(20 mL)was added DIAD (2.78 mL,13.76 mmol)dropwise. The reaction mixture was stirred at15 room temperature for 15 h under a nitrogen atmosphere. The mixture was concentrated in vacuo.20EtOAc (80 mL)was added,washed with brine (30 mL x 3),dried over anhydrous Na2S04,filtered and concentrated in vacuo. The crude residue was purified by silica gel columnchromatography (petroleum ether/EtOAc = 7:3)to give the title compound (2.5 g,81%)as awhite solid.
Stage #1: 2-bromo-N-methylbenzenesulfonamide; 2-formylbenzene boronic acid With potassium phosphate In 1,4-dioxane; water at 80℃; Inert atmosphere;
Stage #2: (S)-Methyl lactate With methanesulfonic acid In [D3]acetonitrile at 20℃; for 20h; Molecular sieve;
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
The synthesis of the fluorinated derivative, tether T75, was carried out in an analogous matter to that of the related tether T33 starting from 33-A [(S)-methyl lactate] and appropriately substituted phenol 75-0 to provide 4.1 g of Ddz-T75a as a pale yellow solid. Although the first two steps, Mitsunobu reaction and DII3AL reduction, were high yielding, 91% and 98% respectively, isolation of the final product proved difficult after Sonagashira coupling and hydrogenation, lowering the overall yield to 17%. Again, the corresponding (R)-enantiomer, Ddz-T75b, is accessible by substituting (R)-methyl lactate (33-13) in the above procedure.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 5h;
1
At 0 ° C, 250 ml of anhydrous THF was added to the reactor, followed by the addition of (S)-(-)-methyl lactate (10.4 g, 100 mmol), Ph3P (26.23 g, 100 mmol), compound (25.6 g, 100 mmol). ), fully stirred and dissolved,Then, diethyl azodicarboxylate (DEAD, 17.4 g, 100 mmol) was added dropwise, and the mixture was stirred and warmed to room temperature. The reaction was monitored by TLC. After 5 h, the reaction was completed to yield 19.51 g, yield 82%, and R/S was 92/. 8.
dimethyl (2R,2'R)-2,2'-((2-iodo-5-(methoxycarbonyl)-1,3-phenylene)bis(oxy))dipropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
Methyl 3,5-dihydroxybenzoate (8 g, 46 mmol), sodium bicarbonate (11.64 g, 140 mmol, 3equiv), water (80 mL), and THF (24 mL) were stirred at 0 oC. Iodine (23.4 g, 92.4 mmol, 2 equiv) was dissolved in THF (40 mL) and added over 30 min while maintaining the internaltemperature between 2-8 C. After stirring 1 h, diethyl ether (50 mL) was added in one portion,followed by a solution of sodium sulfite (6.4 g, 50 mmol, 2 equiv) in water (24 mL) over 30 min,and keep the internal temperature between 2-10 C. The resulting biphasic mixture waswarmed to ambient temperature and the light yellow product-rich organic phase was separated,dried and concentrated. The crude product was recrystallized from methanol/water to give<strong>[338454-02-7]methyl 4-iodo-3,5-dihydroxybenzoate</strong> as orange needles. Yield: 72% (9.7 g). 1H NMR (400 MHz, DMSO-d6): delta = 10.50 (s, 2H), 6.93 (s, 2H), 3.79 (s, 3H)ppm. The spectroscopic data are in agreement with previous report. Diisopropyl azodicarboxylate (10 mL, 50 mmol, 2.5 equiv) was added dropwise via syringeover 30 minutes to a stirred suspension of <strong>[338454-02-7]methyl 3,5-dihydroxy-4-iodobenzoate</strong> (5.9 g, 20.0mmol), triphenylphosphine (13 g, 50 mmol, 2.5 equiv), and methyl (S)-(-)-lactate (4.85 mL, 50mmol, 2.5 equiv) in THF (100 mL) at 0 C. The reaction mixture was warmed to roomtemperature and stirred overnight. The resulted residue was purified by columnchromatography (Petroleum ether:EtOAc, 3:1) to give 2b as white solid.Yield: 71% (6.62 g); m.p. 92-94 oC; [a]D20 = 11 (c = 0.73, CHCl3); 1H NMR (CDCl3, 500 MHz):delta = 7.01 (s, 2H), 4.88 (q, 2H, J = 7.0 Hz), 3.88 (s, 3H), 3.76 (s, 6H), 1.71 (d, 6H, J = 7.0 Hz) ppm;13C NMR (CDCl3, 125 MHz): delta = 171.6, 166.1, 158.2, 131.7, 107.2, 87.3, 74.1, 55.4, 18.5 ppm; IR(neat): 2949, 1743, 1712, 1573, 1417, 1240, 1132, 1072, 1008, 966, 854 cm-1; HRMS (ESI)Calc?d for C16H20IO8 [M+H]+ 467.0197; found 467.0194.
methyl (2S)-2-(5-bromo-2-chlorophenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43.9 g
With diethyl diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 0 - 35℃;Inert atmosphere;
To a mixture of <strong>[183802-98-4]5-bromo-2-chlorophenol</strong> (31.0 g) , methyl (2R) -2-hydroxypropanoate (31.1 g) , triphenylphosphine (118 g) and THF (dry) (250 mL) was added 2.2 M diethyl (E) -diazene-1, 2- dicarboxylate toluene solution (238 mL) at 0C, and the mixture was stirred at room temperature overnight under nitrogen atmosphere. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue were added hexane and IPE (1:1, 200 mL) , the mixture was stirred at 0C for 20 min, and the reaction solution was concentrated. To the obtained solid were added IPE and ethyl acetate (2:1, 400 ml) and the mixture was stirred at 0C for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (43.9 g) . NMR (300 MHz, DMSO-de) d 1.54 (3H, d, J = 6.7 Hz), 3.70 (3H, s), 5.24 (1H, q, J = 6.8 Hz), 7.18 (1H, dd, J = 8.4, 2.1 Hz), 7.26 (1H, d, J = 2.1 Hz), 7.41 (1H, d, J = 8.4 Hz).
methyl (S)-2-(2-benzoylphenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: 2-Hydroxybenzophenone; (S)-Methyl lactate With triphenylphosphine In dichloromethane at 0℃; for 0.166667h;
Stage #2: With diethylazodicarboxylate In dichloromethane at 0 - 20℃; for 8h;
Methyl (S)-2-(4-benzoylphenoxy)propanoate ((S)-6).
General procedure: To 4-hydroxybenzophenone 1 (182 mg, 0.92mmol) in dry CH2Cl2 (6 mL), methyl D-(+)-lactate 4 (144 mg, 1.38 mmol) and PPh3 (290 mg, 1.10 mmol)was added at 0 °C. After the reaction mixture was stirred for 10 min at 0 °C, DEAD (240 mg, 1.38mmol) was slowly added at same temperature. The reaction mixture was stirred overnight at roomtemperature and partitioned between water and CH2Cl2. The organic layer was washed with brine,dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography(ethyl acetate/n-hexane, 1:9) to give methyl (S)-2-(4-benzoylphenoxy)propanoate ((S)-6) (230 mg,88%). [α]D -42 (c 1, CHCl3).
methyl (S)-2-(4-(2,2,2-trifluoroacetyl)phenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: (S)-Methyl lactate; 2,2,2-trifluoro-1-(4-hydroxyphenyl)ethan-1-one With triphenylphosphine In dichloromethane at 0℃; for 0.166667h;
Stage #2: With diethylazodicarboxylate In dichloromethane at 0 - 20℃; for 8h;
Methyl (S)-2-(4-(2,2,2-trifluoroacetyl)phenoxy)propanoate (S)-33.
To 2,2,2-trifluoro-1-(4-hydroxyphenyl)ethanone 31 (1.175 g, 7.25 mmol) in dry CH2Cl2 (30 mL), D-(+)-lactate 4 (1.132 g, 10.9mmol) and PPh3 (2.282 g, 8.70 mmol) was added at 0 °C. After the reaction mixture was stirred for 10min at 0 °C, DEAD (1.891 g, 10.9 mmol) was slowly added at same temperature. The reaction mixturewas stirred overnight at room temperature and partitioned between water and CH2Cl2. The organiclayer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purifiedby column chromatography (ethyl acetate/n-hexane, 1:9) to give (S)-33 (1.560 g, 78%). [α]D -48 (c 1,CHCl3). 1H-NMR (270 MHz, CDCl3): δ = 7.96 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 4.82 (q, J = 6.8Hz, 1H), 3.70 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). 13C-NMR (67.5 MHz, CDCl3): δ = 178.8 (q, 2JCF = 34.6 Hz),171.4, 163.2, 132.7, 123.4, 116.8 (q, 1JCF = 291.4 Hz), 115.2, 72.5, 52.5, 18.3. HRMS (ESI): m/z calculatedfor C12H11F3O4 + H+ [M + H+]: 277.0688. Found: 277.0674.
methyl (S)-2-(4-benzoylphenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: (S)-Methyl lactate; 4-Hydroxybenzophenone With triphenylphosphine In dichloromethane at 0℃; for 0.166667h;
Stage #2: With diethylazodicarboxylate In dichloromethane at 0 - 20℃; for 8h;
Methyl (S)-2-(4-benzoylphenoxy)propanoate ((S)-6).
To 4-hydroxybenzophenone 1 (182 mg, 0.92mmol) in dry CH2Cl2 (6 mL), methyl D-(+)-lactate 4 (144 mg, 1.38 mmol) and PPh3 (290 mg, 1.10 mmol)was added at 0 °C. After the reaction mixture was stirred for 10 min at 0 °C, DEAD (240 mg, 1.38mmol) was slowly added at same temperature. The reaction mixture was stirred overnight at roomtemperature and partitioned between water and CH2Cl2. The organic layer was washed with brine,dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography(ethyl acetate/n-hexane, 1:9) to give methyl (S)-2-(4-benzoylphenoxy)propanoate ((S)-6) (230 mg,88%). [α]D -42 (c 1, CHCl3). 1H-NMR (270 MHz, CDCl3): δ = 7.81 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 7.4 Hz,2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.87 (q, J = 6.8 Hz, 1H), 3.78(s, 3H), 1.67 (d, J = 6.8 Hz, 3H). 13C-NMR (67.5 MHz, CDCl3): δ = 195.4, 171.9, 161.0, 138.0, 132.5, 131.9,130.9, 129.7, 128.1, 114.4, 72.4, 52.4, 18.3. HRMS (ESI): m/z calculated for C17H16O4 + H+ [M + H+]:285.1127. Found: 285.1120. Chiral HPLC (n-hexane/2-propanol 90:10): tR 25.8 min.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 12h;
100.1 Example 100: Synthesis of (R)-2-((3'-ethoxy-4,5-difluoro-4'-(7-oxo-6,7-dihydro-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-[l,l'-biphenyl]-3-yl)oxy)propanoic acid (Compound 260)
Step 1 : Into a 50 ml round-bottom flask was added 5-bromo-2,3-difluorophenol (500 mg, 2.32 mmol, 1.00 equiv), methyl (S)-2-hydroxypropanoate (479 mg, 2.87 mmol, 1.2 equiv), PPI13 (816 mg, 3.11 mmol, 1.3 equiv), and THF (10 mL). To the above mixture was added DIAD (629 mg, 3.11 mmol, 1.3 equiv) dropwise over 15 min at 0 °C. The resulting mixture was stirred for additional 12 hr at rt, then the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl (R)-2-(5-bromo-2,3- difluorophenoxy)propanoate (450 mg, 58%) as a yellow oil. 'H NMR (300 MHz, DMSO-di) d 7.37 (ddd, J = 9.7, 6.3, 2.3 Hz, 1H), 7.23 (dt, J = 6.7, 2.2 Hz, 1H), 5.33 - 5.11 (m, 1H), 3.70 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H).
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃;
General procedure: DIAD (1.9 mol/L in toluene; 3.40 mL, 6.46 mmol) was added dropwise to a mixture of 2e (1.0 g, 4.31 mmol), methyl l-(-)-lactate (0.448 g, 4.31 mmol), and TPP (1.69 g, 6.46 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with dilute HCl and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with EtOAc-hexane (1:4-2:3) to give the corresponding methyl ester (1.18 g, 86%) as a colorless syrup.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃;
General procedure: DIAD (1.9 mol/L in toluene; 3.40 mL, 6.46 mmol) was added dropwise to a mixture of 2e (1.0 g, 4.31 mmol), methyl l-(-)-lactate (0.448 g, 4.31 mmol), and TPP (1.69 g, 6.46 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with dilute HCl and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with EtOAc-hexane (1:4-2:3) to give the corresponding methyl ester (1.18 g, 86%) as a colorless syrup.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃;
General procedure: DIAD (1.9 mol/L in toluene; 3.40 mL, 6.46 mmol) was added dropwise to a mixture of 2e (1.0 g, 4.31 mmol), methyl l-(-)-lactate (0.448 g, 4.31 mmol), and TPP (1.69 g, 6.46 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with dilute HCl and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with EtOAc-hexane (1:4-2:3) to give the corresponding methyl ester (1.18 g, 86%) as a colorless syrup.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃;
General procedure: DIAD (1.9 mol/L in toluene; 3.40 mL, 6.46 mmol) was added dropwise to a mixture of 2e (1.0 g, 4.31 mmol), methyl l-(-)-lactate (0.448 g, 4.31 mmol), and TPP (1.69 g, 6.46 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with dilute HCl and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with EtOAc-hexane (1:4-2:3) to give the corresponding methyl ester (1.18 g, 86%) as a colorless syrup.
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