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Structure of 17392-83-5 * 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.
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
[2] Green Chemistry, 2013, vol. 15, # 10, p. 2817 - 2824
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 ]
[ 17392-83-5 ]
Yield
Reaction Conditions
Operation in experiment
88.2 % ee
Stage #1: at 25℃; for 0.25 h; Stage #2: With hydrogen In tetrahydrofuran for 6 h;
Methyl pyruvate (51 mg; 0.50 mmol) was dissolved in a reaction vessel in anhydrous THF (3.0 mL) and degassed with argon for 15 minutes. Bis(1,5-cycloocta-diene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand 4a from Example 1 (3.7 mg; 6 μmol; 0.012 equiv) were combined and argon-degassed anhydrous THF (2.0 mL) was added. This solution was stirred at 25° C. under argon for 15 minutes and then added to the solution of 2-acetamidocinnamic acid. The resulting solution was then flushed with hydrogen and pressurized to 0.69-1.38 bars gauge (10-20 psig) hydrogen. The reaction mixture was stirred for 8 hours to afford 90.2percent conversion to methyl (R)-lactate with 88.2percent ee as determined by chiral GC analysis. The analytical properties of methyl lactate were identical to an authentic sample.Chiral GC [Cyclosil-B (JW Scientific) 30 m.x.0.25 mm ID, film thickness 0.25 μm, 75° C. isothermal, 15 psig He]: t&R[methyl (R)-lactate] 7.75 min, tR[methyl (S)-lactate] 9.16 min. tR(methyl pyruvate) 5.16 min.
99.2 % 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.
Reference：
[1] Tetrahedron Letters, 1998, vol. 39, # 14, p. 1941 - 1944
[2] Tetrahedron, 1999, vol. 55, # 25, p. 7787 - 7804
[3] Patent: US6906213, 2005, B1, . Location in patent: Page/Page column 15
[4] Angewandte Chemie - International Edition, 2011, vol. 50, # 21, p. 4913 - 4917
[5] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4070 - 4078
[6] Chinese Journal of Catalysis, 2015, vol. 36, # 4, p. 634 - 638
[7] RSC Advances, 2015, vol. 5, # 124, p. 102481 - 102487
[8] Chemical Communications, 2017, vol. 53, # 23, p. 3346 - 3349
4
[ 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
5
[ 67-56-1 ]
[ 10326-41-7 ]
[ 17392-83-5 ]
Yield
Reaction Conditions
Operation in experiment
10.62 g
at 20℃; for 24 h;
General procedure: was synthesized from corresponding from L-Lactic acid (20 g, 0.225 mole) (5) via diazotization using a reported procedure starting from Alanine (3).[8] The isolated L-lactic acid (10 g, 0.111 mole) was subjected to esterification in MeOH (100 mL, 10 v) with a catalytic amount of sulphuric acid (0.1 mL) to give methyl lactate (7); output: 11.09 g, Yield: 48percent (overall two stages). Similarly methyl-(R)-2-hydroxypropanoate (8) was synthesized by using above procedure from antipode (6), Output: 10.62 g Yield: 46percent (overall two stages). Colorless oil; R-methyl lactate (8) [α]D20 = +4.19° (c 1.7, CHCl3) & S-methyl lactate (7) [α]D20 = - 4.27° (c 2.3, CHCl3); IR (Neat): 3455, 2987, 2957, 1739, 1456, 1271, 1222, 1132, 1048, 979 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J = 6.6 Hz, 3H), 3.28 (bs, 1H), 3.67 (S, 3H), 4.17 (q, J = 6.6 & 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 20.15, 52.30, 66.66, 176.0; GC-Ms : (104, M+).
Reference：
[1] Bulletin de la Societe Chimique de France, 1893, vol. <3>9, p. 678
[2] Patent: CN106187756, 2016, A, . Location in patent: Paragraph 0013-0017
[3] Synthetic Communications, 2018, vol. 48, # 21, p. 2801 - 2808
6
[ 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
7
[ 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
Reference：
[1] European Journal of Organic Chemistry, 2012, # 21, p. 3978 - 4017
14
[ 3724-26-3 ]
[ 67-56-1 ]
[ 91049-50-2 ]
[ 17392-83-5 ]
[ 1454336-61-8 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 34, p. 11301 - 11309
15
[ 186581-53-3 ]
[ 10326-41-7 ]
[ 17392-83-5 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 16, p. 8359 - 8370
16
[ 67-56-1 ]
[ 616-09-1 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 10, p. 2817 - 2824
17
[ 547-64-8 ]
[ 160289-70-3 ]
[ 17392-83-5 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 7, p. 2293 - 2300
18
[ 186581-53-3 ]
[ 17392-83-5 ]
Reference：
[1] Tetrahedron, 1972, vol. 28, p. 3757 - 3766
19
[ 17392-83-5 ]
[ 73246-45-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
With pyridine; thionyl chloride In N,N-dimethyl-formamide at 20 - 55℃; for 5 h;
Step 1, Preparation of Vilmerier Reagent: To a 250 ml four-necked flask was added 71.4 g (0.6 mol 1) of thionyl chloride, ice Water was cooled to 5 to 10 ° C and 52.6 g (0.72 mol) of anhydrous N, N-dimethylformamide was added dropwise as a solvent at a temperature Increased, mechanical stirring 1 ~ 2h reaction to be colorless Vilmerier reagent solution; Step 2, Synthesis of S-2-Chloropropionic Acid Methyl Ester: At 20 to 30 ° C,A small amount of pyridine was added to the Vilmer ier reagent solution obtained in the first step using a constant pressure dropping funnel to obtain a mixed solution,To the mixed solution, 52 g (0.5 mol 1) of R-lactic acid methyl ester was added dropwise to the mixed solution, and the reaction temperature was significant and the gas was generated. After completion of the dropwise addition, the mixture was stirred at 55 ° C for 5 hours, 2 - chloropropionic acid methyl ester solution, gas phase tracking reaction process, after the end of the reaction cooling; Step 3: The S-2-chloropropionic acid methyl ester solution obtained in the second step was washed with water, and the residue was distilled to give the product S-2-chloropropionic acidMethyl ester 56.9 g, yield 90percent, optical purity 99percent.
With pyridine; thionyl chloride In N,N-dimethyl-formamide at 20 - 55℃; for 6 h;
Step I, prepared Vilmerier reagent: To a 250ml four-necked flask was added 71.4g (0.6mol) of thionyl chloride, ice-water was cooled to 5~10 ° C, and a solution of 50.4g (0.69mol) in dry N , N- dimethylformamide as a solvent, the temperature has increased significantly, mechanically stirred 2h to afford a colorless Vilmerier wide reagent solution;Step 2. Synthesis of S-2- chloropropionate: Under 20-30 ° C temperature, with constant pressure dropping funnel Vilmerier reagent solution obtained in the first step I added a small amount of dioxane to obtain a mixed solution , to the mixed solution was added dropwise 62.4g (0.6mol) (R)-lactic acid methyl ester, the reaction was warmed significantly, and there is a gas generation; the addition was complete, warmed to 55 ° C under stirring 6h, the reaction was carried out chloro product solution i.e. S -2-chloropropionate solution, gas phase reaction progress was followed, after the reaction was cooled;Step 3, the S-2- chloropropionate washing solution obtained in step 2, desolventizing distilled to give the product (S)-2-chloropropionic acid methyl ester 54.4g, 86percent yield, the optical purity of 87percent .
With 1H-imidazole In dichloromethane at 20℃; for 2 h;
A mixture of methyl noate (5.1 g, 48.99 mmol), (1226) dichloromethane (50 mL), imidazole (5 g, 75 mmol) and tert-butyldimethylsilyl chloride (8.85 g) was stirred for two hours at room temperature. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by MPLC eluting with 5percent ethyl acetate in petroleum ether to afford methyl (R)-2-((tert-butyldimethylsilyl)oxy)propanoate (10.67 g, 100percent) as a colorless oil.
93%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 6 h;
To a solution of methyl (R)-2-hydroxylpropanoate 12 (2 g, 19.21 mmol) in dry DCM (60 mL) was added imidazole (1.96 g, 28.815 mmol), and the mixture was stirred for 10 min at 0 °C. To this solution tert-butyldimethylsilyl chloride (3.47 g, 23.05 mmol) was added at 0 °C and the mixture was stirred at room temperature for 6 h. After completion of the reaction, the mixture was diluted with cold water and extracted into DCM (3 .x. 75 mL). The combined extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography using hexane/ethyl acetate (97:3) to give pure 13 (3.9 g, 93percent) as a colorless oil. (c 2.8, CHCl3) [Lit.15b +27.2 (c 1.89, CCl4)]; IR (neat, cm-1): νmax 2944, 2894, 2859, 1753, 1255, 1146, 838, 778; 1H NMR (300 MHz, CDCl3): δ 4.25 (q, J = 6.8 Hz, 1H), 3.67 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.04 (d, J = 7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 172.6, 67.5, 50.6, 25.0, 20.5, 17.5, -5.6, -6.0; ESI/MS (m/z): 241 (M+Na+).
85%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere
To a solution of (R)-(+)-methyl lactate (2.95 g, 28.34 mmol) in DMF (20 mL) was added tert-butyldimethyl silyl chloride (6.41 g, 42.51 mmol) and imidazole (6.75 g, 99.18 mmol). After stirring at a room temperature for 18 hr, the reaction mixture was diluted with a saturated aqueous NaCl solution (90 mL) and extracted with petroleum ether (3.x.60 mL). The organic layer was washed with a cold 3percent HCl solution (30 mL) and a saturated aqueous NaCl solution (30 mL), dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel (105 g) with petroleum ether (300 mL), followed by 3percent ethyl acetate in petroleum ether (600 mL). The 3percent ethyl acetate in the petroleum ether fractions was collected and the solvent was removed to give 5.26 g of (R)-(+)-Methyl 2-(tert-butyldimethylsilyloxy)propanoate as colorless oil (85percent yield). 1H NMR (CDCl3): δ 4.26 (q, 1H, J=6.8 Hz, -CH), 3.65 (s, 3H, -OCH3), 1.32 (d, 3H, J=6.8 Hz, -CH3), 0.83 (s, 9H, Si-(CH3)3), 0.03 (s, 3H, Si-CH3), 0.00 (s, 3H, Si-CH3).
67%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 2 h;
Step la: methyl (2R)-2-[(tert-butyIdimethyIsiIyl)oxy]propanoate: into a 250-mL round-bottom flask, was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03 mmol, 1 .00 equiv) and Imidazole (6.5 g, 95.59 mmol, 2.00 equiv) in dichloromethane (100 mL). This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 equiv) in dichloromethane (50 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3x100 mL) and the organic layers combined. The resulting mixture was washed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 7 g (67percent) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxy]propanoate as colorless oil.
67%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 2 h;
into a 250-mL round-bottom flask was placed a solution of methyl (2/?)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and imidazole (6.5 g, 95.59 mmol, 2.00 eq.) in dichloromethane (100 mL), followed by the dropwise addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 eq.) in dichloromethane (50 mL) at 0 °C. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7 g (67percent) of methyl (2R)- 2-[(tert-butyldimethylsilyl)oxy]propanoate as a colorless oil
67%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 2 h;
into a 250-mL round-bottom flask, was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03mmol, 1.00 equiv) and Imidazole (6.5 g, 95.59 mmol, 2.00 equiv) in dichloromethane (100 mL). This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 equiv) in dichloromethane (50 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted withdichloromethane (3x100 mL) and the organic layers combined. The resulting mixture waswashed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 7 g (67percent) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxy]propanoate as colorless oil.
67%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 2 h;
into a 250-mL round-bottom flask, was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03mmol, 1.00 equiv) and imidazole (6.5 g, 95.59 mmol, 2.00 equiv) in dichloromethane (100 mL). This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 equiv) in dichloromethane (50 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated undervacuum to give 7 g (67percent) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxyjpropanoate as colorless oil.
67%
With 1H-imidazole In dichloromethane at 0 - 20℃; for 2 h;
into a 250-mLround-bottom flask was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03mmol, 1.00 eq.) and imidazole (6.5 g, 95.59 mmol, 2.00 eq.) in dichloromethane (100 mL), followed by the dropwise addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 eq.) in dichloromethane (50 mL) at 0 °C. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by the addition of 100 mL ofwater/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7 g (67percent) of methyl (2R)- 2-[(tert-butyldimethylsilyl)oxyjpropanoate as a colorless oil.
Reference：
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durch Digerieren und Stehenlassen ueber ungeloeschtem Kalk;
With novel catalyst In water at 110 - 120℃; for 6h;
1 Example 1
A D-lactic acid methyl ester esterification process steps of:Step 1: feeding,Methanol, D- lactic acid, the novel catalyst by centrifugation Li 3.6L input reactor;Step 2: Heating,Esterified with steam heated to security 110-120 ° C;Step 3: A mixture of, Stirred using a stirrer made 316L.Step 4: the dropwise addition, the dropwise addition of the esterification reaction by centrifugation Li 400L / h methanol.Step 5: with water, with a novel agent for use with water.Step 6: esterification at a temperature of 110-120 ° C, esterification 6h, completion of esterification.In the above steps,If you use conventional electric heating,Equipment failure rate is higher,And there is the possibility of igniting methanol, While the use of steam heating,The temperature of the steam is low,Will not ignite methanol,But also reduces the failure rate of the equipment,In summary, the invention has the advantages of simple process,Low operating costs,Extraction purity is high,Easy to manufacture advantages.
10.62 g
With sulfuric acid at 20℃; for 24h;
Methyl-(S)-2-hydroxypropanoate (7)
General procedure: was synthesized from corresponding from L-Lactic acid (20 g, 0.225 mole) (5) via diazotization using a reported procedure starting from Alanine (3).[8] The isolated L-lactic acid (10 g, 0.111 mole) was subjected to esterification in MeOH (100 mL, 10 v) with a catalytic amount of sulphuric acid (0.1 mL) to give methyl lactate (7); output: 11.09 g, Yield: 48% (overall two stages). Similarly methyl-(R)-2-hydroxypropanoate (8) was synthesized by using above procedure from antipode (6), Output: 10.62 g Yield: 46% (overall two stages). Colorless oil; R-methyl lactate (8) [α]D20 = +4.19° (c 1.7, CHCl3) & S-methyl lactate (7) [α]D20 = - 4.27° (c 2.3, CHCl3); IR (Neat): 3455, 2987, 2957, 1739, 1456, 1271, 1222, 1132, 1048, 979 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J = 6.6 Hz, 3H), 3.28 (bs, 1H), 3.67 (S, 3H), 4.17 (q, J = 6.6 & 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 20.15, 52.30, 66.66, 176.0; GC-Ms : (104, M+).
With triethylamine; In dichloromethane; at 0℃; for 2h;
(R) - (+) - 2-Hydroxypropanoic acid methyl ester (1 g, 9.6 mmol)And triethylamine (2.91 g, 28.8 mmol)Dissolved in anhydrous dichloromethane (32 mL),After the reaction mixture was cooled to 0 C,P-Toluenesulfonyl chloride (2.2 g, 11.5 mmol) was added,After the reaction mixture was reacted at 0 C for 2 hours,Water (16 mL) was added and the organic phase was separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel.1.2 g of methyl (R) -2- (p-toluenesulfonyloxy) propionate (13-6) was obtained in a yield of 49%
With trimethylamine hydrochloride; triethylamine; In acetonitrile; at 0 - 5℃; for 0.333333h;
vi) methyl f27?)-2-{ff4-methylphealphayl)sulfo?yl]oxy?prorhoanoateA solution of methyl (i?)-(+)-lactate (6.66g) in acetonitrile (33ml) was cooled to 5C and triethylamine (9.8ml) added followed by trimethylamine hydrochloride (0.62g). A separate solution ofp-toluenesulfonyl chloride (11.6g) in acetonitrile (33ml) was added dropwise over 20 min maintaining the temperature below 5C. The reaction mixture was filtered and concentrated, Diethylether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.7Ig). 1H NMR CDCl3: delta 7.82 (2H, d), 7.35 (2H7 d), 4.95 (IH, q), 3.67 (3H, s), 2.45 (3H, s), 1.51 (3H5 d).
With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine; In ethyl acetate; at 6 - 25℃; for 2h;
tep 9A. Lactate Tosylate Formation OMeTo a 50 L RBF was added 1.50 kg R-methyl lactate, which was then dissolved in EtOAc (7.5 L) with 3.02 kg tosyl chloride. The batch was cooled with ice to 6 0C. A mild endotherm was noted on mixing.DABCO (242 g) and triethylamine (3.01 L) were separately dissolved in the 7.5 L of EtOAc. The solution was charged to a 50 L vessel, maintaining the temperature below 25 0C. The reaction was aged 2 h at room temperature. A mild to moderate delayed exotherm was seen. A white slurry formed during the addition.To a 50 L extractor 4 L of water and 3 L of EtOAc were added with stirring. Water (3.5 L) was added to the reaction vessel, and the biphasic solution was transferred to the extractor. The vessel was then rinsed with 4.5 L EtOAc. To the stirred extraction was added 7.5 L of 2 N HCl, bringing the total extraction volume to 40 L. The extraction was aged 10 min and phase separated. The organic was washed with 7.5 L of water and then 15 L of 4 % NaHCO3 (aq). The organic solution was then transferred to clean plastic carboys, and dried over Na2SO4 (5 kg) in the carboys.The batch was then filtered through a 20 uM poly cap filter into a Buchi rotary evaporator, yielding the product as an oil containing residual ethyl acetate (3 wt%) and 700 PPM water. The batch was transferred to a container and was stored in a cold room until it was used. The product had an ee of 98.2 %.
With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine; In ethyl acetate; at 6 - 25℃; for 2h;
Lactate Tosylate Formation OMeTo a 50 L RBF was added 1.50 kg R-methyl lactate, which was then dissolved in EtOAc(7.5 L) with 3.02 kg tosyl chloride. The batch was cooled with ice to 6 0C. A mild endotherm was noted on mixing.'DABCO (242 g) and triethylamine (3.01 L) were separately dissolved in the 7.5 L of EtOAc. The solution was charged to a 50 L vessel, maintaining the temperature below 25 0C. The reaction was aged 2 h at room temperature. A mild to moderate delayed exotherm was seen. A white slurry formed during the addition.To a 50 L extractor 4 L of water and 3 L of EtOAc were added with stirring. Water (3.5 L) was added to the reaction vessel, and the biphasic solution was transferred to the extractor. The vessel was then rinsed with 4.5 L EtOAc. To the stirred extraction was added 7.5 L of 2 N HCl, bringing the total extraction volume to 40 L. The extraction was aged 10 min and phase separated. The organic was washed with 7.5 L of water and then 15 L of 4 % NaHCO3 (aq). The organic solution was then transferred to clean plastic carboys, and dried over Na2SO4 (5 kg) in the carboys.The batch was then filtered through a 20 uM poly cap filter into a Buchi rotary evaporator, yielding the product as an oil containing residual ethyl acetate (3 wt%) and 700 PPM water. <n="14"/>The batch was transferred to a container and was stored in a cold room until it was used. The product had an ee of 98.2 %.
With silver(l) oxide; In acetonitrile; at 85℃; for 16h;
Ag20 (6.1 g, 26.4 mmol, 1.10 eq.) was addedto a solution of iodomethane (27.3 g, 192 mmol, 8.00 eq.) and methyl (2R)-2-hydroxypropanoate (2.5 g, 24 mmol, 1.00 eq.) in acetonitrile (30 mL) and the solution was stirred for 16 hours at 85 C in an oil bath. The solids were filtered and the mixture was diluted with DCM (100 mL). The resulting mixture was washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2 g (70%) ofmethyl (2R)-2-methoxypropanoate as colorless oil.[0529] ?H NMR (400MHz, CDC13): oe 3.92-3.87 (m, 1H), 3.76 (s, 3H), 3.40 (s, 3H), 1.42- 1.40 (d, J= 6.8 Hz, 3H).
70%
With silver(l) oxide; In acetonitrile; at 85℃; for 16h;
Ag20 (6 1 g, 26 4 mmol, 1 10 eq.) was added to a solution of iodomethane (27.3 g, 192 mmol, 8.00 eq.) and methyl (2R)-2- hydroxypropanoate (2.5 g, 24 mmol, 1.00 eq.) in acetonitrile (30 mL) and the solution was stirred for 16 hours at 85 C in an oil bath. The solids were filtered and the mixture was diluted with DCM (100 mL). The resulting mixture was washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2 g (70%) of methyl (2R)-2-methoxypropanoate as colorless oil. [0475] lH NMR (400MHz, CDC13): delta 3.92-3.87 (m, 1H), 3.76 (s, 3H), 3.40 (s, 3H), 1.42- 1.40 (d, J = 6.8 Hz, 3H).
70%
With silver(l) oxide; In acetonitrile; at 85℃; for 16h;
Ag20 (6 1 g, 26 4 mmol, 1 10 eq.) was added to a solution of iodomethane (27.3 g, 192 mmol, 8.00 eq.) and methyl (2R)-2- hydroxypropanoate (2.5 g, 24 mmol, 1.00 eq.) in acetonitrile (30 mL) and the solution was stirred for 16 h at 85 C in an oil bath. The solids were filtered and the mixture was diluted with DCM (100 mL). The resulting mixture was washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 2 g (70%) of methyl (2R)- 2-methoxypropanoate as colorless oil. XH NMR (400MHz, CDC13): delta 3.92-3.87 (m, 1H), 3.76 (s, 3H), 3.40 (s, 3H), 1.42-1.40 (d, J= 6.8 Hz, 3H).
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 silver(l) oxide; In diethyl ether; at 20℃; for 2h;Heating / reflux;
Example 1 - Exemplary Precursors; IA. Protected Diol Aldehyde 102; Benzyl bromide (7.0 mL, 57.7 mmol) and freshly prepared Ag2O (11.0 g, 48.1 mmol) were added successively to an Et2O (150 mL) solution of R- (+) -methyl lactate (5.0 g, 48.1 mmol) at rt (room temperature). The resulting suspension was brought to reflux and stirred for 2 h. The reaction was cooled to rt, filtered through a pad of Celite and concentrated in vacuo. Chromatography on silica gel (10% EtOAc/hexanes) afforded 7.5 g (80%) of benzyl ether Al as a colorless oil:[00293] Al: Rf (15% EtOAc/hexanes)=0.66; IR 2988, 2952, 2874, 1750, 1497, 1454, 1372, 1275, 1207, 1143, 1066, 1025, 739, 698 cm"1; 1H NMR (300 M Hz, CDCl3) delta 1.44 (3H, d, J=6.8 Hz, C27), 3.75 (3H, S, CH3O), 4.07 (IH, q, J=6.8 Hz, C26), 4.45 (IH, d, J=I 1.7 Hz, CH2Ph), 4.69 (IH, d, J=I 1.7 Hz, CH2Ph), 7.28-7.37 (5H, m, Ph); 13C NMR (75 M Hz, CDCl3) delta 18.6, 51.8, 71.9, 73.9, 127.7, 127.8, 128.3, 137.4, 173.6; HRMS Calcd for C11H14O3 (M+): 194.0943. Found: 194.0942.
80%
With silver(l) oxide; In diethyl ether; at 20℃;Inert atmosphere; Reflux;
Benzyl bromide (7.0 mL, 57.7 mmol) and freshly prepared Ag2O (11.0 g, 48.1 mmol) were added successively to an Et2O (150 mL) solution of R-(+)-methyl lactate (5.0 g, 48.1 mmol) at rt (room temperature). The resulting suspension was brought to reflux and stirred for 2 h. The reaction was cooled to rt, filtered through a pad of Celite and concentrated in vacuo. Chromatography on silica gel (10% EtOAc/hexanes) afforded 7.5 g (80%) of benzyl ether Al as a colorless oil:A1: Rf (15% EtOAc/hexanes)=0.66; IR 2988, 2952, 2874, 1750, 1497, 1454, 1372, 1275, 1207, 1143, 1066, 1025, 739, 698 cm-1; 1H NMR (300 M Hz, CDCl3) delta 1.44 (3H, d, J=6.8 Hz, C27), 3.75 (3H, S, CH3O), 4.07 (1H, q, J=6.8 Hz, C26), 4.45 (1H, d, J=11.7 Hz, CH2Ph), 4.69 (1H, d, J=11.7 Hz, CH2Ph), 7.28-7.37 (5H, m, Ph); 13C NMR (75 M Hz, CDCl3) delta 18.6, 51.8, 71.9, 73.9, 127.7, 127.8, 128.3, 137.4, 173.6; HRMS Calcd for C11H14O3 (M+): 194.0943. Found: 194.0942.
80%
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at 75℃; for 16h;
sodium hydride (3.7 g, 154.17 mmol, 1.20 eq.) was added to a solution of methyl (2R)-2-hydroxypropanoate (8 g, 76.85 mmol, 1.00 eq.) in DMF (100 mL) and tetrahydrofuran (100 mL) followed by addition of (bromomethyl)benzene (14.4 g, 84.19 mmol, 1.10 eq.). The resulting solution was stirred for 16 hours at 75 C, the reaction was then quenched with water. The resulting solution was extracted with ethyl acetate and the organic combined layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 12 g (80%) of methyl (2R)-2-(benzyloxy)propanoate as yellow oil.
75%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
Example 23 (Compound 249); Synthesis of (R)-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; Method B Alternatively Compound 199 may be prepared starting from racemic methyl lactate following procedures described below for the preparation of the enantiomers of Compound 199, which are Compounds 248 and 249. Preparation of (7?)-methyl 2-(benzyloxy)propanoate; Sodium hydride (60% dispersion in mineral oil, 10.6 g, 0.266 mol) was added portionwise to (+)-methyl-D-lactate (25.2 g, 0.242 mol)) and benzyl bromide (41.4 g, 0.242 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 (35.2 g, 75%).
72%
The benzyl-protected lactate derivative was prepared as previously described (Tetrahedron 2004, 60, 7693-7704).Briefly, NaH (60% dispersion in mineral oil; 750 mg, 18.8 mmol) was washed three times with pentane in dry vialunder nitrogen before suspending in 150 mL dry THF and cooling to 0 C. Methyl (R)-lactate (1.5 mL, 15.7 mmol);purchased from AK Scientific) was added dropwise over 5 min, followed by 30 min of stirring at 0 C. Benzylbromide (2.1 mL, 17.3 mmol) was added dropwise over 2 min. The reaction mixture was stirred 15 min at 0 C beforewarming to room temp for 6 hrs. The reaction was quenched with 100 mL sat. Na2S2O3 and 200 mL water, then dilutedwith 150 mL ether. Separation of the phases, extraction of the aqueous phase with three portions of 200 mL ether,followed by washing the combined organics with 150 mL brine, drying over anhydrous sodium sulfate, filtering toremove solids, and concentrating under vacuum afforded the crude product. Purification by flash chromatographyover silica (2.5 to 12.5% ethyl acetate:hexanes, increasing in 2.5% increments; loaded residue with PhMe) yielded 2.2g of the benzylated lactate derivative S10 as a clear, colorless liquid (72% yield).
With sodium hydride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at -30 - 50℃; for 1.5h;
At -30C, benzyl bromide (9.86 g) and 60% sodium hydride (2.11 g) were dissolved in a mixed solution of dimethyl formamide (DMF) and tetrahydrofuran (THF) (50 mL, 3:2 volume ratio). <strong>[17392-83-5](R)-Methyl lactate</strong> (5.0g, 99%ee) was added to the solution. At the same temperature, the resultant mixture was stirred for 30 minutes. Thereafter, the mixture was stirred at room temperature for 30 minutes and further at 50C for 30 minutes. Water and diisopropyl ether were added to the reaction mixture, and the organic layer was washed with water and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resultant residue was subjected to chromatography on a silica gel column to afford the title compound as a yellow oil (8.87 g, 92.1%ee).1H-NMR (CDCl3) delta:1. 44 (3H, d, J=6. 8Hz), 3. 75 (3H, s), 4. 07 (1H, q, J = 6. 9Hz), 4. 45 (1H, d, J = 1 1. 7H z), 4. 69 (1H, d, J=11. 7Hz), 7. 22-7. 37 (5H, m)
A stirred solution of ( ?)-methyl 2-hydroxypropanoate (l .Og, 9.61 mmol) in toluene (15 mL) was cooled to 0C. Methanesulfonyl chloride (0.82 mL, 10.6 mmol) was added drop wise. After 2 h, the solution was warmed to room temperature and further stirred for 45 min. The resulting heavy white precipitate was removed by vacuum filtration and the clear solution was concentrated to provide 1.75 g (99%) of (i?)-methyl 2-((methylsulfonyl)oxy)propanoate as a colorless oil. 1H NMR (400 MHz, CDCls) delta 5.14 (q, J = 7.0 Hz, 1H), 3.81 (d, J = 4.5 Hz, 3H), 3.16 (d, J = 4.5 Hz, 3H), 1.62 (d, J = 7.0 Hz, 3H).
96.4%
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice;
001049] To a solution of compound 459 (300 mg, 2.88 mmol) and Et3N (0.6 mL, 4.32 mmol) in dry DCM (10 mL) was added dropwise MsCI (264 umL, 3.46 mmol) in an ice water bath. Then the mixture was stirred at room temperature for 1 hour. TLC showed the reaction was completed. Water (30 mL) was added. Then the aqueous layer was extracted with DCM (2 x 15 mL) and dried over Na2S04. The solvent was removed in vacuo to give compound 460 (505 mg, 96.4%).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Inert atmosphere;
A solution of (R)-methyl 2-hydroxypropanoate (30 g, 0.28 mol) and TEA (80 mL, 0.56 mol) in DCM (300 mL) was chilled to 0 C and methanesulfonyl chloride (33.6 mL, 0.42 mol) was added dropwise at 0 C over 1 h. The mixture was stirred at 10-20 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 Na2S04 and concentrated to afford the crude product (R)-methyl 2-(methylsulfonyloxy)propanoate (50 g, 95.2%) as brick red oil which was used without purification.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Inert atmosphere;
A solution of (R)-methyl 2-hydroxypropanoate (30 g, 0.28 mol) and TEA (80 mL, 0.56 mol) in DCM (300 mL) was chilled to 0o C and methanesulfonyl chloride (33.6 mL, 0.42 mol) was added dropwise at 0o C over 1 h. The mixture was stirred at 10-20o C for 1.5 h. The reaction mixture was quenched with ice-water (100 mL). The organic layer was separated, washed with water (2 x 50 mL) and brine, dried over Na2SO4 and concentrated to afford the crude product (R)-methyl 2- (methylsulfonyloxy)propanoate (50 g, 95.2%) as brick red oil which was used without purification.
With 1H-imidazole; In dichloromethane; at 20℃; for 2h;
A mixture of methyl noate (5.1 g, 48.99 mmol), (1226) dichloromethane (50 mL), imidazole (5 g, 75 mmol) and tert-butyldimethylsilyl chloride (8.85 g) was stirred for two hours at room temperature. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by MPLC eluting with 5% ethyl acetate in petroleum ether to afford methyl (R)-2-((tert-butyldimethylsilyl)oxy)propanoate (10.67 g, 100%) as a colorless oil.
98%
With 1H-imidazole;
[00176] The synthesis of a 4-hydroxy nitro sugar is described in Scheme E5. Methyl (R)-2- hydroxyproanoate (14) was treated with tert-butyldimethylsilyl chloride and imidazole to afford the silyl protected alcohol 15 (98% yield), which was then reduced to aldehyde 16 in 82% yield. An asymmetric copper catalyzed Henry reaction to couple 16 and nitromethane employed the chiral bis(oxazaline) derivative 20, and formed the protected nitro diol 17 in 99% yield as a single isomer. Deprotection to give (25,3R)-1-nitrobutane-2,3-diol (18) in92% yield was accomplished by treatment with pyridinium hydrofluoride. Cyclization of diol18 with glyoxal yields the 4-hydroxy nitro sugar (19) as an anomeric mixture. Initial precipitation gave only the x-anomer in 29% yield. Treatment of the mother liquor with HC1- dioxane promotes epimerization of the less crystalline f3-anomer providing a second crop of the x-anomer and bringing the overall yield to 41%. Nitro sugar 19 can be converted to Dmycaminose via the reduction and methylation step described in Scheme El.
97%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 24h;
General procedure: 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.
93%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 6h;
To a solution of methyl (R)-2-hydroxylpropanoate 12 (2 g, 19.21 mmol) in dry DCM (60 mL) was added imidazole (1.96 g, 28.815 mmol), and the mixture was stirred for 10 min at 0 C. To this solution tert-butyldimethylsilyl chloride (3.47 g, 23.05 mmol) was added at 0 C and the mixture was stirred at room temperature for 6 h. After completion of the reaction, the mixture was diluted with cold water and extracted into DCM (3 × 75 mL). The combined extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography using hexane/ethyl acetate (97:3) to give pure 13 (3.9 g, 93%) as a colorless oil. (c 2.8, CHCl3) [Lit.15b +27.2 (c 1.89, CCl4)]; IR (neat, cm-1): numax 2944, 2894, 2859, 1753, 1255, 1146, 838, 778; 1H NMR (300 MHz, CDCl3): delta 4.25 (q, J = 6.8 Hz, 1H), 3.67 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.04 (d, J = 7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3): delta 172.6, 67.5, 50.6, 25.0, 20.5, 17.5, -5.6, -6.0; ESI/MS (m/z): 241 (M+Na+).
85%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
To a solution of (R)-(+)-methyl lactate (2.95 g, 28.34 mmol) in DMF (20 mL) was added tert-butyldimethyl silyl chloride (6.41 g, 42.51 mmol) and imidazole (6.75 g, 99.18 mmol). After stirring at a room temperature for 18 hr, the reaction mixture was diluted with a saturated aqueous NaCl solution (90 mL) and extracted with petroleum ether (3×60 mL). The organic layer was washed with a cold 3% HCl solution (30 mL) and a saturated aqueous NaCl solution (30 mL), dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel (105 g) with petroleum ether (300 mL), followed by 3% ethyl acetate in petroleum ether (600 mL). The 3% ethyl acetate in the petroleum ether fractions was collected and the solvent was removed to give 5.26 g of (R)-(+)-Methyl 2-(tert-butyldimethylsilyloxy)propanoate as colorless oil (85% yield). 1H NMR (CDCl3): delta 4.26 (q, 1H, J=6.8 Hz, -CH), 3.65 (s, 3H, -OCH3), 1.32 (d, 3H, J=6.8 Hz, -CH3), 0.83 (s, 9H, Si-(CH3)3), 0.03 (s, 3H, Si-CH3), 0.00 (s, 3H, Si-CH3).
67%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
Step la: methyl (2R)-2-[(tert-butyIdimethyIsiIyl)oxy]propanoate: into a 250-mL round-bottom flask, was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03 mmol, 1 .00 equiv) and Imidazole (6.5 g, 95.59 mmol, 2.00 equiv) in dichloromethane (100 mL). This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 equiv) in dichloromethane (50 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3x100 mL) and the organic layers combined. The resulting mixture was washed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 7 g (67%) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxy]propanoate as colorless oil.
67%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
into a 250-mL round-bottom flask was placed a solution of methyl (2/?)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and imidazole (6.5 g, 95.59 mmol, 2.00 eq.) in dichloromethane (100 mL), followed by the dropwise addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 eq.) in dichloromethane (50 mL) at 0 C. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7 g (67%) of methyl (2R)- 2-[(tert-butyldimethylsilyl)oxy]propanoate as a colorless oil
67%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
into a 250-mL round-bottom flask, was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03mmol, 1.00 equiv) and Imidazole (6.5 g, 95.59 mmol, 2.00 equiv) in dichloromethane (100 mL). This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 equiv) in dichloromethane (50 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted withdichloromethane (3x100 mL) and the organic layers combined. The resulting mixture waswashed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 7 g (67%) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxy]propanoate as colorless oil.
67%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
into a 250-mL round-bottom flask, was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03mmol, 1.00 equiv) and imidazole (6.5 g, 95.59 mmol, 2.00 equiv) in dichloromethane (100 mL). This was followed by the addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 equiv) in dichloromethane (50 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated undervacuum to give 7 g (67%) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxyjpropanoate as colorless oil.
67%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
into a 250-mLround-bottom flask was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03mmol, 1.00 eq.) and imidazole (6.5 g, 95.59 mmol, 2.00 eq.) in dichloromethane (100 mL), followed by the dropwise addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 eq.) in dichloromethane (50 mL) at 0 C. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by the addition of 100 mL ofwater/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7 g (67%) of methyl (2R)- 2-[(tert-butyldimethylsilyl)oxyjpropanoate as a colorless oil.
67%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;
into a 250- mL round-bottom flask was placed a solution of methyl (2R)-2-hydroxypropanoate (5 g, 48.03 mmol, 1.00 eq.) and imidazole (6.5 g, 95.59 mmol, 2.00 eq.) in dichloromethane (100 mL), followed by the dropwise addition of a solution of tert-butyl(chloro)dimethylsilane (8.7 g, 57.72 mmol, 1.20 eq.) in dichloromethane (50 mL) at 0 C. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7 g (67%) of methyl (2R)-2-[(tert-butyldimethylsilyl)oxy]propanoate as a colorless oil.
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 21h;
A dry 500 mL flask was charged with imidazole (6.53 g, 96.0 mmol, 2 equiv) and DCM (240 mL) before it was cooled to 0 C. Once cool, (R)-methyl 2-hydroxypropanoate (5 g, 48.0 mmol, 1 equiv) and TBSC1 (9.40 g, 62.4 mmol, 1.3 equiv) were added to the solution sequentially, and the resulting mixture was allowed to warm to room temperature. After stirring for 21 hours, the reaction mixture was filtered, and the solid residue was washed with DCM. The combined filtrate was washed with 1 M HC1 (100 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL), sequentially. The washed organic solution was then dried over sodium sulfate, filtered, and concentrated to give methyl (R)-2-((tert- butyldimethylsilyl)oxy)propanoate as a clear, colorless oil (10.4 g, 100% yield). This material was carried into the next step without further characterization or purification
With dmap; triethylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice;
Step 1: methyl (R)-2-((tert-butyldimethylsilyl)oxy)propanoate TEA (5.82 mL, 43 mmol) and DMAP (0.35 g, 2.88 mmol) were added sequentially to an ice-cooled solution of (+) D-Methyl lactate (3 g, 28.8 mmol) in DCM (60 mL). To the resulting reaction mixture was added a solution of tert-Butyldimethylsilyl chloride (4.75 g, 31.6 mmol) in DCM (15 mL) and the reaction mixture was stirred for 16 h at room temperature, then diluted with water (70 mL) and organic layer was separated off. The organic layer was washed with 1M citric acid solution (50 mL) followed by saturated sodium bicarbonate solution (50 mL) and dried over anhydrous Na2SO4 Solvent was removed under reduced pressure to afford the product (4.78 g, 78%) as colorless oil which was used as such without further purification. 1H NMR (400 MHz, CDCl3): delta 4.31 (q, J=6.7 Hz, 1H), 0.90 (s, 1H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H), LC-MS: [M+H]+ 218.9.
With 2,6-dimethylpyridine; In dichloromethane; at 0℃; for 0.333333h;Inert atmosphere;
Synthesis of Methyl (2J~)-2-[(trifluoromethyl)sulfonyl]oxypropionate) (14).; Following a procedure reported in Damaj, M. I.; Fei-Yin, M.; Dukat, M.; Glassco, W.; Glennon, R. A.; Martin, B. R., J. Pharmacol. Exp. Ther. 1998, 284, 1058-1065 with modification, a solution of methyl-(R)-lactate (13) (5.20 g, 0.05 mol) in anhydrous CH2C12 (200 mL, 0.25 M) was cooled to 0 C and was treated with trifluromethane sulfonic anhydride (8.8 mL, 52.5 mmol) and 2,6-lutidine (6.10 mL, 52.5 mmol) under an N2 atmosphere. After stirring for 20 min at 0 C, the reaction mixture was concentrated to a pink oil residue. Column chromatography on silica gel using CH2C12 as the eluent afforded 9.15 g (77%) of 14 as a light pink oil with characterization data as previously reported:31 [cc]25D +40.5 (c 1.0, CHC13); XH NMR (CDC13) delta 5.27 (q, 1H, J = 6.9 Hz), 3.85 (s, 3H), 1.71 (d, 3H, J = 6.9 Hz); 13C NMR (CDC13) delta 167.8, 79.9, 53.3, 18.0; LCMS (ESI) m/z 240.1 [(M + 4H)+, M = C5H7F305S].
With 2,6-dimethylpyridine; In dichloromethane; at -70℃; for 0.5h;
Stir methyl R-lactate (5.0 g) in CH2Cl2 (40 ml) at -70 C. and add trfluoromethanesulfonic anhydride (7.6 ml), then 2,6-lutidine (7.8 ml). Remove the cooling, stir 0.5 h, wash with 2N HCl and add the organic solution to (S)-methyl 4-bromobenzylamine (9.0 g) and K2CO3 (11.2 g) in water (60 ml). Stir 20 h at RT, dry the organic phase over K2CO3, evaporate and chromatograph on silica gel with Et2O-CH2Cl2 to give the desired product (7.50 g) as a thick oil.
With 2,6-dimethylpyridine; In dichloromethane; at -78 - 20℃;Cooling with acetone-dry ice;
The product of step 1 (11.2 g, 0.033 mol) was dissolved in CH3OH (200 ml) and NaOH (15 g, 0.375 mol) in water (100 ml) was added dropwise. The mixture was stirred at RT for 2.5 h. After the CH3OH was evaporated, the aqueous layer was extracted with Et2O (3×100 ml) and the combined organic portion was washed with brine, dried over Na2SO4, filtered and concentrated to give a free amine. Methyl-R-lactate (4.08 g, 0.039 mol) was dissolved in CH2Cl2 (40 ml) and the mixture was stirred and cooled in acetone-CO2 to -78 C. under N2 atmosphere. Trifluoromethane sulfonic anhydride (10.2 g, 0.036 mmol) and then 2,6-lutidine (6.27 g, 0.059 mol) were added and the mixture was stirred for 5 min at -78 C. The mixture was warmed to RT and stirred for 30 min. More CH2Cl2 was added to the mixture and the solution was washed with 2N HCl. The freshly prepared amine from above was added to the triflate solution followed by K2CO3 (18 g, 0.132 mol) in water (20 ml). The mixture was stirred at RT overnight. Extractive work-up with CH2Cl2 followed by silica gel column chromatography gave a secondary amine (8.27 g, 75% yield, Rf=0.65, hexanes/EtOAc, 3:1) as a yellow syrup.
With 2,6-dimethylpyridine; In dichloromethane; at 0℃; for 0.166667h;
Procedure for synthesis of methyl (2S)-2-(methoxyamino)propanoate (Step-1 ) To a stirred solution of methyl (2R)-2-hydroxypropanoate (16.5 g, 158 mmol, 15.1 mL) in DCM (475 mL) at 0C was added trifluoromethanesulfonic anhydride (49.7 g , 174 mmol) followed after 5mins by 2,6-dimethylpyridine (19.5 g, 182 mmol). The resulting mixture was stirred at 0C for 10 minutes to give a solution of methyl (2R)-2-(trifluoromethylsulfonyloxy)propanoate. Separately, O- methylhydroxylamine hydrochloride (65.98 g, 790.0 mmol) was dissolved in water (130 mL) then sodium hydroxide (50% aqueous) (33.1 mL 632.0 mmol) was added. The solution of O- methylhydroxylamine in water was added to the solution of methyl (2R)-2- (trifluoromethylsulfonyloxy)propanoate in DCM, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and chromatographed on silica eluting with 0- 45% EtOAc in isohexane. Fractions containing product were evaporated to give the desired product as a pale yellow oil (23.5 g). The product appears to have some volatility so caution was taken with the evaporation step. The product was used without further purification.
With 2,6-dimethylpyridine; In dichloromethane; at -5 - 5℃; for 2h;Inert atmosphere; Large scale;
A 50 L reactor under a nitrogen atmosphere was charged with methylene chloride (30 L) and agitated. <strong>[17392-83-5](R)-methyl lactate</strong> (1.44 kg, 13.83 mol) was added, followed by 2,6-lutidine (1.56 kg, 14.56 mol). The stirred mixture was cooled to -5 to 5C using a dry-ice/acetone bath. The reactor was carefully charged with trifluoromethane sulfonic anhydride (3.9 kg, 13.83 mol) using a peristaltic pump while maintaining the internal temperature between -5 and 5C. This addition required more than 1 h. After addition was complete, the reaction was stirred 1 h more while maintaining the temperature between 0 and 5C. The reaction was carefully quenched with deionized water (10 L) and vigorous stirring was continued 1 min longer. Stirring was stopped and the phases were allowed to separate. The bottom (methylene chloride) layer containing the product, was transferred to a holding container while the reactor was cleaned successively with acetone (2 x 10 L) and then methylene chloride (2 x 10 L). The intermediate triflate was used directly without purification
To a cold solution of pyridine in a solvent like DCM was added trifluoromethanesulfonic anhydride at below 0 00. After stirring for 5-60 mm, (R)-methyl 2-hydroxypropanoate was added. The mixture was stirred for 1-10 h at room temperature, filtered, and the filtrate was partially evaporated.
With triethylamine; In dichloromethane; at 0 - 15℃; for 1h;Inert atmosphere;
To a solution of methyl (2R)-2-hydroxypropanoate (46 ml, 482 mmol) and triethylamine (80 ml, 575 mmol) in dichloromethane (250 ml) was added trifluoromethanesulfonic anhydride (90 ml, 545 mmol) under nitrogen atmosphere at 0C and the mixture was stirred at 15 C for 1 h. The reaction mixture was poured into water (300 ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (2 x 300 ml). The combined organic layers were washed with brine (2 x 300 ml), dried over sodium sulfate, filtered and concentrated under vacuum to deliver 119 g (90 % purity, 86 % yield) of the title compound which was used without further purification.-NMR (400 MHz, CDC13) delta [ppm]: 1.72 (d, 3H), 3.86 (s, 3H), 5.25 (q, 1H).
To a cold solution of pyridine in a solvent like DCM was added trifluoromethanesulfonic anhydride at below 0 C. After stirring for 5-60 min, (R)-methyl 2-hydroxypropanoate was added. The mixture was stirred for 1-10 h at room temperature, filtered, and the filtrate was partially evaporated.
With potassium tert-butylate; hydrogen;[tris(mu-chloro)bis((triphos)ruthenium(II))] chloride; In methanol; at 100℃; under 30003 Torr; for 12h;Inert atmosphere; Autoclave;Product distribution / selectivity;
Example 27 Hydrogenation of methyl D-(+)-lactate [Ru2(mu-Cl)3(triphos)2]Cl (8.4 mg), potassium tert-butoxide (18.6 mg), and methyl D-(+)-lactate (optical purity: 99.2% ee) (0.85 g) were added into a 100-ml autoclave equipped with a glass inner tube, and the autoclave was purged with hydrogen. 3.0 ml of methanol was added thereto under an argon atmosphere, the autoclave was purged with hydrogen, and then hydrogen was further included in the autoclave up to 4.0 MPa. The contents of the autoclave were heated and stirred at 100C for 12 hours. After cooling, the reaction liquid was analyzed by gas chromatography, and it was found that (2R) -1, 2-propanediol was produced at a yield of 99. 9% or more. The product was further induced to a bis-benzoate form and was analyzed, and as a result, the optical purity was found to be 93.6% ee.
With hydrogen;C40H39BN2P2Ru; In tetrahydrofuran; at 80℃; under 34503.5 - 37503.8 Torr; for 5h;Product distribution / selectivity;
Example 16 Hydrogenation of methyl (R)-2-hydroxypropionate A ruthenium complex 1 (0.125 mmol) was charged into a 100-mL autoclave equipped with a stirrer, and air inside the autoclave was replaced with nitrogen. Tetrahydrofuran (40 ml) and methyl (R)-2-hydroxypropionate (25 mmol, 99.3% ee) were added thereinto. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 4.6 MPa to 5 MPa at 80 C. for 5 hours. The reaction liquid was analyzed by gas chromatography. As a result, (R)-1,2-propanediol was obtained at a conversion rate of 98.6% and a selectivity of 98.4%. The obtained alcohol had an optical purity of 96.6% ee.
With hydrogen; sodium methylate;[carbonylchlorohydrido{bis[2-(diphenylphosphinomethyl)ethyl]amino}ethylamino] ruthenium(II); In methanol; at 30℃; under 37503.8 Torr; for 16h;Product distribution / selectivity;
Example 2Hydrogenation of methyl(R)-lactate was carried out according to the following reaction scheme. A solution of methyl(R)-lactate (10 mmol) having optical purity of 99.3% ee, the complex 1a (0.01 mmol) produced in Example 1, methanol (7.6 mL), and 0.5 M of sodium methoxide in methanol (0.4 mL) was added to a 100 mL autoclave equipped with a stirrer, and the hydrogenation-reduction was carried out at 30 C. for 16 hrs with hydrogen pressure of 5 MPa. As a result of the analysis of the reaction solution according to gas chromatography, the conversion rate was 96.3%. Optical purity of the alcohol obtained was 99.1% ee.
1.97 g
With sodium tetrahydroborate; at -5℃; for 3.5h;
Example: 4 Preparation of 2-(R)-hydroxypropanol (XII) Sodium borohydride (1 .81 g) was added to a stirred, cold solution of methyl (D)-lactate (5 g) in methanol (25 ml) at -5C in divided portions over a period of 0.5 h. The reaction mixture was stirred at this temperature for 3 h when the reaction was complete as indicated by TLC. The reaction mixture was neutralized with concentrated hydrochloric acid until the pH of the mixture attained the range 6- 7, and then concentrated under reduced pressure at 40C. The residue thus obtained was dissolved in ethyl acetate (30 ml) and filtered. The filtrate was washed with water (1 X 20 ml), brine (1 X 5 ml), dried over sodium sulfate and concentrated under reduced pressure at 40C to give the product XII; yield: 1 .97 g.
With hydrogen; Cinchonidin In acetic acid at 25℃; for 0.5h;
With hydrogen; butan-1-ol In acetic acid at 24.85℃; for 0.5h;
88.2 % ee
Stage #1: In tetrahydrofuran at 25℃; for 0.25h;
Stage #2: pyruvic acid methyl ester With hydrogen In tetrahydrofuran for 6h;
18 Methyl Lactate using the Rhodium Complex of Ligand 4a
Methyl pyruvate (51 mg; 0.50 mmol) was dissolved in a reaction vessel in anhydrous THF (3.0 mL) and degassed with argon for 15 minutes. Bis(1,5-cycloocta-diene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand 4a from Example 1 (3.7 mg; 6 μmol; 0.012 equiv) were combined and argon-degassed anhydrous THF (2.0 mL) was added. This solution was stirred at 25° C. under argon for 15 minutes and then added to the solution of 2-acetamidocinnamic acid. The resulting solution was then flushed with hydrogen and pressurized to 0.69-1.38 bars gauge (10-20 psig) hydrogen. The reaction mixture was stirred for 8 hours to afford 90.2% conversion to methyl (R)-lactate with 88.2% ee as determined by chiral GC analysis. The analytical properties of methyl lactate were identical to an authentic sample.Chiral GC [Cyclosil-B (J&W Scientific) 30 m×0.25 mm ID, film thickness 0.25 μm, 75° C. isothermal, 15 psig He]: tR[methyl (R)-lactate] 7.75 min, tR[methyl (S)-lactate] 9.16 min. tR(methyl pyruvate) 5.16 min.
With 5% Pt/Al2O3; hydrogen; cinchonidine In acetic acid at 19.84℃; optical yield given as %ee; enantioselective reaction;
With recombinant stereospecific carbonyl reductase 3 from Candida parapsilosis; NAD In aq. phosphate buffer at 30℃; for 6h;
99.2 % 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.
> 99 % ee
With hydrogen; acetic acid; (+)-cinchonine at 20℃; for 4h; Autoclave; enantioselective reaction;
> 99 % ee
With C52H89N2O17(1+)*CH3O3S(1-); hydrogen; acetic acid In n-heptane; toluene at 30℃; for 0.166667h; Autoclave; enantioselective reaction;
93 % ee
With hydrogen; quinine; acetic acid at 24.84℃; Autoclave; enantioselective reaction;
With toluene-4-sulfonic acid; In toluene; at 50℃; for 3h;
Dihydropyran (8.98 g, 105.66 mmol) was dropped within 1 h at 50 C to a solution of methyl (d)-lactate (10.00 g, 96.06 mmol) and p-TsOH (165.41 mg, 0.96 mmol) in toluene (100 mL). After stirring for 2 h at this temperature the solution was washed with saturated NaHCO3 solution, dried with Na2SO4, filtrated, and evaporated. Kugelrohr distillation (8.9×10-2 mbar, 70 C) provided THP-ether 14 (16.84 g, 89.47 mmol, 93%) as a colorless liquid. IR (film): 1754 cm-1; 1H NMR (400 MHz, CDCl3): delta=1.34 (d, J=7.0 Hz, 1H, CbetaH3), 1.39 (d, J=7.0 Hz, 2H, CbetaH3), 1.49 (m, 2H, CH2, THP-H [3], [4] and [5]), 1.64 (m, 2H, CH2, THP-H [3], [4] and [5]), 1.79 (m, 2H, CH2, THP-H [3], [4] and [5]), 3.39 and 3.77 (2m, 2H, CH2, THP-H6), 3.68 (s, 3H, OCH3), 4.15 and 4.37 (2 q, J=7.0 Hz, 1H, CalphaH), 4.64 (m, 1H, CH, THP-H2) ppm; 13C NMR (100 MHz, CDCl3): delta=18.7, 19.1, 25.3, 30.4, 51.7, 62.3, 69.9, 97.5, 173.5 ppm; MS (ESI): m/z (%)=206 (4), 211 ([M+Na]+, 100); HRMS (ESI): M++Na, found 211.0941; C9H16NaO4 requires 211.0946.
66%
With pyridinium p-toluenesulfonate; In chloroform; at 0 - 20℃; for 24h;
In a 100 mL round-bottomed flask, pyridinium p-toluene sulfonate (158 mg, 0.63 mmol, 2 mol %) and (R)-(+)-lactic acid methyl ester (3.27 g, 31.5 mmol) were dissolved in CHCl3 (60 mL) at 0 C. Into the solution, dihydropyran (3.71 g, 44.1 mmol) was added dropwise at 0 C. After addition, the mixture was allowed to warm to rt. After 1 day, the reaction mixture was extracted with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography with hexane/EtOAc afforded (R)-6 as a colorless oil in a 66% yield (3.92 g). 1H NMR (CDCl3, 300 MHz): delta 4.82-4.69 (1H, m), delta 4.43 (q, J = 7.0 Hz) and 4.21 (q, J = 6.8 Hz) (1H), delta 3.97-3.80 (1H, m), delta 3.74 (3H, s), delta 3.53-3.44 (1H, m), delta 1.87-1.38 (9H, m).
With camphor-10-sulfonic acid; In dichloromethane; at 20℃; for 2h;
To a stirred solution of (R)-2-hydroxy-propionic acid methyl ester (10 g) and 3,4-dihydro-2H-pyran (15 mL) in DCM (400 mL) was added camphorsulfonic acid (50 mg) (exothermic reaction). The reaction mixture was stirred at ambient temperature for 2 hours, and washed with saturated bicarbonate solution (20 mL). The organic layer was dried, filtered and concentrated to obtain crude (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester, which was used as is in the next step. To a stirred suspension of LAH (4 g) in anhydrous ether (400 mL) at 0-5 C. was added (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester dropwise over 30 minute period. After completion of the addition, the cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was cooled to 0-5 C., and ethyl acetate was added dropwise to quench excess LAH, which was followed by the addition of saturated sodium sulfate solution and solid sodium sulfate. The resulting mixture was stirred at room temperature for 1 hour, the solid was filtered off, and the solid was washed with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography using a silica gel stationary phase (pre-treated with 0.1 triethylamine in hexanes) and hexanes in ethyl acetate to get (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol.1H NMR (400 MHz, CDCl3): delta 4.51-4.75 (1H, m) 3.76-4.02 (2H, m) 3.42-3.62 (3H, m) 1.67-1.90 (2H, m) 1.46-1.63 (4 h, m) 1.10-1.24 (3H, m).
A solution of methyl D-(+)-lactate (25 g, 241 mmol) and imidazole (21 g, 313 mmol, 1.3 eq.) in CH2C12 (125 mL) was cooled in an ice-NaC1 bath. Tert-butyldiphenylchlorosilane (97%, 66 mL, 253 mmol, 1.05 eq.) was added dropwise over 30 minutes. The resulting slurry was stirred for an additional 3 h afier which time analysis by TLC (100% CH2C12, KMnO4 staining) indicated the starting alcohol had been completely consumed. The reaction was diluted with CH2C12 (400 mL) and brine (500 mL). Following phase separation, the aqueous phase was extracted with CH2C12 (200 mL). The combined extracts were dried (Mg504). The drying agent was removed by filtration and the filtrate was concentrated to dryness under reduced pressure giving the silylether as a translucent, pale yellow oily-liquid (82 g, 99%). FIG. 1
97%
With 1H-imidazole; lithium aluminium tetrahydride; In tetrahydrofuran; dichloromethane; Petroleum ether; at 0 - 20℃; for 2h;
Example 89 Synthesis of 2-[1-[(2R)-2-[(2R)-2-hydroxypropoxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxo-1H,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid (I-258) Synthesis of Compound 89.2. Into a 250-mL 3-necked round-bottom flask was placed dichloromethane (100 mL), methyl (2R)-2-hydroxypropanoate (10 g, 96.06 mmol, 1.00 equiv) and 1H-imidazole (9.8 g, 143.95 mmol, 1.50 equiv). This was followed by the addition of TBDPSCl (29.1 g, 112.45 mmol, 1.17 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature and then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). Purification afforded 32 g (97%) of 89.2 as a colorless oil. Synthesis of Compound 89.3. Into a 500-mL 3-necked round-bottom flask was placed tetrahydrofuran (200 mL) and 89.2 (28 g, 81.75 mmol, 1.00 equiv). This was followed by the addition of LiAlH4 (1.56 g, 41.11 mmol, 0.50 equiv) in portions at -30 C. The resulting solution was stirred for 30 min at -30 C. The reaction was then quenched by the addition of 100 mL of NH4Cl (sat., aq.). The resulting solution was extracted with 3*200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 11.8 g (46%) of (2R)-2-[(tert-butyldiphenylsilyl)oxy]propan-1-ol (89.3) as a colorless oil. Synthesis of Compound 89.4. Compound 89.4 was prepared from 57.2 and compound 89.3 in a manner analogous to compound 57.3. Isolated a colorless oil in 1% yield.
With dmap; triethylamine; In dichloromethane; for 15h;
General procedure: A solution of tert-butyldiphenylchlorosilylane (3.02 g, 11 mmol) in CH2Cl2 (3 ml) was slowly added to a solution containing methyl (S)-lactate (1.04 g, 10 mmol), TEA (1.09 g, 1.5 ml, 11 mmol) and DMAP (50 mg, 0.04 equiv) in dry CH2Cl2 (2 ml). After 15 h the suspension was treated with saturated NH4Cl (5 ml) and extracted with CH2Cl2 (3 × 20 ml). The organic phases were washed with NH4Cl, dried and evaporated. Purification on column chromatography (Hex/EA 95:5) gave a colorless liquid (3.15 g, 92%).
Stage #1: 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)ethanone With sodium hydride In tetrahydrofuran for 0.25h;
Stage #2: (R)-Methyl lactate In tetrahydrofuran at 20℃; for 18h; Further stages.;
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -5 - 20℃; for 14h;
Preparation 38 (2S)-2-(Quinolin-5-yloxy)-propionic acid methyl ester Triphenylphosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of diisopropyl azodicarboxylate (1.47 mL, 7.56 mmol) in tetrahydrofuran (25 mL) at -5° C. <strong>[578-67-6]5-Hydroxyquinoline</strong> (1.0 g, 6.90 mmol) and methyl-(R)-lactate (0.66 mL, 6.90 mmol) were added and the solution was allowed to stir at room temperature for 14 hours. The reaction mixture was then diluted with ethyl acetate (50 mL), washed with water (30 mL), saturated potassium carbonate solution (30 mL) and brine (30 mL). The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluding with pentane:ethyl acetate, 80:20 to 60:40, to afford the title compound as a white solid in 81percent yield, 1.30 g. LRMS (ES+): m/z [M+H]+ 232
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 5 - 20℃; for 18h;
A solution of di-iso-propyl azodicarboxylate (2.95 mL, 15.2 mmol) in tetrahydrofuran (40 mL) was cooled to 5 °C and triphenylphosphine (4.34 g, 16.6 mmol) added portionwise to give a pale yellow solution. (R)- methyl lactate (1.32 mL, 13.8 mmol) and <strong>[578-67-6]5-hydroxyquinoline</strong> (2.0 g, 13.8 mmol) were then added and the solution stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was separated and washed with water (20 mL), 10percent w/v aqueous potassium carbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure, the residue was triturated with pentane: ethyl acetate (4:1 v/v, 30 mL) and t he p recipitated t riphenylphosphine o xide removed b y f iltration. T he f iltrate w as evaporated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a gradient system changing from pentane: ethyl acetate, 80: 20 to pentane: ethyl acetate 20: 80 to afford the title compound as a colourless oil, 2.77 g. LRMS (APCI+): m/z [M+H]+ 232
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -5 - 20℃; for 14h;
Preparation 1 (2S)-2-(Quinolin-5-yloxy)-propionic acid methyl ester Triphenylphosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of di-isopropyl azodicarboxylate (1.47 ml, 7.56 mmol) in THF (25 ml) at -5° C. <strong>[578-67-6]5-Hydroxyquinoline</strong> (1.0 g, 6.90 mmol) and methyl (R)-lactate (0.66 ml, 6.90 mmol) were then added and the solution allowed to stir at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 ml). The solution was dried (MgSO4) and solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluding with a gradient system of pentane:ethyl acetate (4:1) changing to pentane:ethyl acetate (3:2). The title compound was obtained as a white solid (1.30 g). LRMS (APCI+): m/z [M+H]+ 232.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18h; Cooling with ice;
1
Diisopropyl azodicarboxylate (4mL, 20mmol) in tetrahydrofuran (15mL) was added dropwise to an ice-cooled solution of f methyl vanillate ( 3.64g, 20mmol), (R)-methyl lactate (2.08g, 20mmol) and triphenyl phosphine (5.24g, 20mmol) in tetrahydrofuran (30mL) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then evaporated under reduced pressure and the residue was stirred in a mixture of diethyl ether (50mL) and hexane (50mL). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. P urification of the residue by column chromatography on silica gel, eluting with hexane: ethyl acetate, 85 : 15 to 75 : 25 afforded the title compound in 71 % yield, 3.8g LRMS (ES+): m/z [M+H]+ 269
71%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 18h;
6 3-Methoxy-4-[(1S)-1-methoxycarbonyl-ethoxy]-benzoic acid methyl ester
Preparation 6 3-Methoxy-4-[(1S)-1-methoxycarbonyl-ethoxy]-benzoic acid methyl ester Diisopropyl azodicarboxylate (4 mL, 20 mmol) in tetrahydrofuran (15 mL) was added dropwise to an ice-cooled solution of methyl vanillate (3.64 g, 20 mmol), methyl (R)-lactate (2.08 g, 20 mmol) and triphenyl phosphine (5.24 g, 20 mmol) in tetrahydrofuran (30 mL) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then evaporated under reduced pressure and the residue was stirred in a mixture of diethyl ether (50 mL) and hexane (50 mL). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with hexane:ethyl acetate, 85:15 to 75:25 afforded the title compound in 71% yield, 3.8 g LRMS (ES+): m/z [M+H]+ 269
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18.0h;
Preparation 56 (2S)-2-(4-Bromo-2-trifluoromethoxy-phenoxy)-propionic acid methyl ester Diisopropyl azodicarboxylate (414 muL, 2.14 mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 55 (500 mg, 1.95 mmol) methyl (R)-lactate.(202 mg, 1.95 mmol) and triphenyl phosphine (614 mg, 2.34 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 18 hours and was then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 10% potassium carbonate solution (2*10 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluding with dichloromethane:methanol, 95:5, to afford the title compound as a colourless oil in 76% yield, 638 mg. LRMS (APCI+): m/z [M+H]+ 305/307
With hydrogen;dihydridotetrakis(triphenylphosphine)ruthenium; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; In methanol; at 80℃; under 37503.8 Torr; for 13h;Inert atmosphere; Autoclave;
Example 43 Hydrogenation of methyl D-(+)-lactate Methyl D- (+) -lactate (optical purity: 99.2% ee) (0.52g), RuH2(PPh3)4 (11.5 mg), triphos (6.2 mg), and 3 ml of methanol were added into a 100-ml autoclave having a stirrer placed inside, under a nitrogen atmosphere. The autoclave was purged with hydrogen, and then hydrogen was further included in the autoclave up to 5.0 MPa. The contents of the autoclave were heated and stirred at 80C for 13 hours. After cooling, the reaction liquid was analyzed by gas chromatography, and it was found that (2R)-1,2-propanediol was produced at a yield of 82.5%. The product was further induced to a carbonate form and was analyzed, and as a result, the optical purity was found to be 88.9% ee.
With hydrogen;carbonylhydrido(tetrahydroborato)[bis(2-diphenylphosphinoethyl)amino]ruthenium(II); In isopropyl alcohol; at 80℃; under 37503.8 Torr; for 16h;Product distribution / selectivity;
Example 14Hydrogenation of methyl(R)-lactate was carried out according to the following reaction scheme. Methyl(R)-lactate (10 mmol) with optical purity of 99.3% ee, the complex 1b (0.01 mmol) produced in Example 1, and isopropanol (7.6 mL) were added to a 100 mL autoclave equipped with a stirrer, and the hydrogenation-reduction was carried out at 80 C. for 16 hrs with hydrogen pressure of 5 MPa. As a result of the analysis of the reaction solution according to gas chromatography, it was found that the conversion rate was 98.4%. Optical purity of the alcohol thus obtained was 81.8% ee.
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 methansulfinate; potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h;
D-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 sulfate 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 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 0.56g (46%) 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 marine microbial esterase; In aq. phosphate buffer; at 37℃; for 1h;pH 7.5;Resolution of racemate; Enzymatic reaction;
A standard 500-muL hydrolytic reaction system containing140 mug 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.
methyl (S)-4-((1-methoxy-1-oxopropan-2-yl)oxy)-3-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1h;
1.I Part I -- Synthesis of Methyl (S)-4-((1-methoxy-1-oxopropan-2-yl)oxy)-3-nitrobenzoate
j00305j Methyl-4-hydroxy-3-nitrobenzoate (3 g, 13.76 mmol), methyl-(R)-lactate (1.433 g, 13.8 mmol), and triphenylphosphine (4.33 g, 16.5 mmol) were suspended in dichloromethane (36 mL), and diisopropyl azodicarboxylate (3.25 mL, 16.51 mmol) was addeddropwise. The reaction mixture was stirred at room temperature for an hour, and then the crude was washed with water, dried (Na2504), and concentrated to provide a residue. The residue was purified via MPLC eluting with a gradient of ethyl acetate in hexanes, followed by a second MPLC purification eluting with dichloromethane to afford methyl (S)-4-((1-methoxy-1- oxopropan-2-yl)oxy)-3-nitrobenzoate (2.56 g, 66%) as a light yellow oil. ‘H-NMR (400 MHz, DMSO-d6) 8.37 (s, 1H), 8.12 (d, 1H), 7.36 (d, 1H), 5.40 (q, 1H), 3.83 (s, 3H), 3.65 (s, 3H), 1.54 (d, 3H).
66%
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1h;
1.I Synthesis of Methyl (S)-4-((1-methoxy-1-oxopropan-2-yl)oxy)-3-nitrobenzoate
Methyl-4-hydroxy-3-nitrobenzoate (3 g, 13.76 mmol), methyl-(R)-lactate (1.433 g, 13.8 mmol), and triphenylphosphine (4.33 g, 16.5 mmol) were suspended in dichloromethane (36 mL), and diisopropyl azodicarboxylate (3.25 mL, 16.51 mmol) was added dropwise. The reaction mixture was stirred at room temperature for one hour, and then the crude was washed with water, dried (Na2SO4), and concentrated to provide a residue. The residue was purified via MPLC eluting with a gradient of ethyl acetate in hexanes, followed by a second MPLC purification eluting with dichloromethane to afford methyl (S)-4-((1-methoxy- 1-oxopropan-2-yl)oxy)-3-nitrobenzoate (2.56 g, 66%) as a light yellow oil. 1H-NMR (400 MHz, DMSO-d6) 8.37 (s, 1H), 8.12 (d, 1H), 7.36 (d, 1H), 5.40 (q, 1H), 3.83 (s, 3H), 3.65 (s, 3H), 1.54 (d, 3H).
66%
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1h;
(D)-1-(1-azacyclooctanyl)-2-hydroxy-1-propanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.06%
at 60℃; for 13h; Inert atmosphere; Large scale;
5.1 (1) compound (R)-1-(1-azocanyl)-2-hydroxy-1-propanone(V, n= 5) synthesis
(1) compound (R)-1-(1-azocanyl)-2-hydroxy-1-propanone(V, n= 5) synthesis to 1000L added to the reaction kettle 360 kg (3.46Kmol)-methyl lactate D, through nitrogen protection, dropping 391 kg Azocane (1.0eq), 60 °C stirring reaction under 8h, concentrated off most of the reaction by-product methanol, add 19.6 kg Azacyclooctane (0.05eq), nitrogen protection, 60 °C to continue reaction 5h, concentrating the reaction liquid, shall be orange-yellow oily liquid (R)-1-(1-azocanyl)-2-hydroxy-1-propanone 410 kg (theoretical yield 640 kg), the yield is 64.06%,
64.06%
at 60℃; for 13h; Inert atmosphere; Large scale;
5.1 (1) Synthesis of Intermediate II (n=5)
In a 1000L reactor was added 360Kg (3.46Kmol) D-methyl lactate. under nitrogen protection, was added dropwise 391Kg azacyclooctane (1.0eq) and stirred at 60°C for 8h. Most of the methanol is concentrated off the byproducts produced by the reaction. Additional 19.6Kg azacyclooctane (0.05eq) was added under nitrogen protection and the reaction was continued at 60°C for 5h. The reaction mixture was concentrated giving a orange-yellow oily liquid (D)-1-(1-azacyclooctanyl)-2-hydroxy-1-propanone 410Kg (theoretical yield 640Kg), that intermediate II the yield was 64.06%.
(R)-2-[4-(4-hydroxybenzyl)phenoxy]propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
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.
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 0 - 20℃;
To a solution of starting compound, Ph3P, and ((R)-methyl 2-hydroxypropanoate in a solvent like DCM was added DEAD at 0 C. After stirring for 1 to 24 h at room temperature, the reaction completion was observed by NMR testing of a sample. Aqueous workup was performed. The compound was purified by chromatography.
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 0 - 20℃;
To a solution of starting compound, Ph3P, and ((R)-methyl 2-hydroxypropanoate in a solvent like DCM was added DEAD at 0 C. After stirring for 1 to 24 h at room temperature, the reaction completion was observed by NMR testing of a sample. Aqueous workup was performed. The compound was purified by chromatography.
(R)-methyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 1h;
To a solution of <strong>[67443-38-3]5-bromo-2-chloro-3-nitropyridine</strong> (1.2 g, 5 mmol) and methyl(R)-2-hydroxypropanoate (572 mg, 5.5 mmol) in THF (40 mL) was added slowly 60 % NaH (220 mg, 5.5 mmol) at 0 C. The mixture was stirred at room temperature for 1 h. After water (20 mL) was added, the mixture was treated with brine (100 mL) and extracted with ethyl acetate (50 mL * 2). The combined organic layers were dried over Na2504, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1) to give the title compound as a yellow oil (1.2 g 80 %). ?H NMR (400 MHz, DMSO-d6) oe 8.75 (s, 1H), 8.62 (s, 1H), 5.50-5.34 (m, 1H), 3.67 (s, 3H), 1.56 (d, J= 6.4 Hz, 3H).
47%
With potassium carbonate; In acetonitrile; at 75℃; for 15h;
To a solution of <strong>[67443-38-3]5-bromo-2-chloro-3-nitropyridine</strong> (8.00 g, 33.7 mmol, 1.0 eq), methyl (2R)-2- hydroxypropanoate (10.52 g, 101 mmol, 3.0 eq) in MeCN (250 mL) was added K2CO3 (18.63 g, 135 mmol, 4.0 eq). The reaction was stirred at 75 C for 15 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (4.84 g, 47% yield) as yellow oil.
47%
With potassium carbonate; In acetonitrile; at 75℃; for 15h;
To a solution of <strong>[67443-38-3]5-bromo-2-chloro-3-nitropyridine</strong> (4-1) (8.00 g, 33.7 mmol, 1.0 eq.), methyl (2R)-2-hydroxypropanoate (10.52 g, 101 mmol, 3.0 eq.) in MeCN (250 mL) was added K2CO3 (18.63 g, 135 mmol, 4.0 eq.). The reaction was stirred at 75 C for 15 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (4.84 g, 15.9 mmol, 47% yield) as a yellow oil.
Stage #1: 2-bromo-N-methylbenzenesulfonamide; 2-formylbenzene boronic acid With potassium phosphate In 1,4-dioxane; water at 80℃; Inert atmosphere;
Stage #2: (R)-Methyl lactate With methanesulfonic acid In [D3]acetonitrile at 20℃; for 20h; Molecular sieve;
methyl (S)-2-(2-bromo-3-formylphenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
Methyl (S)-2-(2-bromo-3-formylphenoxy)propanoate (34):2-Bromo-3- hydroxybenzaldehyde (1 mmol) was added to the solution of (+)-methyl-D-lactate (1.38 mmol) in anhydrous THF (6 mL) under a nitrogen atmosphere and the solution was cooled to 0 C. PPh3 (1.20 mmol) was added portion wise and stirred for 10 min followed by the dropwise addition of DEAD (1.50 mmol) over 20 min. The reaction mixture was stirred for 2 h at room temperature. After completion, the solvent was removed under reduced pressure and the crude mixture was purified through column chromatography using ethyl acetate/n- hexane (10:90) to yield methyl ((S)-2-(2-bromo-3-formylphenoxy)propanoate (236 mg, 83%) as a white solid.
methyl (2S)-2-(5-bromo-2-cyanophenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20 g
With diethyl diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 0 - 0.35℃;Inert atmosphere;
To a mixture of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (14.5 g), methyl (2R)-2-hydroxypropanoate (15.25 g), triphenylphosphine (57.6 g) and THF (dry) (150 mL) was added 2.2M diethyl (E)-diazene-1,2-dicarboxylate-toluene (116 mL) at 0 C. 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. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20 g). 1H NMR (300 MHz, DMSO-d6) delta1.57 (3H, d, J=6.8 Hz), 3.71 (3H, s), 5.40 (1H, q, J=6.8 Hz), 7.35 (1H, dd, J=8.3, 1.7 Hz), 7.47 (1H, d, J=1.6 Hz), 7.72 (1H, d, J=8.3 Hz).
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 - 0.35℃;Inert atmosphere;
To a mixture of <strong>[183802-98-4]5-bromo-2-chlorophenol</strong> (31 g), methyl (2R)-2-hydroxypropanoate (31.1 g), triphenylphosphine (118 g) and THF (dry) (250 mL) was added 2.2M diethyl (E)-diazene-1,2-dicarboxylate-toluene (238 mL) at 0 C., 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 diisopropyl ether (1:1, 200 mL), the mixture was stirred at 0 C. for 20 min, and the reaction solution was concentrated. To the obtained solid were added diisopropyl ether and ethyl acetate (2:1, 400 mL) and the mixture was stirred at 0 C. 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). 1H NMR (300 MHz, DMSO-d6) delta1.54 (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).
43.9 g
With triphenylphosphine; diethylazodicarboxylate; 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 2.2M diethyl (E)-diazene-1,2-dicarboxylate toluene solution (238 mL) at 0 C., 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 0 C. 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 0 C. 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). 1H NMR (300 MHz, DMSO-d6) delta 7.41 (d, J=8.4 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.18 (dd, J=8.4, 2.1 Hz, 1H), 5.24 (q, J=6.8 Hz, 1H), 3.70 (s, 3H), 1.54 (d, J=6.7 Hz, 3H).
(S)-methyl 2-(4-bromo-2-iodophenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; for 0.583333h;
To a solution of (F?)-methyl 2-hydroxypropanoate (1.1 ) (1 mmol), <strong>[207115-22-8]4-bromo-2-iodophenol</strong> (1 mmol) and triphenylphosphine (1 .2 mmol) in THF (15 ml_) at 0C was added DIAD (1.2 mmol) dropwise over 20 min. The solution was stirred for a further 15 min at 0 C. The bright yellow solution was allowed to warm to RT and stirred overnight. Volatiles were removed in vacuo to afford a dark orange oil. The crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford (S)-methyl 2-(4-bromo-2- iodophenoxy)propanoate (1.2) (75% yield) as a colourless oil. 1H NMR (300 MHz, CDCI3) delta 7.91 (d, 1 H); 7.37 (dd, 1 H); 6.58 (d, 1 H); 4.73 (q, 1 H); 3.77 (s, 3H); 1.70 (d, 3H); ES-MS: 386 [M+1].
75%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
To a solution of (R)-methyl 2-hydroxypropanoate (1.1) (1 mmol), <strong>[207115-22-8]4-bromo-2-iodophenol</strong> (1 mmol) and triphenylphosphine (1.2 mmol) in THF (15 mL) at 0 C. was added DIAD (1.2 mmol) dropwise over 20 min. The solution was stirred for a further 15 min at 0 C. The bright yellow solution was allowed to warm to RT and stirred overnight. Volatiles were removed in vacuo to afford a dark orange oil. The crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford (S)-methyl 2-(4-bromo-2-iodophenoxy)propanoate (1.2) (75% yield) as a colourless oil. 1H NMR (300 MHz, CDCl3) delta 7.91 (d, 1H); 7.37 (dd, 1H); 6.58 (d, 1H); 4.73 (q, 1H); 3.77 (s, 3H); 1.70 (d, 3H); ES-MS: 386 [M+1].
methyl (R)-2-(2-benzoylphenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: 2-Hydroxybenzophenone; (R)-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 (R)-2-(4-(2,2,2-trifluoroacetyl)phenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: (R)-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).
methyl (R)-2-(4-benzoylphenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: (R)-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).
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-(isopropylsulfonyl)piperazin-1-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.2%
Stage #1: (R)-Methyl lactate With trifluoromethylsulfonic anhydride In dichloromethane at -78℃; for 0.75h;
Stage #2: With 2,6-dimethylpyridine In dichloromethane at -78℃; for 0.75h;
Stage #3: 1-(isopropylsulfonyl)piperazine With triethylamine In dichloromethane at -78 - 20℃; for 4h;
3 Step 3: Synthesis of methyl (S)-2-(4-(isopropylsulfonyl)piperazin-1-yl)propanoate:
To a stirred solution of methyl (R)-2-hydroxypropanoate (1.461 g, 14.042 mmol, 1.5 eq) in DCM (40 ml) at -78 °C was added trifluoromethanesulfonic anhydride (2.67 ml, 15.915 mmol, 1.7 eq). The reaction mixture was stirred at -78 °C for about 45 minutes, at which time, 2,6-lutidine (1.85 ml, 15.915 mmol, 1.7 eq) was added and stirred at same temperature for about 45 minutes. A solution of 1-(isopropylsulfonyl)piperazine (step 2, 1.8 g, 9.361 mmol, 1.0 eq) in DCM (10 ml) followed by triethylamine (3.9 ml, 28.085 mmol, 3.0 eq) were added to the reaction mixture at -78 °C. The reaction mixture was allowed to stir at 0 °C for about 1 hour and stir at room temperature for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, quenched with saturated sodium bicarbonate solution and extracted with DCM (3x250 ml). The combined organic layers were washed with water (100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (1.8 g, 69.2% yield) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): d ppm 3.71 (s, 3H), 3.43-3.31 (m, 5H), 3.23-3.14 (m, 1H), 2.71-2.59 (m, 4H), 1.34 (d, J = 6.9 Hz, 6H), 1.30 (d, J = 7.2 Hz, 3H); ES-MS: m/z 279.40 (M+H)+ .
(S)-methyl 2-(4-bromo-2-propionylphenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.14%
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃;
DIAD (15.9 g, 78.6 mmol) was slowly added to a stirred solution of 1-(5-bromo-2- hydroxyphenyl)propan-1-one (15. Og, 65.5 mmol), (R)-methyl 2-hydroxypropanoate (7.5 g, 72.0 mmol) and triphenylphosphine (20.6g, 78.6 mmol) in 100 mL of dichloromethane previously cooled to 0C. The ice bath was then removed, and the reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-20%ethyl acetate/hexane to get desired product 2 (17.3 g, 84.14%). as a light-yellow oil.1 H NMR (300 MHz, CDCI3) d 7.84 (d, 1 H), 7.52 (dd, 1 H), 6.72 (d, 1 H), 4.91 (q, 1 H),3.81 (s, 3H), 3.18 - 3.07 (m, 2H), 1.73 (d, 3H), 1.23 (t, 3H).
(S)-methyl 2-(2-acetyl-4-bromophenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃;
1.1 Step 1 : Synthesis of (S)-methyl 2-(2-acetyl-4-bromophenoxy) propanoate 2
To a solution of (R)-methyl 2-hydroxypropanoate 1 (3.07 g, 29.44 mmol), 1-(5-bromo-2- hydroxy phenyl)ethanone (6.33 g, 29.44 mmol) and TPP (9.28 g, 35.38 mmol) in 150 ml_ DCM previously cooled to 0°C was slowly added a DIAD (6.96 ml_) with stirring. (0819) The ice bath was then removed, and the mixture stirred at room temperature overnight and then concentrated under reduced pressure. After removal of the solvent, the residue was passed through a short silica gel column (hexane-EtOAc, 25: 1 , 10:1) to give desired product 2 (7.9 g, 89%) as a light yellow oil. (0820) 1 H NMR (300 MHz, CDCh) d 7.83 (d, 1 H); 7.48(dd, 1 H); 6.67 (d, 1 H); 4.87 (q, 1 H); 3.75 (s, 3H); 2.67 (s, 3H); 1.68 (d, 3H).
88.9%
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃;
16.1 Synthesis of (S)-methyl 2-(2-acetyl-4-bromophenoxy) propanoate
DIAD (6.96 mL) was added slowly to a stirred solution of (R)-methyl 2- hydroxypropanoate (3.07 g, 29.44 mmol), 1-(5-bromo-2-hydroxy phenyl)ethanone (6.33 g, 29.44 mmol) and triphenylphosphine (9.28 g, 35.38 mmol) in 150 mL DCM previously cooled to 0°C. The ice bath was then removed, and the mixture stirred at room temperature overnight and then concentrated under reduced pressure. After removal of the solvent, the residue was passed through a short silica gel column (hexane-EtOAc, 25: 1 , 10:1) to give desired product (7.9 g, 88.9%) as a light-yellow oil. 1H NMR (300 MHz, CDCh) d 7.83 (d, 1 H); 7.48(dd, 1 H); 6.67 (d, 1 H); 4.87 (q, 1 H); 3.75 (s, 3H); 2.67 (s, 3H); 1.68 (d, 3H)
(S)-methyl 2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of triethylamine trihydrofluoride (2.1 ml_, 13.1 mmol, 2.0 eq.) in DCM (19 ml_) was successively added XtalFluor-E (6.0 g, 26.2 mmol, 4.0 eq.) and 1-(5-bromo-2- hydroxyphenyl)propan-1-one (1.5 g, 6.5 mmol, 1.0 eq.) and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice, and the resulting mixture was extracted with DCM (2 x 20 ml_). The combined organic phases were washed with water (3 x 25 ml_), dried over magnesium sulphate and concentrated under reduced pressure to volume. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent), the appropriate fractions were collected, concentrated under reduced pressure to approximately 20 ml_. This solution was cooled to 0 C, then treated sequentially with methyl (2R)-2-hydroxypropanoate (0.69 ml_, 7.2 mmol, 1.1 eq.), triphenylphosphine (1.89 g, 7.2 mol, 1.1 eq.) and DIAD (1.4 ml_, 7.2 mol, 1.1 eq.) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified twice by flash column chromatography (Si, 0-10% EtOAc in hexanes, followed by 5-60% EtOAc in hexanes) to give the title compound (1.52 g, 4.5 mmol, 69%) as a yellow oil. UPLC-MS: acidic 2-minute run MS (ES-): m/z 335.0/337.0 (M-H) ; retention time: 1.31 min; purity: 85%. 1 H NMR (400 MHz, Chloroform-d) 2.53 - 2.30 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) <5 -85.67 - -106.78 (m).
To the mixture of methyl (2R)-2-hydroxypropanoate (20.0 g, 192 mmol, 1 eq.) and benzyl 2, 2, 2-trichloroethanimidate (51.0 g, 202 mmol, 1.05 eq.) in the solution of DCM (66.5 mL) and Hexane (133 mL) was added trifluoromethanesulfonic acid (1.11 mL) dropwise at 0 C. The mixture was stirred at 20 C for 50 hours, and then filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel column (Petroleum ether: EtOAc, from 100:1 to 100:3) to afford methyl (2S)-2-benzyloxyprop anoate (8.00 g, 37.0 mmol, 19% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.32-7.17 (m, 5H), 4.61 (d, J = 11.6 Hz, 1H), 4.37 (d, J = 11.6 Hz, 1H), 3.99 (m, 1H), 3.67 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H)
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