* 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.
Stage #1: With sodium hydroxide In water at 50 - 120℃; for 1 - 4 h; Stage #2: With hydrogenchloride In water
The D-mandelate (R,S,S salt 2, 266.5 g, 1 mol) was dissolved in 20percent sodium hydroxide solution (400 ml) and stirred at 50° C. for one hour. This resulted in a clear solution. The bath temperature was increased to 120° C. and the released S,S-DiMeMo was distilled off in an azeotrope with water (at 100° C.) by means of a distillation apparatus. After approx. 300 ml of condensate had distilled over, the distillation receiver was cooled to room temperature and acidified with 10percent HCl. The precipitated mandelic acid was filtered off with suction and dried under reduced pressure. An analysis of the optical purity showed that the D-mandelic acid had racemized fully.The condensate which had distilled over was saturated by adding solid NaOH; an organic phase separated out and was diluted with MTBE (200 ml). Extraction was effected with MTBE (2.x.100 ml), and the extracts were combined, dried over Na2SO4 and concentrated by rotary evaporation. 101 g of crude product were obtained and were fractionated in a water-jet pump vacuum. The pure S,S-DiMeMo distilled over at 37-39° C./14 mm. 88 g (18percent based on trans-DiMeMo racemate used) of S,S-DiMeMo were obtained as clear oil.Rotation [α]D=-6.15°(pure, d=0.94 g*cm-3). According to GC analysis, the optical purity of the isolated S,S-DiMeMo was 97.9percent ee.
DL-Mandelic acid 1b (30.4 g; 0.20 mol) was gradually introduced into a solution of 40percent HBr (56 mL) and concentrated H2SO4 (22 mL). The mixture was refluxed for 3 h, cooled and poured onto ice (150 g). The solution was then extracted twice with diethyl ether (2.x.75 mL), dried over MgSO4 and concentrated on a rotary evaporator. The remaining brown solution was distilled under reduced pressure. The crude product was crystallised from hexane, yielding pure α-bromophenylacetic acid 2b as light-yellow crystals (33.5 g, 78percent yield), mp 83-84 °C (lit.:12 mp 68-69 °C), Rf (benzene/ethyl acetate/AcOH, 1:3:1 v/v/v) 0.70.
75%
With sulfuric acid; hydrogen bromide In water for 3 h; Reflux
dl-Mandelic acid 1 (30.4 g; 0.20 mol) was gradually introduced into a solution of 40percent HBr (56 mL) and concentrated H2SO4 (22 mL). The mixture was kept under reflux for 3 h, cooled and poured onto ice (150 g). The solution was then extracted twice with diethyl ether (2.x.75 mL), dried over MgSO4 and concentrated on the rotary evaporator. The remaining brown solution was distilled under reduced pressure. The crude product was crystallised from hexane, yielding pure α-bromophenylacetic acid 2 as light-yellow crystals; yield: 75percent, mp 83-84 °C (lit.:refPreviewPlaceHolder34 mp 82-84 °C), Rf (benzene/ethyl acetate, 1:3 v/v) 0.70.
Reference：
[1] Tetrahedron, 2012, vol. 68, # 18, p. 3616 - 3625
[2] Tetrahedron, 2011, vol. 67, # 44, p. 8502 - 8508
[3] Journal of the Chemical Society, 1957, p. 4789,4792
[4] Journal fuer Praktische Chemie (Leipzig), 1917, vol. <2> 96, p. 286[5] Journal fuer Praktische Chemie (Leipzig), 1919, vol. <2> 99, p. 205
[6] Zeitschrift fuer Chemie, 1868, p. 142
[7] Zeitschrift fuer Chemie, 1868, p. 142
5
[ 19078-72-9 ]
[ 4870-65-9 ]
[ 100-52-7 ]
[ 611-71-2 ]
[ 65-85-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 945 - 951
6
[ 10035-10-6 ]
[ 611-71-2 ]
[ 4870-65-9 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1890, vol. 258, p. 76,86
[2] Zeitschrift fuer Chemie, 1868, p. 142
7
[ 611-71-2 ]
[ 1198-84-1 ]
[ 17119-15-2 ]
[ 1678-71-3 ]
[ 100-52-7 ]
[ 65-85-0 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 5, p. 1185 - 1189
8
[ 611-71-2 ]
[ 21210-43-5 ]
Reference：
[1] Tetrahedron Asymmetry, 2005, vol. 16, # 12, p. 2113 - 2117
[2] Tetrahedron Asymmetry, 2005, vol. 16, # 12, p. 2113 - 2117
[3] Biochemische Zeitschrift, 1927, vol. 181, p. 51
[4] Crystal Growth and Design, 2014, vol. 14, # 7, p. 3549 - 3556
[5] Crystal Growth and Design, 2014, vol. 14, # 7, p. 3549 - 3556
9
[ 67-56-1 ]
[ 611-71-2 ]
[ 21210-43-5 ]
[ 20698-91-3 ]
Reference：
[1] Beilstein Journal of Organic Chemistry, 2010, vol. 6, p. 1043 - 1055
10
[ 611-71-2 ]
[ 21210-43-5 ]
[ 20698-91-3 ]
[ 947-94-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 16, p. 2290 - 2304
11
[ 611-71-2 ]
[ 15206-55-0 ]
[ 21210-43-5 ]
[ 20698-91-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 8, p. 1234 - 1240
12
[ 4358-87-6 ]
[ 17199-29-0 ]
[ 21210-43-5 ]
[ 611-71-2 ]
[ 20698-91-3 ]
Reference：
[1] Tetrahedron Asymmetry, 2002, vol. 13, # 12, p. 1337 - 1345
[2] Tetrahedron Asymmetry, 2003, vol. 14, # 23, p. 3679 - 3687
[3] Advanced Synthesis and Catalysis, 2007, vol. 349, # 7, p. 1119 - 1127
13
[ 4358-87-6 ]
[ 21210-43-5 ]
[ 611-71-2 ]
Reference：
[1] Canadian Journal of Chemistry, 1990, vol. 68, p. 314 - 316
14
[ 29071-09-8 ]
[ 611-71-2 ]
[ 7322-88-5 ]
Yield
Reaction Conditions
Operation in experiment
49%
With immobilized lipase B from Candida antarctica; ammonia In di-isopropyl ether at 25℃; for 12 h; Resolution of racemate; Enzymatic reaction
General procedure: A 25 ml round-bottom flask was charged with Racemic α-hydroxyl acid ester of 0.5 mmol, 10 mLisopropyl ether and immobilized CALB (Novozym 435), the flask was sealed and anhydrous ammonia was added through the solution. The resulting mixture was stirred at 35 °C for a certain time. Samples were taken at 1 h intervals, each time 20 µl of solution were used for analyzing. When the reaction was complete, the solution was filtered through a pad of cotton and the solvent was removed in vacuum. The resulting residues were purified by chromatography on silica gel with petroleum ether–ethyl acetate (1:1 –1:5) to afford the corresponding α-hydroxyl acid, yields and ee values of the desired product were summarized in Table 2.
With lipase LC2-8 from P. stutzeri LC2-8 In di-isopropyl ether at 30℃; Resolution of racemate; Enzymatic reaction
The resolution of (R,S)-mandelic acid was carried out in isopropyl ether containing 300 mM vinyl acetate and 30 mM mandelic acid. The reaction was carried out with shaking at 180 rpm, and was catalyzed by 10 mg/mL (30 U/mL) lipase LC2-8 powder at 30°C. A control reaction was done by performing the above procedure in the absence of enzyme.
Reference：
[1] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1992, vol. 334, # 6, p. 526 - 528
[2] Journal of Molecular Catalysis B: Enzymatic, 2013, vol. 85-86, p. 105 - 110
[3] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 99, p. 108 - 113
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, # 22, p. 7114 - 7116
[2] Bulletin de la Societe Chimique de France, 1995, vol. 132, # 4, p. 428 - 452
[3] Farmaco, 1995, vol. 50, # 6, p. 455 - 469
[4] Synthesis, 2004, # 13, p. 2173 - 2180
[5] Bulletin de la Societe Chimique de France, 1988, # 4, p. 610 - 617
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 601 - 606
[7] Journal of Molecular Catalysis B: Enzymatic, 2010, vol. 66, # 1-2, p. 95 - 100
[8] Journal of Natural Products, 2016, vol. 79, # 7, p. 1783 - 1790
19
[ 51804-83-2 ]
[ 64201-09-8 ]
[ 64201-03-2 ]
[ 2019-71-8 ]
[ 611-71-2 ]
Reference：
[1] Photochemistry and Photobiology, 2007, vol. 83, # 3, p. 570 - 583
Stage #1: With hydrogenchloride; zinc In methanol; water at -5 - 0℃; Stage #2: With ammonia In dichloromethane; water at 30℃; for 0.25 h; Stage #3: at 20 - 25℃;
Example 23; Preparation of trans-(lR,2S)-2-(3, 4-difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt; [0127] Trans-(lR,2S)-2-(3,4-difluorophenyl)-l-nitrocyclopropane (215.0 g) was added to the pre-cooled methanolic hydrochloric acid (6.0percent to 7percent w/w HC1, 4300 ml), followed by cooling the mass to -5 to 0°C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at -5 to 0°C. The reaction mass was stirred further for 2 hours at -5 to 0°C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2 x 215 ml). The main filtrate and washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and then cooled to 10 to 15°C. 25percent Aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30°C. The resulting reaction mass was stirred for 15 minutes, followed the by layer separation. The resulting aqueous layer was extracted with dichloromethane (2 x 537.5 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was extracted thrice with aqueous hydrochloric acid (645 ml of cone, hydrochloric acid mixed with 1935 ml water, 3 x 865 ml). The aqueous acidic layer containing the product was combined and washed with dichloromethane (645 ml). Dichloromethane (1075 ml) was added to the acidic aqueous layer, followed by the addition of 25percent aqueous ammonia solution (1505 ml) while maintaining the temperature at below 30°C. The resulting reaction mass was extracted with dichloro methane (2 x 645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml) and evaporated to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(-)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining temperature at 20 to 25 °C. The resulting slurry was stirred further for 12 hours at 20 to 25 °C, followed by further cooling to 0 to 5°C. The cooled solution was stirred for 2 hours and the solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45°C to obtain 127 g of pure trans- (lR,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt as a white solid (Yield : 36.61percent; HPLC Purity: 99.87percent by area; [R]25D = -97.0° (c 1, methanol)).
36.61%
Stage #1: With hydrogenchloride; zinc In deuteromethanol at -5 - 0℃; Stage #2: at 0 - 25℃; for 14 h;
Example 22 Preparation of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(−)-mandelate salt Trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitro cyclopropane (215.0 g) was added to the pre-cooled methanolic hydrochloric acid (6.0percent to 7percent w/w HCl, 4300 ml), followed by cooling the mass to −5 to 0° C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at −5 to 0° C. The reaction mass was stirred further for 2 hours at −5 to 0° C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2×215 ml). The main filtrate and washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and then cooled to 10 to 15° C. 25percent Aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30° C. The resulting reaction mass was stirred for 15 minutes, followed the by layer separation. The resulting aqueous layer was extracted with dichloromethane (2×537.5 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was extracted thrice with aqueous hydrochloric acid (645 ml of conc. hydrochloric acid mixed with 1935 ml water, 3×865 ml). The aqueous acidic layer containing the product was combined and washed with dichloromethane (645 ml). Dichloromethane (1075 ml) was added to the acidic aqueous layer, followed by the addition of 25percent aqueous ammonia solution (1505 ml) while maintaining the temperature at below 30° C. The resulting reaction mass was extracted with dichloromethane (2×645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml) and evaporated to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(−)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining temperature at 20 to 25° C. The resulting slurry was stirred further for 12 hours at 20 to 25° C., followed by further cooling to 0 to 5° C. The cooled solution was stirred for 2 hours and the solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45° C. to obtain 127 g of pure trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(−)-mandelate salt as a white solid (Yield: 36.61percent; HPLC Purity: 99.87percent by area; [R]25D=−97.0° (c 1, methanol)).
A solution of the compound of formula IX (1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl formamide (3.5 g, 17.7 mmol)Was added 30percent sodium hydroxide (21.3 g, 160.0 mmol)5.2percent sodium hypochlorite (30.0 g, 21.0 mmol),Stirring at 25 to 40 degrees for 16 hours,Plus 50 ml of isopropyl acetate extraction,The oil phase was dried with anhydrous sodium sulfate,Was added dropwise to a solution of R-mandelic acid (2.7 g, 17.7 mmol) dissolved in 20 ml of isopropyl acetate,10 minutes drop finished,Stirred at room temperature for 1 hour,0 to 5 degrees stirring for 3 hours,filter,Cold isopropyl acetate wash,60 degrees decompression drying,To give the compound of formula II (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylmethylamine-R-mandelate (4.0 g, 12.5 mmol). Yield 70.1percent.
46.4%
at 20 - 25℃; for 14 h;
500ml four-necked flask was added compound (21.0g, 0.11mol) and 30percent aqueous sodium hydroxide solution (127.8g, 0.96mol). Under stirring, temperature at 0 ~ 5 , was added dropwise 10.5percent aqueous sodium hypochlorite solution (188.8g, 0.27mol), about 1h dropwise. After stirring at 0 ~ 5 continued until the reaction solution clarified rapidly warmed to 55 , reaction was continued for 1h. The reaction solution was cooled to 0 ~ 5 . Temperature not exceeding 10 , was added dropwise concentrated hydrochloric acid (about 100g) adjusted pH8 ~ 9. Was added dichloromethane (200ml), liquid separation. The aqueous layer (100ml × 2) and extracted with methylene chloride, the organic layers were combined, washed with water (200ml × 2). Dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give a yellow oil compound (14.2g). Under stirring, temperature at 20 ~ 25 , methanol to the compound (60ml) was added dropwise a solution of D- mandelic acid (12.8g, 0.08mol) in methanol (76 ml of) solution dropwise for about 2h. At 20 ~ 25 , stirring was continued for 12h. Filtered cake was recrystallized from methanol to give a white solid compound (15.8g, 46.4percent), HPLC purity 99.7percent, ee value 99.9percent.
Reference：
[1] Patent: CN107892693, 2018, A, . Location in patent: Paragraph 0035; 0060; 0062; 0064; 0104; 0145
26
[ 611-71-2 ]
[ 376608-71-8 ]
Yield
Reaction Conditions
Operation in experiment
7.56 g
at 18 - 45℃; for 2.5 h;
To a solution of 9 g R-mandelic acid in 300 ml of methanol at 45 C, was added a solution of 10 g of 2-(3.4-difluorophenyl)cyclopropanamine in 300 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25 C, stirred for 1 h, then further cooled slowly to 18 C and maintained for another 1 h. The crystalized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 7.56 g of product as a white crystalline solid. 1H NMR in (400MHz, DMSO d6) 5 1 .13 -1 .16 (2H, m), 1.25 - 1.28 (2H, m), 2.20-2.23 (1 H, m), 2.65 - 2.67 (1 H, m), 4.64(1 H, s), 6.94 -6.96 (1 H, m). 7.1 1 -7.36 (8H, m)
Stage #1: With Trimethyl borate In acetonitrile at 28 - 58℃; for 1.5 h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile at 58℃; for 12 h; Reflux
To a stirred solution of R-Mandelic acid (97.61 g) in acetonitrile (1000 mL), trimethylborate (66.66 g) was added at 28°C (±2). After addition of trimethylborate, reaction temperature was raised to 58°C (±2) and maintained for 90 minutes. To this solution, 2-(4-Nitro-phenyl)- ethylamine hydrochloride (NPA HCI) (100.0 g) was added at same temperature. To this solution, N, N-Diisopropylethyl amine (82.92 g) was added slowly and then reaction temperature was set to reflux for 12 hrs. The reaction temperature was lowered to 30°C (±2) and then diluted with ethyl acetate (1100 mL) and aqueous HCI (1M) solution (1400 mL). The separated organic layerwas washed successively with 1M hydrochloric acid aqueous solution. The organic layer was washed with 5percent sodium hydroxide aqueous solution and brine. The organic layer was concentrated in vacuo; the residue was recrystallized from toluene (500 mL). The solid was filtered, washed with toluene and dried under vacuo at 48°C (±2) to obtain pale yellow crystals of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl] -2-phenylacetamide. VYield: 125 g (84.3percent); Purity by HPLC: 98.65percent.
80.03%
With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine In N,N-dimethyl-formamide at 30℃; for 6 h;
(R) - mandelic acid (15.0g, 0.0986mol) and nitrobenzene hydrochloride (20.0g, 0.0986mol) in 75mlN, N- dimethyl formamide, stirring triethylamine, last added HOBT and EDC, 30 reaction 6h.TLC monitoring (GF254TLC plate, developing solvent: ethyl acetate: methanol = 5, if the heavy edges add 3 drops of triethylamine) to p-nitrophenyl ethylamine hydrochloride fluorescent spots disappear.Water was added and extracted with ethyl acetate, and concentrated under reduced pressure to remove ethyl acetate to give a yellow solid (III) 23.08g, yield: 80.03percent.
129.8 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 25 - 30℃; for 15 h;
Example-1: Preparation of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (or) (Formula-4) (R)-2-hydroxy-2-phenylacetic acid compound of formula-2 (75 gms), triethylamine (49.8 gms), hydroxybenztriazole (HOBt) (66.6 gms) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (94.5 gms) were added to a mixture of 2-(4-nitrophenyl)ethylamine hydrochloride compound of formula-3a (100 gms) in N,N-dimethylformamide (370 ml) at 25-30°C and stirred for 15 hrs at the same temperature. Water (1860 ml) was added to the reaction mixture at 25-30°C and stirred for 30 mins at the same temperature. Ethyl acetate (1500 ml) was added to the reaction mixture at 25-30°C and stirred for 30 mins. Separated the both aqueous and organic layers and the organic layer was washed with 1M HCl solution, followed by 20percent (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide aqueous potassium carbonate solution and finally with water. Distill off the solvent completely from the organic layer under reduced pressure. Toluene (600 ml) was added to the obtained compound, heated the reaction mixture to 80-85°C and stirred for 15 mins at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 12 hrs at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound. Yield: 129.8 gms.
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 20, p. 3665 - 3673
[2] Patent: WO2015/44965, 2015, A1, . Location in patent: Page/Page column 32
[3] Patent: CN105481705, 2016, A, . Location in patent: Paragraph 0017; 0018; 0019
[4] Patent: EP1440969, 2004, A1, . Location in patent: Page 5-6
[5] Patent: EP1559427, 2005, A1, . Location in patent: Page/Page column 5-6
[6] Patent: WO2014/132270, 2014, A2, . Location in patent: Page/Page column 17-18
[7] Patent: WO2016/24284, 2016, A2, . Location in patent: Page/Page column 28-29
Reference：
[1] Patent: WO2016/24284, 2016, A2,
[2] Organic Process Research and Development, 2016, vol. 20, # 11, p. 1993 - 1996
[3] Organic Process Research and Development, 2016, vol. 20, # 11, p. 1993 - 1996
[4] Organic Process Research and Development, 2016, vol. 20, # 11, p. 1993 - 1996
[5] Acta Chimica Slovenica, 2018, vol. 65, # 1, p. 239 - 245
In methanol;Resolution of racemate; Heating / reflux;Purification / work up;
[0140] General procedure for Enantiomeric Separation of 2- benzylaminopropanes [(R)-10-14, (S)-10-14]. The appropriate racemic 2- benzylaminopropane (1 eq) was combined with the appropriate optically active mandelic acid (1 eq) in methanol (c= 0.5 M) and refluxed until the solution homogenized, then cooled to RT. The crystals were filtered, collected, and recrystallized twice from methanol (c = 0.3 M) to afford the optically active 2- benzylaminopropane ? mandelic acid salt. The salts were converted to the free amine for the purpose of collecting NMR and rotation data by partitioning the mandelic acid salt between 10% K2CO3 and CHCl3, drying organic extracts (Na2SO4) and evaporating; [0144] (S)-(+)-l-(4'-Methoxyphenyl)-2-benzylaminopropane [(S)-Il]. A sample of 3.36 g (13.2 mmol) of the racemate l-(4'-methoxyphenyl)-2-benzylaminopropane (42) was reacted with 2.0 g (13.2 mmol) of (7?)-(-)-manderic acid to give 740 mg (44% based on enantiomeric abundance) of the free amine after workup. 1H NMR, (CDCl3) delta 1.10 (d, 3H, J = 6.2 Hz), 2.55-2.76 (m, 2H), 2.88-2.95 (m, IH), 3.73-3.88 (m, 2H), 3.79 (s, 3H), 6.80 (d, 2H, J = 8.7 Hz), 7.08 (d, 2H, J= 8.4 Hz), 7.15-7.30 (m, 5H); MS (APCI+) m/z (rel): 256 (100); [alpha]D= +30.5 (c = 1.1 MeOH).
To a stirred solution of R-Mandelic acid (97.61 g) in acetonitrile (1000 mL), trimethylborate (66.66 g) was added at 28C (±2). After addition of trimethylborate, reaction temperature was raised to 58C (±2) and maintained for 90 minutes. To this solution, 2-(4-Nitro-phenyl)- ethylamine hydrochloride (NPA HCI) (100.0 g) was added at same temperature. To this solution, N, N-Diisopropylethyl amine (82.92 g) was added slowly and then reaction temperature was set to reflux for 12 hrs. The reaction temperature was lowered to 30C (±2) and then diluted with ethyl acetate (1100 mL) and aqueous HCI (1M) solution (1400 mL). The separated organic layerwas washed successively with 1M hydrochloric acid aqueous solution. The organic layer was washed with 5% sodium hydroxide aqueous solution and brine. The organic layer was concentrated in vacuo; the residue was recrystallized from toluene (500 mL). The solid was filtered, washed with toluene and dried under vacuo at 48C (±2) to obtain pale yellow crystals of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl] -2-phenylacetamide. VYield: 125 g (84.3%); Purity by HPLC: 98.65%.
80.03%
With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide; at 30℃; for 6h;
(R) - mandelic acid (15.0g, 0.0986mol) and nitrobenzene hydrochloride (20.0g, 0.0986mol) in 75mlN, N- dimethyl formamide, stirring triethylamine, last added HOBT and EDC, 30 reaction 6h.TLC monitoring (GF254TLC plate, developing solvent: ethyl acetate: methanol = 5, if the heavy edges add 3 drops of triethylamine) to p-nitrophenyl ethylamine hydrochloride fluorescent spots disappear.Water was added and extracted with ethyl acetate, and concentrated under reduced pressure to remove ethyl acetate to give a yellow solid (III) 23.08g, yield: 80.03%.
67%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
(2R)-2-hydroxy-2-phenyl-acetic acid (2.70 g, 18.00 mmol),4-Nitrophenylethylamine hydrochloride (3 g, 14.81 mmol)Add N,N-dimethylformamide (30 mL) to a 100 mL single-mouth bottle.Triethylamine (2.50 mL, 18.00 mmol),Then add HOBT (2.45g, 17.8mmol),EDCI (3.44g, 17.8mmol),The reaction was stirred at room temperature for 2 hours.Add ethyl acetate (150 mL), wash with water (50 mL×3),The mixture was washed with saturated brine (30 mL×2).The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 10/1)The title compound was obtained as a pale yellow solid(3g, 67%).
67%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
(2R)-2-hydroxy-2-phenyl-acetic acid (2.70 g, 18.00 mmol),4-Nitrophenylethylamine hydrochloride (3 g, 14.81 mmol)Add N,N-dimethylformamide (30 mL) to a 100 mL single-mouth bottle.Triethylamine (2.50 mL, 18.00 mmol),Then add HOBT (2.45g, 17.8mmol),EDCI (3.44g, 17.8mmol),The reaction was stirred at room temperature for 2 hours.Join BEthyl acetate (150 mL), washed with water (50 mL×3), brine (30 mL×2), dried over anhydrous sodium sulfateThe residue was purified by column chromatography (dichloromethane / methanol (v / v) = 10/1)The title compound was obtained as a pale yellow solid (3 g, 67%).
67%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
(2R)-2-hydroxy-2-phenyl-acetic acid (2.70 g, 18.00 mmol),4-nitrophenethylamine hydrochloride (3 g, 14.81 mmol) in a 100 mL single-mouth bottle,Add N,N-dimethylformamide (30 mL), triethylamine (2.50 mL, 18.00 mmol),Then HOBT (2.45 g, 17.8 mmol), EDCI (3.44 g, 17.8 mmol) were added, and the reaction was stirred at room temperature for 2 hours.Add ethyl acetate (150 mL), wash with water (50 mL×3),Wash with saturated brine (30 mL×2), dry over anhydrous sodium sulfate and then concentrate.The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 10/1)Get the title compound asLight yellow solid (3g, 67%).
67%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
(2R)-2-hydroxy-2-phenylacetic acid (2.70 g, 18.00 mmol), 4-Nitrophenylethylamine hydrochloride (3 g, 14.81 mmol) Add N,N-dimethylformamide (30 mL) to a 100 mL single-mouth bottle. Triethylamine (2.50 mL, 18.00 mmol), Then add HOBT (2.45g, 17.8mmol), EDCI (3.44g, 17.8mmol), The reaction was stirred at room temperature for 2 hours. Add ethyl acetate (150 mL), Washed (50mL×3), Saturated saline solution (30mL × 2), The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 10/1) The title compound was obtained as a pale yellow solid (3 g, 67%).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 L of N,N-dimethylformamide, 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0.28 kg of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with 110 L of water and extracted with ethyl acetate (60 L and 30 L). The organic layer was washed successively with 60 L of a 1M hydrochloric acid aqueous solution, 60 L of a 20 % potassium carbonate aqueous solution and water (60 L and 60 L), and then concentrated in vacuo at 10 to 19C. The residue was dissolved in 35 L of toluene by heating (at 87C), cooled, and then stirred at 20C overnight. A formed crystal was collected by filtration and washed with 10 L of toluene, followed by drying in vacuo. There was thus obtained 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as a pale yellow crystal. 1H-NMR (DMSO-d6, 400 MHz) ? (ppm) = 2.87 (2H, t, J = 7.2 Hz), 3.30 to 3.46 (2H, m), 4.85 (1H, d, J = 4.8 Hz), 6.12 (1H, d, J = 4.8 Hz), 7.20 to 7.33 (5H, m), 7.40 (2H, d, J = 8.0 Hz), 8.04 to 8.12 (3H, m). FAB-MS m/z: 301 (M+H)+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 liters of N,N-dimethylformamide were added 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) followed by stirring at about room temperature for 2 hours. EDC (0.28 kg) was further added thereto and the mixture was stirred at about room temperature throughout one night. The reaction solution was diluted with 110 liters of water and extracted with ethyl acetate (60 liters, 30 liters). The organic layer was successively washed with 60 liters of 1M aqueous hydrochloric acid, 60 liters of 20% aqueous solution of potassium carbonate and water (60 liters, 60 liters) and concentrated in vacuo at 10 to 19C. The residue was dissolved in 35 liters of toluene with heating at 87C, cooled and stirred at 20C throughout one night. The resulting crystals were filtered and washed with 10 liters of toluene. This was driedin vacuo to give 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as light yellow crystals. 1H-NMR (DMSO-d6, 400 MHz) delta (ppm) = 2.87 (2H, t, J = 7.2 Hz), 3.30-3.46 (2H, m), 4.85 (1H, d, J = 4.8 Hz), 6.12 (1H, d, J = 4.8 Hz), 7.20-7.33 (5H, m), 7.40 (2H, d, J = 8.0 Hz), 8.04-8.12 (3H, m). FAB-MS m/z: 301 (M+H)+.
129.8 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25 - 30℃; for 15h;
Example-1: Preparation of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (or) (Formula-4) (R)-2-hydroxy-2-phenylacetic acid compound of formula-2 (75 gms), triethylamine (49.8 gms), hydroxybenztriazole (HOBt) (66.6 gms) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (94.5 gms) were added to a mixture of 2-(4-nitrophenyl)ethylamine hydrochloride compound of formula-3a (100 gms) in N,N-dimethylformamide (370 ml) at 25-30C and stirred for 15 hrs at the same temperature. Water (1860 ml) was added to the reaction mixture at 25-30C and stirred for 30 mins at the same temperature. Ethyl acetate (1500 ml) was added to the reaction mixture at 25-30C and stirred for 30 mins. Separated the both aqueous and organic layers and the organic layer was washed with 1M HCl solution, followed by 20% (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide aqueous potassium carbonate solution and finally with water. Distill off the solvent completely from the organic layer under reduced pressure. Toluene (600 ml) was added to the obtained compound, heated the reaction mixture to 80-85C and stirred for 15 mins at the same temperature. Cooled the reaction mixture to 20-25C and stirred for 12 hrs at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound. Yield: 129.8 gms.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25 - 30℃; for 15.5h;
(R)-2-hydroxy-2-phenylacetic acid (75g), triethylamine (50g), hydroxybenzotriazole (HOBt) (33.3g) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC.HC1) (50g) were added to a mixture of 2-(4-nitrophenyl)ethylamine hydrochloride (100g) in Nu,Nu-dimethylformamide (375ml) at 25-30C. The mixture was stirred for 30 minutes followed by addition of another lot of HOBt (33.3g) and EDC.HC1 (50g) in reaction mixture. The reaction mixture was maintained at 25-30C for 15 hours under stirring. After completion of reaction, water (1850ml) was added to the reaction mixture and stirred. Subsequently, ethyl acetate (1500ml) was added to the reaction mixture at 25-30C and stirred. The organic phase was separated from aqueous phase, and was washed sequentially with 1M HC1 solution, 20%aqueous potassium carbonate solution and water. The organic solvent was distilled out under reduced pressure to obtain residue comprising of (2R)-2-hydroxy-N-[2-(4- nitrophenyl)ethyl] -2 -phenyl ethanamide of Formula (IX)
5-[(2R)-2-[2-(2-ethoxyphenoxy)ethyl]amino}propyl]-2-methoxybenzene-1-sulfonamide mandelate salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In ethyl acetate; at 20 - 78℃; for 1h;
5 obtained in Step 3 of Example 1 - [(2R) -2 - [{2- (2- ethoxy-phenoxy) ethyl} amino] propyl] -2-methoxy-benzenesulfonamide (59.0g, 0.144 mol, 1.0eq) and ethyl acetate (1180ml) only while stirring to mandelic acid (24.2g, 0.159mol, 1.1eq) and the resulting solid to fall after cooling to room temperature (20 ) by stirring for 1 hour under reflux at 78 filtered and dried for 12 hours at 40 . By filtration and the dried compound water (750ml), it was added to the resulting solid in a mixture of acetone (40ml) cooling to room temperature in 78 (20 ) and then refluxed for 1 hour 5 - [(2R) -2- [{2- (2-ethoxy-phenoxy in) ethyl} amino] propyl] -2-methoxy benzenesulfonamide was obtained a mandelate salt (69g, yield 86%).
In ethyl acetate; for 1h;
Example: Purification of tamsulosin. 260ml of ethylacetate and 5.8g of mandelic acid were added to 13.0g of the tamsulosin prepared in the Reference Example above. The resultant mixture was refluxed under stirring for 1 hour, cooled, filtered and dried to obtain 16.5g of tamsulosin mandelate in the form of precipitates. The tamsulosin mandelate was dissolved in a mixed solvent of 65ml of methanol and 80ml of isopropanol under heating, and then 20ml of 4.5N HCl (in isopropanol) was slowly added thereto. The resulting mixture was cooled, filtered and dried to yield 12.9g of high purity tamsulosin hydrochloride (Impurity content: 0.25%)
Into a I-L, three-necked, RB flask was charged 100 g of crude (3S, 4R)-trans-3- carbomethoxy-4- (4-fluorophenyl)-N-methyl-piperidine obtained according to the procedure given in Example 3 step (iii), 450 mL of isopropanol, and 60 g of (-)-mandelic acid. The reaction mass was heated to 55-60 C to get a clear solution. The reaction mass was slowly cooled to 25-30 C and kept under stirring for 12-15 hr. The reaction mass was further cooled-to 5-10 C and filtered the mass. The wet cake thus obtained was washed with 50 mL of isopropanol and dried to get 135 g of white solid. Melting point is 120 C. Optical rotation is-69.4 (c = 1, MeOH).
PREPARATION 1 Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate STR6 Ethyl-3-pyridylacetate (100 g, 0.606 mol) was dissolved in ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g) and hydrogenated at 60 C. and 60 psi hydrogen gas overnight. The catalyst was removed by filtration and the solvent evaporated to give a brown liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600 ml) and treated with L-(+)-mandelic acid in warm ethyl acetate (600 ml). After cooling in the refrigerator for four hours, the solid was collected and the crystallization fluid reserved for processing to the other enantiomer, infra. The solid was again recrystallized from ethyl acetate (1.55-1.6 liters, overnight at ambient temperature) to give the desired title product as white needles. Yield: 81.6 grams, 41%.
(+)-mandelic acid salt of (+)-3-amino-1,2,3,4-tetrahydrocarbazole[ No CAS ]
racemic 3-amino-1,2,3,4-tetrahydrocarbazole[ No CAS ]
[ 611-71-2 ]
[ 61894-99-3 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Example 71 (+)-3-Amino-1,2,3,4-tetrahydrocarbazole STR87 18.6 g (0.1 mol) of racemic 3-amino-1,2,3,4-tetrahydrocarbazole are heated together with 15.2 g (0.1 mol) of (+)-mandelic acid in 100 ml of tetrahydrofuran under reflux. Once a clear solution has been obtained, it is allowed to cool and a spatula tip of the (+)-mandelic acid salt of (+)-3-amino-1,2,3,4-tetrahydrocarbazole (enantiomer A, Example 59) is added as seed crystals. The mixture is stirred overnight, and the crystals which have separated out are filtered off with suction. In this way 6.05 g of enantiomerically enriched material are obtained. 4.7 g of these crystals are dissolved in 330 ml of boiling methyl isobutyl ketone and, after cooling slightly, the solution is seeded and stirred as cooling is continued. After filtration with suction and washing with methyl isobutyl ketone, 3.4 g of (+)-3-amino-1,2,3,4-tetrahydrocarbazole are obtained as the (+)-mandelic acid salt.
With toluene-4-sulfonic acid; benzyl alcohol; In chloroform; benzene;
EXAMPLE 5 Preparation of cephalotaxyl L-mandelate, trichloroethylcarbonate ester STR9 L-Mandelic acid (10 g.), 6.91 g. of benzyl alcohol, and 75 mg. of p-toluenesulfonic acid in 70 ml. of benzene was refluxed under a Dean-Stark trap for a total of 28 hours on 4 consecutive days. The crude benzyl ester was obtained by successively concentrating the liquor and cooling it to about 10 C. a number of times. The fractions melting between 97 C. and 105 C. were combined, dissolved in CHCl3 and washed twice with 15-ml. portions of 5% aqueous NaHCO3 solution. After evaporation of the CHCl3, the product was recrystallized from benzene to give benzyl L-mandelate, m.p. 104-106 C., yield 42%.
With toluene-4-sulfonic acid; benzyl alcohol; In benzene;
(1) Benzyl D-mandelate STR53 A solution of 85.1 g (559 mmol) of D-mandelic acid, 65 ml (628 mmol) of benzyl alcohol, and 1.01 g (5.35 mmol) of p-toluenesulfonic acid in 700 ml of benzene was refluxed for 6.5 hours. The mixture was washed with water and concentrated. The residue was recrystallized from ether to give 123.5 g of the aimed compound D-2 in 91% yield. Mp. 103.5-105 C. Anal. Calcd. (%) for C15 H14 O3: C, 74.36; H, 5.82; Found (%): C, 74.53; H, 5.90. 1 H-NMR(CDCl3 -TMS) delta ppm: 3.44(d, J=5.6 Hz, 1H), 5.14(ABq, Apart, J=12.3 Hz, 1H), 5.22(d, J=5.6 Hz, 1H), 5.24(ABq, Bpart, J=12.3 Hz, 1H), 7.15~7.50(m, 10H). [alpha]D =-55.7+-1.0 (CHCl3, C=1.003%, 24 C.).
The D-mandelate (R,S,S salt 2, 266.5 g, 1 mol) was dissolved in 20% sodium hydroxide solution (400 ml) and stirred at 50 C. for one hour. This resulted in a clear solution. The bath temperature was increased to 120 C. and the released S,S-DiMeMo was distilled off in an azeotrope with water (at 100 C.) by means of a distillation apparatus. After approx. 300 ml of condensate had distilled over, the distillation receiver was cooled to room temperature and acidified with 10% HCl. The precipitated mandelic acid was filtered off with suction and dried under reduced pressure. An analysis of the optical purity showed that the D-mandelic acid had racemized fully.The condensate which had distilled over was saturated by adding solid NaOH; an organic phase separated out and was diluted with MTBE (200 ml). Extraction was effected with MTBE (2×100 ml), and the extracts were combined, dried over Na2SO4 and concentrated by rotary evaporation. 101 g of crude product were obtained and were fractionated in a water-jet pump vacuum. The pure S,S-DiMeMo distilled over at 37-39 C./14 mm. 88 g (18% based on trans-DiMeMo racemate used) of S,S-DiMeMo were obtained as clear oil.Rotation [alpha]D=-6.15(pure, d=0.94 g*cm-3). According to GC analysis, the optical purity of the isolated S,S-DiMeMo was 97.9% ee.
4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol D-mandelate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 20℃;Reflux;
Example 11[00152] A 100 ml one necked flask equipped with a magnetic stirrer was charged with ODV base (3 g, 11.39 mmol) and EtOH 95% (9ml), the suspension being stirred at reflux. D-Mandelic acid (1.9g 12.49 mmol) was added and a clear solution was obtained. After overnight stirring at room temperature, the mixture was cooled to - 1O0C. Heptane (6 ml) was added and a clear solution appeared. The mixture was evaporated to dryness to get amorphous ODV.Mandelate. X-ray powder diffraction pattern is depicted in Figure 11.
(R)-5-[2-[(2-(2-ethoxyphenoxy)ethyl)amino]propyl]-2-methoxybenzenesulfonamide (R)-mandelate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetone; at 15 - 25℃;
4.87 g of 2-methoxy-5-(2-oxopropyl)benzenesulfonamide, 3.62 g of 2-(2-ethoxyphenoxy)ethylamine and 10 mg of sodium acetate were added to 30 ml of acetonitrile. The mixture was heated while stirred under reflux for about 1 hour. Then, the solvent was evaporated off in vacuo, to give 7.84 g of an imine compound as a powder. The obtained imine compound was again dissolved in 70 ml of acetonitrile, and to this was added 1.0 g of anhydrous magnesium sulfate. The mixture was cooled to -3 to 3C under argon atmosphere. To this mixture was added the whole amount of the above catalyst-containing mixture, and stirring continued at the same temperature for about 30 minutes. To this was added dropwise 12.0 ml of a mixed solution of formic acid/triethylamine (molar ratio: 5/2), and then stirring further continued at the same temperature for about 5 hours. After that, the reaction mixture was gradually returned to room temperature, and stirring continued overnight for completion of the reaction. After that, the solvent was evaporated off in vacuo and the residue was dissolved in methyl isobutyl ketone. Following this, extraction with aqueous methanesulfonic acid solution was performed. After the aqueous layer was rendered weakly alkaline with aqueous sodium hydroxide solution, separated oily material was extracted with methyl ethyl ketone. The extract solution was washed with saturated brine, dried and concentrated, to give 7.96 g of 5-[2-[(2-(2-ethoxyphenoxy)ethyl)amino]propyl]-2-methoxybenzenesulfonamide (crude crystal containing excess R-isomer) as a light brown powder. The obtained compound was analyzed using a chiral chromatography column (CHIRALPAK AD-H; manufactured by Daicel Chemical Industries, Ltd.) with a solvent made of n-hexane/2-propanol/diethylamine (800/200/1). The result showed that the optical purity of the R-isomer was 70.7%ee. Then, 6.0 g of the crude crystal was dissolved in 42.0 ml of aqueous acetone containing 10% water and to this was added 3.36 g of (R)-mandelic acid. The mixture was heat-dissolved, and then allowed to stand at 15 to 25C overnight. The precipitate was collected by filtration, washed with acetone and dried, to give 4.56 g of (R)-tamuslosin (R)-mandelate, i.e., (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide (R)-mandelate as a colorless crystal. The optical purity of the R-isomer of the obtained compound was 97.0%ee. Moreover, recrystallization from aqueous acetone containing 10% water was performed to give 3.29 g of a purified product. The optical purity of the R-isomer of the purified product was 100%ee.Optical rotation: [alpha]D20 -31.90 (C = 0.5, MeOH) NMR: 1H-NMR (200MHz, DMSO-d6): delta 0.99-1.03 (3H, d), 1.23-1.30 (3H, t), 2.47-2.59 (1H, q), 2.97-3.05 (1H, q), 3.10-3.30 (1H, m), 3.14-3.20 (2H, t), 3.88 (3H, s), 3.94-4.04 (2H, q), 4.09-4.15 (2H, t), 4.43 (2H, m), 4.75 (1H, s), 6.82-7.43 (9H, m), 7.04 (2H, m), 7.58-7.60 (1H, d)
Example 4; Preparation of (R)-i-naphthylethylamine mandalate salt; Racemic 1-naphthylethylamine (2.63 moles, 450 gms) was suspended in ethanol (3.1 Its). D-mandelic acid (2.63 moles, 400 gms) was added under stirring. Pure (R)- naphthylethylamine mandalate (3-4 gms) was added as a seed and heated at 55-6O0C until a clear solution was obtained. The solution was cooled gradually to 25-3O0C and stirred for about 12 hours to obtain a solid. The solid was suspended in ethanol (2.3 Its) and heated at a temperature of 55-6O0C for about half an hour. The suspension was cooled gradually to 25-3O0C and stirred to obtain a solid. The solid was washed with ethanol and dried at 50-550C to obtain the title compound (250 gms, Yield 70%, chiral purity >;99.0%).
Example 5; Preparation of (S)-i-naphthylethylamine mandalate salt; Racemic 1-naphthylethylamine (2.63 moles, 450 gms) was suspended in isopropyl alcohol (3.1 Its). D-mandelic acid (1.32 moles, 200 gms) was added under stirring and heated at 55-6O0C until a clear solution was obtained. The solution was cooled gradually to 25-3O0C and stirred for about 12 hours to obtain a solid. The solid was suspended in isopropyl alcohol (2.3 Its) and heated at a temperature of 55-6O0C for about half an hour. The suspension was cooled gradually to 25-3O0C and stirred to obtain a solid. The solid was washed with isopropyl alcohol and dried at 50-550C to obtain the title compound (225 gms, Yield 62%, chiral purity >;99.0%).
Example 14; (Rasagiline D-mandelate) Rasagiline base (0.69g) was dissolved in 2-propanol (20 ml) and was combined with solution of D-(-)-mandelic acid (0.61 g) in 2-propanol (10 ml). To this combined solution 20 ml of heptane was slowly added, then left the solution to evaporate slowly until crystals of <strong>[136236-51-6]rasagiline</strong> D-mandelate formed.
In isopropyl alcohol;
Rasagiline base (0.69g) was dissolved in 2-propanol (20 ml) and was combined with solution of D-(-)-mandel ic acid (0.61 g) in 2-propanol (1 0 ml ). To th is combined solution 20 ml of heptane was slowly added, then left the solution to evaporate slowly until crystals of <strong>[136236-51-6]rasagiline</strong> D-mandelate formed.
Example 23; Preparation of trans-(lR,2S)-2-(3, 4-difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt; [0127] Trans-(lR,2S)-2-(3,4-difluorophenyl)-l-nitrocyclopropane (215.0 g) was added to the pre-cooled methanolic hydrochloric acid (6.0percent to 7percent w/w HC1, 4300 ml), followed by cooling the mass to -5 to 0°C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at -5 to 0°C. The reaction mass was stirred further for 2 hours at -5 to 0°C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2 x 215 ml). The main filtrate and washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and then cooled to 10 to 15°C. 25percent Aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30°C. The resulting reaction mass was stirred for 15 minutes, followed the by layer separation. The resulting aqueous layer was extracted with dichloromethane (2 x 537.5 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was extracted thrice with aqueous hydrochloric acid (645 ml of cone, hydrochloric acid mixed with 1935 ml water, 3 x 865 ml). The aqueous acidic layer containing the product was combined and washed with dichloromethane (645 ml). Dichloromethane (1075 ml) was added to the acidic aqueous layer, followed by the addition of 25percent aqueous ammonia solution (1505 ml) while maintaining the temperature at below 30°C. The resulting reaction mass was extracted with dichloro methane (2 x 645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml) and evaporated to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(-)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining temperature at 20 to 25 °C. The resulting slurry was stirred further for 12 hours at 20 to 25 °C, followed by further cooling to 0 to 5°C. The cooled solution was stirred for 2 hours and the solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45°C to obtain 127 g of pure trans- (lR,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt as a white solid (Yield : 36.61percent; HPLC Purity: 99.87percent by area; [R]25D = -97.0° (c 1, methanol)).
36.61%
Example 22 Preparation of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(?)-mandelate salt Trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitro cyclopropane (215.0 g) was added to the pre-cooled methanolic hydrochloric acid (6.0percent to 7percent w/w HCl, 4300 ml), followed by cooling the mass to ?5 to 0° C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at ?5 to 0° C. The reaction mass was stirred further for 2 hours at ?5 to 0° C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2×215 ml). The main filtrate and washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and then cooled to 10 to 15° C. 25percent Aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30° C. The resulting reaction mass was stirred for 15 minutes, followed the by layer separation. The resulting aqueous layer was extracted with dichloromethane (2×537.5 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was extracted thrice with aqueous hydrochloric acid (645 ml of conc. hydrochloric acid mixed with 1935 ml water, 3×865 ml). The aqueous acidic layer containing the product was combined and washed with dichloromethane (645 ml). Dichloromethane (1075 ml) was added to the acidic aqueous layer, followed by the addition of 25percent aqueous ammonia solution (1505 ml) while maintaining the temperature at below 30° C. The resulting reaction mass was extracted with dichloromethane (2×645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml) and evaporated to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(?)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining temperature at 20 to 25° C. The resulting slurry was stirred further for 12 hours at 20 to 25° C., followed by further cooling to 0 to 5° C. The cooled solution was stirred for 2 hours and the solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45° C. to obtain 127 g of pure trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(?)-mandelate salt as a white solid (Yield: 36.61percent; HPLC Purity: 99.87percent by area; [R]25D=?97.0° (c 1, methanol)).
(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine[ No CAS ]
[ 611-71-2 ]
[ 376608-71-8 ]
Yield
Reaction Conditions
Operation in experiment
70.1%
In Isopropyl acetate; at 0 - 20℃; for 4h;
A solution of the compound of formula IX (1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl formamide (3.5 g, 17.7 mmol)Was added 30percent sodium hydroxide (21.3 g, 160.0 mmol)5.2percent sodium hypochlorite (30.0 g, 21.0 mmol),Stirring at 25 to 40 degrees for 16 hours,Plus 50 ml of isopropyl acetate extraction,The oil phase was dried with anhydrous sodium sulfate,Was added dropwise to a solution of R-mandelic acid (2.7 g, 17.7 mmol) dissolved in 20 ml of isopropyl acetate,10 minutes drop finished,Stirred at room temperature for 1 hour,0 to 5 degrees stirring for 3 hours,filter,Cold isopropyl acetate wash,60 degrees decompression drying,To give the compound of formula II (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylmethylamine-R-mandelate (4.0 g, 12.5 mmol). Yield 70.1percent.
46.4%
In methanol; at 20 - 25℃; for 14h;
500ml four-necked flask was added compound (21.0g, 0.11mol) and 30percent aqueous sodium hydroxide solution (127.8g, 0.96mol). Under stirring, temperature at 0 ~ 5 , was added dropwise 10.5percent aqueous sodium hypochlorite solution (188.8g, 0.27mol), about 1h dropwise. After stirring at 0 ~ 5 continued until the reaction solution clarified rapidly warmed to 55 , reaction was continued for 1h. The reaction solution was cooled to 0 ~ 5 . Temperature not exceeding 10 , was added dropwise concentrated hydrochloric acid (about 100g) adjusted pH8 ~ 9. Was added dichloromethane (200ml), liquid separation. The aqueous layer (100ml × 2) and extracted with methylene chloride, the organic layers were combined, washed with water (200ml × 2). Dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give a yellow oil compound (14.2g). Under stirring, temperature at 20 ~ 25 , methanol to the compound (60ml) was added dropwise a solution of D- mandelic acid (12.8g, 0.08mol) in methanol (76 ml of) solution dropwise for about 2h. At 20 ~ 25 , stirring was continued for 12h. Filtered cake was recrystallized from methanol to give a white solid compound (15.8g, 46.4percent), HPLC purity 99.7percent, ee value 99.9percent.
In methanol; at 20 - 25℃; for 12h;
Step-5: Preparation of trans-(lR,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(-)- mandelate saltTo a pre-cooled methanolic hydrochloric acid solution (6-7percent> w/w HC1, 4300 ml) was added trans-(lR,2S)-2-(3,4-difluorophenyl)-l-nitrocyclopropane (215 g), and the mixture was cooled to -5 to 0°C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at -5 to 0°C. The reaction mass was stirred further for 2 hours at -5 to 0°C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2 x 215 ml). The main filtrate and the washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and the solution was cooled to 10 to 15°C. 25percent aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30°C. The resulting reaction mass was stirred for 15 minutes, followed by layer separation. The aqueous layer was extracted with dichloromethane (2 x 537.5 ml), followed by combining with the main dichloromethane layer. The combined dichloromethane layer was extracted thrice with aqueous hydrochloric acid (645 ml of concentrated hydrochloric acid mixed with 1935 ml of water, 3 x 865 ml). The aqueous acidic layers containing the product were combined, followed by washing with dichloromethane (645 ml). Dichloromethane (1075 ml) and 25percent aqueous ammonia solution (1505 ml) were added to the acidic aqueous layer while maintaining the temperature at below 30°C. The resulting reaction mass was extracted twice with dichloromethane (2 x 645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml), followed by and evaporation to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(-)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining the temperature at 20 to 25°C. The resulting slurry was stirred further for 12 hours at 20 to 25°C, followed by cooling the slurry to 0 to 5°C. The cooled solution was stirred for 2 hours and the resulting solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45°C to produce 127 g of pure trans-(lR,2S)-2-(3,4- difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt as a white solid (Purity by HPLC: 99.87percent; [R]25D = -97.0° (c 1, methanol)).
Example: 3.; Preparation of <strong>[112101-81-2]5-[(2R)-2-aminopropyl]-2-methoxybenzenesulfonamide</strong> Mandalate; 50 gm <strong>[112101-81-2]5-[(2R)-2-aminopropyl]-2-methoxybenzenesulfonamide</strong> is dissolved in a solvent mixture of 500 ml of methanol and water (9.5: 0.5 v/v) on heating. 33.8 gm D (-) mandelic acid is added slowly at 65C in the reaction mixture, maintained the temperature for 6 hours. The crystals were collected by filtration, ished with methanol and dried to provide 30.40 gm mandalate salt of 5-[(2R)-2-aminopropyl]- 2-ethoxybenzenesulfonamide e mandalte.
[Pd(2,2'-bipyridine)(mandelate dianion)]*4H2O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
General procedure: [Pd(bpy)Cl2] (0.20 g, 0.60 mmol) was suspended in water (25 mL). Silver nitrate (0.20 g, 1.19 mmol) in water (5 mL) was added and the reaction mixture was stirred for 6 h at 60 C and then at room temperature, always in absence of light. The resulting solution was centrifuged and filtered to remove AgCl. A few drops of water, glycolic acid (0.05 g, 0.66 mmol) and 1 M NaOH (1.20 mL) were added to the filtrate. The resulting solution was stirred for 5 days and concentrated at 60 C to 5 mL on a rotary evaporator. The mixture was cooled to room temperature and the yellow powder was filtered off and dissolved from water and again concentrated to 5 mL. Yellow single crystals suitable for X-ray diffraction were obtained from the resulting solution by slow evaporation at room temperature.
trans-2-(3,4-difluorophenyl)cyclopropanamine[ No CAS ]
[ 611-71-2 ]
[ 376608-71-8 ]
Yield
Reaction Conditions
Operation in experiment
7.56 g
In methanol; at 18 - 45℃; for 2.5h;
To a solution of 9 g R-mandelic acid in 300 ml of methanol at 45 C, was added a solution of 10 g of 2-(3.4-difluorophenyl)cyclopropanamine in 300 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25 C, stirred for 1 h, then further cooled slowly to 18 C and maintained for another 1 h. The crystalized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 7.56 g of product as a white crystalline solid. 1H NMR in (400MHz, DMSO d6) 5 1 .13 -1 .16 (2H, m), 1.25 - 1.28 (2H, m), 2.20-2.23 (1 H, m), 2.65 - 2.67 (1 H, m), 4.64(1 H, s), 6.94 -6.96 (1 H, m). 7.1 1 -7.36 (8H, m)
With [2-[(2,2,6,6-tetramethylpiperidin-1-yl)methyl]phenyl]boronic acid; In toluene; for 12h;Reflux; Molecular sieve;
General procedure: [EXPERIMENTAL EXAMPLES 13 to 48]With use of the various catalysts shown in Table 2 and Table 3, the amide condensation between various alpha-hydroxycarboxylic acid compounds and various amine compounds was performed to obtain the corresponding carboxylic acid amide compounds. The synthesis procedures were similar to those in Experimental Examples 1 to 12, except that the reaction in Experimental Example 15 was performed under weakly acidic conditions by adding benzoic acid (1.0 equivalent) and that the reaction in Experimental Example 47 was performed in xylene (boiling point 144C) under weakly acidic conditions by adding benzoic acid (0.10 equivalent). The results are described in Table 2 and Table 3. Experimental Examples 14, 15, 19, 22, 26, 32, 37, 40, 43, 46 and 47 correspond to Inventive Examples, and the other Experimental Examples are Comparative Examples.
General procedure: The mixture of 0.077 g (0.5 mmol) of (S)-mandelic acid (S)-1 and 0.080 g (0.5 mmol) of (S)-phenylalanine (S)-2 was dissolvedi n 20.0 mL of ethanol and concentrated to give 0.156 g of the (S)-1(S)-2 diastereomeric salt. The diastereomeric salts listed in Table 1 were prepared according to the representative procedure A from the corresponding pure enantiomers (S)-1 or (R)-1 and (S)-2, (S,S)-3 or (S)-4.
2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With pyridine; dmap; In tetrahydrofuran; at 50℃; for 48h;Inert atmosphere;
Preparation of (S)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid A solution of <strong>[32703-87-0]2,5-dioxopyrrolidin-1-yl 3-((tert-butoxycarbonyl)amino)propanoate</strong> (1.04 g, 3.62 mmol), mandelic acid (457 mg, 3.00 mmol), and 4-dimethylaminopyridine (29 mg, 0.24 mmol) in tetrahydrofuran (18 mL) was treated with pyridine (0.40 mL, 5.0 mmol) and heated at 50 C. under a nitrogen atmosphere for 48 h. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with aqueous 10% citric acid (2*25 mL) and water (25 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (2*25 mL). The combined aqueous bicarbonate layers were acidified to pH ?2 with 6 N hydrochloric acid and extracted with ethyl acetate (4*25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide (S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid (791 mg, 81%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 7.50-7.36 (m, 5H), 5.99 (s, 1H), 5.18 (br s, 1H), 3.48-3.45 (m, 2H), 2.69-2.62 (m, 2H), 1.43 (s, 9H), CO2H proton not observed.
8-(hydroxy(phenyl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; for 16h;Reflux;
A mixture of <strong>[6972-82-3]5,6-diamino-1-methylpyrimidine-2,4(1H,3H)-dione</strong> (4.0 g, 25.6 mmol) and 2-hydroxy-2-phenylacetic acid (7.8 g, 51.2 mmol) in H20 (100 mL) was heated to reflux and stirred for 16 h. Then NaOH (2.0 g, 51.2 mmol) was added and the mixture was stirred for 18 h at reflux. The reaction mixture was cooled to 0 °C and neutralized with AcOH to PH = 78. The precipitate was collected, dried in vacuo and purified by flash chromatography (10percent MeOHIDCM) to afford the title compound. ESI: m/z 273.1 (M+H)t
(2S)-hydroxy-2-phenylacetyl-4’-[2-[((2R)hydroxy-2-phenyl)ethylamino]ethyl]acetanilide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In water; at 20℃;
0.77 g (3 mmol) of (R)-2-(4-amino phenethyl)amino-1-phenylethanol (2) is suspended in 9 ml of water, then 1.5 ml of 2.02 M hydrochloric acid and 0.46 g (3 mmol) of (R)-mandelic acid (6) are added while mixing. After a short mixing 0.63 g of EDC hydrochloride is added and then themixture is stined at room temperature. The precipitated hydrochloride of the title material is filtered, washed with water, then after drying it is recrystallized from hydrous ethanol. ?H-NMR (DMSO-d6; 600 MHz): 10.02 (s, 1H); 8.99 (br, 2H); 7.66 (d, J=8.6 Hz, 2H); 7.51 (-d, 2H); 7.39 (m, 4H); 7.35 (?-t, 2H); 7.31 (m, 1H); 7.28 (?-t, 1H); 7.17 (d, J=8.6 Hz, 2H); 6.45 (d, J=4.9 Hz, 1H); 6.21 (br d, J=4.1 Hz, 1H); 5.11 (d, J=4.9 Hz, 1H); 4.97 (m, 1H); 3.15 (m, 1H);3.14 (m, 2H); 3.01 (dd, J1=12.5 Hz, J2=10.6 Hz, 1H); 2.94 (m, 2H).
With C12H22O3Zr*2C8F17O3S(1-); In acetonitrile; at 10℃; for 4h;
Add 1.0 mmol of mandelic acid (R2 = H) and a 25 mL round bottom flask<strong>[116-02-9]3,3,5-trimethylcyclohexanol</strong> (R1 = 3,3,5-trimethylcyclohexyl) 1.05 mmol,1 mol% of a catalyst whose main structure is IV (M = Zr, perfluoroalkyl group is perfluorooctyl group, X = H2O)Acetonitrile 2 mL was added and the reaction was carried out at 10 C for 4 h. After completion of the reaction, the target compound cyclodesolate (R1 = 3,3,5-trimethylcyclohexyl, R2 = H) was separated by column chromatography to give a white solid in 95% yield with a selectivity of 100% .
Intermediate product 2, i.e. (1R,2R)-trans-2(3,4-difluorophenyl)cyclopropyl carboxamide and 25percent by weight of NaOH solution were mixed and heated to 20C. At a temperature of 30° C., a 8percent by weight aqueous solution of NaOCl was prepared and once the addition was complete, the reaction mixture was immediately stirred at 30° C. for an additional 3 hours. The resulting mixture was then heated to 38° C. and stirred at this temperature for an additional 1.5 h. After cooling to 15° C., MTBE (methyl tert-butyl ether) was added, and the layers were separated and washed twice with water. R-mandelic acid ethanol solution was added, stirred for 1.5 hours, and dried to obtain Intermediate Product 5.
With sodium hydroxide; In chloroform; at 40 - 50℃; for 5.0h;
20g benzaldehyde,2g benzyl triethyl ammonium chloride,60g of chloroform was added to the reactor,Warming up to 40 C,Start adding 35% of liquid alkali 100g,Add 2h,Warming up to 50 C,Insulation for 3h,Add 285g of soft water and mix and dilute.After standing for 2 h, the lower layer of chloroform was separated, and the aqueous layer was extracted with 50 g of chloroform. The chloroform layer was separated, and the organic layer was combined to recover chloroform. The aqueous layer was acidified with 25 g of concentrated sulfuric acid. The ethyl ester was extracted three times with water three times, each time 60 g, and distilled under reduced pressure at 50 C to give a crude product. The crude product was added to 60 g of toluene solvent, warmed to 100 C, and kept warm for two hours, slowly dropped to normal temperature, a white solid was precipitated, suction filtered, washed with 90 g of petroleum ether, and dried and weighed. The yield was 18.8 g, the content was 98.6%, and the yield was 65.5%. Fully meet customer needs
General procedure: A 0.5-dram vial equipped with a magnetic stirring bar wascharged with stock solutions of 2-formylphenylboronicacid (0.10 M, 200 muL, 0.02 mmol), pinacol (0.10 M, 200 muL,0.02mmol) and 5c (0.25M, 80 muL, 0.02mmol). The solventswere removed in vacuo. CHCl3 (50 muL) was added undera positive pressure of argon. The reaction was stirred at 50°C for 30 min. The volatiles were then removed under highvacuum. [Pd(allyl)Cl]2 (0.13 M in CHCl3, 40 muL, 5.0 mumol)was added under a positive pressure of argon and thereaction stirred at 23°C for 15 min. Allyl acetate rac-7(0.01 M in CHCl3, 10 muL, 0.10 mmol), bis(trimethylsilyl)acetamide (49 muL, 0.20 mmol), diethyl malonate (30 muL,0.20 mmol) and potassium acetate (0.50 mg, 5.0 mumol)were added sequentially. The reaction was stirred at 23°Cfor 24 hours. The crude reaction mixture was then filteredthrough a short plug of Celite and rinsed three times withCH2Cl2. An aliquot of the reaction mixture (5.0 muL) wasused for conversion and ee analyses using HPLC. HPLCconditions: Chiralpak IA column, 2.0percent isopropanol/hexanes,0.5 mL/min, 254 nm, tr: 22.9 and 29.2min.
General procedure: A 0.5-dram vial equipped with a magnetic stirring bar wascharged with stock solutions of 2-formylphenylboronicacid (0.10 M, 200 muL, 0.02 mmol), pinacol (0.10 M, 200 muL,0.02mmol) and 5c (0.25M, 80 muL, 0.02mmol). The solventswere removed in vacuo. CHCl3 (50 muL) was added undera positive pressure of argon. The reaction was stirred at 50°C for 30 min. The volatiles were then removed under highvacuum. [Pd(allyl)Cl]2 (0.13 M in CHCl3, 40 muL, 5.0 mumol)was added under a positive pressure of argon and thereaction stirred at 23°C for 15 min. Allyl acetate rac-7(0.01 M in CHCl3, 10 muL, 0.10 mmol), bis(trimethylsilyl)acetamide (49 muL, 0.20 mmol), diethyl malonate (30 muL,0.20 mmol) and potassium acetate (0.50 mg, 5.0 mumol)were added sequentially. The reaction was stirred at 23°Cfor 24 hours. The crude reaction mixture was then filteredthrough a short plug of Celite and rinsed three times withCH2Cl2. An aliquot of the reaction mixture (5.0 muL) wasused for conversion and ee analyses using HPLC. HPLCconditions: Chiralpak IA column, 2.0percent isopropanol/hexanes,0.5 mL/min, 254 nm, tr: 22.9 and 29.2min.
General procedure: A 0.5-dram vial equipped with a magnetic stirring bar wascharged with stock solutions of 2-formylphenylboronicacid (0.10 M, 200 muL, 0.02 mmol), pinacol (0.10 M, 200 muL,0.02mmol) and 5c (0.25M, 80 muL, 0.02mmol). The solventswere removed in vacuo. CHCl3 (50 muL) was added undera positive pressure of argon. The reaction was stirred at 50C for 30 min. The volatiles were then removed under highvacuum. [Pd(allyl)Cl]2 (0.13 M in CHCl3, 40 muL, 5.0 mumol)was added under a positive pressure of argon and thereaction stirred at 23C for 15 min. Allyl acetate rac-7(0.01 M in CHCl3, 10 muL, 0.10 mmol), bis(trimethylsilyl)acetamide (49 muL, 0.20 mmol), diethyl malonate (30 muL,0.20 mmol) and potassium acetate (0.50 mg, 5.0 mumol)were added sequentially. The reaction was stirred at 23Cfor 24 hours. The crude reaction mixture was then filteredthrough a short plug of Celite and rinsed three times withCH2Cl2. An aliquot of the reaction mixture (5.0 muL) wasused for conversion and ee analyses using HPLC. HPLCconditions: Chiralpak IA column, 2.0% isopropanol/hexanes,0.5 mL/min, 254 nm, tr: 22.9 and 29.2min.
The synthesis method of the novel uric acid compound Arhalofenate intermediate, the specific steps of the synthesis are as follows: step 1: Place 2.8 g of <strong>[7138-34-3]p-chloromandelic acid</strong> in a 100 mL single-mouth bottle, add 30 mL of a 95% ethanol solution, stir until all dissolved, then add 1.9 mL of (R)-phenylethylamine dropwise while stirring, and mix. After heating and refluxing for 15 min, the solid was dissolved, then slowly cooled to room temperature, and filtered to obtain a crude product of 2.413 g; Step 2: The crude product obtained in the step 1 was recrystallized twice from 95% ethanol to obtain (R)-phenethylamine·(R)-<strong>[7138-34-3]p-chloromandelic acid</strong> 1.25 g; Step 3: The (R)-phenethylamine·(R)-<strong>[7138-34-3]p-chloromandelic acid</strong> obtained in the step 1 is dissolved in 16 mL of water, and the pH of the solution is adjusted to 1 by adding hydrochloric acid, and then extracted three times with ethyl acetate, and the organic phase is combined with anhydrous sulfuric acid. The sodium was dried, and the solvent was evaporated under reduced pressure to give a white solid (R)-p-chloro-mandelic acid (0.67 g).
4,6-di-tert-butyl-3-phenylbenzofuran-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With nickel(II) triflate; at 160℃; for 12h;Green chemistry;
Adding a mandelic acid derivative (R1=H) 1.0 mmol and 3,5-di-tert-butylphenol (R2=3,5-di-tert-butyl) 0.05 mmol into a 25 mL reaction tube, and adding 10 mol of a nickel triflate catalyst %, 160 C solvent-free vacuum reaction for 12 h. After completion of the reaction, the target compound benzofuranone compound (R1=H, R2=3,5-di-tert-butyl) is obtained by column chromatography.A white solid was obtained in a 97% yield.
β,ε-carotene-3,3'-diyl di(2-hydroxy-2-phenylethanoate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With Novozyme 435; In methanol; toluene; at 37℃; for 6h;Darkness; Enzymatic reaction;
General procedure: 50 mL of toluene and 5 mL of methanol were added to a mixture of 2 mmol of <strong>[127-40-2]lutein</strong> or astaxanthin and 4 mmol of the acid (benzoic, 4-methylbenzoic, nicotinic, or mandelic. 0.1 g of catalyst (Novozyme 435) was added to the mixture. The mixture was stirred during 6 h at 37, protecting from light. The obtained mixture was passed through a column filled with 2.5 g of alumina, collecting the second colored fraction. The obtained fraction was washed with 95% ethanol and water and dried in vacuum (20-25 mmHg) during 2 h at 40.
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