* 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.
Reference:
[1] Synlett, 2006, # 2, p. 194 - 200
[2] Synthesis, 2009, # 16, p. 2797 - 2801
[3] Synthesis (Germany), 2013, vol. 45, # 12, p. 1675 - 1682
[4] Canadian Journal of Chemistry, 1992, vol. 70, # 1, p. 89 - 99
[5] Canadian Journal of Chemistry, 1992, vol. 70, # 1, p. 89 - 99
[6] Chemische Berichte, 1886, vol. 19, p. 2268
[7] Journal of the Chemical Society, 1922, vol. 121, p. 2175
[8] Chemische Berichte, 1901, vol. 34, p. 4213
[9] Tetrahedron Letters, 1990, vol. 31, # 6, p. 873 - 874
[10] Canadian Journal of Chemistry, 1992, vol. 70, # 1, p. 89 - 99
[11] Journal of Physical Organic Chemistry, 2016, vol. 29, # 8, p. 382 - 393
[12] Russian Journal of Organic Chemistry, 2018, vol. 54, # 1, p. 131 - 138[13] Zh. Org. Khim., 2018, vol. 54, # 1, p. 131 - 138,8
3
[ 123-56-8 ]
[ 507-40-4 ]
[ 128-09-6 ]
Reference:
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 3856
4
[ 123-56-8 ]
[ 7782-50-5 ]
[ 128-09-6 ]
Reference:
[1] Journal of the Chemical Society, 1922, vol. 121, p. 2175
5
[ 123-56-8 ]
[ 516-12-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
With [bis(acetoxy)iodo]benzene; iodine In benzene at 20℃; for 15 h; Darkness
[00172] A mixture of succinimide (1.0 g, 10.1 mmol), PhI(OAc)2 (1.95 g, 6.06 mmol), I2 (1.67 g, 6.57 mmol) and benzene (20 mL) was stirred for 15 h at rt and for 1 h at 0 to 5 °C. The precipitated solid was filtered, washed on the filter with cold benzene and dried in vacuo to give 2.2 g (99percent) of N-iodosuccinimide.
Reference:
[1] Patent: WO2015/68159, 2015, A2, . Location in patent: Paragraph 00171-00172
[2] Journal of Organometallic Chemistry, 1983, vol. 255, # 3, p. 295 - 298
6
[ 123-56-8 ]
[ 7553-56-2 ]
[ 67-64-1 ]
[ 516-12-1 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1870, vol. Suppl.7, p. 119
7
[ 4553-62-2 ]
[ 110-15-6 ]
[ 123-56-8 ]
[ 29553-51-3 ]
Yield
Reaction Conditions
Operation in experiment
96 %Chromat.
With phosphoric acid In water at 270℃; for 2 h;
Example 5 Preparation of a Mixture of Imides From Pure MGN and From Bio-Sourced Succinic Acid [0169] In a 100 mL reactor, are introduced 23 g of 2-methyl-glutaronitrile and then 25 g of succinic acid obtained by fermentation are added. Stirring is applied and 0.1 g of 85percent ortho-phosphoric acid are added. The reaction medium is heated up to 270° C. and these conditions are maintained for 2 hours. By GC analysis, the following results are obtained: [0170] TT percent (MGN)=98percent [0171] RR percent (MGI)=96percent [0172] RR percent (succinimide)=97percent
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 707 - 710
[2] Journal of Chemical Research, 2009, # 3, p. 198 - 200
[3] Letters in Organic Chemistry, 2010, vol. 7, # 2, p. 144 - 148
[4] Archives of Pharmacal Research, 2011, vol. 34, # 4, p. 519 - 526
9
[ 123-56-8 ]
[ 109-64-8 ]
[ 88661-56-7 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 5, p. 1371 - 1375
[2] Journal of Organic Chemistry, 2004, vol. 69, # 18, p. 6105 - 6114
[3] Tetrahedron Letters, 2007, vol. 48, # 9, p. 1571 - 1575
[4] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2577 - 2580
[5] European Journal of Organic Chemistry, 2016, vol. 2016, # 17, p. 2944 - 2953
10
[ 123-56-8 ]
[ 81055-36-9 ]
[ 88661-56-7 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1992, # 3, p. 227 - 231
11
[ 56-86-0 ]
[ 541-59-3 ]
[ 123-56-8 ]
[ 109-97-7 ]
[ 57-57-8 ]
[ 108-99-6 ]
[ 64-17-5 ]
[ 64-19-7 ]
[ 107-13-1 ]
[ 3680-71-5 ]
[ 75-05-8 ]
[ 107-12-0 ]
Reference:
[1] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 32, p. 7696 - 7704
12
[ 56-86-0 ]
[ 636-41-9 ]
[ 616-45-5 ]
[ 142-08-5 ]
[ 541-59-3 ]
[ 123-56-8 ]
[ 109-97-7 ]
[ 3680-71-5 ]
[ 75-05-8 ]
Reference:
[1] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 32, p. 7696 - 7704
13
[ 123-56-8 ]
[ 1441063-52-0 ]
[ 3181-38-2 ]
Reference:
[1] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 5832 - 5842
14
[ 128-08-5 ]
[ 99-04-7 ]
[ 123-56-8 ]
[ 6515-58-8 ]
Yield
Reaction Conditions
Operation in experiment
61%
for 2.75 h; Irradiation; Heating / reflux
Synthesis of 3-bromomethylbenzoic acid: In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75percent power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75percent power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to-20 °C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to-20 °C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3 x 300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61percent) of 3- bromomethylbenzoic acid as a white crystalline power.
Reference:
[1] Journal of Organic Chemistry, 1983, vol. 48, # 16, p. 2743 - 2747
16
[ 123-56-8 ]
[ 3303-84-2 ]
[ 32703-87-0 ]
Reference:
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 39, # 9, p. 773 - 785
17
[ 123-56-8 ]
[ 814-68-6 ]
[ 38862-24-7 ]
Reference:
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 6, p. 1341 - 1350
18
[ 123-56-8 ]
[ 143-07-7 ]
[ 14565-47-0 ]
Reference:
[1] Journal of Controlled Release, 2010, vol. 144, # 1, p. 55 - 64
19
[ 123-56-8 ]
[ 544-63-8 ]
[ 69888-86-4 ]
Reference:
[1] Journal of Controlled Release, 2010, vol. 144, # 1, p. 55 - 64
20
[ 123-56-8 ]
[ 67-63-0 ]
[ 924-88-9 ]
Reference:
[1] Journal of the Chinese Chemical Society, 2004, vol. 51, # 2, p. 359 - 362
[2] Journal of the Chinese Chemical Society, 2014, vol. 51, # 2, p. 359 - 362
21
[ 123-56-8 ]
[ 57295-33-7 ]
[ 57295-32-6 ]
[ 24973-22-6 ]
[ 90163-04-5 ]
Reference:
[1] Liebigs Annalen der Chemie, 1985, vol. 1985, # 7, p. 1413 - 1421
[2] Liebigs Annalen der Chemie, 1985, vol. 1985, # 7, p. 1413 - 1421
[3] Liebigs Annalen der Chemie, 1985, vol. 1985, # 7, p. 1413 - 1421
22
[ 123-56-8 ]
[ 87808-48-8 ]
[ 128577-47-9 ]
Reference:
[1] Patent: US5639906, 1997, A,
23
[ 123-56-8 ]
[ 133081-25-1 ]
[ 133081-26-2 ]
Yield
Reaction Conditions
Operation in experiment
84%
With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 25℃; for 17 h; Inert atmosphere
To a solution of 6-Boc-hydrazinopyridine-3-carboxylicacid 4b (0.57 g, 2.26 mmol) and N-hydrosuccinimide (0.27g, 2.26 mmol) in DMF DCC (0.47 g, 2.26 mmol) was added.The reaction mixture became cloudy after 1h. After 16h, thereaction mixture was concentrated to dryness and the residuewas purified by chromatography on silica gel with ethyl acetateas eluant to give a white solid (0.66 g, 84percent). Mp =174°C. IR (ATR, cm-1) 3321; 2979; 1729; 1594; 1365; 1240;1198; 1068; 974; 641. 1H NMR (DMSO) 9.46 (s, 1H), 9.20(s, 1H), 8.76 (d, 1H, J= 2.1 Hz), 8.11 (d, 1H, J= 8.1 Hz),6.67 (d, 1H, J= 9 Hz), 2.88 (s, 4H), 1.44 (s, 9H). 13C NMR(DMSO) 172.8; 170.5; 160.9; 155.4; 151.8; 110.0; 79.6;28.0; 25.5. MS (ESI+) [M+H]: 351.00. HRMS (ESI+)[M+H]+: 351.1299 observed, 351.1305 calculated forC15H19N4O6.
Reference:
[1] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
N-(Morpholinomethyl)<strong>[123-56-8]Succinimide</strong> (SMF) was synthesized by Mannich condensation reaction [21-23] among succinimide, morpholine and formaldehyde in 1:1:1M ratio. <strong>[123-56-8]Succinimide</strong> (5.00g, 0.05M) and morpholine (4.5ml, 0.05M) mixed with the less amount of ethanol was stirred until the content becomes homogenous. To this mixture 40% formaldehyde solution (3.8ml, 0.05M) was poured slowly in drops, as the stirring action continued. Once the adding process was over, stirring continued for 2hat 60C and then it was made to cool in refrigerator. The solid mass obtained was rinsed using distilled water, desiccated and the final residue was recrystallized from acetonitrile to yield a colourless crystalline powder (Yield: 88%).
In ethanol; at 20℃; for 12h;
General procedure: The mixture of 3-benzhydryl- (5), 3-isopropyl- (6), 3-metyl- (7) and <strong>[123-56-8]pyrrolidine-2,5-dione</strong> (8) (0.01 mol), 40% formaldehyde solution (0.01 mol) and corresponding 4-substituted piperazines, piperidine or morpholine (0.01 mol) in 96% ethanol (40 mL) was left for ca. 12 h at room temperature (or was refluxed for 0.5 h additionally), and then refrigerated at ca. -10oC for 24 h. The precipitated crude products were washed with cold ethanol, separated by filtration and recrystallized from 96% ethanol. Due to oily form of 11, 13, 16, 18, 20, 23, 25, 27 and 32 they were converted into hydrochloride salts in anhydrous ethanol saturated with HCl gas.
Procedure E: a) Succinimide (500 g; 5.0 mol), ethylene carbonate (444.34 g; 5.0 mol) and sodium carbonate (26.74 g; 0.25 mol) were mixed and slowly heated to 130C under stirring for 7 hours. The product was distilled via vacuum distillation to yield the product as colourless substance (628.14 g; 87% of theory)
SUCCINIMIDE is provided to a reactor at 23% by weight in water. Methanol is provided to the reactor at a 1.5 : 1 methanol to succinimide ratio in an absence of added ammonia. The ammonia integrated within the succinimide provides a 1: 1 ammonia to succinate species ratio. The reactor is pressurized with nitrogen and sealed. The reactor is heated to 300C AND is maintained at temperature for 5 hours. Samples are collected at least every hour during the reaction. Product analysis is conducted to determine conversion and product selectivity. Analysis of the 4 hour sample indicates a succinimide conversion of greater than or equal to 96%. The yield of N-methyl succinimide (NMS) is greater than or equal to 80%.
With potassium carbonate; In neat (no solvent); at 60 - 65℃; for 0.0666667h;Microwave irradiation; Green chemistry;
General procedure: A mixture of phthalimide (4.8 mmol, 0.70 g), alkyl halide(6.0 mmol), 4a or 4b (0.3 mmol, 3 mol%) and potassiumcarbonate (18.8 mmol, 2.6 g) was heated in a commercialmicrowave oven in an open Erlenmeyer flask at 60 8C-65 8Cfor the required time (as shown in Table 3) according to a50:10-s heating: cooling cycle, each at an 80% power level.The completion of the reaction was monitored using TLC.After cooling to r.t., the reaction mixture was extracted withmethylene chloride (2 25 mL). Then the extracts weredried over anhydrous Na2SO4, filtered, and the solvent wasevaporated to dryness to give the crude product. Solids werepurified through recrystallization in absolute EtOH, and liquids were purified over a silica gel column using hexane:EtOAc (96:4) as the eluent. The successful formation of theproducts was confirmed by 1H NMR, 13C NMR and FT-IRspectra.
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
With formamide; In neat (no solvent); for 0.416667h;Milling; Heating; Green chemistry;
General procedure: A mixture of anhydride (1 mmol), formamide (1.1 mmol for monoanhydrides and 2.2 mmol for dianhydrides) and 1 g clay was ground together in a mortar using pestle for the time described in Table 1. The reaction mixture was warmed. After completing the reaction (monitored by TLC, after observing no anhydride presence in the reaction mixture), the product was extracted by washing clay with chloroform (2×15 mL), the solvent was removed under vacuum to afford the relevant N-unsubstituted cyclic imide. The solid imide was washed thoroughly with water, dried, and then recrystallized from ethanol. The solid clay portion was washed with methanol and dried at 120 C under a reduced pressure to be reused in the subsequent reactions which showed the gradual decrease in the activity (Table 1). Isolated products were characterized by melting points, IR, 1H NMR spectrometric data and were compared with the literature or authentic samples.
90%
With ammonium hydroxide; toluene-4-sulfonic acid; at 50 - 200℃; for 13h;
Add succinic anhydride (100g, 1.0mol) to the 1L reaction flask,Slowly add NH3-H2O (110mL, 1.0mol) at room temperature,Control the reaction temperature within 50 C.Add a catalytic amount of p-toluenesulfonic acid (5g, 5%),Then the temperature was raised to 120 C for 1 hour,Continue to warm to 200 C for 12 hours.Cool to 60 C, add H2O (200mL),Discoloration of activated carbon (5g).Cool, filter, and recrystallize ethanol to obtain the product as a white solid (89 g, yield: 90%).
With ammonium carbonate; at 300℃; for 2h;
In a reaction flask, succinic acid (12.0 g, 120.0 mmol) was fused with ammonium carbonate (12.48 g, 130 mmol) with continuous stirring at 300 C. For 2 h till completion, then reaction was cooled to room temperature, product was washed with distilled water and purified product was driedin desiccator.m.p. 121-124 C
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;
al .3) l-Succinimidyl-2-quinolin-2-yl-ethane The compound from Example al .2 (2.5 g, 15 mmol), pyrrolidine-2,5-dione (2 g, 20 mmol) and PPh3 (5.25 g, 20 mmol) were dissolved in THF (50 ml). The solution was added DEAD (6.1 g, 35 mmol). The mixture was stirred at r.t. overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (PE/EA=2/1) to get the title compound as yellow oil (2.5 g, 66%). LC-MS (ESI+): m/e 255 (M+H)+, Rt: 1.15 min.
2.97 g (30.0 mmol) of succinic imide, 29.7 g of toluene and 0.37 g (3.0 mmol) of N,N-dimethylaminopyridine were added, and the temperature of the mixture was adjusted to 25C. Into this solution, a solution composed of 8.79 g (40.3 mmol) of di-tert-butyl dicarbonate and 4.83 g of toluene was dropped over a period of 30 minutes, and the mixture was thermally insulated at 25C for 24 hours. To this solution was added 10.9 g of 1% hydrochloric acid and mixed, then, liquid-partitioning was caused. Next, the resultant organic layer was washed with 5.0 g of a 5% sodium hydrogen carbonate aqueous solution, and further washed with 5.0 g of water. The resultant organic layer was concentrated under reduced pressure, to obtain 5.21 g of an oily substance containing 4.22 g (21.2 mmol) of N-tert-butoxycarbonyl-succinic imide. The yield of N-tert-butoxycarbonyl-succinic imide with respect to succinic imide was 70.7%. The determinate quantity of N-tert-butoxycarbonyl-succinic imide was obtained by gas chromatography. As the column, DB-1 [0.25 mmphi x 30 m, 0.25 mum] manufactured by J&J was used.
With tetrabutylammomium bromide; potassium carbonate; In acetonitrile; at 85℃; for 12.0h;Inert atmosphere;
Under nitrogen protection,Add 1-L reaction flask to N-succinimide (100g, 1.0mol),1,2-Dibromoethane (190g, 1.0mol),Bu4NBr (1.0g),K2CO3 (140g, 1.0mol)And acetonitrile (600 mL).The reaction mixture was heated to 85 C. and refluxed to complete reaction for 12 h.Water (300 mL) was added to the reaction mixture to quench the reaction, and then extracted three times with toluene (500 mL x 3).The organic phases were combined, washed once with saturated brine (200 mL), and the solvent was removed under reduced pressure.The residue was quickly purified using silica gel column chromatography to obtain the intermediate compound of formula IV (X = Br, 182 g, yield 88%) as a colorless oil.The product is directly converted into the next step.
70.4%
With potassium carbonate; In acetonitrile; at 20℃;Heating / reflux;
1- (2-BROMO-ETHYL)-PYRROLIDINE-2, 5-DIONE To a mixture of dihydro-furan-2, 5-dione (396 mg, 4.00 mmol) and 1,2-dibromo-ethane (1.50 g, 8.00 mmol) in CH3CN (20 ml) was added K2CO3 (829 mg, 6.00 mmol) at room temperature. The mixture was stirred at reflux overnight and the solvent was evaporated. The mixture was diluted with EtOAc (150 mL), washed with water, sat. NA2CO3AQ., brine, and dried over MGS04. The solvent was evaporated to give 1- (2-BROMO-ETHYL)-PYRROLIDINE- 2,5-dione that was used for next step without further purification (580 mg, 70.4%).
With [bis(acetoxy)iodo]benzene; iodine; In benzene; at 20℃; for 15h;Darkness;
[00172] A mixture of succinimide (1.0 g, 10.1 mmol), PhI(OAc)2 (1.95 g, 6.06 mmol), I2 (1.67 g, 6.57 mmol) and benzene (20 mL) was stirred for 15 h at rt and for 1 h at 0 to 5 °C. The precipitated solid was filtered, washed on the filter with cold benzene and dried in vacuo to give 2.2 g (99percent) of N-iodosuccinimide.
With ammonium peroxydisulfate; silver nitrate; In water; at 20℃; for 2h;
0.13 g of pyroglutamic acid, 1mmol was placed in the reaction tube ,AgNO3 (1.7 mg, 0.01 mmol) was weighed, (NH4)2S2O8 (0.50 g, 2.2 mmol) was added, 3 mL of water was added and stirred at room temperature for 2h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give succinimide. The prepared succinimide was added to deuterated chloroform,Filter, test succinimideThe NMR spectrum is shown in Fig.1
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In 1,4-dioxane; at 100℃; for 10h;Inert atmosphere;
Under nitrogen protection,Add 1-L reaction flask to N-succinimide (100g, 1.0mol),1-bromo-2-dichloroethane(145g, 1.0mol),Bu4N + Br- (1.0g, 1%),K2CO3 (140 g, 1.0 mol) and dioxane (400 mL).The reaction mixture was heated to 100 C for 10 hours.Water (300 mL) was added to the reaction mixture to quench the reaction,It was then extracted three times with ethyl acetate (300 mL x 3).The organic phases were combined, washed once with saturated brine (200 mL), and the solvent was removed under reduced pressure.The residue was quickly purified using silica gel column chromatography to obtain the intermediate compound of formula IV (X = Cl, 128 g, yield 80%) as a colorless oil.The product is directly converted into the next step.
NaH (11.08 g, 60%, 87.24 mmol, 4 eq.) was washed three times with THF then suspended in THF (13 mL). At 0 C, a solution of succinimide (10.8 g, 109.0 mmol, 5 eq.) dissolved in DMF (27 mL) was added dropwise to the suspension. The reaction mixture was heated up to 30 C until all H2 was released. A solution of the 5-(2-Bromoethyl)benzo[d][1,3]dioxole 7 (5 g, 21.81 mmol) was dissolved in THF (4 mL) and added to the sodium succinimidate suspension. The mixture was heated to 50 C and stirred for 20 h. To the reaction were added water (35 mL) and AcOEt (25 mL), layers were separated and the aqueous layer was extracted three times with AcOEt, dried over MgSO4 and filtrated. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography(cyclohexane/ethyl acetate, 1:1) to give the imide 8 as a white solid. Yield: 4.21 g (78%). IR (film, nu cm-1): 2343, 1777, 1701, 1503, 1485. 1H NMR (300 MHz, CDCl3) delta (ppm): 2.65 (s, 4H), 2.80 (t, J = 7.6 Hz,2H), 3.63 (t, J = 7.6 Hz, 2H), 5.90 (s, 2H), 6.61e6.72 (m, 3H). 13C NMR (75 MHz, CDCl3) delta ppm: 28.1 (2 CH2), 33.3 (CH2), 40.1 (CH2), 101.0(CH2), 108.3 (CH), 109.2(CH), 121.8 (CH), 131.6 (C), 146.4 (C), 147.8 (C), 176.9 (2 CO). HRMS (ESI) m/z calcd. for C13H13NO4Na = 270.0742, (M + Na) found 270.0743.
With pyridine; In dichloromethane; at 0 - 20℃; for 51h;Inert atmosphere;
General procedure: Under argon, a mixture of pyrrolidine-2,5-dione (2.97g, 30mmol) and pyridine (2.54mL, 31.5mmol) in anhydrous dichloromethane (50mL) was added dropwise to crotonoyl chloride (2.55mL, 31.5mmol) in dichloromethane (100mL) at 0C for more than half an hour, after which the mixture was stirred for 3h at 0C. Next, the reaction mixture was allowed to warm to room temperature for 48h. The reaction mixture was then poured into saturated sodium hydrogen carbonate and extracted with dichloromethane. The combined organic layers were washed with 30mL of hydrochloric acid solution (1M), brine, dried over magnesium sulfate, and concentrated in vacuo. The crude residue was passed through a flash silica gel column by eluting with dichloromethane to provide analytically pure 2f (3.3g, 66%).
General procedure: A mixture of 50 mg of imide and the required amount of K2CO3 were placed in a 10 mL stainlesssteel grinding jar and milled for 1 hour at 30 Hz. Upon completion, the required amount of alkylhalide was added and milling was continued for 1 hour in the presence of 100 muL of dry DMF(LAG experiment, eta = 2 muL mg-1). The obtained mixture was suspended in dichloromethane andwashed with water. The organic layers were collected and the solvent was evaporated. Where itwas necessary, the products were separated by using column chromatography
57%
With potassium carbonate; In N,N-dimethyl-formamide; at 55℃;
Intermediate 53; 1-(Phenylmethyl)-2,5-pyrrolidinedione; To 2,5-pyrrolidinedione (2.5 g, 25.2 mmol) in DMF (50 ml.) was added K2CO3 (4.18 g, 30.3 mmol) followed by benzyl bromide (3.00 ml_, 25.2 mmol), and the reaction mixture was stirred overnight at 55 0C. Water was added to the reaction mixture (-200 ml.) and a precipitate was immediately observed. The precipitate was filtered, and the white solid was washed with water and dried to afford the title compound (2.7 g, 57%). 1H NMR (400 MHz, CDCI3): delta 2.73 (s, 4H), 4.68 (s, 2H), 7.28 - 7.37 (m, 3H), 7.39 - 7.44 (m, 2H).
57%
With potassium carbonate; In N,N-dimethyl-formamide; at 55℃;
To 2,5-pyrrolidinedione (2.5 g, 25.2 mmol) in DMF (50 ml.) was added K2CO3 (4.18 g, 30.3 mmol) followed by benzyl bromide (3.00 ml_, 25.2 mmol), and the reaction mixture was stirred overnight at 55 0C. Water was added to the reaction mixture (-200 ml.) and a precipitate was immediately observed. The precipitate was filtered, and the white solid was washed with water and dried to afford the title compound (2.7 g, 57%). 1H NMR (400 MHz, CDCI3): delta 2.73 (s, 4H), 4.68 (s, 2H), 7.28 - 7.37 (m, 3H), 7.39 - 7.44 (m, 2H).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;
In 200 mL of carbon tetrachloride, 18.4 g of toluene, 42.6 g of bromosuccinimide and 0.65 g of azobisisobutyronitrile were added and the reaction was heated at reflux for 5 h.Carbon tetrachloride was removed by distillation under reduced pressure, 100 mL of dimethylformamide and 45 g of potassium carbonate were added, and the mixture was heated to 80 C for 3 h.Then, 50 mL of concentrated hydrochloric acid was added and the mixture was heated to 100 C for 3 h.Cool to room temperature, filter out part of the succinic acid, extracted with 50mL of ethyl acetate to further remove the succinic acid.The pH of the reaction system was adjusted to 7 with sodium hydroxide and extracted twice with 100 mL of ethyl acetate. The ethyl acetate phase was combined and the ethyl acetate was distilled off under reduced pressure to obtain 13.8 g of benzylamine in a yield of 64.4%.
With potassium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 60℃;
To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg, 3.7 mmol) and pyrrolidine-2,5-dione (succinimide, 733.3 mg, 7.4 mmol) in dimethylformamide (15 ml) was added potassium carbonate (2.0 g, 14.8 mmol) and sodium iodide (277 mg, 1.9 mmol). The reaction mixture was warmed to 60 C and kept at 60 C overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate aqueous solution, twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (100% ethylacetate) to afford 1-[2-(4-fluoro-phenyl) -ethyl]-pyrrolidine-2,5-dione 309 (570 mg, 2.6 mmol, 70%) as a solid. 1H NMR (CDCl3) delta 7.14 (m, 2H), 6.94 (t, 2H), 3.68 (t, 2H), 2.84 (t, 2H), 2.63 (s, 4H).
70%
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg, 3.7 mmol) and pyrrolidine-2,5-dione (succinimide, 733.3 mg, 7.4 mmol) in dimethylformamide (15 ml) was added potassium carbonate (2.0 g, 14.8 mmol) and sodium iodide (277 mg, 1.9 mmol). The reaction mixture was warmed to 60 C and kept at 60 C overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate aqueous solution, twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (100% ethylacetate) to afford 1-[2-(4-fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (570 mg, 2.6 mmol, 70%) as a solid. ¹H NMR (CDCl3) No. 7.14 (m, 2H), 6.94 (t, 2H), 3.68 (t, 2H), 2.84 (t, 2H), 2.63 (s, 4H).
In chloroform; for 2.75h;Irradiation; Heating / reflux;
Synthesis of 3-bromomethylbenzoic acid: In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75% power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75% power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to-20 C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to-20 C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3 x 300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61%) of 3- bromomethylbenzoic acid as a white crystalline power.
EXAMPLE 23 STR99 EXAMPLE 23A STR100 To a -78 C. solution under nitrogen of 1-triisopropylsilylpyrrole (2.8 g, 12.6 mmol) in THF (30 ml) was added NBS (2.23 g, 12.6 mmol) via a solid addition funnel. The reaction mixture was stirred at -78 C. for 1 hour and then was warmed to ambient temperature over 1 hour. The reaction mixture was concentrated, carbon tetrachloride was added to precipitate the succinimide and the solid was filtered and washed with carbon tetrachloride. The filtrate was concentrated, and the crude product was purified by flash chromatography (hexanes) to afford 3-bromo-1-triisopropylsilylpyrrole (3.18 g) as a colorless oil.
45
t BuOCl[ No CAS ]
(methylthio) indolone[ No CAS ]
[ 4455-13-4 ]
[ 328-74-5 ]
[ 123-56-8 ]
Yield
Reaction Conditions
Operation in experiment
With N-chloro-succinimide; triethylamine; In tetrachloromethane; dichloromethane;
4.6-bis-(Trifluoromethyl)-1H-indol-2,3-dione Freshly prepared t BuOCl (2.2 g, 20 mmol) was added dropwise to a stirred cold (-65 C.) solution of 3,5-bis-(trifluoromethyl)aniline (4.58 g, 20 mmol) in anhydrous CH2 Cl2 (25 mL). After 10 minutes, neat ethyl (methylthio)acetate (2.68 g, 20 mmol) was added and the mixture; stirred at -65 C. for 1 hr. Triethylamine (2.68 g, 20 mmol) was added and then the mixture was allowed to warm to room temperature. The reaction mixture was quenched with water, the organic layer was separated and then rotary evaporated. The oily residue (6.35 g) was dissolved in hexanes and boiled for several hours and then allowed to cool. The precipitated beige solid was filtered and washed with hexanes to afford 3.67 g of pure (methylthio) indolone intermediate. N-chlorosuccinimide (1.31 g, 9.8 mmol) was added to a stirred solution of (methylthio) indolone (2.95 g, 9.4 mmol) in CCl4 (150 mL). The mixture was stirred at room temperature for 6.5 hours. The suspension was filtered, washed with CCl4 and the filtrate was rotary evaporated at 25-30 C. The residual light-brown oil was dissolved in a minimum volume (~5-10 mL) of CCl4 and kept in an ice bath. The precipitated last traces of succinimide were filtered and washed with hexanes.
With N-chloro-succinimide; triethylamine; In tetrachloromethane; dichloromethane;
4,6-bis-(Trifluoromethyl)-1H-indol-2,3-dione Freshly prepared t BuOCl (2.2 g, 20 mmol) was added dropwise to a stirred cold (-65 C.) solution of 3,5-bis-(trifluoromethyl)aniline (4.58 g, 20 mmol) in anhydrous CH2 Cl2 (25 mL). After 10 minutes, neat ethyl (methylthio)acetate (2.68 g, 20 mmol) was added and the mixture stirred at -65 C. for 1 hr. Triethylamine (2.68 g, 20 mmol) was added and then the mixture was allowed to warm to room temperature. The reaction mixture was quenched with water, the organic layer was separated and then rotary evaporated. The oily residue (6.35 g) was dissolved in hexanes and boiled for several hours and then allowed to cool. The precipitated beige solid was filtered and washed with hexanes to afford 3.67 g of pure (methylthio) indolone intermediate. N-chlorosuccinimide (1.31 g, 9.8 mmol) was added to a stirred solution of (methylthio) indolone (2.95 g, 9.4 mmol) in CCl4 (150 mL). The mixture was stirred at room temperature for 6.5 hours. The suspension was filtered, washed with CCl4 and the filtrate was rotary evaporated at 25-30 C. The residual light-brown oil was dissolved in a minimum volume (~5-10 mL) of CCl4 and kept in an ice bath. The precipitated last traces of succinimide were filtered and washed with hexanes.
With phosphoric acid; nitrogen;silica gel; In diphenylether; acetone;
Example 4 To a reaction vessel equipped with a Dean-Stark trap, 30 g of aspartic acid, 150 g of diphenyl ether and 15 g of 85% phosphoric acid were charged. The mixture was stirred at 145 C. for 0.5 hour under atmospheric pressure to carry out azeotropic dehydration. The reaction became heterogeneous, bulk material was stirred and the reaction was progressed. Thereafter the Dean-Stark trap was removed from the reaction vessel, and Dean-Stark trap was removed from the reaction vessel, and a column packed with 20 g of molecular sieves 3A was mounted on the vessel so as to return the distilled solvent to the vessel after passing through the column. Further, 100 g of NMP was added to the reaction mixture, and the reaction was continued at 180 C. for 16 hours under atmospheric pressure while bubbling nitrogen gas. The water content of the solvent was 3 ppm after passing through the molecular sieves. After finishing the reaction, acetone was added to the reaction mixture. Precipitate formed was filtered, washed with acetone, successively washed with water and dried at 60 C. for 4 hours under reduced pressure of 5 mmHg and at 110 C. for 4 hours reduced pressure of 5 mmHg. Polysuccinimide thus obtained was 19.9 g (yield 90.9%). The polymer had eta of 0.24 dl/g and Mw of 60,000.
Example 2 To a reaction vessel equipped with a Dean Stark trap, 30 g of aspartic acid, 150 g of diphenyl ether and 0.6 g of magnesium oxide catalyst were charged. The resulting suspension was stirred at 190 C. for 6 hours under reduced pressure of 135 mmHg to carry out azeotropic dehydration. Thereafter the Dean-Stark trap was removed from the reaction vessel and a column packed with molecular sieves 3A was mounted on the vessel so as to return the distilled solvent to the vessel after passing through the column. The reaction was further continued at 190 C. for 15 hours under reduced pressure of 135 mmHg. The water content of the solvent was 5 ppm after passing through the molecular sieves. After finishing the reaction, the suspension was filtered, washed with acetone and dried at 110 C. for 6 hours under reduced pressure of 5 mmHg. Polysuccinimide thus obtained was 19.7 g (yield 90.0 %). The polymer had eta of 0.15 dl/g and Mw of 30,000.
90.0%
In diphenylether;
Comparative Example 1 The reaction was carried out at 210 C. for 20 hours under atmospheric pressure by using 30 g of aspartic acid and 150 g of diphenyl ether. The suspension was filtered washed with acetone and dried at 110 C. for 6 hours under reduced pressure of 5 mmHg. Polysuccinimide thus obtained was 19.7 g (yield 90.0%). The polymer had eta of 0.074 g dl/g and Mw of 10,000.
Example 6 Example 4 was repeated with 150 g of aspartic acid instead of 50 g. About 150 g of polysuccinimide was recovered having a nitrogen content of 14,5%.
With N-Bromosuccinimide; In carbontetrachloride (CCl4);
Methyl-3-fluoro-4-bromomethyl benzoate (6) A mixture of 7.32 g (43.6 mmol) methyl-3-fluoro-4-methylbenzoate, 4.92 g N-bromosuccinimide (NBS) and a few mg of 2,2-azobisisobutyronitrile (AIBN) in 80 ml of carbontetrachloride (CCl4) were brought to reflux and illuminated with a high intensity lamp. The reaction was rapid and within 2 hours, all of the NBS has been converted to succinimide. TLC and NMR analysis indicated a 1:1 mixture of product and starting material as judged by the appearance of a new signal at 4.49 corresponding to bromination of the methyl group. The mixture was worked up by filtering the succinimide and washing the CCl4 solution, first with aqueous sodium sulfate (Na2 S2 O3) and then with aqueous sodium bicarbonate (NaHCO3). The product obtained after drying and removal of the solvent was recycled with additional NBS and treated as above to yield 7.46 g of yellow oil which was an 8:1 mixture of product and starting material and was used as such in the next step.
EXAMPLE 5 Preparation of N-ortho- and N--para-trifluoromethoxybenzyl)succinimide STR10 The procedure of Example 1 was again repeated, but the reactants were 100 g anhydrous HF (5 moles), 16.2 g (0.1 mole) trifluoromethoxybenzene and 12.9 g (0.1 mole) N-hydroxymethylsuccinimide. The reaction was carried out at 10 C. for 3 hours. 18 g of a reaction mixture containing about 15% N--ortho-trifluoromethoxybenzyl)succinimide and about 85% N--para-trifluoromethoxybenzyl)succinimide were obtained.
With sodium hydroxide; N-chloro-succinimide; In dichloromethane;
(c) 4-Methoxy-6-(methylthiomethyl)-2-(alpha,alpha,alpha-trifluoromethyl)aniline was prepared by substituting 4-methoxy-2-(alpha,alpha,alpha-trifluoromethyl)aniline as follows: In a 250 ml three-necked flask equipped with an overhead stirrer was placed 20.12 g (0.105 mol) of 4-methoxy-2-(alpha,alpha,alpha-trifluoromethyl)aniline in 100 ml of methylene chloride. To the solution was then added 15.63 g (0.117 mol) of N-chlorosuccinimide was added with vigorous stirring. After cooling to 0 C. under a nitrogen atmosphere, a solution of 9.2 ml (8.02 g, 0.129 mol) dimethylsulfide in 40 ml of methylene chloride was then added over a one hour period while maintaining the temperature below 5 C. The reaction mixture became very thick. The ice bath was removed and after stirring at room temperature for one hour, 200 ml of ice cold 5% aqueous sodium hydroxide solution was added. The methylene chloride layer was separated, dried over anhydrous potassium carbonate, filtered and the solvent removed under reduced pressure. To the residue was then added 60 ml of 1,2-dichloroethane and 1.00 g (10 mmol) of succinimide. After refluxing for twelve hours under a nitrogen atmosphere, the reaction mixture was cooled, washed twice with 100 ml of 5% sodium hydroxide solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford 24.9 g of a black oil. This was distilled under reduced pressure to afford 16.5 g (63% yield) of the desired product as a clear, colorless liquid (Bp 106-110 at 0.35 mm Hg) of 95% purity as assayed by gas chromatography; 1 H NMR analysis indicated: (delta, CDCl3) 6.94 (d, J=1.8 Hz, 1H), 6.78 (d, J=1.8 Hz, 1H), 4.32 (br s, 2H, NHz), 3.54 (s, 3H), 3.51 (s, 2H) and 1.82 (s, 3H). Mass spectrum analysis indicated: (m/e) 251 (M+), 204 (100%) and 181.
Example 2 To a flask equipped with a magnetic stirrer, Dean-Stark trap, thermometer, reflux condensor and nitrogen inlet was added 50.0 grams of polyisobutenylsuccinic anhydride (0.040 moles, saponification number = 90.6) where the polyisobutenyl group has an approximate molecular weight of 950 and 9.3 grams of <strong>[119-34-6]4-amino-2-nitrophenol</strong>. The mixture was heated to 160C for sixteen hours, then cooled to room temperature and diluted with 1.5 L of hexane. The organic phase was washed twice with 1% aqueous hydrochloric acid, once with water and once with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvents removed in vacuoto yield 51.0 grams of product as a brown oil. The oil was chromatographed on silica gel eluding with hexane, followed by hexane/ethyl acetate/ethanol (90:8:2) to yield 21.0 grams of the desired succinimide as a brown oil.
With triethylamine; In 5,5-dimethyl-1,3-cyclohexadiene;
Step 1 4-tert-Butyl-1-(2,5-dioxo-1-pyrrolidinyl)-2-nitrobenzene To a solution of <strong>[6310-19-6]4-tert-butyl-2-nitroaniline</strong> (1.04 g, 5.35 mmol) in xylene (25 m) was added succinic anhydride (0.0535 g, 5.35 mmol) and triethylamine (0.75 mL, 5.35 mmol). The reaction mixture was heated at the reflux temp. for 24 h, cooled to room temp. and diluted with Et2O (25 mL). The resulting mixture was sequentially washed with a 10% HCl solution (50 mL), a saturated NH4CL solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash cromatography (60% EtOAc/40% hexane) to yield the succinimide as a yellow solid (1.2 g, 86%): mp 135-138 C.; 1H NMR (CHCl3) delta 1.38 (s, 9H), 2.94-2.96 (m, 4H), 7.29-7.31 (m, 1H), 7.74-7.78 (m, 1H), 8.18-8.19 (m, 1H).
1-(3-bromo-4-fluorobenzyl)pyrrolidine-2,5-dione <strong>[78239-71-1]2-bromo-4-(bromomethyl)-1-fluorobenzole</strong> (type X) (1.96 g, 7.3 mmol) and succinimide (type W, commercial available) (1.5 g, 15 mmol) were dissolved in acetone (30 mL) and refluxed for 2 hours. After the reaction mixture had cooled to RT, it was added to water (100 mL). The acetone was removed and the aqueous phase extracted with chloroform (2*100 mL). The organic phase was dried (MgSO4) and evaporated to low bulk and the product purified by column chromatography (hexane). (Yield: 1.55 g, 54%)
With potassium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
General procedure for the synthesis of potassium imidomethyltrifluoroborates (3): To a dry flask containing a magnetic stir bar, KH [0.63 g, 15.8 mmol, from 30% in oil; the KH in oil was washed with hexane (3 x 10 mL) and dried under vacuum and weighed] was added under a nitrogen atmosphere. The flask was cooled to 0 oC and anhydrous THF (16.5 mL) and anhydrous DMF (3.3 mL) were added. A mixture of phthalimide (1a) (2.32 g, 15.8 mmol) and <strong>[166330-03-6]pinacol (bromomethyl)boronate</strong> (2) (3.49 g, 15.8 mmol) in anhydrous THF (16.5 mL) and anhydrous DMF (3.3 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at room temperature for 24 h. The THF was removed under vacuum. The residue was diluted with MeOH (29.5 mL) and cooled to 0 oC. A solution of KHF2 (4.93 g, 63.2 mmol) in H2O (14 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum and the residue was dried under vacuum for overnight. The residue was dissolved in DMSO (60 mL) and filtered. The DMSO was removed from the filtrate by vacuum distillation using a short-path vacuum distillation apparatus. The solid obtained was triturated with boiling acetone (3 x 30 mL) followed by hot MeOH (3 x 30 mL). The resulting white powder was washed with cold ether (3 x 20 mL) and dried to give the potassium phthalimidomethyltrifluoroborate (3a).
The appropriate compound of formula (V) (0.0178 mol), potassium carbonate (0.051 mol) and a catalytic amount of potassium iodide (0.3 g) were stirred while heating under reflux in acetone or acetonitrile (100 ml). After 60 minutes, the appropriate dihalogenoalkane (IV) (0.0195 mol) was added dropwise. Reaction progress was monitored by TLC. After spots originating from the substrate (V) disappeared, inorganic precipitate was filtered off while hot and the filtrate was concentrated under reduced pressure. Product (III) was purified using column chromatography with the solvent system ethyl acetate/n-hexane, 3:7, 4:6 or 8:2 v/v as eluent. Structure of prepared compounds was confirmed by MS data and by 1H-NMR analysis.
With N-ethyl-N,N-diisopropylamine; triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 8h;Inert atmosphere;
To a solution of <strong>[1044870-39-4]2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one</strong> (0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenyl phosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02 mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To this stirred solution was added diethylazodicarboxylate (0.35 g, 2.02 mmol). The reaction mixture was stirred at room temperature for 8 hours under nitrogen. Ethyl acetate (400 mL) was added. The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (4:96 methanol:CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.3 g. (49%). 1H NMR (400 MHz, CDCl3): delta 9.30 (br s, 1H), 7.66 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z: 452.51 (M+1) (100%)
49%
With N-ethyl-N,N-diisopropylamine; triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 8h;Inert atmosphere;
Example 102 Preparation of 1-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)pyrrolidine-2,5-dione To a solution of <strong>[1044870-39-4]2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one</strong> (0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenyl phosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02 mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To this stirred solution was added diethylazodicarboxylate (0.35 g, 2.02 mmol). The reaction mixture was stirred at room temperature for 8 hours under nitrogen. Ethyl acetate (400 mL) was added. The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (4:96 methanol:CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.3 g. (49%). 1H NMR (400 MHz, CDCl3): delta 9.30 (br s, 1H), 7.66 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z: 452.51 (M+1) (100%).
Example 5 Preparation of a Mixture of Imides From Pure MGN and From Bio-Sourced Succinic Acid [0169] In a 100 mL reactor, are introduced 23 g of 2-methyl-glutaronitrile and then 25 g of succinic acid obtained by fermentation are added. Stirring is applied and 0.1 g of 85% ortho-phosphoric acid are added. The reaction medium is heated up to 270 C. and these conditions are maintained for 2 hours. By GC analysis, the following results are obtained: [0170] TT % (MGN)=98% [0171] RR % (MGI)=96% [0172] RR % (succinimide)=97%
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 0 - 30℃;
Add 50g (0.2mol) to the 1L reaction flask ( S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol and 600ml of toluene solvent, stirred at room temperature, The system is dissolved, Reduce the temperature of the reaction system to 0 ~ 5 C, add 63.8 g of triphenylphosphine(0.24 mol, 1.2 eq) and 23.76 g(0.24 mol, 1.2 eq) succinimide, Add diisopropyl azodicarboxylate 48.5g(0.3mol, 1.5eq), After the addition is completed, the system is heated to 20 to 30 C for 3 to 5 hours. Add 150ml of water and stir at room temperature 5~10 minutes, liquid separation, The organic layer was washed with saturated brine (100 ml × 2).Dry over anhydrous MgSO4, Concentrated to give a white solid Compound IIa 54.68g, The yield was 82.3%.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃;
49.3 g (S)-1-([1,1?-biphenyl]-4-yl)-3-chloropropan-2-ol in 600 g toluene was added into a 1000ml four-necked flask at about 70-80 C, and stirred until dissolved. The mixture was filtered andtransferred to another reactor. Under nitrogen protection the solution was cooled down to about0-5 C and then 57.64 g triphenylphosphine and 20.79 g succinimide were added. After stirringthe mixture, a solution of 40.02 g diethyl azodicarboxylate (DEAD) in 40 g toluene was added at about 0-5 C. Afterwards the toluene was removed under reduced pressure destillation. The title compound was recovered and directly used in the next step.[aID25 + 98.159 (c = 0.Olg/ml, CHCI3)1H-NMR (400 MHz, ODd3) o 2.55-2.66 (m, 4 H, OH2), 3.17-3.30 (m, 2 H, OH2), 3.76 (dd, J=11.2, 4.8 Hz, 1 H, OH2), 4.23 (d, J= 10.8 Hz, 1 H, OH2), 4.67-4.44 (m, 1 H, OH), 7.26 (d, J= 8.4 Hz, 2 H, Ar-H), 7.34-7.38 (m, 1 H, Ar-H), 7.43-7.47 (m, 2 H, Ar-H), 7.54 (d, J = 8.4 Hz, 2 H, Ar- H), 7.58-7.60 (m, 2 H, Ar-H)
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃;Inert atmosphere;
Step 1: (R)-1-(1-([1,1-biphenyl]-4-yl)-3-chloropropan-2-yl)<strong>[123-56-8]pyrrolidine-2,5-dione</strong> [0187] (S)-1-([1,1?-biphenyl]-4-yl)-3-chloropropan-2-ol in 600 g toluene was added into a 1000 ml four-necked flask at about 70-80 C., and stirred until dissolved. The mixture was filtered and transferred to another reactor. Under nitrogen protection the solution was cooled down to about 0-5 C. and then 57.64 g triphenylphosphine and 20.79 g succinimide were added. After stirring the mixture, a solution of 40.02 g diethyl azodicarboxylate (DEAD) in 40 g toluene was added at about 0-5 C. Afterwards the toluene was removed under reduced pressure destillation. The title compound was recovered and directly used in the next step. [0189] [alpha]D25+98.159 (c=0.01 g/ml, CHCl3) [0190] 1H-NMR (400 MHz, CDCl3) delta 2.55-2.66 (m, 4H, CH2), 3.17-3.30 (m, 2H, CH2), 3.76 (dd, J=11.2, 4.8 Hz, 1H, CH2), 4.23 (d, J=10.8 Hz, 1H, CH2), 4.67-4.44 (m, 1H, CH), 7.26 (d, J=8.4 Hz, 2H, Ar-H), 7.34-7.38 (m, 1H, Ar-H), 7.43-7.47 (m, 2H, Ar-H), 7.54 (d, J=8.4 Hz, 2H, Ar-H), 7.58-7.60 (m, 2H, Ar-H)
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0℃;Flow reactor;
1) Accurately weigh 200g of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol and 212g of triphenylphosphine, dissolved in 1000mL of tetrahydrofuran to form solution A ;Further weigh 144g of diethyl azodicarboxylate and 92g of succinimide,The solution B was dissolved in 1000 mL of tetrahydrofuran.2) Open the constant temperature bath 5 and set the reaction temperature to 0 C.Control the piped reactor 4 through the constant temperature tank 5 (using a coil, the volume of the coil is 4 to 50 mL), the temperature is 0 C; 3) The first constant current pump 1 sets the delivery rate of the solution A to 10 mL/min, and the second constant current pump 2 sets the delivery flow rate of the solution B to 10 mL/min.Transfer solution A and solution B to T-mixer 3 for mixing.The mixed liquid continuously enters the reaction in the pipeline reactor 4(ie, the flow rate of the mixed liquid into the pipeline reactor 4 is 20 mL/min),The reacted feed liquid flows out of the pipeline reactor 4, and after stabilization for a period of time, the reaction liquid is collected by a quenching kettle 6 equipped with a quenching liquid (the quenching liquid quenches the reaction),Collect the sample after the reaction,(R)-1-(1-([1,1'-Biphenyl]-4-yl)-3-chloropropan-2-yl)<strong>[123-56-8]pyrrolidine-2,5-dione</strong> was obtained.
succinimidinium N-sulfonic acid hydrogen sulfate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With sulfuric acid; In dichloromethane; at 20℃; for 0.5h;
In a round-bottomed flask, 0.53 mL sulfuric acid (98 %,d = 1.84) was added drop wise to a succinimide (0.99 g,10 mmol) in 25 mL of dichloromethane on an ice bath.The reaction mixture was stirred at room temperature for 30 min, and then the solvent was evaporated under reduced pressure. The solid residue was washed with Et2O and dried under vacuum. [H-Suc]HSO4 was obtained as a cream solid (1.94 g, 97 %) (M.P. 78 C); FT-IR (neat) nu = 3128,1693, 1404, 1295, 1180, 1071, 1007, 883, 579 cm-1; 1HNMR (400 MHz, DMSO-d6): d = 2.55 (s, 4H, CH2CH2),7.31 (s, 2H, NH2), 10.93 (br s, 1H, HSO4) ppm; 13C NMR(100 MHz, DMSO-d6): d = 29.76 (CH2CH2), 180.14(C=O) ppm. Also and to determine the acidity of the prepared reagent, to 25 mL of an aqueous solution of NaCl(1 M) with a primary pH 5.2, [H-Suc]HSO4 (0.5 g) was added and the resulting mixture was stirred for 2 h at room temperature. The pH of the solution decreased to 1.7. Thisis equal to a loading of 1.23 mmol H+ per gram of the catalyst.
General procedure: b. A mixture of 0.13 g (0.002 mol) of copper nanoparticles, 5 g (0.11 mol) of formamide, and 11.9 g(0.12 mol) of amine Va was stirred for 30 min at 20-40C. An excess of the amine was distilled off, and the residue was distilled. Yield 11.3 g (0.1 mol, 91%).
(4-((2,5-dioxopyrrolidin-1-yl)methyl)phenyl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
520 mg
A) (4-((2,5-dioxopyrrolidin-1-yl)methyl)phenyl)boronic acid [0891] To a solution (10 mL) of pyrrolidine-2,5-dione (500 mg) in DMF was added sodium hydride (60% dispersion in mineral oil, 252 mg) at 0C, and the mixture was stirred for 1 hr. (4-(Bromomethyl)phenyl)boronic acid (903 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and crystallized from ethyl acetate and diisopropyl ether to give the title compound (520 mg).
3-(3-trifluoromethylphenyl)propanoyl succinimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 18h;Inert atmosphere;
In a flame-dried, nitrogen purged 250 mL round-bottom flask equipped with a magnetic stir bar at room temperature were placed 3-(3-Trifluoromethylphenyl)propanoic acid (5.00 g,22.92 mmol), EDC (5.27 g, 27.50 mmol), DMAP (1.120 g, 9.17 mmol), CH2Cl2(92 mL), and succinimide (4.45 g, 45.84 mmol) was then added and the reaction and allowed to stir for a period of no less than 18 hours. The reaction was quenched and extracted using CH2Cl2 (100 mL), one quick wash of 1M HCl (50 mL), anddried over MgSO4. The solvents were removed in vacuo. The crude material was purified by flash column chromatography (cyclohexane/ethylacetate, 7:3) and then triturated using CHCl3/hexanes to yield 3.6414 g (53percent) of the title compound as a white solid. MP = 75-77 oC. 1HNMR (400 MHz, CDCl3): d 2.77 (s, 4H), 3.08 (t, J= 7.4 Hz, 2H), 3.24 (m, 2H), 7.45 (m, 4H).13C NMR (100 MHz, CDCl3): d 28.40, 29.43, 39.97, 123.27 (3J = 3.8 Hz), 124.13 (1J = 270.6 Hz), 125.17 (3J = 3.8 Hz), 129.01, 130.72 (2J = 31.8 Hz), 132.06, 140.90, 171.61,174.28. IR (nujol): 1802, 151, 1707, 917 cm-1.
44%
In a flame-dried, nitrogen purged 250 mLround-bottom flask equipped with a magnetic stir bar at room temperature were placed 3-(3-Trifluoromethylphenyl)propanoic acid (3.287 g, 15.07 mmol), EDC(1.75 g, 9.135 mmol), DMAP (0.265 g, 2.175 mmol), and THF (35 mL). The resulting solution was allowed to stir for 30 minutes. Succinimide (1.72 g, 17.4 mmol) was then added and the reaction and allowed to stir for 48 hours. The reaction was quenched and extracted usingEtOAc (50 mL), two washes of 1M HCl (2 x 50 mL), and dried over MgSO4. The solvents were removed in vacuo. The crude material was purified by flash column chromatography (Cyclohexane/ethyl acetate, 7:3) andthen re-crystallized using EtOAc/hexanes to yield 1.065 g (44percent) of the title compound as a white solid.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 18h;Inert atmosphere;
In a flame-dried, nitrogen purged 250 mLround-bottom flask equipped with a magnetic stir bar at room temperature were placed <strong>[1643-28-3]3-(2-chlorophenyl)propanoic acid</strong> (5.00 g, 27.1 mmol), EDC (6.23 g, 32.5mmol), DMAP (1.32 g, 10.8 mmol), CH2Cl2 (108 mL), and succinimide (5.367 g, 54.16 mmol) was then added and the reaction stirred for 18h. The reaction was extracted using CH2Cl2(100 mL), one quick wash of 1M HCl (50 mL), and dried over MgSO4. The solvents were removed in vacuo. The crude material was purified by flash column chromatography (cyclohexane/ethyl acetate, 7:3) and then triturated using CHCl3/hexanes to yield 4.322 g (60%) of thetitle compound as a white solid. Mp = 52-54oC. 1H NMR (500MHz, CDCl3) delta 2.76 (s, 4H), 3.12-3.15 (m, 2H), 3.22-3.25 (2H, m),7.16 (2H, td, J = 7.5, 2.0 Hz), 7.19(2H, td, J = 7.4, 1.7 Hz), 7.29 (2H,dd, J = 7.2, 2.1 Hz), 7.34 (2H, dd, J = 7.5, 1.8 Hz); 13C NMR(100 MHz, CDCl3) delta 27.7, 28.5, 38.5, 127.0, 128.0, 129.5, 130.9,133.9, 137.5, 171.8, 174.3; IR (neat) 1752, 1709, 752 cm-1. HRMS (ESI) calcd for C13H12ClNO3[M + Na]+ 288.0403, found 288.0402.
In a jacketed reactor equipped with a mechanical stirrer, a nitrogen bubbler and a dropping funnel was dissolved <strong>[39825-33-7]L-alanine isopropyl ester</strong> (20.0 g, 119.3 mmol, 1 equiv) in THF (200 mL) and the internal temperature set to 0 C. To this solution, phenyl phosphorodichloridate (18.8 mL, 95% purity, 119.5 mmol, 1 equiv) was added at 20 C, followed by a dropwise ad- dition of triethylamine (34.8 mL, 250 mmol, 2.1 equiv) over 2 h at 0-7 C, upon which a white precipitate was formed. The solution was stirred at 0 C for 2h 20 min. N- hydroxysuccinimide (17.8 g, 154.7 mmol, 1.3 equiv) was added, followed by additional triethylamine (24.8 mL, 177.9 mmol, 1.5 equiv) which was added dropwise over 56 min. The reaction was stirred at 0 C for 17.5 h, diluted with MTBE (1200 mL), stirred at 0 C for lh and filtered over a Nutsche filter twice. The filtrate was concentrated to 100 mL, diluted with MTBE to a total volume of 600 mL and filtered over a plug of silica (20 g). The resulting clear filtrate (650 mL) was cooled to 20 C. The solution was cooled gradually to -5 C, stirred for 2 h at this temperature and filtered over a Nutsche filter. The solid was dried at 40 C under vacuum to afford 38.7 g II-O (100.7 mmol, 84%, dr = 49.8:50.2 as determined by 31P NMR in DMSO-d6: 5.3 ppm (Rp-diastereomer), 4.3 (Sp-diastereomer)).
1-(4-methylbenzoyl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With dmap; triethylamine; In dichloromethane; at 0 - 23℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask equipped with a stir bar was charged with amine (8.84 mmol, 1.0 equiv), triethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 50 mL), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered. The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. Unless stated otherwise, the crude product was purified by recrystallization (toluene) to give analytically pure product. Note: N-acylsuccinimides are crystalline, bench-stable solids, with no decomposition observed when stored on an open bench-top at ambient conditions for periods >12 months.
75.6%
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
74%
With dmap; triethylamine; In dichloromethane; at 0 - 23℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask equipped with a stir bar was charged with amine (8.84 mmol, 1.0 equiv), triethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 50 mL), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered. The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. Unless stated otherwise, the crude product was purified by recrystallization (toluene) to give analytically pure product. Note: N-acylsuccinimides are crystalline, bench-stable solids, with no decomposition observed when stored on an open bench-top at ambient conditions for periods >12 months.
1-(4-(trifluoromethyl)benzoyl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With dmap; triethylamine; In dichloromethane; at 0 - 23℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask equipped with a stir bar was charged with amine (8.84 mmol, 1.0 equiv), triethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 50 mL), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered. The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. Unless stated otherwise, the crude product was purified by recrystallization (toluene) to give analytically pure product. Note: N-acylsuccinimides are crystalline, bench-stable solids, with no decomposition observed when stored on an open bench-top at ambient conditions for periods >12 months.
66.3%
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
1-(2-methylbenzoyl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With dmap; triethylamine; In dichloromethane; at 0 - 23℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask equipped with a stir bar was charged with amine (8.84 mmol, 1.0 equiv), triethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 50 mL), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered. The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. Unless stated otherwise, the crude product was purified by recrystallization (toluene) to give analytically pure product. Note: N-acylsuccinimides are crystalline, bench-stable solids, with no decomposition observed when stored on an open bench-top at ambient conditions for periods >12 months.
65.8%
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
With dmap; trimethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (5.0 mmol, 1.0 equiv), trimethylamine (typically, 2.0 equiv), 4-dimethylaminopyridine (typically, 0.25 equiv) and dichloromethane (typically, 40 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. Acyl chloride (typically, 1.1 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture were washed with HCl (1.0 N, 30 mL), water (30 mL), brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using petroleum ether/ethyl acetate as eluent.
ethyl 2-(2,5-dioxopyrrolidin-1-yl)-2-(p-tolylamino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With copper(l) chloride; In acetonitrile; at 60℃; for 24h;
General procedure: To a solution of N-arylglycine esters 1 (0.3 mmol) in MeCN(2 mL) were added imides or amides 2 (0.2 mmol) and CuCl(2.0 mg, 0.02 mmol). Then, the reaction mixture was stirred at60 C under air atmosphere until the reaction was completed.Then, the resulting mixture was concentrated under vacuum,and the residue was purified by column chromatography (silicagel, petroleum ether/EtOAc as an eluent) to afford the correspondingproducts 3.(10)
82%
With copper(l) chloride; In acetonitrile; at 60℃; for 24h;
N-4-methylphenylglycine ethyl ester (0.3 mmol) under air atmosphere,A phthalimide compound (0.2 mmol) and cuprous chloride (0.02 mmol) were placed in a dry reaction tube with stirring magnets.Then, an acetonitrile solvent (2 mL) was added to the test tube, and the reaction tube was reacted in an air atmosphere at 60 C for 24 hours.After the reaction was completed, it was cooled to room temperature, and the solvent was distilled off under reduced pressure using a rotary evaporator.The residue was purified by column chromatography to give a pure pale yellow solid 3p.The yield was 82%.
2-chloro-4-methoxy-6-(2,5-dioxopyrrolidyl)-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 55℃; for 15h;Inert atmosphere;
A solution of sodium hydride (8.64 g, 36.0 mmol) in tetrahydrofuran (70 mL)Was added succinimide (3.27 g, 33.0 mmol) under a nitrogen atmosphere and the mixture was stirred. Thereafter, a tetrahydrofuran solution (30 mL) of <strong>[3638-04-8]2,4-dichloro-6-methoxy-1,3,5-triazine</strong> (5.40 g, 30.0 mmol) was added dropwise at 0 C. and the mixture was stirred at 55 C. for 15 hours. After completion of the reaction, the reaction mixture was diluted with 1 M hydrochloric acid and extracted with ethyl acetate. The extracted organic layer was washed with saturated brine and then dried using sodium sulfate. The sodium sulfate was removed by filtration, and after concentrating, the residue was separated and purified by column chromatography (hexane / ethyl acetate = 1: 1) to give compound (II-2) (3.65 g, yield 50 %).
A mixture of 1 (100 mg, 0.384 mmol) and 3,5-difluorobenzoicacid (a, 88.75 mg, 0.384 mmol) was suspended in 2mL ethyl acetateand stirred at room temperature. After one day, the suspensionwas filtered to get the crystals of 1a. The filtrate was left to evaporateslowly at room temperature in a vessel and single crystals of1a were obtained within 3 days. Similar method was used for thepowder and single crystal preparation of cocrystal 1b, 1c, 1d.