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Example 3 4-Aminobenzophenone (10.00 g, 0.0507 mol) was added to a stirred solution of maleic anhydride (4.98 g, 0.0508 mol) in dichloromethane (200 ml). After 10 minutes of stirring at room temperature, yellow precipitate was formed. Stirring was continued for a further 3 hours, following which the solid was collected, washed with dichloromethane (3 x 30 ml) and diethyl ether (2 x 30 ml) and finally air dried to yield the maleamic acid.(Found: C, 68.74; H, 4.57; N, 4.41%. C1713O4equires C, 69.15; H, 4.44; N, 4.74%). H.p.l.c (Kromazil C18 49.95% MeOH, 49.95% H2, 0.1% CF3O2): 99.7% lambdamax06 nm; epsilon 20560. 1-n.m.r (DMSO): delta 10.62 (1H, s, NH); 7.8 - 7.5 (9H, m, phenyl); 6.45 (1H, d; CH = CH); 6.31 (1M, d, CH = CH); 3.38 (1H, S, CO2).
b-Alanine (8.9 g, 100 mmol) was dissolved in 10 mL of water. Maleic anhydride (9.8 g, 100 mmol) was added all at once and the mixture was stirred for 4 hours at ambient temperature. After completion of the reaction, the mixture was filtered and the white power obtained was washed with water (3'10 mL) followed by anhydrous ethanol (3'10 ml), and then anhydrous ether (3'10 mL). After drying, 11.6 g (69%) of the maleamic acid was obtained. 1H NMR (300 MHz, D2O) d 2.45 (t, J=6.4 Hz, 2H), 3.32 (t, J=6.4 Hz, 2H), 6.06 (d, J=12.4 Hz, 1H), 6.26 (d, J=12.4 Hz, 1H); HRMS(FAB) calcd for C7H10NO5 (M+H+) 188.0559, found 188.0558.
In water;
EXAMPLE 1 Preparation of Maleamic Acid of beta-Alanine beta-Alanine (8.9 grams (g), 100 millimole (mmol)) was dissolved in 10 milliliter (ml) of H2 O. Maleic anhydride (9.8 g, 100 mmol) was added all at once and the mixture was stirred vigorously for four (4) hours at ambient temperature. After completion of the reaction, the mixture was filtered and the white powder obtained was washed with several volumes of H2 O followed by anhydrous ethanol, and then anhydrous ether. After drying, 11.5 g of the maleamic acid was obtained.
D-Valine (11.7 g, 100 mmol) was dissolved in 10 mL of water and then maleic anhydride (9.8 g, 100 mmol) was added all at once and stirred for 4 h at ambient temperature. The resulting white powder was filtered, washed with water (3'10 mL) followed by anhydrous ethanol (3'10 ml), and then anhydrous ether (3'10 mL) to give 11.6 g (69%) of the maleamic acid 6(18). [a]D=-15.0 C. (c 1.1, acetone); 1H NMR (300 MHz, CD3COCD3) d 1.01 (d, J=4.9 Hz, 6H) 2.05 (m, 1H), 4.53 (m, 1H), 6.32 (d, J=12.9 Hz, 1H), 6.76 (d, J=12.9 Hz, 1H).
COMPARATIVE EXAMPLE 2 The same procedure as in Example 7 was repeated, except that the washed reaction mixture was directly cooled to 30 C. without conducting distillation of toluene. The precipitate thus formed was collected by filtration and dried at 70 C. for 48 hours. There was obtained 67.6 g (apparent yield: 97.2%) of a pale yellow maleimide powder. The resulting maleimide contained 13.1% toluene and 1.8% mono<strong>[557-24-4]maleamic acid</strong>, had a melting point of 140 to 145 C., and exhibited a non-crystallization rate of 0%.
With sodium acetate; In acetic anhydride;
General Procedure for the Synthesis of N-Substitutedmaleimides and Succmimides. A reaction mixture containing the appropriate <strong>[557-24-4]maleamic acid</strong> (5.23 mmol) in 5 mL of acetic anhydride and sodium acetate (3 mmol) was heated at 90 C. for 2 hours. The reaction was cooled and quenched with water. The aqueous solution was extracted with Et2 O (3*40 mL). The combined ether extracts were dried (Na2 SO4), filtered and the solvent was evaporated. The residue was chromatographed on silica gel with EtOAc/hexane. The fractions containing the pure product were combined and concentrated to afford essentially pure maleimide. The product was further recrystallized from isopropanol/water. In the case of the aspirin analogs 13 and 14 purification on silica gel was not needed as the compounds were crystallized from CHC/3 /hexane.
The continuously stirred solution of <strong>[557-24-4]maleamic acid</strong> 13 in presence of a nitrogen atmosphere was heated in an oil bath maintained at 150-160 for 1.5 h and then at 170-180 for 1.5 h. The reaction was allowed to cool and then poured over crushed ice. Light gray solid obtained on maceration was filtered, washed with water, and dried to give the maleimide 14, m.p. 152-155 C.
With maleic anhydride; malic acid; In 1-methyl-pyrrolidin-2-one; toluene; at 95℃; for 8.0h;Inert atmosphere;
In a glass reaction vessel, under nitrogen atmosphere, a dimer diamine (manufactured by Croda Japan KK "Preamine 1075", molecular weight: 549): 1.0 mol, a mixture composed of toluene and NMP A solvent (mass ratio: toluene / NMP = 80/20) was added and stirred. Next, to this solution , 2.10 mol of maleic anhydride was added, followed by stirring at 25 C. for 1 hour, To obtain a <strong>[557-24-4]maleamic acid</strong> solution. Thereafter, to this solution, 1.8 mol of maleic acid and 1.8 mol of maleic anhydride were added, While stirring, the liquid temperature was raised to 95 C., the heating was continued for 8 hours while maintaining the same temperature, and then cooled to obtain an orange yellow solution. The solid content concentration in this reaction is, 30% by mass. When the NMR of this solution was measured under the above conditions and the conversion was calculated, The conversion rate was 92% Except for using 1,12-dodecanediamine as the diamine, As a result of carrying out the reaction in the same manner as in Example 3, the conversion was 95%.
hydrochloride salt of 9-amino-1-nonanoic acid[ No CAS ]
[ 557-24-4 ]
Yield
Reaction Conditions
Operation in experiment
In acetic acid;
Maleamic acid (25). An aqueous solution of the hydrochloride salt of 9-amino-1-nonanoic acid (24·HCl, 0.3 g, 1.73 mmol) was treated with aqueous potassium carbonate till a pH of 7 was obtained. The aqueous solution was evaporated under vacuo and the resultant white solid was stirred with maleic anhydride (4, 0.17 g, 1.73 mmol) in 10 mL of glacial acetic acid overnight. The resultant crystalline white solid which had seperated out of the reaction mixture was filtered and dried. The crude product was recrystallized from isopropanol/water to afford a white crystalline solid 0.4 g, 85%. mp 165-167 C. 1 H NMR (DMSO-d6) d 9.09 (t, 1H, NH), 6.36-6.43 d, 2H, olefinic H), 6.19-6.25 (d, 2H, olefinic H), 3.1-3.2 (q, 2H, CH2 adjacent to CONH), 2.1-2.2 (t, 2H, CH2 adjacent to COOH), 1.24-1.46 (complex multiplet, 12H, methylenes).
EXAMPLE 9 4-Maleimido-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine To a solution of 5.29 grams of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine in 50 ml of acetone is added dropwise over 10 minutes a solution of maleic anhydride (1.96 grams) in acetone. After heating under reflux for 30 minutes, the intermediate maleamic acid is obtained.
This crude <strong>[557-24-4]maleamic acid</strong> was chromatographed on 60 g of 230-400 mesh silica gel, eluding with CHCl3 /25% NH4 OH in MeOH (4:1). After 90 mls of column volume were voided, 3 ml fractions (numbers 38-80) were collected. NMR was consistent with the desired <strong>[557-24-4]maleamic acid</strong> intermediate. 85 mg of this <strong>[557-24-4]maleamic acid</strong> was dissolved in 4 ml of CHCl3. 151 mul of 1.6 mm acetic anhydride was added followed by 46 mg of anhydrous sodium acetate and the mixture was stirred overnight at 20-25. TLC revealed product formation which was worked up by evaporation under reduced pressure to yield crude product. The entire crude was chromatographed on a medium pressure sytem utilizing a 25 g (230-400 mesh) silica gel column, eluted with CH2 Cl2 /10% NH4 OH in MeOH (8:1). The column volume fraction plus fractions numbers 1-8, yielded the title compound. MS (M+H)+: 508.3570 (PLA2)
amine ether steroid 3-[(3-methoxyestra-1,3,5(10)-trien-17-yl)oxy]-1-propanamine[ No CAS ]
[ 557-24-4 ]
[ 541-59-3 ]
Yield
Reaction Conditions
Operation in experiment
With ammonia; In methanol; 5,5-dimethyl-1,3-cyclohexadiene; chloroform; o-xylene; N,N-dimethyl-formamide;
EXAMPLE 241 1H-Pyrrole-2,5-dione, 1-[3-[(3-melthoxyestra-1,3,5(10)-trien-17-yl)oxy]propyl] 100 mg of the amine ether steroid 3-[(3-methoxyestra-1,3,5(10)-trien-17-yl)oxy]-1-propanamine and 34 mg of maleic anhydride were slurried in 10 ml of o-xylene and refluxed for 1 hour. TLC (CHCl3 /4.2M NH3 in MeOH (12:1)) revealed all starting material gone. After 2 hours total reflux the reaction was stopped and allowed to stand for 2 days. TLC (CHCl3 /25% NH4 OH in MeOH (4:1)) revealed that the maleiamic acid was formed. The reaction mixture was placed on the high vacuum, evaporated under reduced pressure to produce crude product (120 mg). The 120 mg of <strong>[557-24-4]maleamic acid</strong> was slurried in 2 ml of xylene and 1 ml DMF, 9 mg of Amberlyst 15 resin were added and the reaction mixture was heated to reflux. After 3 hours of reflux, TLC (CHCl3 /4.2M NH3 in MeOH (12:1)) revealed no product formation, therefore the mixture was refluxed overnight. TLC in CHCl3 /25% NH4 OH in MeOH (4:1) revealed product formation and that some of the <strong>[557-24-4]maleamic acid</strong> was present. The reaction was cooloed and then was evaporated under reduced pressure under high vacuum to produce crude product (129 mg). The entire crude was chromatographed on 25 g of 230-400 mesh silica gel eluding with 100% CHCl3. After 50 ml (1 column volume) was collected, 2 ml fractions were taken. Fraction numbers 3-9 yielded 10 mg of product. MS C26 H33 NO3: Theory 423.2409, Measured 423.2386. (PLA2)
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