| 78% |
In ethanol; at 0 - 20℃; for 50h;Inert atmosphere; |
Step 6 3-(2-Ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide Under nitrogen and at ambient temperature, 39.7 g of diethoxysquarate were added (over the course of 15 minutes) to a solution of 28 g of <strong>[464913-11-9]3-amino-2-hydroxy-N,N-dimethylbenzamide</strong> in 840 ml of ethanol cooled to 0 C. The reaction medium was stirred for 2 hours at 0 C. and 48 hours at ambient temperature. 700 ml of ethanol were added (which increases the precipitation of the expected product). The solid was filtered off, washed with ambient ethanol and dried. 36.9 g of (2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide were obtained in the form of a light khaki green solid. Yield=78%. |
| 78% |
In ethanol; at 0 - 20℃; for 50.25h;Inert atmosphere; |
Under nitrogen and at ambient temperature, 39.7 g of diethoxysquarate were added (over the course of 15 minutes) to a solution of 28 g of <strong>[464913-11-9]3-amino-2-hydroxy-N,N-dimethylbenzamide</strong> in 840 ml of ethanol cooled to 0 C. The reaction medium was stirred for 2 hours at 0 C. and 48 hours at ambient temperature. 700 ml of ethanol were added (which increases the precipitation of the expected product). The solid was filtered off, washed with ambient ethanol and dried. 36.9 g of (2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide were obtained in the form of a light khaki green solid. Yield=78%. |
| 65% |
In ethanol; for 120h; |
The product from Preparative Example 3 (14.6 g) dissolved in absolute EtOH (100 mL) was added dropwise over 4 hours to a stirred ethanolic (100 mL) solution of diethylsquarate (19 mL, 128 mmol). After 5 days, the reaction mixture was concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 0-5% MeOH/CH2Cl2) gave the product (65%, MH+=305, mp=178.6 C.). |
| ~ 59% |
In ethanol; |
Step 3 : 3 -(2-Ethoxy-3 Lambda-dioxocyclobut- 1 -enylamino V2-hydroxy-N.N- dimethylbenzamide; 3-Amino-2-hydroxy-N,N-dimethylbenzamide (4.2 g, 23 mmol) and 3,4- diethoxycyclobut-3-ene-l,2-dione (4.0 g, 23 mmol) were dissolved in ethanol (40 mL), and stirred overnight. The reaction product was collected with filtration to give 3-(2-ethoxy-3,4- dioxocyclobut-1 -enylamino)-2 -hydroxy -N,N-dimethylbenzamide (4.1 g, yield about 59%). |
|
With potassium carbonate; In ethanol; at 5 - 25℃; for 10h;Heating / reflux; |
A mixture of 25.0 g (86.5 mmol) of compound IV(a), 5.5 g of 5% Pd/C (50% water), 12.3 g (88.8 mmol) of potassium carbonate and 200 ml of ethanol was pressurized under hydrogen at 105 psi with agitation at room temperature for 10 hours. The reaction mixture was analyzed by 1H NMR (400 MHz, CDCN): delta (ppm) 2.9 (s, 6H), 3.9 (br, 2H), 6.47 (q, 1H), 6.55 (m, 2H). If the conversion of compound IV(a) to intermediate IV(i) was found not complete, additional 0.5 g of Pd/C catalyst was charged and the mixture was kept under hydrogen pressure at 105 psi for 5 more hours. The mixture was then filtered through a Celite bed and the cake was washed with 30 ml of ethanol. Caution should be taken to ensure minimum exposure of the product solution to air during the filtration. The filtrate was immediately transferred into one-liter three neck flask fitted with a reflux condenser, mechanic stirrer, and nitrogen inlet. The solution was cooled to 5 C. and a solution of 19.9 g (116.7 mmol, 1.35 eq.) of 3,4-diethoxy-3-cyclobutene-1,2-dione (diethyl squarate) (Compound of formula Q(a)) (Lonza, Inc. Corporate Headquaters, 17-17 Route 208, Fair Lawn, N.J. 07410) in 80 ml ethanol was added in one portion. The solution was slowly warmed up to 25 C. in 2 hours. If there were no product solids precipitating from the reaction mixture, a small amount (100 mg) of potassium carbonate was added. The suspension was stirred for another 5 hours at room temperature. The mixture was then slowly heated to reflux over 1 hour before it was slowly cooled to 10 C. over 2 hours. During the heating, a small amount of compound IV(i) trapped inside the product solids was released and converted to the product V(a). The solids were collected by filtration and the cake was washed with 40 ml of cool ethanol. The solids were dried in a vacuum oven at 60 C. for 5 hours to give 21.3 g (80.9%) of the compound of formula V(a). 1H NMR (400 MHz, CD3CN): delta (ppm) 1.4 (t, 3H), 3.1 (s, 6H), 4.8 (q,2H), 6.9 (dd,3H), 7.2 (d,1H), 7.6 (d,1H), 8.1 (br, 1H), 10.5 (br,1H). Mp: 180-183 C. 13C NMR (100.62 MHz, DMSO): 188.2, 184.1, 178.0, 171.3, 167.9, 146.9, 125.9, 125.8, 125.7, 125.6, 119.3, 68.1, 37.6, 34.6, 15.6. Anal. calcd. for C15H16N2O5 (304.30): C, 59.21; H, 5.30; N, 9.21. Found: C, 59.12; H, 5.29; N, 9.14. |
|
With potassium carbonate; In ethanol; at 20℃; |
A2: Preparation of intermediate A2: 3-(2-Ethoxy-3,4-cUoxo-cydobut-l-enylamino)-2-hydroxy- N,N-dimethyl-benzamide; 2~Hydroxy-N,N«dimethyl-3-nitro-bepsilonnza?iide {67.5 g, 0.32 mol) was dissolved in ErOH/AcOH (1 L) and degassed (4x) by evacuating and purging with argon. 7.5 g of Ru/C {7,5 g) was added and the reaction mixture was degassed (4x) by evacuating and purging with argon. The reaction mixture was healed to reflux and hydrazine inonohydrate (25 nil, 0-51 mol) was added slowly. At 1 h intervals, 3 further portions of hydrazine monohydrate (25 ml, 0.51 mol) were added. The reaction mixture was cooled to room temperature, filtered over Hyflo and washed with EtOH. The filtrate was evaporated in vacuo azeoptroping with toluene (4x). The residue obtained was taken up in H2O (1 L) and EtOAc (1 L). The aqueous layer was extracted with EtOAc (3x). The organic layers were washed with brine (2x), dried over Na?SO-i, filtered and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica (500 g), eluting with EtOAc/hexane (1/1) to yield 3-aniino-2- hydroxy-N,N-dimethyl-benzarnide.3-Amino~2-hydrpxy-N,N-dimethyl«benzamide (44 g, 0.24 mol) was dissolved in EtOH {880 ml). 3,4-diethoxy-3-cyck>buten-l,2 dione (46 g, 0.27 mol) and KiCOi (4.4 g, 0.032 mol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo. The residue obtained was purified by chromatography on silica (500 g) using CFbCh/MeOH (98/2) as the eluent. The product was suspended in iMeOH (1 L) and filtered. This process was repeated a further 3 times to to yield the title compound. [Mn-Hj+ 305. |
|
With potassium carbonate; In ethanol; at 20℃; |
44 g of <strong>[464913-11-9]3-amino-2-hydroxy-N,N-dimethyl-benzamide</strong> are dissolved in 880 ml of EtOH. 46 g of 3,4-diethoxy-3-cyclobuten-1 ,2-dione and 4.4 g of K2CO3 are added and the reaction mixture obtained is stirred overnight at rt. Solvent is evaporated. A residue obtained is purified by column chromatography over 500 g of silica using CH2CI2/Me0H 98/2 as eluent. The product-containing fractions are combined and solvent is evaporated. A residue obtained is suspended in 1 I of MeOH and filtered. This process is repeated a further 3 times. The title compound is obtained. |
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