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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20 - 60℃; for 2h; |
To a suspension of <strong>[215309-01-6]3-(4-methylpiperazin-1-yl)benzoic acid</strong> (0.58 g, 2 mmol) in dichloromethane (50 mL) and DMF (2 drops), oxalyl chloride (0.9 mL, 10 mmol) was added dropwise at RT. After addition the reaction mixture was heated at 60 C. for 2 h. After concentration and stripping with toluene the crude acyl chloride was dissolved in dry THF (7 mL)/triethylamine (3 mmol) and t-butylglycinate (0.286 mL, 2.1 mmol) was added at RT and the reaction mixture was stirred at RT overnight. After concentration obtained 0.66 g (2 mmol, quant.) of tert-butyl N-[3-(4-methylpiperazin-1-yl)benzoyl]glycinate. The above obtained t-butyl ester (0.1 g, 0.3 mmol) was stirred at RT in dichloromethane (4 mL) and trifluoroacetic acid (3 mL) overnight. The solvents were removed under reduced pressure and the crude material stripped three times with toluene. Obtained the corresponding acid (0.080 g. 96% yield). The acid was then reacted as described in Example 1 to afford the title compound. H-NMR (DMSOd6), delta ppm: 2.87 (s, 3 H) 3.13-4.03 (m, 8 H) 7.24-7.95 (m, 6 H) 8.36 (dd, J=4.63, 1.59 Hz, 1 H) 8.52 (d, J=2.44 Hz, 1 H) 9.11 (d, J=7.32 Hz, 1 H) 10.48 (s, 1 H) 11.83-11.96 (m, 1 H) 12.58 (s,1 H) |
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With oxalyl dichloride;Product distribution / selectivity; |
Example 33: lambdaP-(2<:yano-9-methyl-9Hphiurin-6-yl)-lambdaP<:yclopentyl-3-(4-methyl-1 - piperazinyl)benzohydrazide trifluoroacetate.Intermediate 51 (2 g, 9.08 mmol) was dissolved in oxalyl chloride (2OmL) and the mixture was stirred overnight. The solvent was removed under reduced pressure and part of the residue (1.1 g, 4.64 mmol) was added to a solution of Intermediate 16 (300 mg, 1.16 mmol) and DIPEA (FLUKA, 0.794 mL, 4.64 mmol) in THF (50 mL). Potassium tert- butoxide (ALDRICH, 260 mg, 2.32 mmol) was added and the mixture was stirred at rt for 1 day. The solvent was removed under reduced pressure and the crude was purified by preparative HPLC (SUNFIRE 30x150mm, ACN:H2O 0.1%TFA, gradient 10%-100%) to yield the title compound. 1H NMR (300 MHz, DMSO-d6, 8O0C) delta ppm: 10.70 (s, 1 H), 8.27 <n="76"/>(s, 1 H), 7.52-7.38 (m, 3H), 7.23 (d, 1 H), 5.54 (br, 1 H), 3.78 (s, 3H), 3.31 (br., 4H), 2.84 (s, 3H), 2.02-1.78 (m, 4H), 1.74-1.52 (m, 4H). [ES+ MS] m/z 460 (MH)+ |
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Example 41 : lambdaf-{2-cyano-9-[2-(dimethylamino)ethyl]-9Hphiurin-6-yl}-lambdaf <:yclopentyl-3- (4-methyl-1 -piperazinyl)benzohydrazide bis(trifluoroacetate). <n="80"/>Intermediate 51 (0.3 g, 1.36 mmol) was suspended in oxalyl chloride (ALDRICH, 1 ml.) and the mixture was stirred at rt for 16 h. Then, dry DCM (4 ml.) was added and after further 8 h, more oxalyl chloride (ALDRICH, 2 mL) and dry DCM (2 mL) were added. These additions were continued until the reaction was complete. Then, solvent was removed in vacuo yielding the corresponding acid chloride. It was then added over a solution of Intermediate 57 (0.1 1 g, 0.37 mmol), potassium te/f-butoxide (ALDRICH, 0.14 g, 1.28 mmol) and DIPEA (FLUKA, 0.08 mL, 0.45 mmol) in dry THF (12 mL). The reaction mixture was stirred at rt and more Intermediate 51 (0.09 g, 0.29 mmol) in dry THF (2 mL) was added in order to drive the reaction to completion. After 2 days, solvent was removed under reduced pressure and the residue partitioned between DCM and sat. NH4CI. The aqueous phase was basified to pH 10 with 2N NaOH and product was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by preparative HPLC (X-Terra 30x150 mm, ACN:H2O, 0.1%TFA, isocratic 20%, then, re-purified using gradient 20- 60%, and, then, SunFire 19x 150 mm, ACN:H2O, 0.1% TFA, gradient 20- 40%). The product obtained was dissolved in DCM (25 mL) and washed with sat. NaHCO3 (25 mL). The organic layer was washed with brine and then, 4 M HCI in dioxane was added dropwise in order to form the corresponding hydrochloride. It was then purified by preparative HPLC (X-Terra, 3Ox 150 mm, ACN;H2O, 0.1% TFA, isocratic 20%) to give the title compound. 1H NMR (300 MHz, d6-DMSO, 80 0C) delta ppm: 10.86- 10.53 (br., 1 H), 8.48- 8.25 (br., 1 H), 7.56- 7.36 (m, 3H), 7.29- 7.19 (m, 1 H), 6.01- 5.22 (br., 1 H), 4.64- 4.50 (m, 2H), 4.07- 2.91 (br., 10H), 2.88 (s, 3H), 2.81 (s, 6H), 2.07- 1.76 (m, 4H), 1.76- 1.50 (m, 4H). [ES+ MS] m/z 517 (M)+. |
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