3-AMINO-2-PIPERIDINONE HYDROCHLORIDE

General procedure: 3-Formyl-rifamycin SV (RAL)was purchased from LKT Laboratories Inc. (>98%). RAL (250.0mg, 0.34 mmol) was dissolved in 50 ml CH2Cl2 and afterthe addition of catalyst (0.025 mmol HCl/EtOH) respective mixtures wereprepared with each of the following compounds taken separately: 1-adamantylamine, 1-methylpiperazine, 1-(2-pyridyl)piperazine, 1-(4-fluorobenzyl)piperazine, 1-(2, 4, 6-trimethylbenzyl)piperazine, 1-bis(4-fluorophenyl)methylpiperazine, 1-(ethanesulfonyl)piperazine, 1-(methylsulfonyl)piperidin-4-amine, 4-(dimethylamino)-piperidine, 1-(4-pyridyl)piperazine, 1-(2-pyrimidyl)piperazinedihydrochloride, 1, 9-dimethyl-1, 4, 9-triazaspiro[5.5]undecanetrihydrochloride, 3, 4-dihydro-2H-spiro[isoquinoline-1, 4?-piperidine], n-piperidin-4-yl-methanesulfonamide, 1-[3-(trifluoromethyl)pyrid-2-yl]piperazine, 1-(cyclohexylmethyl)-4-piperidinamine, 1, 4?-bipiperidine-4-carboxylic acid dihydrochloride, (4-amino-1-piperidinyl)acetic acid dihydrochloride, 2-oxo-2-(1-piperidinyl)ethanamine, 1-(2-amino-ethyl)-pyrrolidin-2-one, 4-amino-1-Boc-piperidine, 3-amino-2-piperidinonehydrochloride, 1-acetyl-4-aminopiperidine hydrochloride in1 ml of CH3OH. Amines containinghydrochloride were neutralized with an equivalent amount of KOH/EtOH (0.06 mmolor 0.12 mmol or 0.18 mmol) solution. The mixtures were stirred at 40C for halfan hour and after that 3/4 of the solvent volume was distilled off. To thecooled reaction mixture (room temperature) the reductant NaBH3CN (13mg, 0.15 mmol) was added portionwise over 1 min. The reaction mixture wasstirred for one hour. Next the reaction mixture was evaporated to dryness, dissolved in 50 ml of CH2Cl2 and extracted twice with 50ml of water and brine (theses stages were omitted for reactions with1, 4?-bipiperidine-4-carboxylic acid dihydrochloride, (4-amino-1-piperidinyl)acetic acid dihydrochloride). The separated organiclayer was evaporated and the synthesized derivatives of 3-formylrifamycin SV(compounds 1-23) were next purified by column chromatography with silicagel (25 cm × 1 cm, silica gel 60, 0.040-0.063 mm/230-400 mesh ASTM, Fluka) withdichloromethane/methanol (from 200:1 to 3:1) as an eluent.To a solution of Reference 3-(Benzoylamino)tetrahydropyridin-2-one:; Reference : 3-(Pyridin-3'-carbonylamino)tetrahydropyridin-2- one:; Oxalyl chloride (20 mmol) was added to a solution of nicotinic acid (10 mmol) in DCM (40 mL), along with one drop of catalytic DMF. The reaction mixture was stirred for 16 h and then the solvent was removed under high vacuum. The resulting crystals were dissolved in DCM (10 mL). In a separate flask, 3- aminotetrahydropyridin-2-one hydrochloride (10 mmol) and 2C03 (30 mmol) were added to water (30 mL) and stirred, giving a solution to which the acid chloride solution was added. The reaction was worked-up as above to give the product (0.10 g, 5percent):Vmax cm 3257 (N-H, amide), 1642, 1541 (secondary CONH, lactam, NH), 1591 , 1479 (aromatic pyridine ring). NMR: deltaEta (400MHz, CDC13) 9.03 (I H, d, J 2.0, 2-aryl CH), 8.71 (I H, dd, J 5.0, 1.5, 6-aryl CH), 8.12 (I H, dt, J 8.0, 2.0, 4-aryl CH), 7.36 (IH, dd, J 8.0, 5.0, 5-aryl CH), 7.27 (I H, br d, J2.0, C5H4N-CONH), 5.91 (IH, br s, CONH-CH2), 4.45 (IH, dt, J 1 1.0, 5.5, CH-CO), 3.44-3.32 (2H, m, CH2NH), 2.72 (IH, dt, J 14.5, 4.5, NHCH- C 2), 2.06-1.93 (2H, m, lactam CH2), 1.70-1.54 (I H, m, lactam CH2).13C NMR: 6c (100MHz, CDC13) 171.8 (lactam C=0), 166.0 (aryl C=0), 152.5 (aryl N- CH), 148.6 (aryl N-CH), 135.3 (ortho-C(-C )), 133.4 (ipso-C), 123.6 (meta-C), 51.2 (CH-CO), 42.0 (CH2-NH), 27.3 (lactam CH2), 21.3 (lactam CH2). HRMS (+ESI) C, , H 13N302 + H+: calcd 220.1081 ; found 220.1085.Reference : 3-(4, -MethylbenzenesuIfonylamino)tetrahydropyridin-2- one:; Phenyl {3-[(2-aminopyrimidin-5-yl) ethynyl] phenyl} carbamate (Example 23) (50 mg), 3- amino-piperidin-2-one hydrochloride (46 mg) and triethylamine (0.06 mL) in THF (2 mL) were heated at 80°C for 24 hours. The reaction mixture was concentrated in vacuo and the solid triturated with water then diethyl ether, dried under vacuum at 60°C to give the title compound as a beige solid (41 mg, 77percent) ; H NMR (DMSO-d6) 1.49-1. 62 (m, 1H), 1.71-1. 82 (m, 2H), 2.16-2. 28 (m, 1H), 3.10-3. 18 (m, 2H), 3.95-4. 04 (m, 1H), 6.42-6. 48 (d, 2H), 6.98-7. 04 (m, 1H), 7.09 (s, 2H), 7.20-7. 31 (m, 2H), 7.65 (s, 2H), 8.41 (s, 2H), 8.85 (s, 1H) ; MS m/e MH 351.Example 10 ; 3-[({4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyquinazolin-6- yl} methyl) amino] piperidin-2-one; (Process (a)); 4- [ (3-Chloro-2-fluorophenyl) amino]-7-methoxyquinazoline-6-carbaldehyde was coupled with 3-amino-piperidin-2-one (prepared by converting To a solution of [Preparation Example 116] Preparation of 3-[(benzylsulfonyl)(methyl)amino]-N-((1S, 2S, 4R)-2-{[tert- butyl(dimethyl)silyl]oxy}-1-isobutyl-4-methyl-5-oxo-5-{[(3R or 3S)-2- OXOPIPERIDINYL] AMMO} PENTVBENZAMIDE 91 mg (0. 15 mmol) of the compound obtained in Preparation Example 58 was dissolved in 5 ml of N, N-DIMETHYLFORMAMIDE and cooled to 0°C, then 34 mg (0.225 mmol) obtained in Preparation Example 115 and 86 mg (0.225 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N, N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring for 3 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5: 95 mixture of methanol and dichloromethane to obtain 21 mg of the title compound at 20percent yield. 1H NMR (400 MHz, CDC) ; 7.82 (1H, s), 7.59 (1H, d), 7.45-7. 33 (7H, m), 6.79 (1H, d), 6.27 (1H, d), 5.48 (1H, s), 4.50-4. 20 (4H, m), 3.80 (1H, m), 3.23 (3H, s), 3.22-3. 12 (2H, m), 2.54 (1H, m), 2.28 (1H, m), 1.97 (1H, m), 1.92-1. 48 (6H, m), 1.39 (1H, m), 1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.11 (3H, s)24.64 mg of 4 (0.087 mmol), 41.05 mg of sodium 2-ethyl-hexanoate (0.247 mmol), 20.16 mg of 15 (which may be prepared according to the procedures described in WO 2002/081480, and the content of which is incorporated herein by reference) (0.134 mmol) and 2 ml of THF are successively introduced into a 20 ml round-bottomed flask with stirring and under an argon atmosphere. Stirring is continued for 4 days at r.t. 20 ml of EtOAc are added to the reaction medium, which is then washed successively with 20 ml of NaOH solution (0.1 N), 20 ml of water and 20 ml of saturated NaCl solution. As product has visibly dissolved in the aqueous phase, this aqueous phase is extracted twice with a mixture of 50 ml of CH2Cl2 and 5 ml of MeOH. The 3 organic phases are combined, dried, filtered and then evaporated to dryness. The crude product is purified by PCC with a 93/7 CH2Cl2/MeOH mixture. 28.49 mg of product 16 are collected (Yld=83percent). TLC (90/10 CH2Cl2/MeOH): Rf=0.28 1H NMR (400 MHz, CDCl3): delta (ppm)=7.11 (d, 1H); 5.70 (d, 1H); 5.67 (m, 1H); 5.48 (dd, 1H); 4.72 (m, 1H); 4.20 (d, 1H); 4.02 (d, 1H); 3.80 (d, 1H); 3.50 (s, 1H); 3.49 (s, 3H); 3.36 (m, 2H); 2.54 (m, 2H); 1.96 (m, 2H); 1.47 (s, 6H); 1.02 (s, 9H) LCMS (ES+, 30 V): tR=2.92 mn|m/z=797+ (2M+H+); 399+ (M+H+); 341+ (M+H+[(H3C)2CO]); 841 (2 MH+HCOOH); 443 (MH+HCOOH)

Molecular Weight:150.61
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:2
Exact Mass:150.0559907
Monoisotopic Mass:150.0559907
Topological Polar Surface Area:55.1
Heavy Atom Count:9
Complexity:103
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes