1,3,4-Oxadiazole-2-carboxylic acid, 5-methyl-, potassium salt (1:1)

Off-White Solid

Synthesis of Potassium 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (19b). To a slurry of potassium trimethylsilanolate (411 mg, 3.20 mmol) in ether stirring at rt, was added in one portion ethyl 5-methyl-1, 3, 4-oxadiazole-2-carboxylate (0.50 g, 3.20 mmol). Immediate precipitation was observed with the color changing from white to off-white. The precipitate was removed by filtration, was washed with ether and dried to give the title compound as an off-white solid (580 mg, quantitative yield). To a solution of compound 8-5 (1.1 g, 7.0 mmol) in ether (25 mL) was added potassium trimethylsilanolate (0.9 g, 7 mmol) with stirring. The mixture was stirred at rt overnight, there was white solid precipitated out during the reaction process. After the reaction was complete, the mixture was filtered. The filter cake was washed with a little ethanol and dried in vacuo to afford a white solid 8-6 (0.85 g, 73percent).At 0 deg. C An aqueous KOH solution (5 ml, 780 mg, 13.5 mmol) was added dropwise5-methyl-1, 3, 4-oxadiazole-2-carboxylate (2.1 g, 13.5 mmol) in ethanol (50 ml).Followed by stirring at 0 ° C for 1 hour, Filtration to obtain a solid, The solid was washed with ethanol (20 ml)To give potassium 5-methyl-1, 3, 4-oxadiazol-2-carboxylate (1.6 g, 72percent yield).The stirred solution of 5-methyl-1H-tertazole (0.24 mol) and EtEthyl oxalylchloride (3.78 kg) was slowly added to a mixture of 5-methyltetrazole (2.50 kg), triethylamine (2.86 kg) in toluene (32 L) at OMaterial Eq. Mole Mass Volume Density 5-methyltetrazole 1.0 28.54 2.5 kg (2.4 kg) (96 wt. percent) ethyloxalyl 1.03 29.4 4.014 kg 3.29 L 1.22 chloride triethylamine 1.05 29.97 3.033 kg 4.21 L 0.72 toluene 74 L EtOH 61 L (punctilious) MTBE 15 L KOH aq. 8 L *20 wt. percent) 10percent brine 5 L Ethyl oxalylchloride (4.01 kg) was slowly added to a mixture of 5-methyltetrazole (2.50 kg), triethylamine (3.03 kg) in toluene (32 L) at 0° C. at such a rate that the temperature stays below 5° C. The resulting slurry was stirred for 1 hour at 0-5° C. then the triethylamine/HCl salt was filtered off. The solid was washed with 27 L of cold toluene (5° C.). The combined filtrates were kept at 0° C. and were slowly added to a hot solution of toluene (50° C., 15 L) over 40-50 minutes (NUnder inert atmosphere, 31 g (187 mmol) of 5-methyl-l, 3, 4-oxadiazole-2- carboxylic acid potassium salt, 248 ml of toluene and 0.46 ml of DMF were loaded into a 1L flask. To said mixture at a temperature of 0-5C, 16.1 ml (190 mmol) of oxalyl chloride were slowly added and, after 1.5 h, under vacuum, toluene was partially concentrated up to about half of the initial volume, not exceeding the temperature of 60C. Fresh toluene was added and the operation was repeated. The suspension containing 5-methyl-l, 3, 4-oxadiazole-2-carboxylic acid chloride salt (about 185 mmol) was cooled to 20C, and slowly added by dripping to a mixture of 69 ml (497 mmol) of trimethylamine, 401 ml of acetonitrile and 67 g (155 moles) of methanesulphonate of compound (II), obtained as reported in Example 1. The mixture was maintained under stirring in a 2 L flask at a temperature of 50- 55C until completion of the reaction and subsequently cooled to room temperature. The process was carried out by adding 120 ml of water, 40 ml of acetic acid and 400 ml of ethyl acetate to the obtained mixture; after separation of the lower phase, the organic phase was washed with water, which was discarded, and then concentrated to small volume. The residue was diluted with 480 ml of ethanol and concentrated under vacuum and crystallized from ethanol. 60 g (87% yield) of Raltegravir, having chemical purity >99.5% HPLC, were recovered after filtration at 5- l0C and drying.Ice bath, 5-methyl-1, 3, 4-oxadiazole-2-carboxylic acidPotassium (0.20 g, 1.20 mmol) was suspended in acetonitrile (10 mL)Then oxalyl chloride (0.15 g, 1.20 mmol) was added dropwise to the reaction system, Finally, N, N-dimethylformamide was added(0.1 mL), Ice bath for one hour.After the reaction, Under the ice bath, The above reaction solution was directly added dropwise to a solution of 2-methyl-2- (4-nitrophenyl) propylamine (0.108 g, 0.60 mmol) and N-methylmorpholine (0.36 g, 3.60 mmol) in tetrahydrofuran, Ice bath for two hours. After the reaction, The reaction solution was diluted with ethyl acetate, Saturated brine washing, The organic phase was dried with anhydrous sulfuric acid, filter, Spin dry, The crude product was purified by large plate (petroleum ether / ethyl acetate (V / V): 1/1)Methyl-N- (2- (4-nitrophenyl) propan-2-yl) -1, 3, 4-oxadiazole-2-carboxamide (0.07 g)Yield 20%.To a solution of potassium 5-methyl-i , 3 , 4- oxadiazole-2-carboxylate (4.45 mg, 0.027 mmol) in DCM (0.5 mL) was added oxalyl chloride (0.013 mL, 0.027 mmol). After 1 h, the mixture was added to a pre-stirred solution of(S)-2-(6-(aminomethyl)-4-(4, 4-dimethylpiperidin-i-yl)-5-(2-(4-fluoro-2-methylbenzyl)- 1, 2, 3 , 4-tetrahydroi soquinolin-6-yl)-2-methylpyridin-3 -yl)-2-(tert- butoxy)acetic acid (15 mg, 0.024 mmol) and TEA (10.17 pi, 0.073 mmol) in DCM (0.5 mL). The resulting mixture was stired at roomtemp for 2 h and then concentrated and purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4, 4-dimethylpiperidin-i-yl)-5- (2-(4-fluoro-2-methylbenzyl)- 1, 2, 3 , 4-tetrahydroi soquinolin-6-yl)-2-methyl-6-((5 -methyl-1, 3 , 4-oxadiazole-2-carboxamido)methyl)pyridin-3 -yl)acetic acid (1.5 mg, 2.064 .imol, 8.49% yield). 'HNMR (500MHz, DMSO-d6) oe 7.40 - 7.31 (m, 2H), 7.i8 -7.07 (m, 2H), 7.04 (d, J9.9 Hz, iH), 7.02 - 6.96 (m, iH), 6.9i - 6.73 (m, iH), 5.46 - 5.39 (m, iH), 4.34(d, J13.2 Hz, 1H), 4.09 - 3.94 (m, 2H), 3.63 (br. s., 3H), 3.05 (br. s., 1H), 2.88 - 2.79 (m, 3H), 2.77 - 2.68 (m, 4H), 2.58 (s, 3H), 2.39 - 2.30 (m, 3H), 2.10 (br. s., 1H), 1.52 (br. s., 1H), 1.24 (br. s., 2H), 1.14 (br. s., 1H), 1.09 (s, 9H), 0.96 (br. s., 1H), 0.85 (br. s., 3H), 0.63 (br. s., 3H). LCMS (M+H) = 727.2.To a solution of potassium 5-methyl-i, 3 , 4-oxadi azole-2-carboxylate (30 mg, 0.181 mmol) in DCM (0.5 mL) was added oxalyl chloride (0.05 ml, 0.100 mmol). The mixture was stirred at rt for 1 h, concentrated to dryness under vacuum. The residue was dissolved in THF (0.5 mL) and added to a solution of(S)-2-(6-(aminomethyl)-4-(4, 4-dimethylpiperidin- 1 -yl)-5 -(4-(4-fluorophenethoxy)phenyl)-2-methylpyridin-3 -yl)-2-(tert- butoxy)acetic acid (0.018 g, 0.031 mmol) and DIPEA (0.05 ml, 0.286 mmol) in THF (0.5 mL). The mixture was stirred at rt for 1 h and 0.1 ml of water was added and stirred at rt for 0.5 h. then, removed solvent in vacuum and purified by prep-HPLC to afford (S)-2- (tert-butoxy)-2-(4-(4, 4-dimethylpiperidin- 1 -yl)-5 -(4-(4-fluorophenethoxy)phenyl)-2- methyl-6-((5 -methyl- 1, 3 , 4-oxadiazole-2-carboxamido)methyl)pyridin-3 -yl)acetic acid (0.0077 g, 0.011 mmol, 35.9 % yield). LCMS (M+H) = 688.2.To a solution of A round-bottom flask was charged with compound 4-7 (0.15 g, 0.19 mmol), compound 8-6 (0.04 g, 0.23 mmol), EDCI (0.04 g, 0.21 mmol) and HOAT (0.03 g, 0.22 mmol), and then DCM (20 mL) was added under N2. The mixture was cooled to 0 C, and DIPEA (0.1 mL, 0.6 mmol) was added slowly. The resulting mixture was stirred at 30 C for 4 hours. After the reaction was complete, the mixture was quenched with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL) twice. The combined organic layers were washed with saturated aqueous NaC1 (20 mL) and dried over anhydrous Na2504, and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V:V) = 2:1 to give compound 8-7 (0.05 g, 30%) as a white solid. MS (ESI, pos.ion) m/z: 874[M+lfb; and 1H NIVIR (600 IVIFIz, CDC13): 5 10.37 (s, 1H), 8.59 (s, 1H), 7.98-7.85 (m, 2H), 7.62-7.54(m, 1H), 7.15-7.03 (m, 2H), 5.76 (dd, J= 17.6, 9.0 Hz, 1H), 5.59 (s, 1H), 5.07-4.98 (m, 1H), 4.84 (t, J 8.0 Hz, 1H), 4.71 (t, J 7.6 Hz, 1H), 4.64 (d, J= 11.5 Hz, 1H), 4.20 (d, J= 8.8 Hz, 1H), 3.91 (s, 3H), 3.30-3.18 (m, 1H), 2.99-2.88 (m, 1H), 2.79 (s, 2H), 2.70 (s, 4H), 2.53 (s, 3H), 2.33-2.28 (m, 1H), 2.24-2.17 (m, 1H), 1.79-1.68 (m, 3H), 1.42 (d, J= 6.9 Hz, 6H), 1.33-1.27(m, 7H), 0.98-0.85 (m, 4H) ppm.A solution of compound 20-12 (0.2 g, 0.2 mmol) in isopropanol (2 mL) was cooled to 0C, and a solution of HC1 in isopropanol (40%, 5 mL) was added. The mixture was stirred at rt until no more gas evolution. The mixture was filtered; the filter cake was washed with EtOAc (5 mL) and dried in vacuo to give a white solid. A round-bottom flask was charged with the white solid, compound 20-14 (0.1 g, 0.6 mmol), EDCI (0.2 g, 1.5 mmol) and HOAT (0.15 g, 1.1 mmol), and then DCM (10 mL) was added under N2. The mixture was cooled to 0 C, and DIPEA (0.5 mL, 3 mmol) was added slowly. The mixture was stirred at 30 C for 6 hours. After the reaction was complete, the mixture was quenched with water (10 mL). The resulting mixture was extracted with DCM (10 mL) twice. The combined organic layers were washed with saturated aqueous NaC1 (10 mL) and dried over anhydrous Na2504, and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V:V) = 2:1 to give compound 20-15 as a white solid (0.140 g, 60%).MS (ESI, pos.ion) m/z: 890.8[M+lfb; and'HNMR (600 IVIHz, CDC13): 5 10.31 (s, 1H), 8.03 (d, J 7.5 Hz, 1H), 7.93 (s, 1H), 7.84-7.79 (m, 2H), 7.54 (s, 1H), 7.06-7.01 (m, 2H), 5.70 (dd, J= 17.9, 8.7 Hz, 1H), 5.52 (s, 1H), 5.03 -4.98 (m, 1H), 4.76 -4.69 (m, 2H), 4.65 -4.60 (m, 1H), 4.13 -4.09 (m, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.26 - 3.19 (m, 2H), 2.75 (dd, J 13.8, 7.4 Hz, 1H), 2.65 (s, 3H), 2.31 (d, J= 8.6Hz, 1H), 2.07-2.04 (m, 1H), 1.85 (dd, J= 15.5, 9.2 Hz, 2H), 1.78 (dd, J= 10.5, 5.1 Hz, 1H), 1.66 - 1.62 (m, 1H), 1.50 (d, J= 7.3 Hz, 4H), 1.40 (d, J 6.9 Hz, 7H), 1.26 (d, J 4.2 Hz, 3H), 1.20 (s, 3H), 0.86- 0.77 (m, 3H).A reactor (100 ml), equipped with glass impeller was flushed with N2 flow and then cooled to - 10C. The reactor was charged with, N-methylmorpholine (0.21 ml), N- methyl-2-pyrrolidone (NMP) (3.2 ml), acetonitrile (75 ml), and oxadiazole potassium (5g, 1.6eq). To the stirred reaction mixture pivaloyl chloride (2.6 ml, 1.76 eq) was added dropwise at (- 10C). The resulting slurry was stirred at -10C for 15 hour. Then RLT-9-OP (5g, l eq) was added and the resulting mixture was heated to 20C, and stirred at 20C. The solvent was then evaporated to form a residue. A solution of NH4OH 25% (10ml) and isopropanol (1 5ml) were added to the residue and the resulting mixture was stirred at RT for 1 hour. The solvent was then evaporated. 1PA (30ml) and water (60ml) were added to the residue and this mixture was stirred at RT overnight to form a slurry. The slurry was filtered and the collected solid was washed with water (10 ml) and isopropanol (5ml). The product was then dried under vacuum at 50C overnight. Raltegravir (7.1 g) was obtained.To a 0.5 liter reactor was added acetonitrile ( 15 vol), N-methylpyrrolidinone ( 1 vol) and N-methylmorpholine (0.5 g). The resulting solution was cooled to about 0C and then methyl oxadiazole- potassium (8g) was added. Pivaloyl chloride (7.22 ml) was then added dropwise (over 10 min). The resulting mixture was stirred for about 6 h.N-Methylmorpholine (5.9 g) and RLT-9 were then added. The resulting mixture was then heated to 20C and stirred for 16h. The solvent was then evaporated to provide a residue. Water (75 ml) and isopropyl alcohol (25 ml) were added to the residue. The resulting solution was stirred overnight at RT. A precipitate formed and was filtered and washed with water (10 ml) and IPA (20 ml). The product was dried under vacuum at 60C overnight to give 8.76g Raltegravir (85.7% assay, 77% yield). The obtained crude product was purified by slurry in MeOH/Water mixture.5-methyltetrazole (6.25 g, 74 mmol) and triethylamine (7.5 g, 74 mmol) were dissolved in toluene (80 mL) at 0 C, Ethylglyoxyl chloride (10.0 g, 74 mmol) was added dropwise to the reaction solution, After the dropwise addition, The reaction was continued for 30 minutes.The reaction produces a solid filter removed, And washed several times with cold toluene, The combined toluene solution was then added dropwise to hot toluene (50 C)After dripping, The temperature rose to 70 C, The reaction was continued for 1 hour.To be cooled to room temperature, The reaction solution was washed with saturated brine, Dried and concentrated (steamed at 20 C).The crude product was dissolved in ethanol (100 mL)Cooled to below 10 C, A solution of potassium hydroxide (4.17 g, 74 mmol) in water (10 mL) was added dropwise thereto.And the stirring reaction was continued for 30 minutes at this temperature.The resulting solid was collected by filtration, Washed with cold ethanol and t-butyl methyl ether, Dried at 20 C under vacuum, The desired intermediate 18 (8.0 g) was obtained in 65% yield.2 g of compound a was placed in 60 mL of toluene (Toluene), and then 4.95 mL of Et3N was added to form a colorless clear transparent, and the system was cooled to 0 C in a low temperature reaction kettle.Then add 3.2 mL of Cl(O)CCO2Et dropwise during the dropwise addition process.The middle system gradually turned into a yellow viscous shape, and after the completion of the dropwise addition, the reaction was continued at 0 C for 6 hours. After that, the system is reacted from low temperature.The mixture was taken out, immediately filtered, and the solid was washed with white toluene (50 ml) which was cooled in advance, and the filtrate was collected.After that, the filtrate was slowly heated to 70 C, and a large amount of bubbles appeared in the heating process (N2), and no bubble was generated in the system to stop heating.The heating time was about 5 hours, after which the system was washed with 200 mL of saturated NaCl solution.The organic phase was collected, concentrated under reduced pressure to remove toluene, and the residue was dissolved in 30 mL of EtOH.Then add 10mL 40% KOH solution, The system has a large amount of solids, Stirring was continued for 2 hours, and suction filtration gave a yellow solid.Wash with 100 mL of EtOH and 100 mL of MBTE (methyl tert-butyl ether), respectively.3.62g of a pale yellow solid, That is, the compound 5-methyl 1, 3, 4-oxadiazole-2carboxylate potassium c was 92.8%

An intermediate in the preparation of HIV-integrase inhibitors

Molecular Weight:166.18
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:165.97807345
Monoisotopic Mass:165.97807345
Topological Polar Surface Area:79
Heavy Atom Count:10
Complexity:132
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes