Warner Chilcott Co., Inc.

The in vitro acid reactivity of three commercial brands of aluminum and magnesium hydroxide antacid tablets was determined by two methods. A pH-stat test was used to examine the rate and extent of acid neutralization at a constant pH of 3.0. A modified Rossett-Rice test was used to record the length of time during which the antacid products maintained the pH of a simulated gastric solution at between 3.0 and 5.0. Acid neutralization by product A was faster and more complete than that by product B or C. The percent of theoretical acid consuming capacity at 30 minutes of product A (86.8%) was significantly greater than that of product B (56.1%) and product C (57.0%) tablets. The 32-minute Rosett-Rice time A was significantly longer than the 16- and 12-minute times of products B and C, respectively. The differences observed may be attributed to different reactivities of the raw materials used in the products, or formulation and processing variables. It is not known how the data relate to in vivo performance.

4-(3-Hydroxypropyl)pyridine (I) (137 g.) in 1200 cc. Me₂CO containing 125 g. MeBr and the mixture kept at 30° overnight gave 199 g. I.MeBr, m. 78-80° (from EtOH-Me₂CO).I.MeBr (174 g.) in 700 cc. EtOH hydrogenated at 60° and 800 lb., cooled, filtered, and evaporated in vacuo on the steam bath yielded 150 g. 1-methyl-4-(3-hydroxypropyl)piperidine-HBr (II), m. 117-18° (from 600 cc. 1:3 EtOH-Me₂CO).II (17 g.) in 60 cc. EtOH containing 18 g. Me₂NH heated 1.5 hrs. at 82° in a pressure bottle, cooled, and evaporated to dryness in vacuo on the steam bath yielded 6.0 g. 1-methyl-4-(3-dimethylaminopropyl)piperidine-2H Cl (III), m. 245-6° (decomposition) (from 1:2 EtOH-Me₂CO).I (137 g.) in 1600 cc. H₂O containing 65 g. H₂SO₄ treated slowly with stirring at about 50° with 211 g. KMnO₄, the mixture warmed to 80° and filtered, and the filtrate concentrated to 500 cc. and cooled gave 92 g. 3-(4-pyridyl)propionic acid (IV), m. 221-4° (from H₂O).IV (75.5 g.) in slightly more than 0.5 mole 25% aqueous Me₂NH heated until most of the H₂O had evaporated, the acid solution bubbled slowly 14 hrs. at 210° with Me₂NH, the mixture cooled and triturated with 200 cc. C₆H₆ and filtered, and the filtrate evaporated on the steam bath gave 35 g. N,N-dimethylamide (V) of IV, b_0.35 143.5-5°.V (21.5 g.) in 80 cc. Me₂CO kept several hrs. with 24 g. MeBr in a pressure bottle gave 22 g. V.MeBr, m. 113.5-15.5° (from Me₂CO-EtOH).V.MeBr (9.5 g.) in 100 cc. H₂O hydrogenated under ambient conditions over 0.25 g. PtO₂ gave 8 g. 1-methyl-4-(2-dimethylamidoethyl)piperidine-2HBr (VI), m. 134-5° (from Me₂CO).VI (8 g.) added to 30 cc. 30% aqueous K₂CO₃, the org layer separated, the aqueous layer extracted with C₆H₆, the combined organic layer and extract dried and evaporated, the residual oil (5.5 g.) dissolved in 25 cc. dry C₆H₆, the solution added during 15 min. at room temperature with stirring to 1.9 g. LiAlH₄ in 100 cc. dry Et₂O, the mixture refluxed 2 hrs., treated slowly with cooling with 8.8 g. EtOAc and then 10.7 g. NH₄Cl in 30 cc. H₂O and stirred with cooling at 0° while being treated with solid Na₂SO₄, and the organic layer treated with a slight excess of HCl in EtOH yielded 1.5 g. III, m. 254-5° (decomposition). p-O₂NC₆H₄CH₂CO₂H (181 g.) and 300 g. SOCl₂ refluxed 2 hrs. and evaporated in vacuo, the residue dissolved in 200 cc. C₆H₆, the solution added dropwise to 100 g. Me₂NH in 500 cc. C₆H₆ below 10°, the mixture refluxed 1 hr. and filtered hot, and the filtrate chilled gave 87.5 g. p-O₂NC₆H₄CH₂CONMe₂ (VII), m. 88-90°.VII (85 g.) in 800 cc. EtOH hydrogenated at 25° over 1.0 g. PtO₂ gave 58 g. p-H₂NC₆H₄CH₂CONMe₂ (VIII), m. 98-100°.VIII (32 g.), 0.5 g. PtO₂, 15.1 cc. concentrated HCl, 26.6 g. 40% aqueous CH₂O, and 100 cc. 95% EtOH hydrogenated at 25° and 3 atm., the mixture filtered, the filtrate evaporated to dryness in vacuo, the residue dissolved in 100 cc. H₂O, the soln basified strongly with 50% aqueous NaOH and extracted with 100 cc. C₆H₆, the extract treated with 10 cc. Ac₂O, warmed 15 min. on the steam bath, cooled, shaken with 100 cc. 10% aqueous NaOH, and extracted with 125 cc. 1:4 dilute HCl, the acidic extract basified with 50% aqueous NaOH and extracted with C₆H₆, and the extract worked up gave 30 g. p-Me₂NC₆H₄CH₂CONMe₂ (IX), b_0.1 125-30°, m. 78-9°.IX (10.3 g.) in 250 cc. Et₂O added to 1.9 g. LiAlH₄ in 100 cc. Et₂O, the mixture refluxed 0.5 hr., cooled, treated with 13.2 g. EtOAc and then with 10.7 g. NH₄Cl in 35 cc. H₂O, and the Et₂O layer worked up gave 9.0 g. p-Me₂NC₆H₄(CH₂)₂N Me₂ (X), b_0.05 72-5°.X (9.0 g.) in 100 cc. absolute EtOH treated with 8.5 cc. concentrated HCl and diluted with 100 cc. absolute Et₂O gave 10.6 g. X.H Cl, m. 227-8° (decomposition).X (16.5 g.) in 130 g. glacial AcOH hydrogenated 48 hrs. at 25° and 1 atm. over 1.0 g. PtO₂ yielded 11.5 g. 1-dimethylamino-4-(2-dimethylaminoethyl)cyclohexane (XI), m. 280° (decomposition). p-O₂NC₆H₄(CH₂)₂CO₂H was converted similarly to 56% p-O₂NC₆H₄(CH₂)₂CONMe₂, m. 63.5-4.5° (from 1: 1 C₆H₆-ligroine, b. 60-80°).Diacid chloride of trans-cyclohexane-1,4-dicarboxylic acid (XII) (41.8 g.) in 100 cc. dry C₆H₆ added slowly below 20° to 58 g. Me₂NH in 300 cc. dry C₆H₆, the mixture warmed and filtered hot, and the filtrate chilled yielded 12.5 g. 1,4-trans-bis(dimethylcarbamoyl)cyclohexane (XIII), m. 201° (from C₆H₆), which hydrogenated yielded 57%, 1,4-trans-bis(dimethylaminomethyl)cyclohexane (XIV), b_0.03 62°, m. 35°; 37% di-H Cl salt, m. 309-10°.Similarly were prepared 33% cis isomer of XIII, m. 123-3.5°; and the cis isomer of XIV, b_0.05 58° (di-HCl salt, m. 290°). m-HO₂CC₆H₄CH₂CO₂H (39 g.) and 150 cc. SOCl₂ refluxed 1 hr. and evaporated in vacuo on the steam bath, the residue in 150 cc. dry C₆H₆ added slowly below 20° to 45 g. Me₂NH in 300 cc. dry C₆H₆, the mixture cooled, and filtered, and the filtrate washed with 30% aqueous K₂CO₃ and distilled gave 33 g. m-Me₂NOCC₆H₄(CH₂)₂CONMe₂, m. 88-90°, b_0.1 170-5°, which reduced gave 59% m-Me₂NCH₂C₆H₄(CH₂)₂NMe₂, b_0.05 68° (50 % di-HCl salt, m. 253-5°).In the same manner were prepared 54% o-C₆H₄(CH₂CONMe₂)₂, m. 160.5-61° (from C₆H₆); 68% o-C₆H₄(CH₂CH₂NMe₂)₂, b_0.05 85° (81% di-HCl salt, m. 233°); 55% 1,2-bis(2-dimethylaminoethyl)cyclohexane-2HCl, m. 240-2°.Isocinchomeronic acid (100 g.)and 500 g. SOCl₂ refluxed 16 hrs., filtered,and evaporated to dryness in vacuo on the steam bath, the residue dissolved in 250 cc. dry C₆H₆, the solution added slowly below 20° to 162 g. Me₂NH in 700 cc. dry C₆H₆, the mixture refluxed a few min. and filtered hot, and the filtrate chilled yielded 72 g. bisdimethylamide of isocinchomeronic acid (XV), m. 139.5-40.5° (from 500 cc. C₆H₆), which was reduced further to 10% 2,5-bis(2-dimethylaminoethyl)pyridine (XVI), b_0.07 84° (36% di-HCl salt, m. 265°), and 35% piperidine analog of XVI, b_0.05 60° (66% tri-HCl salt, m. 266°) (all HCl salts melted with decomposition).XV (11.1 g.) in 50 cc. Me₂CO containing 9.0 g. MeBr kept 16 hrs. at 65° in a pressure bottle gave 24 g. XV.MeBr, m. 158-61° (from EtOH-Et₂O).XV.MeBr (24 g.) in 100 cc. absolute EtOH hydrogenated about 16 hrs. over 1.0 g. PtO₂ and filtered, the filtrate evaporated in vacuo on the steam bath, the residue in 10 cc. H₂O treated with 50 g. K₂CO₃ in 75 cc. H₂O, the mixture extracted with C₆H₆, and the extract worked up gave 10 g. 1-methyl-2,5-bis(dimethylcarbamoyl)piperidine, b_0.02 145-50°.

3-Methyl-6-pyridazone alkylated as described previously (C.A. 50, 13034e) with Me₂CHCHBrCO₂Et yielded 41% Et α-(3-methyl-6-pyridazon-1-yl)isovalerate (I), b_0.01 95-9°.I refluxed 1 hr. with excess 10% aqueous NaOH, cooled, and acidified with concentrated HCl, and the precipitate recrystallized from H₂O or very dilute EtOH gave α-(3-methyl-6-pyridazon-1-yl)-isovaleric acid (II), m. 148-50°.In the same manner were prepared the following acid analogs of II (m. p. given): butyric (III), 191-1.5°; valeric, 162-3°; caproic, 152-3°; heptanoic, 153-4.5°.3-Phenyl-6-pyridazon-1-ylacetic acid (IV) m. 227-8°.The appropriate acid and a suitable anhydride in pyridine refluxed until the CO₂ evolution ceased gave the corresponding ketone N:CMe.CH:CH.CO.NCHRCOR'(V).III (22 g.), 100 cc. Ac₂O, and 100 cc. refluxed 4 hrs. and evaporated in vacuo on the steam bath, the residue dissolved in 150 cc. C₆H₆, the solution washed with 100 cc. 10% aqueous K₂CO₃, dried, and evaporated, and the residue distilled gave 13.5 g. 3-(3-methyl-6-pyridazon-1-yl)-2-pentanone, b_0.05 84°, n²⁵_D 1.5097.In the same manner were prepared the following compounds: V (R' = Me) (R, % yield, and b.p./mm. given): Pr, 58, 96°/0.10; iso-Pr, 56, 83.5°/0.02; Bu, 51, 118°/0.35; Am, 60, 135°/0.60.V (R = H)(R', % yield, and m.p. given): Et, 44, 95-7°; Pr, 23, 73-5°, iso-Pr, 8, 126-7°; Bu, 20, 84.5-86°; iso-Bu, 19, 102-3°; EtMeCH, 3, 92.5-3.5°; Am, 14, 103-4°; C₆H₁₃, 19, 92-5°; C₇H₁₅, 17, 85-6°.IV (17.5 g.), 75 cc. Ac₂O, and 75 cc. pyridine refluxed 4 hrs., the volatile materials removed in vacuo, and the residue recrystallized 6 times gave 3.0 g. 3-phenyl-6-pyridazon-1-ylacetone, m. 140-2°.3-Methyl-6-pyridazon-1-ylacetic acid (10.5 g.), 70 cc. (EtCO)₂O, and 70 cc. pyridine refluxed 20 hrs., the volatiles removed in vacuo from a steam bath, the residue dissolved in 100 cc. C₆H₆, the solution washed with two 100-cc. portions N NaOH, the alk. wash reëxtd. with 100 cc. C₆H₆, and the C₆H₆ layer and extract evaporated gave 5 g. 1-(3-methyl-6-pyridazon-1-yl)-2-butanone, m. 95-7° (from ligroine, b. 60-70°).3-Methyl-6-pyridazone (VI) (11.0 g.), 8.0 g. CH₂: CHAc, and a tiny chip of Na in 100 cc. absolute EtOH allowed to stand 1 hr., the mixture treated with 2 drops concentrated HCl, the EtOH distilled off in vacuo, and the residue fractionated gave 17 g. 4-(3-methyl-6-pyridazon-1-yl)-2-butanone, b_0.05 113-18°, m. 57-9° (from ligroine); semicarbazone, m. 179-80° (from H₂O).VI (18.0 g.) added to 4.2 g. Na in 200 cc. EtOH, the mixture treated with stirring below 10° with 21.3 g. MeCHClAc, refluxed 2 hrs., and evaporated in vacuo on the steam bath, the residue dissolved in. 100 cc. C₆H₆, and the solution washed with 30% aqueous K₂CO₃, dried, and distilled yielded 8.7 g. 3-(3-methyl-6-pyridazon-1-yl)-2-butanone (VII), b_0.1 90-100°, n²⁵_D 1.5063; semicarbazone, m. 194-7° (from H₂O).Absolute iso-PrOH (100 cc.), 20.4 g. (iso-PrO)₃Al, and VII distilled during 2 hrs. to give 10 cc. distillate, the mixture cooled, acidified with 25.5 cc. concentrated HCl, basified with 24 g. NaOH in 50 cc. H₂O, and extracted with C₆H₆, and the extract worked up gave 15 g. 3-(3-methyl-6-pyridazon-1-yl)-2-butanol, b_0.1 95°, m. 73-6°.VII (16 g.) in 50 cc. Et₂O added slowly at 10° with stirring to MeMgI from 2.64 g. Mg and 17.1 g. MeI in 125 cc. dry Et₂O, the mixture decomposed with 7 g. NH₄Cl in 20 cc. H₂O, treated with excess anhydrous K₂CO₃, and filtered, the solid washed with two 100-cc. portions C₆H₆, the combined Et₂O layer and C₆H₆ washings evaporated on the steam bath in vacuo, the residue distilled, the distillate (12 g.), b_0.02 80-90°, refluxed 2 hrs. with 6.9 g. H₂NCONHNH₂.HCl and 4.9 g. NaOAc in 30 cc. H₂O, and filtered, the filtrate evaporated to dryness on the steam bath in vacuo, the residue treated with 100 cc. C₆H₆, the solid filtered off, and the filtrate distilled gave 7 g. 3-(3-methyl-6-pyridazon-1-yl)-2-methyl-2-butanol, b_0.02 95-100°, m. 57.5-8.5° (from ligroine).