5-Chloro-2-hydroxybenzamide

(300 g, 1.75 mol) and water (900 ml) were placed in a 3 litre, 4- neck round-bottomed flask under a nitrogen atmosphere and stirred. 5-ethyl-2- methyl-pyridine (284 g, 2.27 mol) and n-butyl acetate (900 ml) were added to the mixture. The mixture was cooled to 0-50C (jacket - 100C) and dropwise addition of ethyl chloroformate (233 g, 2.10 mol) was started. This addition continued over a period of approximately one hour. When the addition was completed, the reaction EPO Preparation of N-(5-chlorosalicyloyl)-8-aminocaprylic Acid; [0137] To a clean, dry, 200 gallon glass-lined reactor, 178 L of dry acetonitrile is added. The agitator is set to 100-125 rpm and the reactor contents are cooled to about 9 C. 74 kg of 5-chloro salicylamide, available from Polycarbon Industries of Leominster, Mass., is charged to the reactor and the charging port is closed. 47 L of dry pyridine is charged to the reactor. The resulting slurry is cooled to about 9 C. Cooling is applied to the reactor condenser and valve overheads are set for total reflux. Over 2 hours, 49.7 kg of ethylchloroformate is charged to the 200 gallon reactor while maintaining the batch temperature at about 14 C. Note that ethylchloroformate can contain 0.1% phosgene and is extremely reactive with water. The reaction is highly exothermic and requires the use of a process chiller to moderate reaction temperature. [0138] The reactor contents are agitated for 30 minutes at 10-14 C., once the ethylchloroformate addition is complete. The reactor contents are then heated to about 85 C. over 25 minutes, collecting all distillate into a receiver. The reactor contents are held at 85-94 C. for approximately 6 hours, collecting all distilled material into a receiver. The reaction mixture is sampled and the conversion (>90%) monitored by HPLC. The conversion is found to be 99.9% after 6 hours. The reactor contents are cooled to about 19 C. over a one-hour period. 134 L of deionized water is charged to the reactor. A precipitate formed immediately. The reactor contents are cooled to about 5 C and agitated for 10.5 hours. The product continued to crystallize out of solution. The reactor slurry is centrifuged. 55 L of deionized water is charged to the 200-gallon, glass-lined reactor and the centrifuge wet cake is washed. The intermediate is dried under full vacuum (28 Hg) at 58 C. for 19.5 hours. The yield is 82.6 kg 6-chloro-2H-1, 3-benzoxazine-2, 4(3H)-dione. This intermediate is packaged and stored so that it is not exposed to water. [0139] In the next preparation, absolutely no water can be tolerated in the steps up to the point where distilled water is added. [0140] 222 L of dry dimethylacetamide is charged to a dry 200 gallon glass-lined reactor. The reactor agitator is set to 100-125 rpm. Cooling is applied to the condenser and valve reactor overheads are set for distillation. 41.6 kg of dry anhydrous sodium carbonate is charged to the reactor and the reactor charging port is closed. Caution is used due to some off-gassing and a slight exothermic reaction. 77.5 kg of dry 6-chloro-2H-1, 3-benzoxazine-2, 4(3H)-dione is charged to the reactor. Quickly, 88 kg of dry ethyl-8-bromooctanoate is charged to the reactor. The reaction is evacuated to 22-24 inches of vacuum and the reactor temperature is raised to 65-75 C. The reactor temperature is maintained and the contents are watched for foaming. The reactor mixture is sampled and monitored for conversion by monitoring for the disappearance of the bromo ester in the reaction mixture by gas chromatography. The reaction is complete after 7 hours. The vacuum is broken and the reactor contents are cooled to 45-50 C. The contents are centrifuged and the filtrate sent into a second 200 gallon glass-lined reactor. 119 L of ethanol (200 proof denatured with 0.5% toluene) is charged to the first 200 gallon reactor, warmed to about 45 C. and the filter cake washed with warm ethanol and this wash is charged to the reaction mixture in the second 200 gallon reactor. [0141] The agitator is started on the second 200 gallon reactor. The reactor contents are cooled to about 29 C. 120 L distilled water is slowly charged to the second reactor, with the water falling directly into the batch. The reactor contents are cooled to about 8 C. The intermediate comes out of solution and is held for 9.5 hours. The resultant slurry is centrifuged. 70 L ethanol is charged to the reactor, cooled to about 8 C., and the centrifuge cake is washed. The wet cake is unloaded into double polyethylene bags placed inside a paper lined drum. This yields ethyl 8-(6-chloro-2H-1, 3-benzoxazine-2, 4(3H)-dionyl)octanoate. [0142] 400 L purified water, USP and 45.4 kg sodium hydroxide pellets are charged to a 200 gallon glass-lined reactor and the agitator is set to 100-125 rpm. 123.5 kg of the ethyl 8-(6-chloro-2H-1, 3-benzoxazine-2, 4(3H)-dionyl)octanoate wet cake is charged to the reactor. The charging port is closed. Cooling water applied to the condenser and the valve reactor overheads are set for atmospheric distillation. The reactor contents are heated to about 98 C. and the conversion is monitored by HLPC. Initially (approximately 40 minutes) the reactor refluxes at about 68 C., however, as the ethanol is removed (over 3 hours) by distillation the reactor temperature rises to about 98 C. The starting material disappears, as determined by HPLC, at approximately 4 hours. The reactor contents are cooled to about 27 C. 150 L puri...To a clean, dry, 200 gallon glass-lined reactor, 178 L of dry acetonitrile was added. The agitator was set to 100-125 rpm and the reactor contents were cooled to about 9 C. 74 kg of 5-chloro salicylamide, available from Polycarbon Industries of Leominster, Mass., was charged to the reactor and the charging port was closed. 47 L of dry pyridine was charged to the reactor. The resulting slurry was cooled to about 9 C. Cooling was applied to the reactor condenser and valve overheads were set for total reflux. Over 2 hours, 49.7 kg of ethylchloroformate was charged to the 200 gallon reactor while maintaining the batch temperature at about 14 C. Ethylchloroformate can contain 0.1% phosgene and is extremely reactive with water. The reaction is highly exothermic and requires the use of a process chiller to moderate reaction temperature. The reactor contents were agitated for about 30 minutes at 10-14 C., once the ethylchloroformate addition was complete. The reactor contents were then heated to about 85 C. over about 25 minutes, collecting all distillate into a receiver. The reactor contents were held at 85-94 C. for approximately 6 hours, collecting all distilled material into a receiver. The reaction mixture was sampled and the conversion (>90%) monitored by HPLC. The conversion was found to be 99.9% after 6 hours. The reactor contents were cooled to about 19 C. over a one-hour period. 134 L of deionized water was charged to the reactor. A precipitate formed immediately. The reactor contents were cooled to about 5 C. and agitated for about 10.5 hours. The product continued to crystallize out of solution. The reactor slurry was centrifuged. 55 L of deionized water was charged to the 200-gallon, glass-lined reactor and the centrifuge wet cake was washed. The intermediate was dried under full vacuum (28 Hg) at about 58 C. for about 19.5 hours. The yield was 82.6 kg 6-chloro-2H-1, 3-benzoxazine-2, 4(3H)-dione. This intermediate was packaged and stored so that it was not exposed to water.General procedure: To a dry round-bottom flask equipped with a magnetic stir bar under an Argon atmosphere was added 0.526g (3.07 mmol) of

Molecular Weight:171.58
XLogP3:2.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:171.0087061
Monoisotopic Mass:171.0087061
Topological Polar Surface Area:63.3
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes