Ketorolac tromethamine CAS 74103-07-4
Introduction：Basic information about Ketorolac tromethamine CAS 74103-07-4, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Ketorolac tromethamine Basic information
| Product Name: | Ketorolac tromethamine |
| Synonyms: | KETOROLAC TRIS SALT;KETOROLAC TROMETHAMINE;KETOROLAC TROMETHAMINE SALT;(+/-)-5-BENZOYL-2,3-DIHYDRO-1H-PYRROLIZINE-1-CARBOXYLIC ACID, TRIS (HYDROXYMETHYL) AMINOMETHANE SALT;(+/-)-5-benzoyl-2,3-dihydro-1h-pyrrolizine-1-carboxylic acid tris(hydroxymethyl)methylamine salt;(+/-)-5-BENZOYL-2,3-DIHYDRO-1H-PYRROLIZINE-1-CARBOXYLIC ACID TRIS SALT;KETROLAC TROMETHAMINE SALT;(±)-Form tromethamine salt |
| CAS: | 74103-07-4 |
| MF: | C19H24N2O6 |
| MW: | 376.41 |
| EINECS: | |
| Product Categories: | 11;Other APIs;Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical raw material;API;Acular |
| Mol File: | 74103-07-4.mol |
Ketorolac tromethamine Chemical Properties
| Melting point | 160-161 C |
| storage temp. | 2-8°C |
| solubility | H2O: 15 mg/mL stable at least one month at −20 °C., soluble |
| form | crystalline |
| color | White to Light yellow |
| biological source | synthetic (organic) |
| Water Solubility | H2O: soluble 15mg/mL, clear, colorless to faintly yellow (stable at least one month at -20 °C.) |
| λmax | 322nm(MeOH)(lit.) |
| Merck | 14,5306 |
| Stability: | Hygroscopic |
| InChI | InChI=1S/C15H13NO3.C4H11NO3/c17-14(10-4-2-1-3-5-10)13-7-6-12-11(15(18)19)8-9-16(12)13;5-4(1-6,2-7)3-8/h1-7,11H,8-9H2,(H,18,19);6-8H,1-3,5H2 |
| InChIKey | BWHLPLXXIDYSNW-UHFFFAOYSA-N |
| SMILES | C(N)(CO)(CO)CO.C(C1C=CC=CC=1)(C1=CC=C2C(C(=O)O)CCN12)=O |
| CAS DataBase Reference | 74103-07-4(CAS DataBase Reference) |
Safety Information
| Hazard Codes | T |
| Risk Statements | 25-36/37/38-23/24/25 |
| Safety Statements | 26-45-36/37/39 |
| RIDADR | UN 2811 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | UY7759900 |
| HazardClass | 6.1(a) |
| PackingGroup | II |
| HS Code | 2933995500 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Acute Tox. 3 Oral Eye Irrit. 2 Skin Irrit. 2 STOT SE 3 |
| Description | Ketorolac tromethamine is a nonsteroidal antiinflammatory agent that exhibits analgesicand antipyretic activity. The compound is effective in the management of moderate tosevere postoperative pain. It is, however, the first of this type of agent to beadministered parenterally as an analgesic and is specifically indicated for intramuscularinjection. Ketorolac represents a useful alternative to the narcotic analgesics due to itslack of abuse potential. |
| Description | Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) and a non-selective COX inhibitor (IC50 = 20 nM for both COX-1 and COX-2). It prevents increases in paw swelling, increases paw withdrawal latency in a hot-plate test, and decreases prostaglandin E2 (PGE2) levels in paw tissue in a mouse model of carrageenan-induced inflammation when administered at a dose of 30 mg/kg. Ketorolac is a racemic mixture containing the active (S)-ketorolac and inactive (R)-ketorolac enantiomers. Formulations containing ketorolac have been used to manage postoperative pain and as ophthalmic solutions to treat ocular pain and inflammation. |
| Chemical Properties | Off-White to Pale Yellow Solid |
| Chemical Properties | A carboxylic acid derivative nonsteroidal antiinflammatory agent, ketorolac tromethamine occurs as an off-white crystalline powder with a pKa of 3.54 (in water). More than 500 mg are soluble in one mL of water at room temperature. The commercially available injection is a clear, slightly yellow solution with a pH of 6.9 – 7.9. Sodium chloride is added to make the solution isotonic. Ketorolac tromethamine may also be known as RS-37619-00- 31-3; many trade names are available. |
| Originator | Syntex (USA) |
| Uses | Analgesic;Cyclooxygenase Inhibitor |
| Uses | Ketorolac is used primarily for its analgesic effects for short-term treatment of mild to moderate pain in dogs and rodents. The duration of analgesic effect in dogs is about 8 – 12 hours, but because of the availability of approved, safer NSAIDs for dogs, its use is questionable. |
| Uses | Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory. |
| Definition | ChEBI: An organoammonium salt resulting from the mixture of equimolar amounts of ketorolac and tromethamine (tris). It has potent non-sedating analgesic and moderate anti-inflammatory effects. It is used in the short-term management of post-operative pain, and ineye drops to relieve the ocular itching associated with seasonal allergic conjunctivitis. |
| Indications | Ketorolac tromethamine is a pyrrolol-pyrrole nonsteroidal anti- inflammatory agent that inhibits prostaglandin formation. Prostaglandins mediate inflammation within the eye by disrupting the blood-aqueous barrier, inducing vasodilation and increasing intraocular pressure. Prostaglandins may also cause iris sphincter constriction (miosis) independent of cholinergic mechanisms. Ketorolac tromethamine is marketed for use before cataract extraction in human patients (to prevent miosis during surgery) and for control of post surgical inflammation, especially following cataract surgery. It is also approved for management of conjunctivitis associated with seasonal allergy in people. In veterinary medicine, ketorolac tromethamine is primarily used to control surgical or nonsurgical uveitis particularly in cases with concurrent corneal bacterial infection or ulceration when topical corticosteroids are contraindicated. It is also used in diabetic patients, especially smaller patients, adversely affected by systemic uptake of topically applied corticosteroids. Nonsteroidal agents like ketorolac tromethamine can be combined with topical steroids in patients with severe uveal inflammation. |
| Manufacturing Process | Preparation of 2-bromo-4-chloro-N-methyl-N-phenylbutanamide 4-Chlorobutanoyl chloride (62 g, 440 mmol) and phosphorus tribromide (3 g)were added to a distillation flask, and heated to 90°C. Bromine (77.5 g, 485mmol) was added over eight hours, with the solution being allowed todecolorize between additions. After the addition was complete, and thesolution decolorized, a vacuum was slowly applied, and the acid gases andphosphorus tribromide scrubbed. Unreacted starting material was distilled at98-100°C/22 mm Hg, and the temperature slowly increased to 105°C, wherea mixture of 2-bromo-4-chlorobutanoyl chloride and 2-bromo-4-chlorobutanoyl bromide began to distill. Pure 2-bromo-4-chlorobutanoylbromide distilled at approximately 108°C. The combined yield of 2-bromo-4-chlorobutanoyl chloride and 2-bromo-4-chlorobutanoyl bromide was 100.5 g,with a bromide/chloride ratio of approximately 6:1. The mixture of 2-bromo-4-chlorobutanoyl bromide and chloride is directly usable in the preparation ofthe butanamide, if desired, or may be separated and either component used. 2-Bromo-4-chlorobutanoyl bromide (300 mmol) was added to a solution of Nmethylaniline (320 mmol) and triethylamine (330 mmol) in toluene (340 mL).The reaction was exothermic, and the mixture was cooled to maintain thetemperature at about 40°C. After the addition was complete, the resultingmixture was stirred for 30 minutes, 150 mL water was added, and the mixturewas stirred further. The aqueous and organic phases were separated, and theorganic phase was washed with 5% hydrochloric acid and with water. Thetoluene was evaporated completely under vacuum to yield 86.3 g 2-bromo-4-chloro-N-methyl-N-phenylbutanamide (98% yield, approximately 95-96%pure). A solution of methylmagnesium chloride in butyl diglyme (4.0 L, 2.8 M, 11.2mol, 2.8 equivalents with respect to 2-bromo-4-chloro-N-methyl-Nphenylbutanamide) was added to a 12 L 4-necked round bottom flask fittedwith a mechanical stirrer and two 1 L addition funnels, under a nitrogenatmosphere. 2-Bromo-4-chloro-N-methyl-N-phenyl-butanamide (3.98 mol)was added to the first addition flask, and pyrrole (3.04 equivalents withrespect to 2-bromo-4-chloro-N-methyl-N-phenyl-butanamide) was added tothe second. The pyrrole was slowly added to the methylmagnesiumchloride/butyl diglyme solution at 45-50°C over 3 hours. The resulting viscousmixture was cooled to 25°C and stirred for 30 min. 2-Bromo-4-chloro-Nmethyl-N-phenylbutanamide was added to the resulting mixture over a periodof 2 hours at 25-30°C, and the resulting solution was stirred for another 3hours. The dark colored reaction mixture was transferred into 5.76 mol 2 Nhydrochloric acid with rapid stirring for 1 hour. The aqueous phase wasremoved, and 0.8 L 15 weight % ammonium chloride in water was added tothe organic phase. The resulting mixture was stirred at 35-40°C for 10 min,the aqueous phase then removed, and hexanes (2.4 L) added. The resultingsuspension was cooled to -20°C and maintained at that temperature for a fewminutes. The precipitate was filtered in a 300 mL sintered glass funnel andwashed with hexanes (1 L). Drying of the solid under vacuum at 25-30°Cyielded 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide (81% yield). A solution of 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide in toluenewas added dropwise at 85°C over 40 min to 1 hour to a stirred suspension ofALIQUAT 336 (phase transfer catalyst, 2 mol % with respect topyrrolylbutanamide) and granular sodium hydroxide (3 equivalents) in toluene(50 mL). After the addition was complete, the suspension was stirred under anitrogen atmosphere at a temperature of 85°C for 30 min, then cooled to35°C. Cooled water (200 mL) was rapidly added to the mixture and stirred for15 min at 25°C. The solution was rinsed with water and the layers wereseparated. The organic layer was washed with water, then distilled underatmospheric pressure to recover the toluene and water. The resultant solutionwas cooled to 50°C and allowed to crystallize after the addition of hexane anda seed crystal. The suspension was cooled to 5°C and stirred for 15 minutes.The resultant precipitate was filtered, washed with 100 mL of hexane, anddried under vacuum at 25°C to yield approximately 38 g (63%) N-methyl-Nphenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide. This solid was recrystallizedfrom toluene to yield colorless crystals of N-methyl-N-phenyl-2,3-dihydro-1Hpyrrolizine-1-carboxamide, melting point 112-112.5°C. Benzoyl chloride (4.3 mol) was added dropwise to a rapidly stirring mixture ofpiperidine (4.3 mol), sodium hydroxide (4.7 mol), toluene (1 L), and water(1.7 L) over a period of 70 min. After the addition was complete, the mixturewas stirred at 25°C for one hour. The organic and aqueous phases wereseparated, and the organic phase was washed with 2 N hydrochloric acid,concentrated by rotary evaporation, and distilled under vacuum to yieldbenzoylpiperidine as a colorless liquid which crystallized on standing (95%yield, boiling point 169-171°C). N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (480 mmol) andtoluene (100 mL) were added to a mixture of benzoylpiperidine (1.05 eq.) andphosphorus oxychloride (0.96 eq.), which had been stirred at 25°C for 1 hour.An additional 100 mL toluene was added. The suspension was heated to at40-45°C for 4 hours. The resulting syrup was transferred into a rapidly stirringsolution of sodium hydroxide (4.5 mol), piperidine (1.0 mL), and water (650mL) at 25-35°C and the mixture was stirred for 1 hour. A mixture of toluene(100 mL), water (50 mL), and sodium hydroxide (12 g, 300 mmol) was addedto the reaction flask, and the reaction mixture was stirred at 25°C for 1 hour.The suspension was then heated to 75°C and the layers were separated. Theorganic layer was cooled to 60°C and hexane (100 mL) was slowly added, andthe solution slowly stirred and cooled to -15°C. The precipitate was filtered,washed with toluene/hexane (2:1) and then with hexane, and dried undervacuum at 25°C to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1Hpyrrolizine-1-carboxamide (83.5% yield). Preparation of ketorolac tromethamine. A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80mL methanol was refluxed for 5 hours. The mixture was cooled to roomtemperature, stirred under nitrogen for sixteen hours, and then diluted with80 mL of water. The mixture was extracted with toluene, and the aqueous andorganic phases were separated. The aqueous phase was acidified with 6 Nhydrochloric acid. The resulting precipitate was extracted withdichloromethane. The combined extract was treated with activated claydecolorizing agent (4.5 g) for 30 minutes, filtered, and concentrated byatmospheric distillation. Hexane was added and the mixture allowed to cool to0-5°C. The product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid(ketorolac) was collected by filtration, washed with 100 mL ofhexane/dichloromethane (7:3), and dried at 60°C under vacuum, to yieldketorolac (83.4% yield), melting point 152-162°C. Ketorolac (25 g) and 11.9g tromethamine were dissolved in 175 mL methanol. The solution was filteredand the filter washed with 40 mL methanol. The resulting solution wasconcentrated by vacuum distillation. Ethylacetate was added to precipitate theketorolac tromethamine; and the solution was cooled to room temperature fortwo hours, cooled further to 0°C, and filtered. The precipitate was washedwith ethyl acetate/methanol (4:1) and dried under vacuum at a temperatureof 65°C, to yield ketorolac tromethamine (95% yield). |
| Brand name | Acular (Allergan); Toradol (Roche);Toradol IM. |
| Therapeutic Function | Analgesic, Antiinflammatory |
| General Description | Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards. Ketorolac Tromethamine belongs to the class of non-steroidal anti-inflammatory drugs, and its mode of action involves the inhibition of the bodily synthesis of prostagladins. It exhibits anti-inflammatory, antipyretic and analgesic effects. |
| Biochem/physiol Actions | Ketorolac is a non-steroidal agent that possesses moderate anti-inflammatory activity and is also a potent analgesic. It shows superior analgesic efficacy to that of the opioid analgesics like morphine in patients with moderate to severe postsurgical pain. It inhibits prostaglandin synthesis and platelet aggregation induced by arachidonic acid and collagen. It is a dual COX-1/COX-2 inhibitor. |
| Pharmacokinetics | After oral administration, ketorolac is rapidly absorbed; in dogs peak levels occur in about 50 minutes and oral bioavailability is about 50 – 75%. Ketorolac is distributed marginally through the body. It does not appear to cross the blood-brain barrier and is highly bound to plasma proteins (99%). The volume of distribution in dogs is reported to be about 0.33 – 0.42 L/kg (similar in humans). The drug does cross the placenta. Ketorolac is primarily metabolized via glucuronidation and hydroxylation. Both unchanged drug and metabolites are excreted mainly in the urine. Patients with diminished renal function will have longer elimination times than normal. In normal dogs, the elimination half-life is between 4 – 8 hours. |
| Pharmacology | Like other NSAIDs, ketorolac exhibits analgesic, antiinflammatory, and antipyretic activity probably through its inhibition of cyclooxygenase with resultant impediment of prostaglandin synthesis. Ketorolac may exhibit a more potent analgesic effect than some other NSAIDs. It inhibits both COX-1 and COX-2 receptors. |
| Side effects | The manufacturer indicates that ketorolac tromethamine does not enhance the spread of preexisting corneal fungal, viral or bacterial infections in animal models. Ketorolac tromethamine does not in and of itself induce postoperative pressure elevation other then that which frequently follows cataract extraction in people and animals. |
| Safety Profile | Ketorolac does cross the placenta. In humans, the FDA categorizes this drug as category C for use during the first two trimesters of pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In humans, all NSAIDs are assigned to category D for use during pregnancy during the third trimester or near delivery (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.) Most NSAIDs are excreted in milk. Ketorolac was detected in human breast milk at a maximum milk:plasma ratio of 0.037. It is unlikely to pose great risk to nursing offspring. |
| Veterinary Drugs and Treatments | Ketorolac is used primarily for its analgesic effects for short-termtreatment of mild to moderate pain in dogs and rodents. The durationof analgesic effect in dogs is about 8 – 12 hours, but because ofthe availability of approved, safer NSAIDs for dogs, its use is questionable. |
| Overdosage | Limited information is available. The oral LD50 is 200 mg/kg in mice. GI effects, including GI ulceration are likely in overdoses in small animals. Metabolic acidosis was reported in one human patient. Consider GI emptying in large overdoses; patients should be monitored for GI bleeding. Treat ulcers with sucralfate; consider giving misoprostol early. |
| Precautions | Ketorolac is relatively contraindicated in patients with a history of, or preexisting, hematologic, renal or hepatic disease. It is contraindicated in patients with active GI ulcers or with a history of hypersensitivity to the drug. It should be used cautiously in patients with a history of GI ulcers, or heart failure (may cause fluid retention), and in geriatric patients. Animals suffering from inflammation secondary to concomitant infection, should receive appropriate antimicrobial therapy. Because ketorolac has a tendency to cause gastric erosion and ulcers in dogs, long-term use (>3 days) is not recommended in this species. |
| References | [1] Y ZHANG. Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production.[J]. Journal of Pharmacology and Experimental Therapeutics, 1997, 283 3: 1069-1075. |
Ketorolac tromethamine Preparation Products And Raw materials
| Raw materials | Methylmagnesium chloride-->Diethylene Glycol Dibutyl Ether-->Benzoyl chloride-->Phosphorus tribromide-->Sodium hydroxide-->3-ETHYLANILINE-->Triethylamine-->4-Chlorobutyryl chloride-->Phosphorus oxychloride-->Diglyme-->Pyrrole-->Phosphorus oxitrichloride |
