74103-06-3

Basic information

• Product Name: Ketorolac
• Synonyms: 3-dihydro-5-benzoyl-(+-)-1h-pyrrolizine-1-carboxylicaci;rs37619;5-benzoyl-2,3-dihydro-1h-pyrrolizine-1-carboxylic acid;KETOROLAC;KETOROLAC-D5;KETOROLAC TROMETHAMINE, USP STANDARD;5-(phenylcarbonyl)-2,3-dihydro-1H-pyrrolizine-1-ca;Ketoralac
• CAS NO: 74103-06-3
• Molecular Formula: C₁₅H₁₃NO₃
• Molecular Weight: 255.27
• EINECS: 200-001-2
• Product Categories: API's;Other APIs
• Mol File: 74103-06-3.mol

Chemical Properties

• Melting Point: 160-161°C
• Boiling Point: 223.7 ºC at 760 mmHg
• Flash Point: 89.1 ºC
• Appearance: white crystalline or white powder
• Density: 1.398 g/cm³
• Vapor Pressure: 1.52E-10mmHg at 25°C
• Refractive Index: 1.659
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 3.49 ±0.02(at 25℃)
• Water Solubility: 183mg/L(32 oC)
• CAS DataBase Reference: Ketorolac(CAS DataBase Reference)
• NIST Chemistry Reference: Ketorolac(74103-06-3)
• EPA Substance Registry System: Ketorolac(74103-06-3)

Safety Data

• RIDADR: 3249
• HazardClass: 6.1(a)
• PackingGroup: II
• Hazardous Substances Data: 74103-06-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Ketorolac is used as an analgesic and anti-inflammatory agent for the management of moderate to severe pain and inflammation. It is particularly effective in conditions such as postoperative pain, renal colic, migraine, and dental pain.
Used in Research Applications:
Ketorolac-d5, a labeled analogue of Ketorolac, is used as a research tool in the study of prostaglandin biosynthesis and its role in inflammation and pain. It aids in the development of new drugs and therapies for pain management and inflammation.
Used in Antiarrhythmic Applications:
Ketorolac is also used as an antiarrhythmic agent, helping to regulate abnormal heart rhythms and maintain a stable heart rate. This application is particularly useful in the management of certain cardiovascular conditions.

Pharmacological action

Ketorolac is also called ketorolac, acular and Ketorolac Tromethamine. It is a non steroid analgesic and anti-inflammatory drug, a derivative of pyrrolidone.The chemical structure and pharmacological action is similar to Tolectin, Zoaesthetic acid and Indometacin. By inhibiting cyclooxygenase, it inhibits the synthesis and release of prostaglandins, and produces anti-inflammatory effects. It can reduce the temperature induced by heat source, which is related to the inhibition of the synthesis of prostaglandin in the central nervous system.It has strong analgesic and moderate anti-inflammatory antipyretic and inhibition of platelet aggregation, and has no inhibition of respiration and addiction. In animal experiments, the analgesic effect is stronger than aspirin, indomethacin and naproxen.It is equal to or better than the anti-inflammatory effect of naproxen and indomethacin, phenylbutazone,Its antipyretic effect on rats are stronger than aspirin and phenylbutazone and the same with indomethacin and naproxen.It inhibits the platelet aggregation induced by arachidonic acid and collagen.But it does not inhibit the induction of adenosine diphosphate(ADP) ..This product is quickly and completely absorbed after the intramuscular injection, and is almost completely absorbed after oral administration.Food can slow down the absorption speed, but it does not affect the degree of absorption, and the bioavailability is 80% ~ 100%. 10 minutes after intramuscular injection of 30mg, it usually relieves the pain obviously. After 50 minutes, the peak of plasma concentration is up to 2.2 g/mL.After 30~60 minutes of oral administration, the pain is obviously relieved and the concentration of plasma is peak at 1.5 to 4 hours.The plasma half-life of young people is about 5.3 hours, and for the elderly it is about 7 hours, and the analgesic effect could be maintained for 6~8 hours. 91.4% will be excreted from the urinary tract, the rest will be excreted from the excrement.In patients with renal insufficiency, the total plasma clearance rate decreases and the half-life prolongs, so the dosage should be reduced. Clinical application: ketorolac is mainly used for short-term pain treatment including postoperative pain (such as the abdomen, chest, Urology, gynecology, Department of Stomatology, orthopedic surgery and pain) as well as the acute skeletal muscle pain caused by various causes, such as sprain, dislocation, fracture and soft tissue injury, and other pain caused by other diseases, such as postpartum pain, acute renal colic, toothache, sciatica, late cancer pain, wound pain, biliary colic, etc.. It can be used as a substitute for morphine and pethidine.

Indications

Ketorolac (Toradol), an NSAID chemically related to indomethacin and tolmetin, is mainly used as an analgesic, not for the treatment of inflammatory disease. It is available in oral, parenteral, and topical formulations.

World Health Organization (WHO)

Ketorolac is a nonsteroidal anti-inflammatory agent used in the management of moderate to severe acute post-operative pain. It remains on the market in many countries with restrictions on its use.

Biological Functions

Ketorolac (Toradol) is an NSAID with very mild antiinflammatory and antipyretic activity. It is a potent analgesic for postoperative pain. Its efficacy is equivalent to that of low doses of morphine in the control of pain. For this reason it is often combined with opioids to reduce opioid dose and related side effects while providing adequate pain relief. It is also used to replace the opioids in some patients with opioid sensitivity. The mechanism of action of ketorolac involves the inhibition of COX and decreased formation of prostaglandins. However, some evidence exists that ketorolac may stimulate the release of endogenous opioids as a part of its analgesic activity.

InChI:InChI=1/C15H13NO3/c17-14(10-4-2-1-3-5-10)13-7-6-12-11(15(18)19)8-9-16(12)13/h1-7,11H,8-9H2,(H,18,19)

Synthetic route

Methyl isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1,1-dicarboxylate (157071-66-4) → Ketorolac (74103-06-3)

Conditions	Yield
With sodium hydroxide In methanol Ambient temperature;	99%

ketorolac tromethamine → Ketorolac (74103-06-3)

Conditions	Yield
With hydrogenchloride In water	98%
With hydrogenchloride In water at 0 - 20℃;	83.6%
With hydrogenchloride In water

diethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1,1-dicarboxylate (140947-23-5) → Ketorolac (74103-06-3)

Conditions	Yield
Stage #1: diethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1,1-dicarboxylate With sodium hydroxide In diethyl ether; water for 24h; Reflux; Stage #2: With hydrogenchloride In ethyl acetate at 70℃; for 4h;	80%
With sodium hydroxide In tetrahydrofuran for 9h; Time; Reflux; Green chemistry;	47.5%
With hydrogenchloride; sodium hydroxide 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h; Yield given. Multistep reaction;

5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid-2-propyl ester (66635-74-3) → Ketorolac (74103-06-3)

Conditions	Yield
With potassium carbonate In methanol; water for 0.5h; Heating;	64%
With water In methanol; aq. phosphate buffer at 37℃; pH=8; Kinetics; pH-value;

5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (84023-60-9) → Ketorolac (74103-06-3)

Conditions	Yield
With hydrogen; magnesium oxide; palladium on activated charcoal In methanol; water under 760 Torr; for 2h; Ambient temperature; Yield given;

2-[2-(2-Benzoyl-5-methanesulfonyl-pyrrol-1-yl)-ethyl]-malonic acid dimethyl ester (80965-05-5) → Ketorolac (74103-06-3)

Conditions	Yield
Yield given. Multistep reaction;

ketorolac acid ethyl ester (108061-03-6) → Ketorolac (74103-06-3)

Conditions	Yield
With pooled human serum In water at 37℃; Rate constant; serum metabolism; other reagents and solvent, other temperatures;

ketorolac acid <(N,N-dimethylamino)carbonyl>methyl ester → Ketorolac (74103-06-3)

Conditions	Yield
With pooled human serum In water at 37℃; Rate constant; serum metabolism; other reagents and solvent, other temperatures;

phenyl chloroformate (1885-14-9) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) oxalyl chloride / 1.) ether, ice-bath cooling, 0.75 h, 2.) CH2Cl2, r.t., 15 h 2: 68 percent / K2CO3, n-Bu4NBr / 44 h / Heating 3: 99 percent / 1 N NaOH / methanol / Ambient temperature View Scheme

(1H-pyrrol-2-yl)acetic acid isopropyl ester (157071-48-2) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 96 percent / LDA / tetrahydrofuran / 1.) -75 deg C to -60 deg C, 2.) -70 deg C, 1 h 2: 1.) oxalyl chloride / 1.) ether, ice-bath cooling, 0.75 h, 2.) CH2Cl2, r.t., 15 h 3: 68 percent / K2CO3, n-Bu4NBr / 44 h / Heating 4: 99 percent / 1 N NaOH / methanol / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1: 1.) oxalyl chloride / 1.) ether, ice-bath cooling, 0.75 h, 2.) CH2Cl2, r.t., 40 h 2: 97 percent / LDA / tetrahydrofuran / 1.) -75 deg C to -60 deg C, 2.) -65 deg C to 0 deg C, ca. 0.5 h 3: 68 percent / K2CO3, n-Bu4NBr / 44 h / Heating 4: 99 percent / 1 N NaOH / methanol / Ambient temperature View Scheme

Methyl isopropyl 2-pyrrolylmalonate (157071-53-9) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) oxalyl chloride / 1.) ether, ice-bath cooling, 0.75 h, 2.) CH2Cl2, r.t., 15 h 2: 68 percent / K2CO3, n-Bu4NBr / 44 h / Heating 3: 99 percent / 1 N NaOH / methanol / Ambient temperature View Scheme

Isopropyl (5-benzoylpyrrol-2-yl)acetate (157071-65-3) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / LDA / tetrahydrofuran / 1.) -75 deg C to -60 deg C, 2.) -65 deg C to 0 deg C, ca. 0.5 h 2: 68 percent / K2CO3, n-Bu4NBr / 44 h / Heating 3: 99 percent / 1 N NaOH / methanol / Ambient temperature View Scheme

Methyl isopropyl (5-benzoyl-2-pyrrolyl)malonate (157071-60-8) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 68 percent / K2CO3, n-Bu4NBr / 44 h / Heating 2: 99 percent / 1 N NaOH / methanol / Ambient temperature View Scheme

i-propyl 1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1-carboxylate (66635-71-0) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) POCl3 / 1.) 1,2-dichloroethane, reflux, 1 h, 2.) 1,2-dichloroethane, reflux, 24 h 2: 64 percent / K2CO3 / methanol; H2O / 0.5 h / Heating View Scheme

N,N-dimethylbenzamide (611-74-5) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) POCl3 / 1.) 1,2-dichloroethane, reflux, 1 h, 2.) 1,2-dichloroethane, reflux, 24 h 2: 64 percent / K2CO3 / methanol; H2O / 0.5 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 1.) phosphorus oxychloride / 1.) 1,2-dichloroethane, reflux, 0.75 h, 2.) reflux, 1 h 2: 1.) NaH / 1.) DMF, RT, 1 h, 2.) 55 deg C, 5 h 3: 85percent m-chloroperbenzoic acid / CH2Cl2 / 3 h / 0 °C 4: 95 percent / HCl / 0.5 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 1.) phosphorus oxychloride / 1.) 1,2-dichloroethane, reflux, 0.75 h, 2.) reflux, 1 h 2: 100 percent / 86percent m-chloroperbenzoic acid / CH2Cl2 / 3 h / 5 °C 3: 1.) NaH / 1.) DMF, 2.) 90 deg C, 4 h 4: 95 percent / HCl / 0.5 h / Heating View Scheme

phenyl(1H-pyrrol-2-yl)methanone (7697-46-3) + alkaline iodine-potassium iodide → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 75 percent / manganese triacetate trihydrate, NaOAc / 4 h / 70 °C 2: 50 percent / trifluoroacetic acid, triethylsilane / CH2Cl2 / 48 h / 40 °C 3: 67 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 4: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme
Multi-step reaction with 4 steps 1: 57 percent / manganese triacetate trihydrate, NaOAc / 4 h / 70 °C 2: 50 percent / trifluoroacetic acid, triethylsilane / CH2Cl2 / 48 h / 40 °C 3: 67 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 4: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme
Multi-step reaction with 3 steps 1: 86 percent / triethylborane, O2 / hexane; benzene / 3 h / Ambient temperature 2: 67 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 3: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

triethyl (5-benzoylpyrrol-2-yl)-methanetricarboxylate (136116-84-2) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 83 percent / NaOC2H5 / dimethylformamide / 2 h / Ambient temperature 2: 67 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 3: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme
Multi-step reaction with 2 steps 1: 80 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 2: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

1-(2-chloroethyl)-2-benzoylpyrrole (87549-01-7) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 80 percent / NaI / acetonitrile / 24 h / Heating 2: 1.) 60percent NaH in mineral oil / 1.) DMF, r.t., 0.5 h, 2.) DMF, r.t., 16 h 3: 1.) 60percent NaH in mineral oil, 2.) N-bromosuccinimide / 1.) THF, r.t., 0.5 h, 2.) 0.5 h, r.t. 4: 75 percent / Et3B, O2 / benzene; hexane / 2 h / Ambient temperature 5: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme
Multi-step reaction with 4 steps 1: 80 percent / NaI / acetonitrile / 24 h / Heating 2: 1.) 60percent NaH in mineral oil / 1.) DMF, r.t., 0.5 h, 2.) DMF, r.t., 16 h 3: 96 percent / Mn(OAc)3, NaOAc / acetic acid / 6 h / 80 °C 4: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

1-(2-iodoethyl)-2-benzoylpyrrole (141031-77-8) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) 60percent NaH in mineral oil / 1.) DMF, r.t., 0.5 h, 2.) DMF, r.t., 16 h 2: 1.) 60percent NaH in mineral oil, 2.) N-bromosuccinimide / 1.) THF, r.t., 0.5 h, 2.) 0.5 h, r.t. 3: 75 percent / Et3B, O2 / benzene; hexane / 2 h / Ambient temperature 4: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme
Multi-step reaction with 3 steps 1: 1.) 60percent NaH in mineral oil / 1.) DMF, r.t., 0.5 h, 2.) DMF, r.t., 16 h 2: 96 percent / Mn(OAc)3, NaOAc / acetic acid / 6 h / 80 °C 3: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

diethyl 2-(5-benzoyl-1H-pyrrol-2-yl)malonate (144710-35-0) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 67 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 2: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

1-(3,3-diethoxycarbonyl-3-bromopropyl)-2-benzoylpyrrole (141031-81-4) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / Et3B, O2 / benzene; hexane / 2 h / Ambient temperature 2: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

1-(3,3-diethoxycarbonylpropyl)-2-benzoylpyrrole (141031-78-9) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) 60percent NaH in mineral oil, 2.) N-bromosuccinimide / 1.) THF, r.t., 0.5 h, 2.) 0.5 h, r.t. 2: 75 percent / Et3B, O2 / benzene; hexane / 2 h / Ambient temperature 3: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme
Multi-step reaction with 2 steps 1: 96 percent / Mn(OAc)3, NaOAc / acetic acid / 6 h / 80 °C 2: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

diethyl 5-benzoylpyrrol-2-yl-(α-acetoxy)malonate (144710-34-9) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 50 percent / trifluoroacetic acid, triethylsilane / CH2Cl2 / 48 h / 40 °C 2: 67 percent / n-Bu4NBr, K2CO3 / 24 h / Heating 3: 1.) 20percent aq. NaOH, 2.) conc. HCl / 1.) ether, reflux, 24 h, 2.) ethyl acetate, 70 deg C, 4 h View Scheme

phenyl(1H-pyrrol-2-yl)methanone (7697-46-3) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 77 percent / bromine / CH2Cl2 / 0 deg C to RT, 2.5 h 2: 1.) NaH / 1.) DMF, RT, 1 h, 2.) 75-80 deg C, 4 h 3: HCl / 5 h / 0 deg C to RT 5: magnesium oxide, H2 / 5percent Pd/C / H2O; methanol / 2 h / 760 Torr / Ambient temperature View Scheme

2,3-dibromo-5-benzoylpyrrole (50372-61-7) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaH / 1.) DMF, RT, 1 h, 2.) 75-80 deg C, 4 h 2: HCl / 5 h / 0 deg C to RT 4: magnesium oxide, H2 / 5percent Pd/C / H2O; methanol / 2 h / 760 Torr / Ambient temperature View Scheme

2-(methylthio)-5-benzoylpyrrole (80965-00-0) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaH / 1.) DMF, RT, 1 h, 2.) 55 deg C, 5 h 2: 85percent m-chloroperbenzoic acid / CH2Cl2 / 3 h / 0 °C 3: 95 percent / HCl / 0.5 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 100 percent / 86percent m-chloroperbenzoic acid / CH2Cl2 / 3 h / 5 °C 2: 1.) NaH / 1.) DMF, 2.) 90 deg C, 4 h 3: 95 percent / HCl / 0.5 h / Heating View Scheme

2-(methylsulfonyl)-5-benzoylpyrrole (80965-03-3) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) NaH / 1.) DMF, 2.) 90 deg C, 4 h 2: 95 percent / HCl / 0.5 h / Heating View Scheme

5-[2-(2-Benzoyl-5-methylsulfanyl-pyrrol-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (83727-08-6) → Ketorolac (74103-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85percent m-chloroperbenzoic acid / CH2Cl2 / 3 h / 0 °C 2: 95 percent / HCl / 0.5 h / Heating View Scheme

4-arm-PEG-20K + Ketorolac (74103-06-3) → 4-arm-PEG-20K-ketorolac

Conditions	Yield
With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	95%

4-arm-PEG-40K + Ketorolac (74103-06-3) → 4-arm-PEG-40K-ketorolac

Conditions	Yield
With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	94%

Ketorolac (74103-06-3) + butan-1-ol (71-36-3) → 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid butyl ester (376628-29-4)

Conditions	Yield
With toluene-4-sulfonic acid In benzene for 3h; Heating;	89%
With toluene-4-sulfonic acid In benzene at 120℃; for 0.333333h;

(L)-phenylalanine ethyl ester hydrochloride (3182-93-2) + Ketorolac (74103-06-3) → C26H26N2O4 (1093407-70-5)

Conditions	Yield
Stage #1: Ketorolac With dicyclohexyl-carbodiimide In dichloromethane for 0.5h; Stage #2: (L)-phenylalanine ethyl ester hydrochloride With triethylamine In dichloromethane at 0 - 20℃;	88%

(S)-alanine ethyl ester hydrochloride (1115-59-9) + Ketorolac (74103-06-3) → C20H22N2O4 (1093407-68-1)

Conditions	Yield
Stage #1: (S)-alanine ethyl ester hydrochloride; Ketorolac With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane for 24h;	83%

chloromethyl n-butyrate (33657-49-7) + Ketorolac (74103-06-3) → 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid-(butyryloxy)methyl ester

Conditions	Yield
With potassium carbonate; potassium iodide In acetone at 20℃;	83%
With potassium carbonate; potassium iodide In acetone at 20℃;

n-heptan1ol (111-70-6) + Ketorolac (74103-06-3) → ketorolac heptyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	82%

1-bromoethyl acetate (40258-78-4) + Ketorolac (74103-06-3) → 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid-1-(acetoxy)ethyl ester

Conditions	Yield
With potassium carbonate In acetone at 20℃;	80%
With potassium carbonate In acetone at 20℃;	76%

Ketorolac (74103-06-3) + tert-butyl alcohol (75-65-0) → ketorolac tert-butyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	79%

Ketorolac (74103-06-3) + isopropyl alcohol (67-63-0) → 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid-2-propyl ester (66635-74-3)

Conditions	Yield
With thionyl chloride at 20℃; Cooling with ice;	76%
With thionyl chloride	76%

1,7-heptandiol (629-30-1) + Ketorolac (74103-06-3) → diketorolac heptyl diester (1571587-90-0)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	75%

Ketorolac (74103-06-3) → 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-one

Conditions	Yield
With iron(III) chloride; oxygen In N,N-dimethyl-formamide at 110℃; for 12h; Catalytic behavior; Mechanism; Temperature; Solvent; Reagent/catalyst;	74%

methanol (67-56-1) + Ketorolac (74103-06-3) → 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (80965-09-9)

Conditions	Yield
With thionyl chloride for 14h; Inert atmosphere; Reflux;	73%
With sulfuric acid Reflux;
With toluene-4-sulfonic acid In benzene at 120℃; for 0.333333h;

L-leucine ethyl ester hydrochloride (2743-40-0) + Ketorolac (74103-06-3) → C23H28N2O4 (1093407-72-7)

Conditions	Yield
Stage #1: L-leucine ethyl ester hydrochloride; Ketorolac With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane for 24h;	71%

2-(prop-2-yn-1-yl)pent-4-yn-1-yl 3-hydroxybenzoate + Ketorolac (74103-06-3) → 3-(((2-(prop-2-yn-1-yl)pent-4-yn-1-yl)oxy)carbonyl)phenyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 17h;	71%

L-tryptophan ethyl ester hydrochloride (2899-28-7, 6519-67-1, 61535-49-7, 67557-18-0, 68401-14-9) + Ketorolac (74103-06-3) → C28H27N3O4 (1093407-69-2)

Conditions	Yield
Stage #1: Ketorolac With dicyclohexyl-carbodiimide In dichloromethane for 0.5h; Stage #2: L-tryptophan ethyl ester hydrochloride With triethylamine In dichloromethane at 0 - 20℃;	70%

Ketorolac (74103-06-3) + benzyl alcohol (100-51-6) → ketorolac benzyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	69%

Ketorolac (74103-06-3) + diethyl L-aspartate hydrochloride (16115-68-7) → C23H26N2O6 (1093407-74-9)

Conditions	Yield
Stage #1: Ketorolac; diethyl L-aspartate hydrochloride With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane for 24h;	63%

Ketorolac (74103-06-3) + propargyl alcohol (107-19-7) → C18H15NO3

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 5h;	63%
With dmap In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20℃; for 5h;	63%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 5h;	63%

L-Valine ethyl ester hydrochloride (17609-47-1) + Ketorolac (74103-06-3) → C22H26N2O4 (1093407-71-6)

Conditions	Yield
Stage #1: L-Valine ethyl ester hydrochloride; Ketorolac With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane for 24h;	62%

1-deoxy-1-(octylamino)-D-glucitol + Ketorolac (74103-06-3) → C15H13NO3*C18H39NO

Conditions	Yield
In ethanol at 70℃; for 0.5h; Temperature;	60%

diethyl-L-glutamate hydrochloride (1118-89-4) + Ketorolac (74103-06-3) → C24H28N2O6 (1093407-76-1)

Conditions	Yield
Stage #1: Ketorolac With dicyclohexyl-carbodiimide In dichloromethane for 0.5h; Stage #2: diethyl-L-glutamate hydrochloride With triethylamine In dichloromethane at 0 - 20℃;	59%

Ketorolac (74103-06-3) + silver nitrate → C15H12AgNO3

Conditions	Yield
With ammonia In ethanol; water at 20℃; for 0.25h; pH=8; Darkness;	58%

3-(4-sulfamoylphenoxy)propylammonium trifluoroacetate + Ketorolac (74103-06-3) → 5-benzoyl-N-(3-(4-sulfamoylphenoxy)propyl)-2,3-dihydro-1H-pyrrolizine-1-carboxamide

Conditions	Yield
Stage #1: Ketorolac With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 20℃; for 0.166667h; Stage #2: 3-(4-sulfamoylphenoxy)propylammonium trifluoroacetate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃;	58%

Ketorolac (74103-06-3) + (R)-fluoxetine (54910-89-3, 57226-07-0, 100568-02-3, 100568-03-4) → [1-{[methyl{(R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl}-amino]methyl}-2,3-dihydro-1H-pyrrolizin-5-yl](phenyl)methanone (1331729-86-2)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h;	56%

Upstream product

• 66635-74-3 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid-2-propyl ester 
• 84023-60-9 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid 
• 80965-05-5 2-[2-(2-Benzoyl-5-methanesulfonyl-pyrrol-1-yl)-ethyl]-malonic acid dimethyl ester 
• 140947-23-5 diethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1,1-dicarboxylate 
• 157071-66-4 Methyl isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1,1-dicarboxylate 
• 108061-03-6 ketorolac acid ethyl ester 
• 611-74-5 N,N-dimethylbenzamide 
• 136116-84-2 triethyl (5-benzoylpyrrol-2-yl)-methanetricarboxylate 
• 87549-01-7 1-(2-chloroethyl)-2-benzoylpyrrole 
• 141031-81-4 1-(3,3-diethoxycarbonyl-3-bromopropyl)-2-benzoylpyrrole 
• 7697-46-3 phenyl(1H-pyrrol-2-yl)methanone 
• 80965-00-0 2-(methylthio)-5-benzoylpyrrole 
• 80965-03-3 2-(methylsulfonyl)-5-benzoylpyrrole 
• 80965-04-4 [1-[2-(4,6-dioxo-2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-2-(methanesulfonyl)-5-(benzoyl)]-pyrrole 

Downstream Products

• 113502-52-6 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-one 
• 154476-25-2 (1-hydroxy-2,3-dihydro-1H-pyrrolizin-5-yl)(phenyl)methanone 
• 167105-80-8 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amide 
• 66635-93-6 R-(+)-ketorolac 
• 66635-92-5 S-ketorolac 
• 376628-29-4 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid butyl ester 
• 1007554-36-0 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carbonyl chloride 
• 35168-15-1 N,N'-Dicyclohexylguanidine 
• 863126-60-7 C₂₀H₂₂N₂O₄ 
• 1093407-68-1 C₂₀H₂₂N₂O₄ 
• 1093407-76-1 C₂₄H₂₈N₂O₆ 

Relevant articles and documents

Permeability of ketorolac acid and its ester analogs (prodrug) through human cadaver skin

The in vitro skin permeabilities of ketorolac acid (KA), a potent nonsteroidal analgesic, and its two ester analogs as prodrug through human cadaver skin were investigated. The two esters of KA, namely, the ethyl ester (KEE) and [(N,N-dimethylamino)carbonyl]methyl ester (KDAE), were selected. The melting temperature of the two esters was significantly lower than that of ketorolac free acid. The partition coefficients (K(D/W)) were 600, 3541, and 124 for KA, KEE, and KDAE, respectively. The enzymatic hydrolysis of KEE and KDAE by human pooled serum at 37 °C was investigated. The esters were hydrolyzed to KA by the serum esterases; the metabolic rate constants were 0.0418 and 0.0148 min-1 for KDAE and KEE, respectively. The serum half- life of KDAE was about 3 times shorter than KEE. When split-thickness cadaver skin was incubated with ester solution at 32 °C, the enzymatic hydrolysis of these esters was observed. The metabolic rate in the skin, however, was significantly lower than in the human pooled serum. The skin permeations of KA, KEE, and KDAE through heat-separated epidermis from propylene glycol (PG), PG/glyceryl monocaprylate (GMC) (9:1), and PG/Azone (19:1) vehicle mixtures were evaluated using modified Franz flow-through diffusion cells. The skin fluxes of KA, KEE, and KDAE from PG/GMC (9:1) were 50 ± 10, 15 ± 4, and 57 ± 6 μg/cm2/h, respectively. KA was detected in the receiver compartment, albeit to a lesser extent. In conclusion, KDAE appeared to be a better ester prodrug than KEE because it exhibited relatively higher skin flux and faster enzymatic hydrolysis by human serum to liberate the parent drug.

Transition Metal-Free, Visible Light-Mediated Radical Cyclisation of Malonyl Radicals onto 5-Ring Heteroaromatics

Annulated heteroaromatics can be accessed through the addition of malonyl radicals onto heterocycles. Current methods are applicable to electron-rich heteroaromatics and reliant on transition metals or toxic tin reagents. Here we report a metal-free, visible light-mediated cyclisation of malonates onto 5-ring heteroaromatics using iodomalonates as key intermediates. The iodomalonates are prepared and photolysed in situ to give the desired annulated products, in yields of 46–94% without the need for external catalysts. The scope of this transformation includes N-alkyl, N-acyl and carbon-tethered malonates adding onto a wide range of 5-membered heteroaromatics. (Figure presented.).

Effective mamagement of acute postoperative pain using intravenous emulsions of novel ketorolac prodrugs: in vitro and in vivo evaluations

The aim was to prepare intravenous fat emulsions (IFEs) of ketorolac (KTL) ester prodrugs and to investigate the pharmacokinetics and pharmacodynamics of these formulations. Three prodrugs of KTL (KTL-IS, KTL-AX and KTL-BT) were synthesized as a means to increase the lipid solubility of KTL. All KTL prodrugs with higher Log P values presented increased tendency to partition into a blank IFE using extemporaneous addition method – the encapsulation efficiency of KTL-IS IFE and KTL-BT IFE was more than 97percent. The particle sizes and zeta potentials of these two formulations were comparable to that of the blank IFE. PK studies in rabbits showed significant larger AUC0-8h (646.969 ± 154.326 mg/L?h?1 for KTL-IS IFE and 559.426 ± 103.057 mg/L?h?1 for KTL-BT IFE) than that of ketorolac tromethamine (KTL-T) injectable (286.968 ± 63.045 mg/L?h?1) and approximately 2-fold increases in the elimination t1/2 over KTL-T. In a rat postoperative pain model, the paw withdrawal thresholds and the paw withdrawal latency after I.V. KTL prodrug IFEs were significantly higher than that after I.V. KTL-T at 3~4 h. Effective controlling of acute postoperative pain in a longer duration can be achieved by using non-addictive ketorolac derivatives intraveneous emulsions.

Ketorolac ester derivative intravenous injection lipid emulsion, preparing method and application

The invention belongs to the field of pharmaceutic preparations, and particularly relates to a ketorolac ester derivative intravenous injection lipid emulsion, a preparing method and application. According to the intravenous injection lipid emulsion, ketorolac ester derivatives and caffeine are dissolved in an intravenous emulsion to form emulsion grains as the medicine carrier; a ketorolac esterpro-drug can be dissolved in small oil drops (emulsion grains) of the intravenous emulsion or on an interface membrane, the physical and chemical properties can be kept stable in the storage process under certain conditions, the slow release performance is improved, and the drug function time is prolonged.

Synthesis process of ketorolac

The invention discloses a synthesis process of ketorolac, and relates to the technical field of medicine synthesis. The synthesis process solves the technical problems that the existing process can generate a large amount of liquid and solid wastes, and the environment protection is not facilitated. Hydrogen peroxide with side products being water is used as an oxidizing agent; malysite is used asa catalyst; a large number of manganese salts are replaced; when 1kg of ketorolac is reduced, 3.5 to 6.1kg of discharged liquid and solid wastes are reduced; the green and environment-friendly effects are achieved. Benzoyl chloride is directly used as raw materials; the one-step reaction is reduced; the synthesis process is simpler; the methyl tertiary butyl ether is used for replacing the flammable and combustible diethyl ether; the process production safety is improved. The synthesis process has the advantages that the operation is easy; the process conditions can be easily controlled; thefinal product purification and aftertreatment are simple.

Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis

We report the synthesis of a series of hybrid compounds incorporating 6- and 7-substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with KI values in the low nanomolar-subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration.

COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN

The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II, and methods for treating or preventing or modulating moderate to severe pain in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.

Impact of ester promoieties on transdermal delivery of ketorolac

Different types of ketorolac ester prodrugs incorporating tert-butyl (KT), benzyl (KB), heptyl (KH), and diketorolac heptyl (DKH) promoieties were synthesized for the comparison of percutaneous penetration. The prodrugs were characterized according to their melting point, capacity factor, lipophilicity, solubility in 30% ethanol/buffer, enzymatic hydrolysis, in vitro skin permeation, hair follicle accumulation, and in vivo skin tolerance. Interactions between the prodrugs and esterases were predicted by molecular docking. Both equimolar suspensions and saturated solutions in 30% ethanol/pH 7.4 buffer were employed as the applied dose. All of the prodrugs exhibited a lower melting point than ketorolac. The lipophilicity increased in the following order: ketorolac KT KB KH DKH. The prodrugs were rapidly hydrolyzed to the parent drug in esterase medium, skin homogenate, and plasma, with KT and KB exhibiting higher degradation rates. KT exhibited the highest skin permeation, followed by KB. The flux of KT and KB exceeded that of ketorolac by 2.5-fold and twofold, respectively. KH and DKH did not improve ketorolac permeation but exhibited a sustained release behavior. KT and KH revealed selective absorption into follicles and a threefold greater follicular uptake compared with ketorolac. KB, KH, and DKH slightly but significantly increased transepidermal water loss (TEWL) after consecutive administration for 7 days, whereas ketorolac and KT exhibited no influence on TEWL. According to the experimental results, it can be concluded that an optimal balance between lipophilicity and aqueous solubility is important in the design of a successful prodrug. The acceptable skin tolerance for safe application is also an important consideration.

COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN

The invention relates to the compounds of formula (I) and formula (II) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I) or formula (II), and methods for treating or preventing or modulating moderate to severe pain in a disease may be formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.

Solvent free oxidative radical substitution process. Synthesis of pyrrole fused systems

A xanthate-based, solvent free, homolytic substitution on selected substituted pyrrole systems is described. Additionally, a practical entry for the rapid construction of pyrrole fused systems using this solventless radical addition followed by a double nucleophilic alkylation sequence, is also reported.