156897-06-2

Basic information

• Product Name: Licofelone
• Synonyms: ML 3000;2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetic acid;2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid;Licofelone, ML-3000;[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid;Licofelone;6-(4-Chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl- 1H-pyrrolizine-5-acetic Acid;1H-Pyrrolizine-5-aceticacid, 6-(4-chlorophenyl)-2,3-dihydro-2,2-diMethyl-7-phenyl-
• CAS NO: 156897-06-2
• Molecular Formula: C₂₃H₂₂ClNO₂
• Molecular Weight: 379.88
• EINECS: 1312995-182-4
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors
• Mol File: 156897-06-2.mol
• Article Data: 10

Chemical Properties

• Melting Point: 162-163°C
• Boiling Point: 539.7 °C at 760 mmHg
• Flash Point: 280.2 °C
• Appearance: Yellowish solid
• Density: 1.23
• Vapor Pressure: 1.76E-12mmHg at 25°C
• Refractive Index: 1.626
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform, Methanol
• PKA: 4.47±0.10(Predicted)
• CAS DataBase Reference: Licofelone(CAS DataBase Reference)
• NIST Chemistry Reference: Licofelone(156897-06-2)
• EPA Substance Registry System: Licofelone(156897-06-2)

Safety Data

• Hazardous Substances Data: 156897-06-2(Hazardous Substances Data)

Usage

Description

Cross-talk between lipoxygenase (LO) and cyclooxygenase (COX) pathways has been observed in human osteoarthritic synovial explants which creates an arachidonic acid shunting phenomenon, stimulating interleukin-1β (IL-1β) synthesis. Licofelone is a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LO) pathways, that decreases levels of prostaglandin E2, leukotriene B4, and lipoxins and prevents lipopolysaccharide-stimulated IL-1β expression. The IC50 values for inhibition of human thrombocyte COX and human 5-LO are 0.16 μM and 0.23 μM, respectively. Unlike other non-steroidal anti-inflammatory drugs, licofelone causes little or no damage to the gastric mucosa in rabbit parietal cells. This is presumably the result of licofelone’s affects on acid-secretory mechanisms, mediated by the inhibition of 5-LO activity.

Chemical Properties

Yellowish Solid

Uses

Different sources of media describe the Uses of 156897-06-2 differently. You can refer to the following data:
1. Dual inhibitor of cyclooxygenase and 5-lipoxygenase. Anti-inflammatory
2. Dual inhibitor of cyclooxygenase and 5-lipoxygenase. Anti-inflammatory.

in vitro

the 5-lox and cox inhibitory effect of licofelone was firstly identified via bovine thromobocyte intact cell assay and intact bovine pmn leukocytes. licofelone was also reported to inhibit pge2 in a dose-dependent manner in human whole blood assay. moreover, licofelone was found to suppress in vitro generation of reactive oxygen species and to reduce release of elastase from pmn leukocytes. all above findings revealed that licofelone had an inhibitory effect on cox-1/-2 and 5-lox. [1]

in vivo

the pharmacodynamic properties of licofelone were evaluated in various animal models and compared with those of commonly used nsaids. based on studies from a rat model of incisional pain, orally administration of licofelone had a longer duration of action and was more effective than indomethacin and zileuton. [1]

IC 50

inhibitor of cox-1, cox-2 and 5-lox with ic50 values of 0.16 m, 0.37 m and 0.23 m respectively in human.

references

[1]kulkarni sk and singh vp. licofelone-a novel analgesic and anti-inflammatory agent. curr top med chem. 2007; 7(3): 251-63.

InChI:InChI=1/C23H22ClNO2/c1-23(2)13-19-22(15-6-4-3-5-7-15)21(16-8-10-17(24)11-9-16)18(12-20(26)27)25(19)14-23/h3-11H,12-14H2,1-2H3,(H,26,27)

Synthetic route

ethyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate (156897-35-7) → licofelone (156897-06-2)

Conditions	Yield
With sodium hydroxide In ethanol; water at 80℃;	77%
With sodium hydroxide In ethanol at 80℃; for 0.25h;	77%
With sodium hydroxide In ethanol for 0.166667h; Heating;	75.5%
Stage #1: ethyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate With sodium hydroxide; water In ethanol for 0.5h; Heating / reflux; Stage #2: With hydrogenchloride In ethanol; water Product distribution / selectivity;	64%
With aq. alkaline hydroxide at 60 - 70℃; for 1h;

methyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetate (1061179-20-1) → licofelone (156897-06-2)

Conditions	Yield
Stage #1: methyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetate With sodium hydroxide; water In ethanol for 0.5h; Heating / reflux; Stage #2: With hydrogenchloride In ethanol; water Product distribution / selectivity;	71%
With aq. alkaline hydroxide at 60 - 70℃; for 1h;

[6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl]acetic acid tert-butyl ester (262426-70-0) → licofelone (156897-06-2)

Conditions	Yield
Stage #1: [6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl]acetic acid tert-butyl ester With sodium hydroxide; water In ethanol for 8h; Heating / reflux; Stage #2: With hydrogenchloride In ethanol; water Product distribution / selectivity;	60%
With aq. alkaline hydroxide at 60 - 70℃; for 10h;

C23H20ClNO3 → licofelone (156897-06-2)

Conditions	Yield
With hydrazine hydrate; potassium hydroxide In ethylene diglycol at 85 - 145℃; for 7h; Wolff-Kishner reduction;	55%
With hydrazine hydrate; potassium hydroxide In diethylene glycol at 85 - 145℃; for 7h; Wolff-Kishner reduction;	55%
With hydrazine hydrate; potassium hydroxide In diethylene glycol at 50 - 145℃; Wolff-Kishner reduction;	55.6%

2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetamide (1061179-22-3) → licofelone (156897-06-2)

Conditions	Yield
Stage #1: 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetamide With sulfuric acid; water In methanol for 4h; Heating / reflux; Stage #2: With sodium hydroxide; water In methanol for 4h; Heating / reflux; Stage #3: With hydrogenchloride In methanol; water Product distribution / selectivity;	50%

1-chloro-3-phenyl-2-propyne (3355-31-5) + (1,2-dimethyl-3-zirconacyclopent-1-ene)(C5H5)2 → licofelone (156897-06-2)

Conditions

Yield

Multi-step reaction with 8 steps 1: 90 percent / aq. NaOH, NaI, n-Bu4NI / toluene / 24 h / 50 °C 2: 1.) Et3N, 2.) NaBH(OAc)3 / 1) CH2Cl2, rt, 15 min; 2) CH2Cl2, rt, 12 h 3: 68 percent / pivalic acid / 5 h / 150 °C 4: 77 percent / EtONa / ethanol / 15 h / Ambient temperature 5: 1.) NaH / 1) THF, rt, 1 h; 2) THF, rt, 12 h 6: 92 percent / Pd(PPh3)4, Na2CO3 / tetrahydrofuran; H2O / 1) rt, 1 h; 2) reflux, 1 h 7: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 8: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme

2,2-dimethyl-5-phenylpent-4-ynal (197963-29-4) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: 1.) Et3N, 2.) NaBH(OAc)3 / 1) CH2Cl2, rt, 15 min; 2) CH2Cl2, rt, 12 h 2: 68 percent / pivalic acid / 5 h / 150 °C 3: 77 percent / EtONa / ethanol / 15 h / Ambient temperature 4: 1.) NaH / 1) THF, rt, 1 h; 2) THF, rt, 12 h 5: 92 percent / Pd(PPh3)4, Na2CO3 / tetrahydrofuran; H2O / 1) rt, 1 h; 2) reflux, 1 h 6: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 7: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme
Multi-step reaction with 7 steps 1: 80 percent / NaBH(OAc)3, Et3N / CH2Cl2 / Ambient temperature 2: 68 percent / t-BuCO2H / 150 °C 3: 77 percent / EtONa / ethanol / Ambient temperature 4: 80 percent / NaH / tetrahydrofuran / Ambient temperature 5: 92 percent / Pd(PPh3)4, Na2CO3 / H2O; tetrahydrofuran / Heating 6: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 7: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

2,2-dimethyl-7-phenyl-2,3,5,6-tetrahydro-1H-pyrrolizin-6-one (197963-31-8) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 77 percent / EtONa / ethanol / 15 h / Ambient temperature 2: 1.) NaH / 1) THF, rt, 1 h; 2) THF, rt, 12 h 3: 92 percent / Pd(PPh3)4, Na2CO3 / tetrahydrofuran; H2O / 1) rt, 1 h; 2) reflux, 1 h 4: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 5: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme
Multi-step reaction with 5 steps 1: 77 percent / EtONa / ethanol / Ambient temperature 2: 80 percent / NaH / tetrahydrofuran / Ambient temperature 3: 92 percent / Pd(PPh3)4, Na2CO3 / H2O; tetrahydrofuran / Heating 4: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 5: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

methyl N-(2,2-dimethyl-5-phenylpent-4-ynyl)glycinate (197963-30-7) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: 68 percent / pivalic acid / 5 h / 150 °C 2: 77 percent / EtONa / ethanol / 15 h / Ambient temperature 3: 1.) NaH / 1) THF, rt, 1 h; 2) THF, rt, 12 h 4: 92 percent / Pd(PPh3)4, Na2CO3 / tetrahydrofuran; H2O / 1) rt, 1 h; 2) reflux, 1 h 5: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 6: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme
Multi-step reaction with 6 steps 1: 68 percent / t-BuCO2H / 150 °C 2: 77 percent / EtONa / ethanol / Ambient temperature 3: 80 percent / NaH / tetrahydrofuran / Ambient temperature 4: 92 percent / Pd(PPh3)4, Na2CO3 / H2O; tetrahydrofuran / Heating 5: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 6: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

ethyl 2-(2,2-dimethyl-6-hydroxy-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate (197963-32-9) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaH / 1) THF, rt, 1 h; 2) THF, rt, 12 h 2: 92 percent / Pd(PPh3)4, Na2CO3 / tetrahydrofuran; H2O / 1) rt, 1 h; 2) reflux, 1 h 3: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 4: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme
Multi-step reaction with 4 steps 1: 80 percent / NaH / tetrahydrofuran / Ambient temperature 2: 92 percent / Pd(PPh3)4, Na2CO3 / H2O; tetrahydrofuran / Heating 3: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 4: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

ethyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate (197963-34-1) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 2: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 2: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

ethyl 2-(2,2-dimethyl-7-phenyl-6-trifluoromethanesulfonyloxy-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate (197963-33-0) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / Pd(PPh3)4, Na2CO3 / tetrahydrofuran; H2O / 1) rt, 1 h; 2) reflux, 1 h 2: 1.) p-toluenesulfonhydrazide, p-TsOH*H2O, 2.) NaBH3CN / 1) EtOH, reflux, 7 h; 2) EtOH, reflux, 4 h 3: 77 percent / aq. NaOH / ethanol / 0.25 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1: 92 percent / Pd(PPh3)4, Na2CO3 / H2O; tetrahydrofuran / Heating 2: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 3: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

1-chloro-3-phenyl-2-propyne (3355-31-5) → licofelone (156897-06-2)

Conditions

Yield

Multi-step reaction with 8 steps 1: 90 percent / n-Bu4NI, NaI, NaOH / H2O; toluene / 50 °C 2: 80 percent / NaBH(OAc)3, Et3N / CH2Cl2 / Ambient temperature 3: 68 percent / t-BuCO2H / 150 °C 4: 77 percent / EtONa / ethanol / Ambient temperature 5: 80 percent / NaH / tetrahydrofuran / Ambient temperature 6: 92 percent / Pd(PPh3)4, Na2CO3 / H2O; tetrahydrofuran / Heating 7: 1.) p-toluenesulfonyl hydrazide, p-TsOH, 2.) NaBH3CN / 1.) EtOH, reflux, 2.) EtOH, reflux 8: 77 percent / NaOH / ethanol; H2O / 80 °C View Scheme

4-chlorobenzoylmethyl bromide (536-38-9) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaHCO3 / diethyl ether; ethanol; H2O / 36 h / Ambient temperature 2: Cu / toluene / 0.25 h / Heating 3: 75.5 percent / 10percent aq. NaOH / ethanol / 0.17 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: ethanol / 0.5 h 2.1: tetrahydrofuran / 18 - 25 °C / Inert atmosphere 2.2: 0.33 h / 25 - 30 °C 3.1: hydrazine hydrate; potassium hydroxide / diethylene glycol / 50 - 145 °C View Scheme

5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole (116673-95-1) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaHCO3 / diethyl ether; ethanol; H2O / 36 h / Ambient temperature 2: Cu / toluene / 0.25 h / Heating 3: 75.5 percent / 10percent aq. NaOH / ethanol / 0.17 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / ethanol / 36 h / 20 °C 2.1: tetrahydrofuran / 10 - 15 °C 2.2: 0.33 h / 25 - 30 °C 3.1: hydrazine hydrate; potassium hydroxide / ethylene diglycol / 7 h / 85 - 145 °C View Scheme
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / ethanol; water / 36 h / 20 °C 2: tetrahydrofuran / 10 - 15 °C 3: water / tetrahydrofuran / 0.33 h / 25 - 30 °C 4: hydrazine hydrate; potassium hydroxide / diethylene glycol / 7 h / 85 - 145 °C View Scheme
Multi-step reaction with 3 steps 1.1: ethanol / 0.5 h 2.1: tetrahydrofuran / 18 - 25 °C / Inert atmosphere 2.2: 0.33 h / 25 - 30 °C 3.1: hydrazine hydrate; potassium hydroxide / diethylene glycol / 50 - 145 °C View Scheme

2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (133111-56-5) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Cu / toluene / 0.25 h / Heating 2: 75.5 percent / 10percent aq. NaOH / ethanol / 0.17 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 10 - 15 °C 1.2: 0.33 h / 25 - 30 °C 2.1: hydrazine hydrate; potassium hydroxide / ethylene diglycol / 7 h / 85 - 145 °C View Scheme
Multi-step reaction with 3 steps 1: tetrahydrofuran / 10 - 15 °C 2: water / tetrahydrofuran / 0.33 h / 25 - 30 °C 3: hydrazine hydrate; potassium hydroxide / diethylene glycol / 7 h / 85 - 145 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 18 - 25 °C / Inert atmosphere 1.2: 0.33 h / 25 - 30 °C 2.1: hydrazine hydrate; potassium hydroxide / diethylene glycol / 50 - 145 °C View Scheme

6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid toluene solvate → licofelone (156897-06-2)

Conditions	Yield
In methanol; ethyl acetate at 0 - 5℃; for 5h;

oxalyl dichloride (79-37-8) + 2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (133111-56-5) → licofelone (156897-06-2)

Conditions	Yield
Stage #1: oxalyl dichloride; 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine In tetrahydrofuran at 10 - 25℃; for 0.5 - 0.75h; Stage #2: With water In tetrahydrofuran at 0 - 30℃; for 0.0833333 - 0.166667h; Stage #3: With hydrogenchloride; potassium hydroxide; hydrazine more than 3 stages;

5.5-dimethyl-1,3,2-dioxathiane-2-oxide (1003-85-6) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: dimethyl sulfoxide / 36 h / 100 °C 2.1: pyridine; thionyl chloride / 0 °C 3.1: diethyl ether / 2 h / Reflux 3.2: 3 h / Reflux 4.1: sodium hydrogencarbonate / ethanol / 36 h / 20 °C 5.1: tetrahydrofuran / 10 - 15 °C 5.2: 0.33 h / 25 - 30 °C 6.1: hydrazine hydrate; potassium hydroxide / ethylene diglycol / 7 h / 85 - 145 °C View Scheme

3,3-dimethyl-4-hydroxy butyronitrile (103804-80-4) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: pyridine; thionyl chloride / 0 °C 2.1: diethyl ether / 2 h / Reflux 2.2: 3 h / Reflux 3.1: sodium hydrogencarbonate / ethanol / 36 h / 20 °C 4.1: tetrahydrofuran / 10 - 15 °C 4.2: 0.33 h / 25 - 30 °C 5.1: hydrazine hydrate; potassium hydroxide / ethylene diglycol / 7 h / 85 - 145 °C View Scheme

2,2-Dimethyl-1,3-propanediol (126-30-7) → licofelone (156897-06-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: thionyl chloride / dichloromethane / 5 - 10 °C 2.1: dimethyl sulfoxide / 36 h / 100 °C 3.1: pyridine; thionyl chloride / 0 °C 4.1: diethyl ether / 2 h / Reflux 4.2: 3 h / Reflux 5.1: sodium hydrogencarbonate / ethanol / 36 h / 20 °C 6.1: tetrahydrofuran / 10 - 15 °C 6.2: 0.33 h / 25 - 30 °C 7.1: hydrazine hydrate; potassium hydroxide / ethylene diglycol / 7 h / 85 - 145 °C View Scheme

4-chloro-3,3-dimethylbutyronitrile (116673-94-0) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: diethyl ether / 2 h / Reflux 1.2: 3 h / Reflux 2.1: sodium hydrogencarbonate / ethanol / 36 h / 20 °C 3.1: tetrahydrofuran / 10 - 15 °C 3.2: 0.33 h / 25 - 30 °C 4.1: hydrazine hydrate; potassium hydroxide / ethylene diglycol / 7 h / 85 - 145 °C View Scheme
Multi-step reaction with 5 steps 1.1: magnesium 1.2: 5 h / Reflux 2.1: sodium hydrogencarbonate / ethanol; water / 36 h / 20 °C 3.1: tetrahydrofuran / 10 - 15 °C 4.1: water / tetrahydrofuran / 0.33 h / 25 - 30 °C 5.1: hydrazine hydrate; potassium hydroxide / diethylene glycol / 7 h / 85 - 145 °C View Scheme

C23H19Cl2NO2 (1310936-45-8) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: water / tetrahydrofuran / 0.33 h / 25 - 30 °C 2: hydrazine hydrate; potassium hydroxide / diethylene glycol / 7 h / 85 - 145 °C View Scheme

benzyl chloride (100-44-7) → licofelone (156897-06-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: magnesium 1.2: 5 h / Reflux 2.1: sodium hydrogencarbonate / ethanol; water / 36 h / 20 °C 3.1: tetrahydrofuran / 10 - 15 °C 4.1: water / tetrahydrofuran / 0.33 h / 25 - 30 °C 5.1: hydrazine hydrate; potassium hydroxide / diethylene glycol / 7 h / 85 - 145 °C View Scheme

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + licofelone (156897-06-2) → licofelone-NHS

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃;	100%
With dicyclohexyl-carbodiimide In dichloromethane at 20℃;

licofelone (156897-06-2) + 1,1'-carbonyldiimidazole (530-62-1) → 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-1-(1H-imidazol-1-yl)ethanone (1175530-60-5)

Conditions	Yield
In tetrahydrofuran at 20℃; for 24h;	97%
In tetrahydrofuran at 20℃; for 0.5h;

licofelone (156897-06-2) + 2-amino-2-hydroxymethyl-1,3-propanediol (77-86-1) → 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid tromethamine salt

Conditions	Yield
In ethanol at 47℃; Industry scale;	92%

cholin hydroxide (123-41-1) + licofelone (156897-06-2) → 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid choline salt (1224948-00-8)

Conditions	Yield
In ethanol; water at 75 - 77℃; Product distribution / selectivity; Industry scale;	87%

2,2,2-trichloroethyl 2,3,4-tri-O-tert-butyldimethylsilyl-D-glucopyranuronate + licofelone (156897-06-2) → (2S,3R,4S,5R)-3,4,5-Tris-(tert-butyl-dimethyl-silanyloxy)-6-{2-[2-(4-chloro-phenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-acetoxy}-tetrahydro-pyran-2-carboxylic acid 2,2,2-trichloro-ethyl ester

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -50 - 20℃; for 2h;	72%

1,8-diiodooctane (24772-63-2) + licofelone (156897-06-2) → 8-iodooctyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate (1332505-35-7)

Conditions	Yield
With potassium carbonate In acetone at 56℃;	70.1%

toluene (108-88-3) + licofelone (156897-06-2) → 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid toluene hemisolvate

Conditions	Yield
In diethyl ether at 60℃;	70%

1,3-dibromo-propane (109-64-8) + licofelone (156897-06-2) → 3-bromopropyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate (1332505-34-6)

Conditions	Yield
With potassium carbonate In acetone at 56℃;	68.7%

ethylene dibromide (106-93-4) + licofelone (156897-06-2) → 2-bromoethyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate (1025054-99-2)

Conditions	Yield
With potassium carbonate In acetone at 56℃;	60.3%

1,4-dibromo-butane (110-52-1) + licofelone (156897-06-2) → 4-bromobutyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate (912341-47-0)

Conditions	Yield
With potassium carbonate In acetone at 56℃;	56.9%

1,12-dibromododecane (3344-70-5) + licofelone (156897-06-2) → 12-bromododecyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate (1332505-36-8)

Conditions	Yield
With potassium carbonate In acetone at 56℃;	43.1%

licofelone (156897-06-2) → [2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]acetic acid 2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl ester

Conditions	Yield
With boron trifluoride diethyl etherate In diethyl ether at 20℃; for 0.5h;	1.3%

toluene (108-88-3) + licofelone (156897-06-2) → 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid toluene solvate

Conditions	Yield
In ethyl acetate at 40 - 50℃;

Upstream product

• 100-44-7 benzyl chloride 
• 1310936-45-8 C₂₃H₁₉Cl₂NO₂ 
• 116673-94-0 4-chloro-3,3-dimethylbutyronitrile 
• 126-30-7 2,2-Dimethyl-1,3-propanediol 
• 103804-80-4 3,3-dimethyl-4-hydroxy butyronitrile 
• 1003-85-6 5.5-dimethyl-1,3,2-dioxathiane-2-oxide 
• 1061179-22-3 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetamide 
• 1061179-20-1 methyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetate 
• 262426-70-0 [6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl]acetic acid tert-butyl ester 
• 79-37-8 oxalyl dichloride 
• 133111-56-5 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine 
• 116673-95-1 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole 
• 536-38-9 4-chlorobenzoylmethyl bromide 
• 3355-31-5 1-chloro-3-phenyl-2-propyne 

Downstream Products

• 912341-47-0 4-bromobutyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1332505-35-7 8-iodooctyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1332505-36-8 12-bromododecyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1025054-99-2 2-bromoethyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1332505-34-6 3-bromopropyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1025055-02-0 2-(nitrooxy)ethyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1025055-10-0 3-(nitrooxy)propyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 586347-53-7 4-(nitrooxy)butyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1332505-37-9 8-(nitrooxy)octyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1332505-38-0 12-(nitrooxy)dodecyl 2-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetate 
• 1224948-00-8 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid choline salt 
• 922724-98-9 C₆₂H₉₄ClN₃O₁₄ 

Relevant articles and documents

Licofelone-nitric oxide donors as anticancer agents

Five licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H- pyrrolizin-5-yl]acetic acid) nitric oxide donor conjugates were developed by a parallel synthesis approach. The biological screening revealed that compounds with a propyl (6b), butyl (6c), or octyl (6d) chain between licofelone and the nitric oxide donor exhibited high antiproliferative potency at MCF-7 and MDA-MB-231 breast cancer as well as at HT-29 colon cancer cells. Moreover, 6b-d possessed at least 2-fold higher cytotoxicity at MDA-MB-231 cells than the parent compound licofelone although they showed less inhibitory activity at COX-1 and COX-2. A correlation between COX inhibition and growth inhibitory properties is not visible. However, the high levels of nitric oxide production of the compounds may result in their high cytotoxic activity. Non-steroidal anti-inflammatory drugs possessing nitric oxide donors are promising anti-inflammatory and anticancer drugs. Herein, a series of licofelone-nitric oxide donors was synthesized and evaluated for their primary biological activities.

Synthesis and biological evaluation of licofelone derivatives as anticancer and anti-inflammatory agents

Two C5-substituted licofelone derivatives were developed and investigated for cytotoxicity against mammary (MCF-7 and MDA-MB 231) as well as colon carcinoma (HT-29) cancer cells. Both compounds were at least 2-fold more active than 5-fluorouracil (5-FU) and licofelone against mammary carcinoma cells. At HT-29 cells, they were less active, but nevertheless distinctly as active as 5-FU and still 2-fold more active than licofelone. However, variation of the C5- carboxylic group results in an occasionally remarkable decrease of anti-inflammatory potency in in vitro and in vivo.

A synthesis of licofelone using Fenton's reagent

An efficient synthesis of licofelone, an anti-inflammatory drug currently undergoing phase-III clinical studies, based on Fenton-type radical alkylation of 2,3-dihydro-1H-pyrrolizine 3 with iodoacetonitrile or iodoacetates is reported. The iodoacetates can be replaced by NaI and by the corresponding bromoacetate.