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Lodenafil carbonate

UNII-29X84F932D, CRIS-031  

bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate

5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one. IS THE NAME OF MONOMER

398507-55-6  CAS

Cristalia (Originator)

C47 H62 N12 O11 S2= MF
Molecular Weight	1035.199

Lodenafil is a drug belonging to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. Like udenafil and avanafil it belongs to a new generation of PDE5 inhibitors.

• Sildenafil, tadalafil, vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.

Lodenafil is formulated as a dimer, lodenafil carbonate, which breaks down in the body to form two molecules of the active drug lodenafil. This formulation has higher oral bioavailability than the parent drug.^[1]

It is manufactured by Cristália Produtos Químicos e Farmacêuticos in Brazil and sold there under the brand-name Helleva.^[2]

Helleva (Lodenafil Carbonate) is an oral PDE5 inhibitor prescribed to treat men suffering from erectile dysfunction. It operates by relaxing muscles and dilating blood vessels in the penis to increase circulation making it easier to attain and maintain an erection.

It has undergone Phase III clinical trials,^[3][4][5] but is not yet approved for use in the United States by the U.S. Food and Drug Administration.

lodenafil

………..

SYNTHESIS

WO 2002012241 OR US7148350

MONOMER synthesis

PIPERAZINE

AND

ETHYL CHLORO ACETATE

WILL GIVE

Ethyl 1-piperazinylacetate

SEE RXN 1 BELOW

Reaction 1:

Synthesis of Piperazine Ethyl Acetate

To a reaction blend containing 100 g (3 Eq, 0.515 mol, MW=194) of piperazine, 26.3 mL (1.1 Eq, 0.189 mol, MW=101, d=0.726) of triethylamine in 200 mL of isopropanol, add to a solution previously prepared of 18.4 mL (1 Eq., 0.172 mol, MW=122.55, d=1.15) of chloroacetate of ethyl in 140 mL of isopropanol under stirring, at room temperature. Keep the reaction medium under stirring, monitoring the reaction termination by means of a chromatography of the thin layer (about 2–3 hours). Add a solution of 40.6 g (0.344 mol) of succinic acid in 140 mL of isopropanol. Keep the system under stirring for about 30 minutes to assure total precipitation of the succinate salt of piperazine formed. Filter this salt and concentrate the filtrate containing the mono and dialkyled derivatives. We obtain a slightly yellowish oil, which is used in later phases without purification.

Mass obtained=33 g

GC/MS: Monoalkylated derivative 72%, and dialkylated 22%.

NEXT

Piperazine Ethyl Acetate

AND

5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one

WILL REACT TO GIVE… 5-{2-ethoxy-5-[(4-ethyl acetate 1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-di-hydro-7H-pyrazole[4,3-d]pyrimidin-7-one AS IN RXN 4 BELOW

Reaction 4:

Synthesis of 5-{2-ethoxy-5-[(4-ethyl acetate 1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-di-hydro-7H-pyrazole[4,3-d]pyrimidin-7-one.

Suspend 24.6 g (60 mmol, MW=410.9) of 5-(5-chlorosulfonyl-2-etoxyphenyl)-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one in 900 mL of ethanol absolute. Under stirring and at room temperature, add at only one time, a solution containing 31.0 g (3 Eq., 180 mmol MW=172) of N-piperazine ethyl acetate (Reaction 1) dissolved in 150 mL of ethanol absolute. In an interval of 2–10 minutes, all solid is consumed, forming a clean and homogeneous solution, and after that starts the precipitation of the expected product. At the end of the reaction, which lasts 2–3 hours (monitored by chromatography of thin layer), the product is vacuum filtered and the solid is washed with two portions of 50 mL of iced absolute ethanol. 29 g are obtained (yielding=89%) from the product as a white solid of MP=165.5–166.5° C.

Reaction 7:

Intermediate 1

5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one.  IS MONOMER

please note during LAH redn  …………. the PIP CH2-C=O-O CH2 CH3     BECOMES        PIP-CH2CH2-OH

To a suspension of lithium aluminum hydride (0.74 g 2.2 Eq. MW=37.9) in 25 mL of THF, slowly add, under stirring and at room temperature, a suspension of 5.0 g (9.1 mmol, MW=546.6) of 5-{2-ethoxy-5-[(4-ethyl acetate 1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-di-hydro-7H-pyrazole[4,3-d]pyrimidin-7-one in 50 mL of THF. The system is maintained under stirring, monitoring the consumption of the product by chromatography of thin layer, until the complete consumption of the starting reagent (about 5–6 hours). Slowly add water to the reaction medium and, when there is no longer release of H₂, add HCl 1M regulating pH for 7. Extract the product with 3 200 mL-portions of chloroform, dry with anhydrous sodium sulfate and vacuum concentrate the product. It is obtained 3.8 g of the product as a cream solid MP=183–187° C. yielding 83%. The same was crystallized from methanol and DMF yielding a slightly yellowish solid with melting point at 189–192° C.

 

note …………. the PIP CH2-C=O-O CH2 CH3 BECOMES  PIP-CH2CH2-OH

 

HOMODIMER CARBONATE

 

EXAMPLE 1B

Homodimer Carbonate of Intermediate 1—Alternative Method

A phosgene solution (3.5 g, 35 mmol) dissolved in 20 mL of toluene was added dropwise to a solution of 2.02 g (4 mmol) of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, suspended in 44 mL of toluene. The reaction mixture resulting is stirred and followed by chromatography analysis of thin layer every hour until the reagent conversion in its chloroformate was completed. When the analysis indicates the complete consumption of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, the volatile compounds of the reaction are vacuum removed (solvents and phosgene), yielding the esther chloroformate raw derivative of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one.

The raw chloroformate obtained above (4.0 mmol, 2.27 g) is dissolved in about 30 mL of dichloromethane, to which is added 2.07 g (4.1 mmol) of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, followed by the addition of 4 mL of dichloromethane containing 450 mg of triethylamine. The reaction mixture is maintained under stirring, being followed by chromatography of thin layer every hour until this indicates the end of the reaction (disappearing of chloroformate derivative). The reaction mixture is then diluted with 60 mL of dichloromethane, washed with NaCl saturated solution, after with sodium bicarbonate saturated solution and again with NaCl saturated solution. Organic phase is separated and dry with anhydrous sodium sulfate. The solvent is then evaporated to dry, yielding the dimer carbonate as a slightly yellowish solid.

This compound is re-crystallized from ethanol:DMF, yielding a pale white solid. Yielding m=3.2 g (76%)

Microanalysis: Theoretical C, (54.53%); H, (6.04%); N, (16.24%);

Obtained C, (54.45%); H, (6.02%); N, (16.17%).

 

INFO ABOUT INTERMEDIATE

5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one

CAS No.	139756-22-2
Chemical Name:	5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
Synonyms:	Sildenafil Chlorosulfone IMpurity;Sildenafil Chlorosulfonyl IMpurity;5-(5-CHLOROSULFONYL-2-ETHOXY PHENYL)-1-METHYL-3-N-PROPYL-1;3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo-(4-3-d)-pyrimidine-5;5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;3-(4,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-benzenesulfonyl Chloride;4-Ethoxy-3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyriMidin-5-yl)benzene-1-sulfonyl chloride
CBNumber:	CB11175931
Molecular Formula:	C17H19ClN4O4S

http://www.chemicalbook.com/ChemicalProductProperty_EN_CB11175931.htm

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SYNTHESIS OF

http://www.google.co.in/patents/US6362178

EXAMPLE 10A 2-(2-Ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

 

 

7.16 g (45 mmol) of 2-butyrylamino-propionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and, after addition of a spatula tip of DMAP, heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70° C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography using ethyl acetate and crystallization afford 4.00 g (28%) of a colourless solid, R_f=0.42 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex, 2H; 2.67, s, 3H; 3.00, t, 2H; 4.26, quart., 2H; 7.05, m, 2H; 7.50, dt, 1H; 8.17, dd, 1H; 10.00, s, 1H.

EXAMPLE 15A 4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride

 

 

At 0° C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred ovemight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H; 1.61, t, 2H; 1.92, hex, 2H; 2.67, s, 3H; 3.10, t, 2H; 4.42, quart., 2H; 7.27, t, 1H; 8.20, dd, 1H; 8.67, d, 1H; 10.18, s, 1H.

Example 22 2-[2-Ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

 

 

By the same method, starting with 0.04 g (0.097 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine, 46 mg (91%) of 2-[2-ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.

R_f=0.08 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H; 1.59, t, 3H; 1.90, sex., 2H; 2.49, m, 6H; 2.62, s, 3H; 2.71, m, 4H; 3.00, t, 2H; 3.55, t, 2H; 4.31, quart., 2H; 7.14, d, 1H; 8.05, dd, 1H; 8.60, d, 1H.

…………..

Methods of analysis

The development of lodenafil carbonate was reported by Toque et al. (2008). They observed the effects of lodenafil carbonate on rabbit and human corpus cavernosum relaxation, activity of PDE5 in human platelets, stability and metabolic studies in comparison with sildenafil and lodenafil, as well as the pharmacological evaluation of lodenafil carbonate after intravenous and oral administration in male beagles.

The determination of PDE activity, stability of lodenafil carbonate in human, dog and rat plasma and the pharmacokinetic parameters after a single intravenous or oral dose was carried out by LC-MS/MS analysis

Codevilla et al. (2011a) developed a stability-indicating reversed-phase liquid chromatography method using ultraviolet (UV) detection for the quantitative determination of lodenafil carbonate in tablets. The method can be useful for routine quality control assay and stability studies.

Another study for the determination of lodenafil carbonate in tablets was developed by Codevilla et al. (2011b). As an alternative to the LC method the authors suggested a UV-spectrophotometric method for the analysis of lodenafil carbonate in pharmaceutical form. The UV method offers advantages over other analytical methods due to its rapidity, simplicity, and lower cost. Recently, Codevilla et al. (2012) developed and validated a capillary zone electrophoresis (CZE) method for determination of lodenafil carbonate in drug products. There are some advantages to use the CZE method, such as rapid analysis, small sample and reagent consumption, high separation efficiency (Furlanetto et al., 2001; Yang et al., 2010). The results obtained from the UV-spectrophotometric method and CZE method were compared statistically with the LC method (Codevilla et al., 2011a) and the results showed no significant difference between these methods.

 

References