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GISEDENAFIL

Gisadenafil besylate C23H33N7O5S.C6H6O3S [334827-98-4]GISEDENAFIL BESYLATE

334826-98-1 free form
334827-98-4 (as besylate)

  • UK 369003
  • UK-369,003
  • UK0369,003
  • UNII-S6G4R7DI1C

THERAPEUTIC CLAIM Treatment of lower urinary tract
symptoms associated with BPH

LEARN SPECTROSCOPY USING GISADENAFIL INTERMEDIATES

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CHEMICAL NAMES FREE FORM

1. ……..7H-Pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[(4-ethyl-1-
piperazinyl)sulfonyl]-3-pyridinyl]-3-ethyl-2,6-dihydro-2-(2-methoxyethyl)-

2. …….5-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]pyridin-3-yl}-3-ethyl-2-(2-
methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

3………1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine

MOLECULAR FORMULA C23H33N7O5S

MOLECULAR WEIGHT 519.6

CODE DESIGNATION UK-369,003

CAS REGISTRY NUMBER 334826-98-1

5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-7-one

Phosphodiesterase PDE5A Inhibitors , Treatment of Erectile Dysfunction

Pfizer (Originator)

UK-369003 is a phosphodiesterase V (PDE V) inhibitor which had been under development for the treatment of erectile dysfunction, pulmonary hypertension and for the treatment of lower urinary tract symptoms, but no recent development has been reported for these indications. Trials for the treatment of benign prostatic hyperplasia were discontinued.

Gisadenafil besylate (USAN)

D09622, 334827-98-4

M.Wt:677.79

5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl)-3-ethyl-2-(2-methoxyethyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one benzenesulfonate

1-[[6-Ethoxy-5-[3-ethyl-4,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridinyl]sulfonyl]-4-ethylpiperazine Monobenzenesulfonate

Formula:C23H33N7O5S.C6H6O3S

Certificate of Analysis
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Biological Activity:Potent and selective PDE5 inhibitor (IC50: 1.23 nM) with improved selectivity over PDE6(PDE5/6 selectivity value 117 and >3000-fold selectivity over other PDEs).Gisadenafil has the potential for oral bioavailability and dose-proportional pharmacokinetics. Close analogue of Sildenafil (Viagra; Axon 2046)

Gisadenafil besylate is a PDE5 inhibitor. Inhibition of PDE5 prevents the breakdown of cyclic phosphodiester secondary messenger molecules. This has the effect of prolonging and enhancing signal transduction.

CLINICAL TRIALS

http://clinicaltrials.gov/search/intervention=UK-369,003

………………………….

PAPERS

Links

Bioorganic and Medicinal Chemistry, 2012 ,  vol. 20,  1  p. 498 – 509

http://www.sciencedirect.com/science/article/pii/S0968089611008303

Full-size image (6 K)

Full-size image (36 K)

Scheme 1.

Reagents and conditions: (i) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, hydroxybenzotriazole, di-isopropylethylamine, THF, 20 °C, 20 h; (ii) caesium carbonate, alkyl mesylate or alkyl chloride, DMF, 20 °C, 20 h; (iii) KHMDS, R1OH, 120 °C, 20 h.

Full-size image (20 K)

Scheme 2.

Reagents and conditions: (i) KHMDS, nBuOH, 120–130 °C, pressure vessel (ii) TFA, CH2Cl2; (iii) methanesulphonyl chloride, NEt3, CH2Cl2; (iv) HOAc, NaCNBH3, CH2O (v) KHMDS, nBuOH, reflux.

Full-size image (37 K)

Scheme 3.

Reagents and conditions: (i) caesium carbonate, RCl, DMF; (ii) 50 psi H2, 10% Pd/C (iii) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, HOBT, di-isopropylethylamine, THF, 20 °C, 20 h; (iv) KHMDS, ethanol, 120 °C, pressure vessel; (v) TFA, CH2Cl2; (vi) CH2O, HOAc, NaCNBH3; (vii) R1OH, KHMDS, 120 °C.

Full-size image (28 K)

Scheme 4.

Reagents and conditions: (i) NaNO2, HCl, H2O; (ii) TFAA, Et2O; (iii) ethyl propynoate, xylene, reflux, 2 h; (iv) NaOH, H2O, dioxan; (v) HNO3/H2SO4, 40–55 °C; (vi) (COCl)2, CH2Cl2, DMF; (vii) NH3, THF; (viii) 10% Pd/C, EtOH, 60 psi H2, 20 °C, 14 h; (ix) acid chloride of 3, NEt3, CH2Cl2; (x) KHMDS, EtOH, 130 °C, 14 h, pressure vessel; (xi) methoxyethanol, KHMDS, reflux, 14 h.

……………………………

PAPERS

Links

Org. Proc. Res. Dev., 2004, 8 (4), pp 674–679
DOI: 10.1021/op0300241

http://pubs.acs.org/doi/abs/10.1021/op0300241

Abstract Image

………………………….

PAPERS

Yousef Hajikarimian, Steve Yeo, Robert W. Ryan, Philip Levett, Christopher Stoneley and Paul Singh
Org Process Res Dev 2010, 14(4): pp 1027–1031
Publication Date (Web): June 25, 2010 (Article)
DOI: 10.1021/op100141g

Figure

UK-369,003 was nominated for development as the lead candidate for treatment of benign prostatic hyperplasia (BPH). The free base was found to be moderately crystalline with a melting point of 168 °C. Solubility of the free base at physiological pH was found to be poor hence necessitating a comprehensive screen for a suitable salt form of the API. Benzenesulfonic acid was found to form the most suitable counterion for the API with a melting point of 248 °C and satisfied all our requirements for primary and secondary processing. The process for the formation of the benzenesulfonic acid salt involved the use of water/methyl ethyl ketone (4% water by volume) as the reaction medium. The water level at 4% ensured an optimum balance between product quality (purging of impurities) and the reaction yield. The cyclisation reaction (step 2/Scheme 01) involves the use of ethanol as the reaction media. Any residual amount of ethanol in the isolated step 2 product was therefore considered to be a considerable risk factor in the potential formation of ethyl besylate during the final step processing (step 3/Scheme 01).

Figure

Scheme 1. Manufacturing route to UK-369,003-26a 

aCDI = carbonyl diimidazole; MEK = methyl ethyl ketone; EtOAc = ethyl acetate; KOtBu = potassium tertiary butoxide; EtOH = ethanol.

……………………

SYNTHESIS

Links

US6407259

Compound 1E is also known as 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or alternatively as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridyl sulphonyl}-4-ethylpiperazine (the compound of Example 103 of WO 01/27113 and exemplified hereinafter as Example 1).

Preparation 1

2,2-dimethoxybutane:

Methyl ethyl ketone (672 mL) was charged to a 2 L round bottomed flask and stirred at room temperature before being treated with, trimethylorthoformate (763 mL) and para-toluenesulphonic acid (6.65 g, 0.5 mol %). Over a 15 min period the internal temperature rose to 46° C., so the reaction was cooled to 0° C. for 30 min. The reaction was then stirred at room temperature for 2 h. The reaction was then neutralised by pouring onto sodium carbonate (ca. 750 g) with constant stirring. The resultant slurry was filtered under vacuum and the resultant filtrate was distilled at atmospheric pressure. The fraction boiling in the range 118° C.-124° C. was collected as a colourless liquid, 582 g, 70%.

1H NMR (CDCl3): δ=0.88 (3H, t), 1.24 (3H, s), 1.61 (2H, q), 3.17 (6H, s).

Example 1 N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide

(a) Ethyl 3-ethyl-1H-pyrazole-5-carboxylate (IIA) from (IlI) and (V)

Figure US06407259-20020618-C00033

To a stirred solution of 2,2-dimethoxybutane (10 g, 84.7 mMol) in CH2Cl(50 mL) under a nitrogen atmosphere at 0° C. was added pyridine (13.7 mL, 169.5 mMol). The reaction mixture was maintained at 0° C. and a solution of trichloroacetyl chloride (18.9 mL, 169.5 mMol) in CH2Cl(35 mL) was added over 1 hour with constant stirring. The yellow-orange solution begins to precipitate a white solid as the reaction progresses. The reaction mixture is allowed to warm to room temperature over 20 h. The reaction mixture was diluted with ethanol (150 mL) and re-cooled to 0° C. before treatment with hydrazine hydrate (8.2 mL, 169.5 mMol) as a solution in ethanol (35 mL) over 30 min. The reaction was heated to 50° C. and solvent was distilled at atmospheric pressure. The temperature was increased until the head temperature reached 78° C. Reflux was maintained for a further 2 h, before cooling to room temperature. The reaction mixture was diluted with water (250 mL) and ethanol was removed by evaporation at reduced pressure. The resultant mixture was extracted with CH2Cl(3×200 mL). The combined organics were dried (MgSO4), filtered and evaporated at reduced pressure to afford the title compound as a brown oil, 12.05 g, 85%.

1H NMR (300 MHz, CDCl3): δ=1.20 (3H, t), 1.28 (3H, t), 2.67 (2H, q), 4.29 (2H, q), 6.55 (1H, s), 12.56 (1H, s).

LRMS m/z=167.1 [M-H]+, C8H12N2Orequires 168.2.

(b) Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid (IIA) from (IIA) via route 1

Figure US06407259-20020618-C00034

Aqueous sodium hydroxide solution (10M; 100 ml, 1.0 mol) was added dropwise to a stirred suspension of the title compound of Example (a) (66.0 g, 0.39 mol) in methanol and the resulting solution heated under reflux for 4 hours. The cool reaction mixture was concentrated under reduced pressure to ca. 200 ml, diluted with water (200 ml) and this mixture washed with toluene (3×100 ml). The resulting aqueous phase was acidified with concentrated hydrochloric acid to pH 4 and the white precipitate collected and dried by suction to provide the title compound (34.1 g). δ (DMSOd6): 1.13 (3H,t), 2.56 (2H,q), 6.42 (1H,s).

(c) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxylic acid

Fuming sulphuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting solution heated to 50° C., then 3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull., 1984, 32,1568; 16.4 g, 0.106 mol) added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The white precipitate was collected, washed with water and dried by suction to yield the title compound (15.4 g), m.p. 170-172° C. Found: C, 42.35; H, 4.56; N, 21.07. C7H9N3O4requires C, 42.21; H, 4.55; N, 21.10%. δ (DMSOd6): 0.90 (3H,t), 1.64 (2H,m), 2.83 (2H,m), 14.00 (1 H,s).

(d) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid (IIA) to (AA) via route 2

Figure US06407259-20020618-C00035

Obtained from the title compound of Example (b), by analogy with the process of Example (c), as a brown solid (64%). δ (DMSOd6): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1 H,s).

(e) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxamide

A solution of the title compound of Example (c) (15.4 g, 0.077 mol) in thionyl chloride (75 ml) was heated under reflux for 3 hours and then the cool reaction mixture evaporated under reduced pressure. The residue was azeotroped with tetrahydrofuran (2×50 ml) and subsequently suspended in tetrahydrofuran (50 ml), then the stirred suspension ice-cooled and treated with gaseous ammonia for 1 hour. Water (50 ml) was added and the resulting mixture evaporated under reduced pressure to give a solid which, after trituration with water and drying by suction, furnished the title compound (14.3 g).

m.p. 197-199° C. Found: C, 42.35; H, 5.07; N, 28.38. C7H10N4Orequires C, 42.42; H, 5.09; N, 28.27%. δ (DMSOd6): 0.90 (3H,t), 1.68 (2H,m), 2.86 (2H,t), 7.68 (1 H,s), 8.00 (1 H,s).

(f) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide BA from AA via route 3

Figure US06407259-20020618-C00036

Obtained from the title compound of Example (d), by analogy with Example (e), as a white solid (90%). δ (DMSOd6): 1.17 (3H,t), 2.87 (2H,m), 7.40 (1H,s), 7.60 (1H,s), 7.90 (1H,s). LRMS: m/z 185 (M+l)+.

(g)(i) 5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide CA from BA via route 4

Figure US06407259-20020618-C00037

A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5 kg, 13.6 Mol), sodium carbonate (1.8 Kg, 17.0 Mol) and 2-bromoethyl methyl ether (1.98 kg, 14.2 Mol) in THF (22.5 L) and water (2.5 L) was heated under reflux and stirred for 20 hours. The mixture was cooled to ambient temperature and CH2Cl(67.5 L) and water (22.5 L) were added. The resultant organic and aqueous layers were separated. The aqueous phase was extracted with CH2Cl(22.5 L) and the combined organic solution was distilled under atmospheric pressure and replaced with ethyl acetate (33 L) to a final volume of 17 L. The cooled mixture was granulated at ambient temperature for 2 hours, filtered and washed with ethyl acetate (2.5 L). This afforded 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a white crystalline solid, 2.10 kg, 57%. m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4Orequires C, 44.63; H, 5.79; N, 23.14%.

δ (CDCl3): 1.18 (3H, t), 2.98 (2H, q), 3.22 (3H, s), 3.77 (2H, t), 4.28 (2H, q), 6.03 (1H, s), 7.36 (1H, s).

LRMS: m/z=243 (M+1)+

(g)(ii) 5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide.

A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25 g, 0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide (20.4 g, 0.136 Mol) were suspended in ethyl methyl ketone (125 mL) at room temperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol) was added and the mixture was heated to reflux and stirred for 70 hours. The mixture was cooled to ambient temperature and water (250 mL) was added. The resultant slurry was warmed to reflux and held at that temperature for 30 min before cooling to room temperature. The resultant precipitate was granulated at room temperature for 3 h, filtered and vacuum dried to afford 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a yellow crystalline solid 24.3 g, 74%. Data as reported for Example (g)(i).

(h) 4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (IA) from CA via route 5

Figure US06407259-20020618-C00038

A mixture of 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide (20 g, 82.6 mMol) and 5% Pd/C (1 g) in methanol (200 mL) was pressurised at 50psi/25° C. in a sealed vessel and stirred for 15 hours. At the end of the reaction the mixture was filtered through arbocel and the filter cake was washed with methanol. The methanolic solution was distilled at atmospheric pressure and replaced with ethyl acetate to a final volume of 100 mL. The cooled mixture was granulated at ambient temperature for 2 h filtered and washed with ethyl acetate (20 mL) to afford 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide as a white crystalline solid, 15 g, 88%. m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4Orequires C, 50.94; H, 7.55; N, 26.42%. δ (CDCl3): 1.20 (3H, t), 2.63 (2H, q), 3.32 (3H, s), 3.74 (2H, t), 3.95 (2H, s), 4.15 (2H, t), 5.27 (1H, s), 6.59 (1H, s).

LRMS: m/z=213 (M+1)+

(i) N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide.

Figure US06407259-20020618-C00039

2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (2.31 kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and 1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 40 minutes and then the reaction was stirred for a further 40 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (1.5 kg, 7.06 Mol) was added to the cooled mixture, and the reaction stirred for a further 15 hours under reflux. The mixture was cooled filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL /g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide as an off white crystalline solid, 3.16 kg, 88%. m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.

δ (CDCl3): 1.04 (3H, t), 1.22 (3H, t), 1.60 (3H, t), 2.44 (2H, q), 2.54 (4H, m), 2.96 (2H, q), 3.12 (4H, m), 3.36 (3H, s), 3.81 (2H, t), 4.27 (2H, t), 4.80(2H, q), 5.35(1H, s), 6.68 (1H, s), 8.66 (1H, d), 8.86 (1H, d), 10.51 (1H, s).

LRMS: m/z=539 (M+1)+

(i) 1-(6-Ethoxy-5-[3-ethyll-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine•ethyl acetate solvate.

Figure US06407259-20020618-C00040
 

GISADENAFIL

A mixture of N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide (1.18 kg, 2.2 Mol), potassium tert-butoxide (500 g, 4.4 moles) and ethyl acetate (193 g) in ethanol (11.8 L) was heated at 120° C. for 20 hours. The reaction mixture was then concentrated under reduced pressure, in total approx. 10 L of solvent were distilled. To the residue water (2.9 L) was added and the mixture stirred at room temperature while aqueous HCl was added until pH 7.5 was obtained. Ethyl acetate (7.5 L) was added and the two phase mixture was warmed to 55° C. The organic phase was separated and the aqueous phase was extracted with further ethyl acetate (3.0 L). The combined organic phases were distilled at atmospheric pressure to a final volume of 4 L. The precipitated solids were granulated at 5° C. for 1 h, filtered and washed with ethyl acetate (1.2 L) and dried under vacuum. This afforded 1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine as a light yellow crystalline solid, 877 g, 78%. m.p.=157° C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5CO2CHrequires C, 53.21; H, 6.49; N, 18.25%.

δ (CDCl3): 1.07 (3H, t), 1.42 (3H, t), 1.61 (3H, t), 2.44 (2H, q), 2.57 (4H, m), 3.08 (2H, q), 3.15 (4H, m), 3.32 (3H, s), 3.92 (2H, q), 4.48 (2H, q), 4.77 (2H, q), 8.65 (1H, d), 9.06 (1H, d). The spectrum also has signals that correspond to a solvate with ethyl acetate.

LRMS: m/z=520 (M+1)+

……………..

WO2001027113A2

Example 102

1-(6-Ethoxy-5-f3-ethyll-6,7-dihvdro-2-(2-methoxyethvn-7-oxo-2r7-pyrazoler4.3- cf1pyrimidin-5-vn-3-pyridylsulfonyl)-4-ethylpiperazine»ethyl acetate solvate.

Figure imgf000150_0001

To prepare the compound of Example 8 a mixture of Λ/-[3-carbamoyl-5-ethyl- 1 -(2-methoxyethyl)-1 /-/-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1 -piperazinyl sulfonyl) nicotinamide (1.18 kg, 2.2 Mol), potassium tert-butoxide (500 g, 4.4 moles) and ethyl acetate (193 g) in ethanol (11.8 L) was heated at 120°C for 20 hours. The reaction mixture was then concentrated under reduced pressure, in total approx. 10 L of solvent were distilled. To the residue water (2.9 L) was added and the mixture stirred at room temperature while aqueous HCl was added until pH 7.5 was obtained. Ethyl acetate (7.5 L) was added and the two phase mixture was warmed to 55°C. The organic phase was separated and the aqueous phase was extracted with further ethyl acetate (3.0 L). The combined organic phases were distilled at atmospheric pressure to a final volume of 4L. The precipitated solids were granulated at 5°C for 1 h, filtered and washed with ethyl acetate (1.2 L) and dried under vacuum. This afforded 1 -(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo- 2H-pyrazole[4,3-o pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine as a light yellow crystalline solid, 877 g, 78%. m.p. = 157°C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5C02CH3 requires C, 53.21 ; H, 6.49; N, 18.25%.

δ(CDCI3): 1.07 (3H, t), 1.42 (3H, t), 1.61 (3H, t), 2.44 (2H, q), 2.57 (4H, m), 3.08 (2H, q), 3.15 (4H, m), 3.32 (3H, s), 3.92 (2H, q), 4.48 (2H, q), 4.77 (2H, q), 8.65 (1 H, d), 9.06 (1 H, d). The spectrum also has signals that correspond to a solvate with ethyl acetate.

LRMS: m/z = 520 (M+1)+

Example 103

1-(6-ethoxy-5-r3-ethyl-6.7-dihvdro-2-(2-methoxyethvn-7-oxo-2H-pyrazolor4.3- dlpyrimidin-5-vn-3-pyridylsulfonyl)-4-ethylpiperazine

Figure imgf000151_0001
 

GISADENAFIL

10g (0.019 mol) of the compound of Example 8 and Example 102, 1-{6- ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3- d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine ethyl acetate solvate, was charged followed by 12ml/g (120mls) of 16% water in ethyl alcohol. The slurry was heated to reflux to yield a solution and 6ml/g (60mls) distilled off at atmospheric pressure. The solution was then cooled to room temperature with crystallisation occurring at 40°C. The slurry was then cooled to 5-10°C and granulated for 30 minutes following which it was filtered and washed with 2ml/g ethyl alcohol (20 mis). The damp solid was dried in vacuo overnight at 55-60 °C to yield a white crystalline solid. (Yield 7.6g, 76%). Melting Point 162- 165°C.

δ (CDCI3): 1.05 (3H,t), 1.42 (3H,t), 1.58 (3H,t), 2.43 (2H,q), 2.57 (4H,t), 3.09 (2H, t), 3.15 (4H,t), 3.30 (3H,s), 3.93 (2H,t), 4.48 (2H,t), 4.90 (2H,q), 8.65 (1 H,d), 9.05 (1 H,d), 10.65 (1 H,s).

In the process of Example 103, water and pharmaceutically acceptable alcohols such as methanol, ethanol, propanol, butanol and mixtures thereof can be used to prepare the compound of Examples 8 and 102.

BESYLATE SALT

Example 104 1-(6-ethoxy-5-r3-ethyl-6,7-dihvdro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolor4.3- d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine benzene-sulfonate salt.

Figure imgf000152_0001

170g (0.33 mol) of the compound of Example 103, 1-{6-ethoxy-5-[3-ethyl-6,7- dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3- d]pyrimidin-5-yl]-3- pyridylsulfonyl}-4-ethylpiperazine, was charged followed by a water/ 2- butanone (4% v/v) at 10 ml/g (1.7 litres) and warmed to reflux. 53g (0.33 mol) of benzene sulfonic acid dissolved in water (23mls, resulting in 70 % w/w solution) was added to the refluxing solution over 30 minutes.5.3ml/g (0.9 litres) of 2-butanone were striped and replaced and the slurry cooled. The slurry was cooled to 5-10°C and granulated for 2 hours after which it was filtered and washed with 2ml/g (0.3 litres) of 2-butanone. The salt was dried overnight in vacuo at 55-60°C to yield a white crystalline solid. Yield 215g, 96.4%. Mpt 242-244°C. δ (DMSO): 1.17 (3H, t), 1.28 (3H, t), 1.35 (3H, t), 2.73 (2H, q), 2.97 (2H, q), 3.2 (3H, s), 3.58 (2H, t), 3.78 (3H, t), 3.81 (2H, t), 4.49 (2H, t) 4.51 (2H, q), 7.29-7.33 (3H, m), 7.57-7.60 (2H, m), 8.28 (1 H, d), 8.73 (1 H, d), 9.13 (1 H,s), 11.90(1 H,s).

The powder X-ray diffraction (PXRD) pattern for this salt, having Mpt 242- 244°C, was determined using a Siemens D5000 powder X-ray diffractometer fitted with a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. The specimen was rotated whilst being irradiated with copper K-alpha1 X-rays (Wavelength = 1.5046 Angstroms) filtered with a graphite monochromator (λ = 0.15405nm) with the X-ray tube operated at 40 kV/mA. The main peaks (in degrees θ) of the PXRD pattern are illustrated in Table I.

Table

Figure imgf000154_0001
Figure imgf000155_0002

The same besylate salt, as defined by the XRD pattern described in Table 1 , when made via alternative routes can have a melting point in the range of from 235-246°C (measured using a Perkin Elmer DSC7 at a heating rate of 20°C/minute).

Links

References

1  The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics
Bioorg Med Chem 2012, 20(1): 498………….MP 161 – 162 °C

2. Hajikarimian, Y.; Yeo, S.; Ryan, R.W.; Levett, P.; Stoneley, C.; Singh, P.
Investigation into the formation of the genotoxic impurity ethyl besylate in the final step manufacturing process of UK-369,003-26, a novel PDE5 inhibitor
Org Process Res Dev 2010, 14(4): 1027

3. Bentham; Dawson; Dunn; Papadopoulos; Taylor; Mitchell; Snowden; Taylor
Organic Process Research and Development, 2004 ,  vol. 8,   4  PG. 674 – 679 ………….AS ENTRY B

  • Bloch, W., et al.: Prostate, 33, 1 (1997)
  • • Glowienke, S., et al.: Mutat. Res., 581, 23 (1997)
  • • Chapple, C., et al.: Eur. Urol., 54, 563 (1997)
  • • Elder, D., et al.: J. Pharm. Pharmacol., 61, 269 (1997)

PATENTS

1. WO 2010062366

2. WO 2007072156

3  WO 2007072156

4.US2002/22732 A1,

5.US2002/28799 A1,

6.

WO1998049166A1 * Apr 10, 1998 Nov 5, 1998 Mark Edward Bunnage PYRAZOLOPYRIMIDINONES WHICH INHIBIT TYPE 5 CYCLIC GUANOSINE 3′,5′-MONOPHOSPHATE PHOSPHODIESTERASE (cGMP PDE5) FOR THE TREATMENT OF SEXUAL DYSFUNCTION
WO1999054333A1 * Mar 25, 1999 Oct 28, 1999 Mark Edward Bunnage Pyrazolopyrimidinone cgmp pde5 inhibitors for the treatment of sexual dysfunction
US4666921 * 15 окт 1985 19 май 1987 Ludwig Heumann & Co. Gmbh Pyrazole derivatives, processes for their preparation and pharmaceutical preparations containing these compounds
US5808092 * 15 окт 1997 15 сен 1998 Ube Industries, Ltd. Process for preparing-1-ethyl-5-hydroxypyrazole
US6015911 * 24 мар 1998 18 янв 2000 Dow Agrosciences Llc Process for preparing 1-alkyl-4-(2-chloro-3-alkoxy-4-alkylsulfonylbenzoyl)-5-hydroxypyrazole and related compounds
EP0463756A1 7 июн 1991 2 янв 1992 Pfizer Limited Pyrazolopyrimidinone antianginal agents
EP0812845A1 4 июн 1997 17 дек 1997 Pfizer Limited Process for preparing sildenafil
EP0994115A2 11 окт 1999 19 апр 2000 Pfizer Limited Process for preparation of pyrazolo-(4,3-d)pyrimidin-7-ones and intermediates thereof
EP0995750A1 15 окт 1999 26 апр 2000 Pfizer Inc. Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
WO1998049166A1 10 апр 1998 5 ноя 1998 Mark Edward Bunnage PYRAZOLOPYRIMIDINONES WHICH INHIBIT TYPE 5 CYCLIC GUANOSINE 3′,5′-MONOPHOSPHATE PHOSPHODIESTERASE (cGMP PDE5) FOR THE TREATMENT OF SEXUAL DYSFUNCTION
WO1999054333A1 25 мар 1999 28 окт 1999 Mark Edward Bunnage Pyrazolopyrimidinone cgmp pde5 inhibitors for the treatment of sexual dysfunction
WO2001027112A1 4 окт 2000 19 апр 2001 Charlotte Moira Norfo Allerton 5-(2-substituted-5-heterocyclylsulphonylpyrid-3-yl)-dihydropyrazolo[4,3-d]pyrimidin-7-ones as phosphodiesterase inhibitors
WO2001027113A2 11 окт 2000 19 апр 2001 Mark Edward Bunnage PYRAZOLO `4,3-d! PYRIMIDINE DERIVATIVES

PDE5 inhibitors mirodenafil

Figure imgf000078_0002

sildenafil

Figure imgf000078_0003

tadalafil

Figure imgf000079_0001

udenafil 3-(l-methyl-7-oxo-3-propyl-4H-pyrazolo[5,4-e]pyrimidin-5-yl)-N- [2-(l -methylpyrrolidin-2-yl)ethyl] -4-propoxybenzenesulfonamide

Figure imgf000080_0001

vardenafil 4-[2-ethoxy-5-(4-ethylpiperazin-l-yl)sulfonyl-phenyl]-9-methyl-7- propyl- 3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one

Figure imgf000080_0002

avanafil 4-[(3-chloro-4-methoxy-phenyl)methylamino]-2-[(2S)-2- (hydroxymethyl)pyrrolidin- 1 -yl] -N-(pyrimidin-2- ylmethyl)pyrimidine-5-carboxamide

Figure imgf000080_0003

dasantafil 7-[(3-bromo-4-methoxyphenyl)methyl]-l-ethyl-8-[[(lR,2R)-2- hydroxycyclopentyl]amino]-3-(2-hydroxyethyl)purine-2,6-dione

Figure imgf000081_0001

NM 702 (Nissan Chemical Industries)

Figure imgf000081_0002

SLX 101 (Surface Logix) – Structure Not Available

UK 369003 (Pfizer) – Gisadenafil besylate

Figure imgf000081_0003
 
 
 
 
Cut paste from my blog on  organic spectroscopy international
SEE  BELOW OR FOLLOW LINK
 
GISEDENAFIL
Gisadenafil besylate C23H33N7O5S.C6H6O3S [334827-98-4]GISEDENAFIL BESYLATE
334826-98-1 free form

334827-98-4 (as besylate)

  • UK 369003
  • UK-369,003
  • UK0369,003
  • UNII-S6G4R7DI1C
THERAPEUTIC CLAIM Treatment of lower urinary tract

symptoms associated with BPH

 break dancer animation
LEARN NMR STEP BY STEP
can can  animation1…………..
Ethyl 3-ethyl-1H-pyrazole-5-carboxylate
 
Figure US06407259-20020618-C00033
1H NMR (300 MHz, CDCl3):
δ=1.20 (3H, t), METHYL OF  -CH2-CH3
1.28 (3H, t),  METHYL OF  -C=O-O-CH2-CH3
 2.67 (2H, q), CH2 OF  OF  -CH2-CH3
4.29 (2H, q),  CH2  OF  -C=O-O-CH2-CH3
6.55 (1H, s), LONE PYRAZOLE PROTON ON RING
12.56 (1H, s). NH PROTON
LRMS m/z=167.1 [M-H]+, C8H12N2Orequires 168.2.
dancer  animation

 
2………. Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid
 
Figure US06407259-20020618-C00034
 
 δ (DMSOd6):
1.13 (3H,t), METHYL OF  -CH2-CH3
2.56 (2H,q), CH2 OF-CH2-CH3
6.42 (1H,s).LONE PYRAZOLE PROTON ON RING
VERY EASY..FEELING HAPPY..1H NMR IS EASY
dancer  animation

shark

3………..
3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid
Figure US06407259-20020618-C00035
 δ (DMSOd6):
1.18 (3H,t), METHYL OF  -CH2-CH3
2.84 (2H,m), CH2  OF  -CH2-CH3
13.72 (1 H,s). NH PROTON
ALERT……….LONE PYRAZOLE PROTON ON RING LOST DUE TO NITRO SUBSTITUTION
hula dancing  animation

 
4………..
3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide
Figure US06407259-20020618-C00036
 
 δ (DMSOd6):
1.17 (3H,t), METHYL OF  -CH2-CH3
2.87 (2H,m),CH2 OF  -CH2-CH3
7.40 (1H,s),
7.60 (1H,s),
7.90 (1H,s).
ALL NH AND NH2 SIGNALS
DO IT YOURSELF………….NMR IS EASY
LRMS: m/z 185 (M+l)+.
liz hurlley dancing  animation
5………..
5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide
Figure US06407259-20020618-C00037
m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4Orequires C, 44.63; H, 5.79; N, 23.14%.
δ (CDCl3):
1.18 (3H, t), METHYL OF  -CH2-CH3
2.98 (2H, q),CH2 OF  -CH2-CH3
 3.22 (3H, s), METHYL OF -OCH3
3.77 (2H, t), CH2 OF NCH2-CH2-O-CH3
4.28 (2H, q), CH2 OF NCH2 –CH2-O-CH3
6.03 (1H, s), NH2
7.36 (1H, s).NH2
 
LRMS: m/z=243 (M+1)+
african carnival dancing  animation
 art    animation
 
 
 
6……
4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide
Figure US06407259-20020618-C00038
 m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4Orequires C, 50.94; H, 7.55; N, 26.42%.
 δ (CDCl3):
 1.20 (3H, t),
 2.63 (2H, q),
 3.32 (3H, s),
3.74 (2H, t),
3.95 (2H, s), NH2 OF PYRAZOLE
4.15 (2H, t),
5.27 (1H, s),C=0-NH2
 6.59 (1H, s).C=O-NH2
NITRO IS CONVERTED TO AMINO….DO IT YOURSELF
 
LRMS: m/z=213 (M+1)+
ballerina  animation
 




7…………………
 
N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide.
Figure US06407259-20020618-C00039
m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.
δ (CDCl3):
1.04 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING
1.22 (3H, t), METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN
1.60 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING
2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING
2.54 (4H, m), 4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM
2.96 (2H, q), CH2 OF  –CH2-CH3 ON PYRAZOLE SIDE CHAIN
3.12 (4H, m), 4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP
3.36 (3H, s), METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN
3.81 (2H, t), CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.27 (2H, t), CH2 OF NCH2 –CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.80(2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING
5.35(1H, s), C=0–NH2
6.68 (1H, s), C=O-NH2
8.66 (1H, d) ,PYRIMIDINE AROM H …..AWAY/PARA TO C=O-NH -PYRAZOLE GP
 8.86 (1H, d), PYRIMIDINE AROM H …..CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift to delta 9.06 after cyclization in next step ie formation of GISADENAFIL
10.51 (1H, s). NH
LRMS: m/z=539 (M+1)+
 
modern dancers  animation


shark



FINAL
1-(6-Ethoxy-5-[3-ethyll-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine•ethyl acetate solvate.
Figure US06407259-20020618-C00040
 
 m.p.=157° C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5CO2CHrequires C, 53.21; H, 6.49; N, 18.25%.
δ (CDCl3):

1.07 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING

1.42 (3H, t),  METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN

1.61 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING

2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING

2.57 (4H, m),4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM

3.08 (2H, q), CH2 OF  –CH2-CH3 ON PYRAZOLE SIDE CHAIN

3.15 (4H, m),4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP

3.32 (3H, s),METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN

3.92 (2H, q),  CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.48 (2H, q), CH2 OF NCH2 –CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.77 (2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING

8.65 (1H, d), PYRIMIDINE AROM H …..AWAY/PARA TO C=O-NH -PYRAZOLE GP

9.06 (1H, d). PYRIMIDINE AROM H …..CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift from 8,86 delta to  9.06 after cyclization in this step ie formation of GISADENAFIL

The spectrum also has signals that correspond to a solvate with ethyl acetate.

 
LRMS: m/z=520 (M+1)+

1 Comment

  1. medchemnintabelle says:

    Reblogged this on MedCheminAustralia.

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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