Scientia Pharmaceutica Article

A Facile, Improved Synthesis of Sildenafil and Its Analogues Ambati. V. Raghava Reddy 1,2, *, Garaga Srinivas 1 , Chandiran Takshinamoorthy 1 , Badarinadh Gupta Peruri 1 and Andra Naidu 2 1

Aurobindo Pharma Limited Research Centre-II, Survey No. 71&72, Indrakaran Village, Sangareddy Mandal, Medak District 502329, Telangana, India; [email protected] (G.S.); [email protected] (C.T.); [email protected] (B.G.P.) 2 Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500085, Telangana, India; [email protected] Article * Correspondence: [email protected]; Tel.: +91-08455-223759

AAcademic Facile, Synthesis of Sildenafil and Editor: Improved Thomas Erker Received: 17 July 2015; Accepted: 18 October 2015; Published: 18 October 2015 Its Analogues Abstract: This paper describes the facile synthesis of sildenafil citrate (1) and its related compounds 1,2,*, Garaga Srinivas 1, ChandiranTakshinamoorthy 1, Badarinadh Ambati. Reddy throughV.anRaghava improved chlorosulfonation reaction using chlorosulfonic acid and thionyl chloride. 1 2 Gupta Peruri and Andra This synthesis results in Naidu pure sildenafil with high yield. The structures of the compounds were 1 H-NMR and 13 C-NMR spectroscopic methods, and high resolution determined with infrared (IR), 1 Aurobindo Pharma Limited Research Centre-II, Survey No. 71&72, Indrakaran Village, Sangareddy mass spectroscopy (HRMS) analysis. Mandal, Medak District, 502329, Telangana, India; [email protected] (G.S.); [email protected] (C.T.); [email protected] (B.G.P.)

Keywords: sildenafil; chlorosulfonation; novel analogues Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally,

2

*

Hyderabad500085, Telangana, India; [email protected] (A.N.) Correspondence: [email protected]; Tel.: +91-08455-223759

Academic Editor: Thomas Erker Received: 17 July 2015; Accepted: 18 October 2015; Published: 18 October 2015

1. Introduction

Sildenafil citrate (1) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific Abstract: This paper describes the facile synthesis of sildenafil (1) and its related compounds phosphodiesterase type 5 (PDE5), which is responsible forcitrate the degradation of cGMP in the through an improved chlorosulfonation reaction using chlorosulfonic acid and thionyl chloride. corpus cavernosum. ThisSildenafil synthesis isresults sildenafil with high yield. The structures of the used in in pure the treatment of erectile dysfunction in males andcompounds it is also were used 1H-NMR and 13C-NMR spectroscopic methods, and high resolution determined with infrared (IR), for hypertension [1,2]. It is chemically known as 5-{2-ethoxy-5-[(4-methylpiperazinyl)sulfonyl] mass spectroscopy (HRMS) analysis. phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one-2-hydroxy-1,2,3-propan etricarboxylate. As per the first process disclosed in the literature [3], sildenafil (4) was prepared Keywords: sildenafil; chlorosulfonation; novel analogues by reacting 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimid-7-one (2) with chlorosulfonic acid to produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,61. Introduction dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one (3), which was further converted into sildenafil by reacting with N-methyl piperazine. water solublemonophosphate Sildenafil (4) is (cGMP)-specific converted in to Sildenafil citrate (1) is a selective Finally, inhibitorpoorly of cyclic guanosine Sildenafil citrate (1)type (Figure 1) by treating with citric acidfor monohydrate to improve its solubility and phosphodiesterase 5 (PDE5), which is responsible the degradation of cGMP in the corpus bioavailability (Scheme 1). cavernosum. O O N H3C

N

O S

CH3 N

HN

CH2COOH

N .

N OC2H5

CH3

C(OH) COOH CH2COOH

Structure of sildenafil citrate (1). Figure 1. Structure

Sildenafil is used in the treatment of erectile dysfunction in males and it is also used for hypertension [1,2]. It is chemically known as 5-{2-ethoxy-5-[(4-methylpiperazinyl)sulfonyl] phenyl}1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one-2-hydroxy-1,2,3Sci. Pharm. 2016, 84, 447–455; doi:10.3390/scipharm84030447 www.mdpi.com/journal/scipharm propanetricarboxylate. As per the first process disclosed in the literature [3], sildenafil (4) was prepared by reacting 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3d]pyrimid-7-one (2) with chlorosulfonic acid to produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-

Sci. Pharm.2016, 84, 447-page Sci. Pharm. 2016, 84, 447–455 Sci. Pharm.2016, 84, 447-page O

2 448 N

O HNCH 3

ClSO3H RT, 4 days 97% Cl CH3 RT, 4 days 97%

OCH2CH3 CH3 OCH2CH(2) 3 N

O

ClSO3H

N

NN N

HN

O

CH3 Cl

O

S

N OCH2CH3

H3C

N CH3

N CH3

CH3 RT, 18 h 43%

OCH2CH3 CH3

(3)

RT, 18 h 43%

(3) O

H3C N

HN

N

N

O

HN

N

N

O

(2)

O S NN

CH3

HN

S

N

HN

O

2

CH3

O

CH3 N

O HNCH 3 O O N S HN ON N N

N

N

OCH2CH3 CH3 OCH2CH3

O

CH2COOH C(OH) COOH CH2COOH CH2COOH C(OH) COOH CH3 CH2COOH 85%

85%

(4)

O N

N

H3C

N

H3C

O O S HN N

O S

CH3 N

CH HN3 N N N .

N OC2H5

OC2H5 CH3

CH2COOH N . CH2COOH C(OH) COOH CH2COOH C(OH) CH3COOH CH2COOH

(1)

(4)

(1)

Scheme 1. 1. Reported Reported route route for for synthesis synthesis of of sildenafil sildenafil citrate. Scheme citrate. Scheme 1. Reported route for synthesis of sildenafil citrate.

In the above reported synthesis, preparation of compound 3 from compound 2 was critical as it

In the above reported synthesis, preparation of compound 3 from compound 2 was critical as it highly influenced the yield and quality of the end product. The chlorination of compound compound 5 was a highly influenced the yield and quality of the end product. The chlorination of compound 5 was a 2,[4]), reversible reaction (Scheme 2, [4]), so so the the experimental experimental conditions conditions had had to to be be adjusted adjusted to obtain the reversible reaction (Scheme 2,[4]), so the experimental conditions had to be adjusted to obtain the sulfonyl chloride chloride (compound (compound 3). 3). maximum conversion of compound 2 into sulfonyl maximum conversion of compound 2 into sulfonyl chloride (compound 3). O

O

N

HNN

HN

N

N

N

N

OC2H5 OC2H5

O

HO

S

HN

OO

HO

N

O

CH3

CH3

O3 CH

CH3

N

N N

OHN O S HO N

NHN N

S OH O

O HO

O S

Cl

N

CH3

OC2H5 OC H 2 5

O

S OH Cl

S OH

O

O

O

O S

Cl

N HCl

HCl

CH3

CH3

OC2H5

HN

O

S Cl

CH3 O

CH3

N

N

O

HN N

N

OC2H5

(3)

(5)

N

(5) O

O

CH3

N

OC2H5

N CH3

(5)

CH3

(5)

HN

O S

+ Cl Cl S OH

+

O

(2)

(2)

O

O

O

O

CH3

CH3

N N

H2SO4

CH3

CH3

OC2H5

H2SO4

(3)

Scheme 2. Synthetic path of chlorosulfonation. Scheme 2. Synthetic Scheme 2. Synthetic path path of of chlorosulfonation. chlorosulfonation.

2. Materials and methods

2. Materials 2. Materialsand andmethods Methods

General Procedures: All melting points were determined with the Polmon melting point General Procedures: Procedures: All melting points determined with the Polmon melting melting point point 1H-NMR andwith 13C-NMR General AllLtd., melting points were were determined the Polmon apparatus(Polmon Instruments Pvt. Hyderabad, India). spectra were 11H-NMR and 13 13C-NMR spectra were apparatus(Polmon Instruments Pvt. Ltd., Hyderabad, India). apparatus(Polmon Pvt. Ltd., Hyderabad, India). H-NMR Chemical and C-NMR were recorded on a Bruker 300Instruments & 500 spectrometer (Bruker, Fällanden, Switzerland). shifts spectra (δ) recorded on a Bruker 300 & 500 spectrometer (Bruker, Fällanden, Switzerland). Chemical shifts (δ) recorded on a Bruker 300 & 500 spectrometer (Bruker, Fällanden, Switzerland). Chemical shifts (δ) were were reported in ppmdownfield with TMS as internal standard, multiplicities are described as s: were reported in ppmdownfield with TMS as internal standard, multiplicities are described as s: reported in ppmdownfield with TMS as internal standard, multiplicities areHRMS described as s: singlet, singlet, d: doublet, t: triplet, dd: double doublet, m: multiplet, brs: broad singlet. The spectra singlet, d: doublet, t: triplet, dd: double doublet, m: multiplet, brs: broad singlet. The HRMS spectra were d: measured the Perkin PEdoublet, SCIEX-API 2000 mass brs: spectrometer (Waters, United doublet,on t: triplet, dd:Elmer double m: multiplet, broad singlet. TheMA, HRMS spectra were were measured on the Perkin Elmer PE SCIEX-API 2000 mass spectrometer (Waters, MA, United States). An analytical HPLC (Waters, MA, United States) was run with the Symmetry C 18 , 210 × 4.6 measured on the Perkin Elmer PE SCIEX-API 2000 mass spectrometer (Waters, MA, United States). States). An analytical HPLC (Waters, MA, United States) was run with the Symmetry C , 210 4.6 mm column at 290 nm. An analytical HPLC (Waters, MA, United States) was run with the Symmetry C18 , 21018× 4.6 ×mm

mm column atnm. 290 nm. column at 290

2.1. Preparation of 5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-one (3) of 5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,32.1. Preparation

d]pyrimidin-7-one (3)

Sci. Pharm. 2016, 84, 447–455

449

2.1. Preparation of 5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one (3) 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimid-7-one (2, 25 g, 80.13 mmol) followed by thionyl chloride (9.53 g, 80.13 mmol) were added to chlorosulfonic acid (50 mL) portion-wise at 0–10 ◦ C. The reaction mass temperature was raised to 20–30 ◦ C and stirred for 4 h to complete the reaction. The reaction mass was poured onto ice (~500 g) slowly and the product was extracted with dichloromethane (250 mL). The dichloromethane layer was separated and washed with 5% w/w aqueous sodium bicarbonate (100 mL). The dichloromethane layer containing compound 3 was taken to the next step as such. 2.2. Preparation of 5-[2-Ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro7H-pyrazolo[4,3-d]pyrimidin-7-one (Sildenafil, 4) N-methylpiperazine (9.6 g, 96 mmol) was added to the dichloromethane layer containing sulfonyl chloride compound 3 (obtained from example 1) and stirred for 1 h at 20–25 ◦ C. Then the reaction mass was washed with 5% w/w aqueous sodium bicarbonate (100 mL) followed by demineralised (DM) water (100 mL). The dichloromethane layer was concentrated at