Showing posts with label PATENT REVIEW. Show all posts
Showing posts with label PATENT REVIEW. Show all posts

Saturday, 13 December 2014

Sildenafil .........US 20010009962 Patent review



This invention relates to a process for the preparation of 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine(otherwise known as sildenafil or Viagra™), and 1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine and key intermediates thereof.
[0002] 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (otherwise known as sildenafil) has been found to be particularly useful in the treatment of, inter alia, male erectile dysfunction (WO-A-94/28907), and a process for its preparation is disclosed in EP-A-0463756 (example 12) and Drugs of the Future 1997, 22(2): 138-143. An improved process for preparing sildenafil (over that of EP0463756) is disclosed in EP-A-0812845, with the characterising final step involving cyclisation under basic, neutral or acidic conditions to form sildenafil. A process for the preparation of 1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine is disclosed in WO 98/49166 (example 5B).
[0003] The present inventors have now found a process for preparing sildenafil and 1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine which has advantages over the aforementioned prior art processes.
[0004] According to the present invention there is provided a process for preparing a compound of formula (IA) and (IB)
Figure US20010009962A1-20010726-C00003
[0005] comprising reacting a compound of (IIA) and (IIB) respectively in the presence of OR, wherein R in the case of formation of compound (IA) is CH2CHand R in the case of formation of compound (IB) is CH2CH2CH3, where X is a leaving group:
Figure US20010009962A1-20010726-C00004
[0006] A particular advantage of the present process over that of the prior art is the elimination of steps by carrying out a substitution reaction and ring closure in ‘one pot’.
[0007] The intermediates of general formula (IIA) and (IIB) form a further aspect of the invention.
[0008] A key intermediate of the general formula (IIIA) and (IIIB) (see schemes 1 and 2 hereafter) have been identified in various reactions showing that such reactions at least partially go via a pathway of cyclisation then nucleophilic substitution. Accordingly intermediates of general formula (IIIA) and (IIIB) form yet a further aspect of the invention (wherein X is a leaving group).
[0009] A further major intermediate of formula IVA and IVB have also been identified, suggesting that there is also nucleophilic substitution before cyclisation (and these intermediates, where novel, form a further aspect of the invention).
[0010] Thus the proposed reaction pathways for the formation of compounds (IA) and (IB) are as follows
Figure US20010009962A1-20010726-C00005

Figure US20010009962A1-20010726-C00006

[0061] (1e) 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-pronyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine. (Compound IA)
[0062] Potassium t-butoxide (0.74 g, 6.60 mmol) was added to a suspension of the title compound of example (1d) (1.00 g, 2.20 mmol) in ethanol (5 ml) and the mixture was heated under reflux for 48 hours. The reaction mixture was stripped down to an oil and purified by dissolving in dichloromethane and washing with saturated sodium bicarbonate solution. Hexane was added to the organic solution over 10 minutes, a precipitated solid filtered and dried to afford the title compound (1.1 g, 100%) as a white solid. Recrystallisation of the title compound from ethyl acetate affords a solid with m.p. 184-186° C. Found: C, 55.49; H, 6.35; N, 17.72. C22H31N6O4S requires C, 55.58; H, 6.53; N, 17.68. δ (DMSO): 0.96 (3H, t), 1.30 (3H, t), 1.72 (2H, m), 2.13 (3H, s), 2.36 (4H, m), 2.72 (2H, t), 2.90 (4H, m), 4.18 (5H, m), 7.32 (1H, d), 7.80 (2H, m). m/z (Found: 475.214800 ([M+H]+, 100%). C22H31N6O4S. requires 475.212751).




Systematic (IUPAC) name
1,3-thiazole-5-carboxylic acid
Clinical data
Trade namesUloric, Adenuric, Atenurix
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.
Legal status
Pharmacokinetic data
Bioavailability~49% absorbed
Protein binding~99% to albumin
Metabolismvia CYP1A22C82C9,UGT1A11A31A92B7
Half-life~5-8 hours
ExcretionUrine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)
CAS number144060-53-7 
ATC codeM04AA03
PubChemCID 134018
ChemSpider118173 Yes
UNII101V0R1N2E Yes
KEGGD01206 Yes
Chemical data
Mol. mass316.374 g/mol

Febuxostat is an inhibitor of xanthine oxidase, and was developed by Teijin pharma. This compound is known as a new drug that is effective against gout and hyperuricemia, and it has been 40 years since the last time a drug of this kind of drug was developed.
Febuxostat has therefore gained a lot of popularity and it has already been accepted as a drug in Europe, USA, Korea and Japan. The synthesis of this molecule have been reported in patents by Teijin pharma as shown below.[1,2]

Recently, Itami group was reported the rapoid synthesis of febxostat by using Ni-catalyzed direct coupling of azoles and arylhalides[3]
  • References

Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32
[1] Hasegawa, M.; A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile. Heterocycles 1998, 47, 2, 857. [2] Hasegawa, M.;  Hasegawa, M.; Komoriya, K. (Teijin Ltd.); Cyano cpds. and their preparation method. JP 1994345724 . [3] “Nickel-Catalyzed Biaryl Coupling of Heteroarenes and Aryl Halides/Triflates”
Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 200911, 1733-1736. DOI: 10.1021/ol9001587
Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)2/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)2/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.