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LOSARTAN

December 17, 2013 7:47 am / 1 Comment on LOSARTAN

LOSARTAN

DuP-753
E-3340
L-158086
MK-0954
MK-954
Ex-89 (free acid)

launched 1994, merck

COZAAR (losartan potassium, cas 124750-99-8) is an angiotensin II receptor (type AT₁)antagonist. Losartan potassium, a nonpeptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is C₂₂H₂₂ClKN₆O, and its structural formula is:

COZAAR® (LOSARTAN POTASSIUM TABLETS) Structural Formula Illustration

Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

COZAAR is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide.

COZAAR 25 mg, 50 mg and 100 mg tablets contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively. COZAAR 25 mg, COZAAR 50 mg, and COZAAR 100 mg may also contain carnauba wax.

LOSARTAN POTASSIUM

Country	Patent Number	Approved	Expires (estimated)
Canada	1334092	1995-01-24	2012-01-24
Canada	2085584	2003-02-11	2011-06-07
United States	5210079	1993-11-11	2010-11-11
United States	5608075	1992-03-04	2009-03-04

Losartan (rINN) /l oʊ ˈ s ɑr t ən / is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure (hypertension). Losartan was the first angiotensin II antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade nameCozaar. Losartan is available in generic form.

As with all angiotensin II type 1 receptor (AT₁) antagonists, losartan is indicated for the treatment of hypertension. It may also delay progression of diabetic nephropathy, and is also indicated for the reduction of renal disease progression in patients with type 2 diabetes, hypertension and microalbuminuria (>30 mg/24 hours) or proteinuria (>900 mg/24 hours).

Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most patients (from both efficacy and cost points of view), an angiotensin II receptor antagonist such as losartan is recommended as first-line treatment in patients under the age of 55 who cannot tolerate an ACE inhibitor.The LIFE study demonstrated losartan was significantly superior to atenolol in the primary prevention of adverse cardiovascular events (myocardial infarction or stroke), with a significant reduction in cardiovascular morbidity and mortality for a comparable reduction in blood pressure. A study hints that losartan has a beneficial effect on mitochondria by reversing age related dysfunction in maintaining normal blood pressure and cellular energy usage. The maximal effects on blood pressure usually occur within 3–6 weeks upon starting losartan.

Losartan is also available as hydrochlorothiazide/losartan, a combination drug with a low dose thiazide diuretic to achieve an additive antihypertensive effect.

Activation of AT₁ receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes those tissues to constrict. Blocking of vasoconstriction mediated by AT₁ receptors has been found to be beneficial to patients with hypertension.
[0003]

AT₁ receptors are activated by an octa-peptide, angiotensin II. Angiotensin II helps to maintain constant blood pressure despite fluctuations in a person’s state of hydration, sodium intake and other physiological variables. Angiotensin II also performs the regulatory tasks of inhibiting excretion of sodium by the kidneys, inhibiting norephedrin reuptake and stimulating aldosterone biosynthesis.
[0004]

Inhibiting angiotensin II binding to AT₁ receptors with an AT₁ receptor antagonist disrupts the vasoconstriction mediated by AT₁ receptors that contributes to hypertension.
[0005]

In the early 1970s, it was discovered that certain oligopeptides competitively inhibited angiotensin receptors (at that time the existence of two receptor subtypes, AT₁ and AT₂, was unknown). This discovery spurred interest in development of therapeutic oligopeptides with increased potency, but interest in peptide analogs waned due in part to their poor oral bioavailability.
[0006]

In 1982, Furukawa. Kishimoto and Nishikawa of Taketa Chemical Indus. discovered a class of non-peptide-containing imidazoles that also inhibited the vasoconstriction effect of angiotensin II. See U.S. Patents Nos. 4,340,598 and 4,355,040. Later, U.S. Patent No. 5,138,069 was obtained by Carini, Denucia and Pancras of E.I. DuPont de Nemours on another class of imidazoles, which encompasses the compound losartan. In 1995, losartan (CA Index: 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl] -4-yl]methyl]-1H-imidazole-5-methanol) (formula I):

became the first nonpeptide AT₁ antagonist approved by the U.S. Food and Drug Administration for clinical use. Losartan can be administered orally as its monopotassium salt. Losartan potassium is available by prescription in tablet form as a sole active ingredient (Cozaar®: Merck) and as a co-active ingredient with hydrochlorothiazide (Hyzaar®: Merck).
[0007]

Losartan has been prepared by a variety of synthetic pathways. In several of these synthetic pathways, the penultimate product is 2-butyl-4-chloro-1-[[2′-(2-triphenylmethyl-2H-tetrazol-5-yl) [1,1′-biphenyl] -4-yl]methyl]-1H-imidazole-5-methanol (“trityl losartan”). Trityl losartan is an intermediate in processes described in U.S. Patents Nos. 5,138,069; 5,962,500 and 5,206,374.
[0008]

In a process described in Example 316 of U.S. Patent No. 5,138,069, the tetrazole ring of losartan is formed by reacting 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole with trimethyltin azide. The reaction gives a trimethylstannyl substituted tetrazole compound directly. The trimethylstannyl group is cleaved from the product by reacting with trityl chloride. This reaction results in attachment of the trityl group to the tetrazole ring. In the last step, the trityl group is cleaved with acid to give losartan (Scheme 1).
[0009]

In the last step, trityl losartan was suspended in methanol and cooled to ~10°C. 3.4 N Hydrochloric acid was added to the slurry. After a period of time, the pH of the reaction mixture was raised to 13 with 10 N NaOH. Methanol was then distilled off while makeup water was added. After distillation, additional water and toluene were added. The toluene phase was separated and the aqueous phase was extracted once more with toluene. Ethyl acetate and acetic acid were then added to the aqueous phase. Losartan was recovered from the aqueous phase as a solid and further purified by slurrying in ethyl acetate. Losartan was obtained in 88.5% yield and 98.8% purity as determined by HPLC. This process is also described in U.S. Patents Nos. 5,128,355 and 5,155,188.
[0010]

U.S. Patent No. 5,962,500, Examples 3-5, describe a process for preparing losartan in which the tetrazole ring of losartan is present in the starting material, 5-phenyltetrazole. The ‘500 patent process, depicted in Scheme 2, is convergent and uses a Suzuki coupling reaction (Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457) in the convergent step. On one branch of the synthesis, 5-phenyltetrazole is converted into the boronic acid coupling partner for the Suzuki reaction by ortho metalation with n-butyl lithium, followed by reaction with trisopropylborate. The tetrazole ring is protected from reacting with the strong allcyl lithium base with a trityl group. The trityl group is conventionally attached by reacting the tetrazole with trityl chloride in the presence of a non-nucleophilic base. On the other branch of the convergent synthesis, 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde is alkylated with 4-bromobenzylbromide, followed by reduction of the aldehyde with sodium borohydride to yield the other Suzuki coupling partner.
[0011]

The direct product of Suzuki coupling is trityl losartan. In the next and last step, the tetrazole ring of trityl losartan is deprotected with 4N H₂SO₄ in THF. In that step, the acidic solution was aged overnight at 20 to 25°C. The solution was then extracted with isopropyl acetate and residual organic solvent was removed from the aqueous phase under vacuum. The solution was then carried forward to from the potassium salt without intermediate isolation of losartan. This process is also described in U.S.Patents Nos, 5,206,374, Example 21, and 5,310,928, Example 21.
[0012]

Larsen, R.D et al. [J. Org. Chem. (1994), 59, 6391-6394] discloses a similar convergent synthesis of lasartan, whereby the trityl lasartan, generated by Suzuki coupling, is deprotected using 0.7 M H₂SO₄ in a 50 : 50 mixture of acetonitrile /water.
[0013]

U.S. Patent No. 5,206,374 Examples 1 and 4-8 describe another process for making Iosartan that also involves a Suzuki coupling reaction. However, unlike the ‘500 patent process, the ‘374 patent process is not convergent. The ‘374 patent process is depicted in Scheme 3.
[0014]

In the ‘374 patent process, as in the `500 patent process, the tetrazole ring of 5-phenyltetrazole is protected with a trityl group before orthometallation of the phenyl moiety with n-butyl lithium in preparation for making the boronic acid Suzuki coupling partner. In the Suzuki coupling step, the boronic acid is reacted with 4-bromotoluene. The methyl group attached to one of the phenyl rings of the Suzuki product is then halogenated with N-bromosuccinamide and the benzylic bromine atom of that product is displaced with 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde. Reduction of the aldehyde group with sodium borohydride yields trityl losartan. The tetrazole group of trityl losartan was deprotected with 12% aqueous HCl in THF. After 12 hours, the pH of the reaction mixture was raised to 12.5 with 30% NaOH. The THF was then distilled off while make-up water was added to the mixture. After distillation, the mixture was cooled and the triphenyl methanol byproduct of deprotection, which had precipitated, was removed by filtration. The filtrate and rinsate, with which it was combined, were extracted with toluene. Then, ethyl acetate was added and 36% HCI was added until the pH of the reaction mixture was lowered to 3.8. The mixture was cooled, causing losartan to precipitate from the solution. Losartan was obtained in 83% theoretical yield starting from trityl losartan.

EP 253310 discloses a process, wherein 2-n-butyl-4-chloro-1H-imidazolyl-5-methanol (III) is coupled with 5-(4′-bromomethyl-1,1′-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole (IV) in N,N-dimethylformamide as solvent in presence of sodium methoxide as the base to furnish trityl losartan. The other bases that have been claimed are sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate and amine bases such as triethyl amine and pyridine.

The coupling reaction results in a mixture of trityl losartan and its regio isomer (V). These are separated by column chromatography.

U.S. Pat. Nos. 5,130,439 and 5,310,928 disclose a method for coupling (IV) and (VI) in N,N-dimethylacetamide solvent in the presence of anhydrous potassium carbonate as base. The imidazole aldehyde (VI) gives predominantly the desired regio isomer (VII). The intermediate VII is then reduced with sodium borohydride to furnish the trityl losartan. The product is isolated by extraction into toluene from aqueous N,N-dimethylacetamide, concentration of the toluene solution and crystallization using ethyl acetate or ethanol as solvent. The synthesis steps are depicted as follows.

In a process published in J. Med. Chem. (1991), 34, 2525-2547, Losartan is prepared by coupling (III) and (IV) in N,N-dimethylformamide in the presence of sodium methoxide. The desired compound is isolated after vacuum distillation of solvent followed by extractive work-up. The resultant product mixture is purified by chronmatography.

The U.S. Pat. Nos. 5,138,069, 5,128,355 and 5,155,118 describe a process for the preparation of losartan, wherein the tetrazole ring of losartan is formed by reacting 1-((2′-cyanobiphenyl-4-yl)methyl)-2-butyl-4-chloro-5-hydroxymethylimidazole with trimethyltin azide. The reaction results in trimethylstannyl substituted tetrazole compound, which is then reacted with trityl chloride and sodium hydroxide.

The trityl losartan thus formed is treated with 3.4N hydrochloric acid in methanol at about 10° C. to give losartan.

The U.S. Pat. Nos. 5,138,069, 5,128,355 and 5,155,118 also disclose another process for making trityl losartan, where in the coupling between IV and VI is carried out in a biphasic solvent system comprising of chlorinated solvent and water. The reaction is carried out at room temperature in presence of sodium hydroxide as the base and aliquat 336 as the phase transfer catalyst. The resulting intermediate VII is then reduced in situ with sodium borohydride to furnish trityl losartan.

U.S. Pat. No. 5,206,374, 5,310,928 and 5,962,500 disclose another process for preparing losartan in which 5-phenyltetrazole (X) is converted into the boronic acid coupling partner (XII) for the Suzuki reaction by tritylation of phenyltetrazole with trityl chloride in presence of a non-nucleophilic base, ortho metalation with n-butyl lithium, followed by reaction with triisopropylborate. 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (VI) is alkylated with 4-bromobenzylbromide, followed by reduction of the aldehyde with sodium borohydride to yield the other Suzuki coupling partner (XIII). The product of Suzuki coupling is trityl losartan. This process is published in J. Org. Chem. (1994), 59, 6391-6394.

European patents EP 470,794 and EP 470,795 describe a method for the manufacture of biphenyl carbonitriles (XVI). These patents also describe a method of preparation of trityl losartan by coupling of intermediates (III) and (IV) employing the procedure described in EP 253,310.

Losartan potassium exhibits polymorphism. Several polymorphic forms have been prepared and characterized. The following paragraphs briefly describe various polymorphs.

U.S. Pat. No. 5,608,075 discloses the polymorphic forms of losartan, wherein the trityl losartan is deprotected with H₂SO₄in 50:50 acetonitrile:water and the free acid is treated with KOH solution. The aqueous solution containing losartan potassium is added slowly to a refluxing azeotropic mixture of cyclohexane/iso propanol and the ternary azeotrope cyclohexane/iso propanol/water is distilled till the water content of the pot is less than 0.05%. The white crystalline solid thus obtained is polymorphic form-I, which is characterized by DSC, XRD and IR. Polymorphic form-II is prepared by heating form-I in a DSC cell. This process is also described in U.S. Pat. No. 5,859,258.

U.S. Pat. No. 6,710,183 discloses the synthesis of losartan potassium starting from trityl losartan, wherein trityl losartan is reacted in an alcohol of formula R—OH (where R is C₁to C₄straight chain alkyl group) with 0.1 to 1 equivalent KOH. Losartan potassium thus formed is isolated after crystallizing out by changing the solvent to an aprotic or weakly protic solvent. The alcohol used is preferably methanol and the protic dipolar solvent used for the crystallization of the final product is preferably acetonitrile or straight or branched chain or cyclic aliphatic hydrocarbons.

EP 1294712 (WO 02/094816) discloses the process to manufacture losartan potassium form-I, wherein trityl losartan or losartan is suspended in a solvent and KOH is added to obtain a clear solution, which is then concentrated under reduced pressure to remove most of the solvent. An anti solvent is added to crystallize losartan potassium. The solvents to prepare losartan potassium include methanol, ethanol, and butanol but preferably the salt formation is carried out in methanol. Anti solvent is selected from common solvents such as ethyl acetate, acetonitrile, toluene and acetone, but the preferred anti solvent is acetone.

US application 2004/0006237 (WO 03/048135) relates to novel amorphous and novel crystalline forms III, IV, V of losartan potassium and the processes for their preparation. The patent also discloses novel processes for preparing losartan potassium forms I and II. The preparation of amorphous losartan includes the step of dissolving losartan potassium in a solvent to form a solution and distilling the solvent form the solution to dryness. Losartan form III (hydrated) is obtained by exposing losartan potassium amorphous or form I to an atmosphere having high relative humidity. Losartan potassium form IV is obtained by treating a saturated solution of losartan potassium in ethanol with methylene chloride. Losartan form V is obtained by treating a saturated solution of losartan potassium in ethanol with hexane. Losartan potassium form II is obtained by adding a saturated solution of losartan potassium in ethanol to xylene to form a mixture and evaporating ethanol from the mixture. Losartan form I is obtained by treating a saturated solution of losartan potassium in ethanol or iso propanol, with less soluble solvent like ethyl acetate, toluene, acetone, methyl ethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate or hexane.

US application 2004/0034077 (WO 03/093262) discloses a process for preparing losartan and losartan potassium, wherein trityl losartan is treated with an acid in a diluent comprising a ketone. Especially preferred liquid ketones are acetone, methyl ethyl ketone and methyl isobutyl ketone, and acetone being the most preferred. Acids, which have been found suitable, include hydrochloric acid, sulphuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid and formic acid. After the trityl losartan has been substantially converted to losartan, reaction mixture is basified. Preferred bases are alkali metal hydroxides and alkoxides. After addition of the base, the liquid ketone is evaporated under vacuum. After separation of triaryl methyl alcohol the residue is acidified to yield losartan. Free losartan is suspended in an alcohol and treated with a solution of potassium ions. Finally losartan potassium is precipitated from the alcohol. The alcohol is selected from the group consisting of isopropyl alcohol, butyl alcohol and isobutyl alcohol. The potassium ion solution is prepared by dissolving potassium iso propoxide, potassium butoxide and potassium iso butoxide or potassium hydroxide in the diluent.

US application 2004/0097568 discloses a process for preparing form III of losartan potassium, wherein trityl losartan is treated with aqueous solution of potassium hydroxide in methanol to obtain losartan potassium. The solvent is evaporated under vacuum and traces of water are removed as an azeotrope with toluene. Methanol and carbon are added to the resulting mixture. The carbon is filtered and the methanol is distilled. The resulting mixture is cooled to 20-25° C. to obtain crystalline form III losartan potassium.

US 5,138,069 and

WO 93/10106. The advantages provided by pharmaceutical products in the crystalline form in terms of easiness of processes for the preparation of related medicaments are well known. Crystalline compounds are in fact known to be more suited to the formulation of galenic forms, thanks both to their flowability in the form of powders or granulates, and to the surface properties of the crystals which promote adhesion, for example during the preparation of tablets. Furthermore, the solubility of crystalline compounds in aqueous solutions, in particular in the gastric juices, can also be significantly different than that of the corresponding amorphous compounds. There is therefore the need to discriminate between the crystalline and the amorphous forms of biologically active compounds, so as to fulfil the various pharmaceutical requirements.

A number of crystalline and amorphous forms of losartan potassium are known from

WO 95/17396 and

WO 03/048135. According to

WO 95/17396, crystalline losartan potassium is prepared by salification of acid losartan with an alkali hydroxide. The losartan potassium aqueous solution is then added to a isopropanol-cyclohexane azeotropic mixture under reflux. Water is then removed by azeotropic distillation of the resulting water-isopropanol-cyclohexane ternary mixture, which boils at 64°C. When the solution is anhydrous, the head temperature raises to 69°C and losartan potassium crystallizes.

US 5,859,258 discloses another crystallization process which comprises dissolution of losartan potassium in isopropanol-water, distillation of the binary azeotrope to an approx. 2.6% water content, precipitation by addition of a losartan potassium suspension in cyclohexane, subsequent distillation of the ternary azeotrope to a water content ranging from 0.02 to 0.11 %, and finally drying crystalline losartan potassium under vacuum at a temperature of approx. 45-50°C.

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An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann

, Ian R. Baxendale

, Steven V. Ley

and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

Corresponding author email

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

The imidazole ring of losartan, an antihypertensive and angiotensin II blocker is formed in a condensation reaction between valeroamidine 160 and dihydroxyacetone [50]. It was found that direct chlorination of the imidazole 162also forms the dichlorination product 164 (as shown in Scheme 33) with formaldehyde as a by-product which proved difficult to suppress and made purification of the reaction mixture problematic. Hence, a sequence involving silyl protection, chlorination and deprotection was established which gave the desired product in 90% overall yield (Scheme 33).

Scheme 33: Synthesis of functionalised imidazoles towards losartan.

Alternatively, glycine can be reacted with methyl pentanimidate 169 to form the corresponding amidine 171 in high yield. Cyclisation, followed by a Vilsmeier-type reaction then furnishes the key chloroimidazolyl building block 172in good yield (Scheme 34) [51].

Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.

50———Shi, Y.-J.; Frey, L. F.; Tschaen, D. M.; Verhoeven, T. R. Synth. Commun. 1993, 23, 2623–2630.doi:10.1080/00397919308012598
51—-Griffiths, G. J.; Hauck, M. B.; Imwinkelried, R.; Kohr, J.; Roten, C. A.; Stucky, G. C.; Gosteli, J. J. Org. Chem. 1999,64, 8084–8089. doi:10.1021/jo9824910
52–Zhong, Y.-L.; Lee, J.; Reamer, R. A.; Askin, D. Org. Lett. 2004, 6, 929–931. doi:10.1021/ol036423y

……………………..

NMR

Losartan potassium hydrate.

NMR: (¹H, DMSO, 300 mHz): δ 0.80 (3H, t, J=10. CH₃), 1.25 (2H, sext, J=10. CH₃CH₂), 1.45 (2H, quin, J=10. CH₃CH₂CH₂), 2.45-2.55 (2H, m, CH₃CH₂CH₂CH₂), 4.25 (2H, d, J= 3, CH₂OH), 5.15-5.25 (3H, m, CH₂Ar and OH), 6.88 (d, 2H, J=12, ArH), 7.08 (d, 2H, J=12, ArH), 7.23-7.36 (3H, m, ArH), 7.50-7.55 (1H, ArH).

SEACOND SET

http://www.google.co.in/patents/US7915425

IR v max (KBR): 3201.01, 1580.73, 1460.18, 764.81, 540.09

¹H NMR (MeOD) δ, 0.87 (t, 3H), 1.33 (sext, 2H), 1.53 (quint, 2H), 2.56 (t, 2H), 4.43 (s, 2H), 5.24 (s, 2H), 6.89-7.53 (m, 8H).

¹³C NMR (MeOD) δ, 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72

MS (m/z)=423.3 (M+1).

……………………………..

LOSARTAN FREE BASE

Melting point: 179-180.2

IR, v max (KBR): 3376.27, 1579.77, 1468.86, 762.88, 556.4

¹H NMR (CDCl₃) δ, 0.87 (t, 3H), 1.31 (sext, 2H), 1.54 (quint, 2H), 2.57 (t, 2H), 4.45 (s, 2H), 5.30 (s, 2H), 7.01-7.68 (m, 8H).

¹³C NMR (CDCl₃) δ, 14.07, 23.24, 27.40, 30.92, 126.71, 126.86, 127.35, 128.21, 130, 130.8, 131, 131.19, 131.81, 136.09, 142.21, 149.97, 162.72

MS (m/z)=423.5 (M+1).

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ADDITIONAL WRITEUP FOR READERS, NUMBERINGS ARE ALL NEW

Losartan and its potassium salt, having the formulae (1) & (2) respectively are angiotensin-II receptor (Type AT1) antagonists.

In adults Losartan is currently indicated for the treatment of hypertension (in hypertensive patients with left ventricular hypertrophy, it is also indicated to reduce the risk of stroke).

Losartan Potassium having the formula 2 and its principle active metabolite block the vasoconstrictor and aldosterone. Secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g., vasicular smooth muscle, adrenal gland) otherwise called as angiotensin receptor blockers (ARBs).

The present invention relates to a short, simple and practical process for the preparation of Losartan 1 which belongs to a novel class of tetrazole-imidazole compounds.

There are many processes recorded in literature. The latest prior art information for the preparation of Losartan is the disclosure made in the patent application of Novartis in their PCT WO 2005/014602 dated 17 Feb. 2005.

The process described in the application comprises the reaction of 4′-(Bromomethyl)-2-cyanobiphenyl (BromoOTBN) of the formula 3 with 2-n-butyl-4-chloro-5-formyl imidazole (BCFI) of the formula of 4 in the presence of Potassium carbonate and acetonitrile to give ‘cyano aldehyde’ of the formula 5. The Cyano aldehyde of the formula 5 is reduced with sodium borohydride to get ‘cyano alcohol’ of the formula 6. The Cyano alcohol is reacted with diethyl aluminium azide in the presence of triethyl aluminium to give Losartan of the formula 1.

The reaction scheme of the process is shown in the Scheme 1

Even though the process is simple, handling of triethyl aluminium used needs special attention like very anhydrous conditions, reactions are to be performed under nitrogen or argon and transferring of triethyl aluminium from the containers needs anhydrous systems. The neat liquid and dense solutions of triethyl aluminium are known to ignite very easily at room temperature in presence of air (Pyrophoric). So handling of both triethyl aluminium and diethyl aluminium needs special attention like anhydrous conditions, nitrogen atmosphere etc.,

In EP 0578125A1 of Takeda Chemical Industries dated 12 Jan. 1994, yet another method for the preparation of Losartan has been disclosed in which Trioctadecyl or Trioctyl tin azide has been used as a tetrazole-forming agent. This method also uses the Cyano alcohol of the formula (6). The process comprises reacting the cyano alcohol of the formula (6) with tri-n-octyl tin azide in presence of toluene to give tri-n-octyl tetrazole derivative, which was treated with nitrous acid to give Losartan of the formula (1) in 94.7% yield. The process is shown in the reaction scheme 2

Even though the yields are better (94.7%) in this process again handling of tri-n-octyl tin azide is involved.

Dupont/Merck in their patents and papers always described that trityl Losartan of the formula 7 is detritylated to get Losartan 1 For example they described in J. Med. Chem., 1991, 34, 2525-2547, the preparation of Losartan of the formula 1, from trityl Losartan of the formula 7 using mineral acids such as Hydrochloric acid and sulfuric acid in 93% yield. The reaction scheme of the process is shown in the scheme 3

In this paper ‘Aldehyde Tetrazole’ of the formula 8 is isolated from trityl tetrazole aldehyde of the formula 21 and were further used for preparing derivatives of aldehyde such as benzene sulfonyl hydrazones of the formula 9 but not for Losartan. This process is shown in the scheme 4

In J. Org. Chem 1994, 59, 6391-6394 again by Merck team reported Trityl Losartan and Losartan synthesis by coupling of boronic acid derivative 11 with 3-(4-bromobenzyl) derivative of BCBMI of the formula 10. The formed trityl Losartan of the formula 7 is converted to Losartan of the formula 1 with acid. The whole process is described in Scheme 5

The Compound of the formula 10 is prepared from the reaction of BCFI of the formula 4 with p-bromo benzyl bromide of the formula 12 in potassium carbonate and Dimethyl formamide followed by reduction with sodium borohydride (NaBH₄). The details are given in the Scheme 6

The Compound of the formula 11 is prepared from 5-phenyl tetrazole of the formula 14 by reacting with trityl chloride to get N-trityl-5-phenyl tetrazole of the formula 13, which on reaction with butyl lithium and triisopropyl borate followed by hydrolysis to give compound of the formula 11. This process is shown in the Scheme 7

In one of the first patent filed by Dupont/Merck (date of filing 9 Jul. 1987, priority 11 January 1986 EP0253310) reported a procedure for the preparation of Losartan. Bromo OTBN of the formula 3 is reacted with BCHMI of the formula 15 in the presence of a base to give cyano alcohol of the formula 6, and its regioisomer of the formula 14. Separation of the isomer needs column chromatography. The cyano alcohol 6 is reacted with sodium/ammonium azide in DMF for 13 days to get Losartan 1 in 21% yield. The process is shown in the Scheme 8

The drawbacks of the above process are

1). Separation of the regioisomer using column chromatography which is industrially not feasible for the preparation of large scale (ton) material/product
2). The tetrazole formation takes 13 days with 21% yield, which is unproductive.
3). Dupont/Merck uses BCHMI 15 as the starting material for preparing cyano alcohol of the formula 6. BCHMI 15 is an expensive intermediate compared to BCFI 4, and also the formation of unwanted regio isomer 14 is higher. The process is schematically described in scheme 8. Even though the process looks simple it has two problems.

First: Cyano alcohol is produced as a mixture of regioisomers and needs column chromatography for purification.

Second: Tetrazole formation. This takes 13 days with 21% yield, which limits commercialization of the process.

In U.S. Pat. No. 4,820,843 and U.S. Pat. No. 4,879,186, Dupont prepares Losartan by reaction of BCFI of the formula 4 and N-Triphenylmethyl-5-[2-(4′-bromomethyl biphenyl)]tetrazole of the formula 16 in the presence of base, followed by reduction with sodium borohydride to give Trityl Losartan of the formula 7, which is treated with mineral acid to give Losartan 1.

The process is shown in scheme 9

In U.S. Pat. No. 4,874,867 of Dupont/Merck, a process for the preparation of N-Triphenylmethyl-5-[2-(4′-bromomethyl biphenyl)]tetrazole of the formula 16 is described by the reaction of OTBN of the formula 20 with trimethyl tin azide to give the compound 17, which is treated with Hydrochloric acid to give tetrazole derivative of OTBN of the formula 18. The tetrazole derivative of OTBN of the formula 18 is protected with trityl chloride to give compound of the formula 19, followed by bromination with N-bromosuccinimide to give N-Triphenylmethyl-5-[2-(4′-bromomethyl biphenyl)]tetrazole of the formula 16.

The process is shown in the scheme 10.

In all the above papers and patents by Dupont/Merck, the process yields in many steps are good 75-95% and in some steps are less to moderate 21-49%. The drawbacks, or the problems in all these processes is, the number of unit operations.

For example:

1). In J. Med. Chem 1991, 34, 2525-2547 the number of steps are six (6) to prepare Losartan of the formula 1 from the readily available intermediates.
2). In J. Org. Chem 1994, 59, 6391-6394 the number of steps are nine (9) to prepare Losartan of the formula 1 from the readily available intermediates.
3). In EP 0253310 patent the number of operations are two (2) but the problem is time & yields i.e., 13 days and poor yield (21%), also the uneconomical column chromatographic separation of regioisomer.
4). In U.S. Pat. Nos. 4,820,843 and 4,879,186 the number of steps are six (6).
5). In U.S. Pat. No. 4,874,867 the number of steps are seven (7).

………………………..

INTERMEDIATES

(1-(2′-Cyano biphenyl-4-methyl)-2-butyl-4-chloro-5-formyl imidazole) of the formula 5.

Figure US07915425-20110329-C00016

Melting point: 107-108° C.

HPLC Purity: >98%

IR. v max (KBR): 2218 (—CN), 1662.40 (—CHO)

¹H NMR (CDCl₃) δ, 0.91 (t, 3H), 1.38 (sext, 2H), 1.73 (quint, 2H), 2.67 (t, 2H), 5.61 (s, 2H), 7.16-7.77 (m, 8H), 9.77 (s, 1H).

¹³C NMR (CDCl₃) δ, 13.51, 22.18, 26.33, 29.04, 47.74, 110.05, 118.36, 124.11, 126.59, 127.65, 129.16, 129.81, 132.76, 133.61, 136.01, 137.69, 142.96, 144.33, 154.46, 177.73

Pazopanib, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид

December 17, 2013 4:20 am / 2 Comments on Pazopanib, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид

Pazopanib

パゾパニブ塩酸塩

Пазопаниба Гидрохлорид

5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide

Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.

Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline.

GW 786034

M.Wt: 437.53
C21H23N7O2S

Pazopanib CAS No.: 444731-52-6

CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)

ChemSpider 2D Image | Pazopanib Hydrochloride | C21H24ClN7O2S

Pazopanib Hydrochloride

CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)

MFC₂₁H₂₄ClN₇O₂S
MW473.979

GW786034;Votrient;Armala;GW 786034;GW-786034

GW786034GW786034, VOTRIENT

5-({4-[(2,3-Dimethyl-2H-indazol-6-yl)(methyl)amino]-2-pyrimidinyl}amino)-2-methylbenzenesulfonamide hydrochloride (1:1)

Antineoplastic; Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors; Renal Cell Carcinoma Therpay; Soft Tissue Sarcoma Therapy

パゾパニブ塩酸塩
Pazopanib Hydrochloride

C₂₁H₂₃N₇O₂S▪HCl : 473.98
[635702-64-6]

Pazopanib (trade name Votrient) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.^[2]^[3]^[4]^[5]

Pazopanib (Votrient®; GlaxoSmithKline, Brentford, U.K.) is currently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of patients with metastatic renal cell carcinoma (mRCC)

Medical uses

It is approved by numerous regulatory administrations worldwide (including the FDA (19 October 2009), EMA (14 June 2010), MHRA(14 June 2010) and TGA (30 June 2010)) for use as a treatment for advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas.^[1]^[2]^[3]^[4]^[5] In Australia and New Zealand, it is subsidised under the PBS and by Pharmac respectively, under a number of conditions, including:^[6]^[7]

The medication is used to treat clear cell variant renal cell carcinoma.
The treatment phase is continuing treatment beyond 3-months.
The patient has been issued an authority prescription for pazopanib
The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST)
This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.

It has also demonstrated initial therapeutic properties in patients with ovarian and non-small cell lung cancer,^[8] though plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.^[9]^[10]

Pazopanib

SYNTHESIS

Pazopanib hydrochloride drug substance is manufactured by Glaxo Wellcome Manufacturing Pte. Limited, Jurong, Singapore

NDA 22-465 was submitted by GlaxoSmithKline (GSK) for VOTRIENT™ (pazopanib), an immediate release tablet for oral administration containing either 200 mg or 400 mg of pazopanib free base (GW786034X) as the hydrochloride salt (GW786034B). Pazopanib is a new molecular entity and is submitted for review pursuant to Section 505(b)(1) of the Food, Drug and Cosmetic Act. Reference is made to one active Investigational New Drug application, IND 65,747.

Quality by Design (QbD) approach and risk management to increase their understanding of the process and drug substance properties. A number of Critical Quality Attributes (CQAs) were identified. These are: Identity by IR, Chloride Identity, Crystalline Form, Content by HPLC, Drug-related Impurities (including named impurities and genotoxic (b) (4) (b) (4) (b) (4) (b) (4) Executive Summary Section CMC Review #1 Page 9 of 262 CMC REVIEW OF NDA 22-465 impurities content), Residue on Ignition, Particle Size, Residual Solvents, Water Content by Karl Fischer, Description, Pd Content, and Heavy Metals.

CQA are mainly controlled by controlling starting material attributes, intermediate attributes (e.g. specifications of GW786034 quality process parameters, and by following the manufacturing process. A risk based method (e.g. failure mode and effects analysis (FMEA)) was used to identify the Quality Critical Process Parameters (QCPPs), Quality Process Parameters (QPPs), CQAs and Quality Attributes (QAs) for the pazopanib hydrochloride manufacturing process. The inputs to the FMEA were knowledge gained through the work to develop the impurity fate map, spiking and purging studies, the Design of Experiments (DOE) work to establish potential QCPPs/QPPs, one factor at a time experiments to establish parameter proven acceptable ranges, and 6 years of plant experience preparing over batches of pazopanib hydrochloride in 3 plants throughout the GSK network. It was concluded from this risk assessment that there are no QCPP but a few QPP in the drug substance (DS) manufacturing process. Stages 1 and 2 had no QPP, the few were only present in stages 3 and 4. All the QPP were scale invariant. A combination of multivariate DOE and univariate experimentation was used to determine the Proven acceptable Ranges (PAR) for the variables. The risks for combining univariate and multivariate experimentation were found to be minimal, on the basis of outcome from the robustness study. For this study, all the process parameters were all set at the lower limit of the PARs to create a worst-case scenario for impurity purging. Neither new impurities nor elevated levels of known impurities were detected. This data demonstrated that multivariate interactions will not lead to elevated levels of impurities.

Drug Product Pazopanib Tablets, 200 mg and 400 mg are film-coated IR oral tablets. The two strengths contain 216.7 mg and 433.4 mg pazopanib hydrochloride, respectively, which are equivalent to 200 mg and 400 mg pazopanib (free base), respectively. Excipients in the tablet core are: microcrystalline cellulose, sodium starch glycolate, povidone, and magnesium stearate. Pazopanib Tablets, 200 mg are modified capsule-shaped, gray film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS JT’. Pazopanib Tablets, 400 mg are modified capsule-shaped, yellow film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS UHL’. The tablets are manufactured at Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom. Primary packaging of tablets will be performed by either Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom or GlaxoSmithKline Inc, 1011 North Arendell Avenue, Zebulon, North Carolina 27597, USA.

Pazopanib hydrochloride is a new molecular entity of Biopharmaceutics Classification System (BCS) Class 2 (poor solubility, high permeability) and a crystalline solid. Its solubility in pH 1.1 is 0.65 mg/mL. The conjugate acids of the basic nitrogens have the following acidity constants: pKa – pK1 = 2.1 (indazole), pK2 = 6.4 (pyrimidine), pK3 = 10.2 (sulfonamide).

“Synthetic approaches to the 2009 new drugs”
Kevin K.-C. Liua, Subas M. Sakyab, Christopher J. O’Donnellb, Andrew C. Flickb, Jin Lic,
Bioorganic & Medicinal Chemistry, Volume 19, Issue 3, Pages 1136–1154

“An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals”., Beilstein J. Org. Chem., 2011, 7, 442–495.

PATENT

https://www.google.com/patents/WO2015068175A2?cl=en

Pazopanib is marketed as hydrochloride salt by Glaxoshiithkline under the trade name VOTRIENT^® is tyrosine kinase inhibitor and indicated for the treatment of patients with advanced renal cell carcinoma (RCC) and treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

U.S. Patent No (s). US 7105530 (“the ‘530 patent”), US7262203 (“the ‘203 patent”) and US8114885 (“the ‘885 patent”) discloses a variety of pyrimidineamines and their derivatives such as Pazopanib, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof.

The process disclosed in the ‘530 patent is schematically represented as follows:

Patent publication No. WO 2011/050159 (“the Ί59 publication”) disclosed process for preparation of Pazopanib hydrochloride, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dicMoropyrimidine of Formula B in a solvent like industrial methylated sprit and specific reaction conditions like, in presence of a base, sodium bicarbonate having a particle size distribution of > 250μηι or 50 to 150μηι selected to ensure that the pH of the reaction mixture is less than 7 for the reaction time period not more than 300 min to obtain N-(2-c oropyrimidin-4-yl)- 2,3-dimethyl-2H-indazol-6-amine of Formula II. The compound of Formula Π was methylated in presence of a methylating agent in an organic solvent like dimethylformamide by using specific reaction conditions like, in presence of a base i.e. Potassium carbonate having a particle size distribution D99 of > 300μηι or D99 of < 200μηι selected to ensure that the reaction time needs to reduce the starting material to less than 2% in less than 8 his to obtain N-(2-cMoropyrimidin-4-yl)-N-2,3-trimemyl-2H-mdazol-6-amine of Formula III. The resultant methylated compound was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of 4M HC1 and methanol to yield Pazopanib hydrochloride.

WO Ί59 publication disclosed that use of sodium bicarbonate with specific particle size distribution of > 250μπι or 50 to 150μηι is key element in condensation of compound of Formula A and Formula B to niinimize the formation of Impurity of Formula 1 within

WO Ί59 publication also disclosed that use of potassium carbonate with specific particle size distribution D99 of > 300μπι or D99 of < 200μηι is key element in methylation of compound of Formula II to reduce the formation of Impurities of Formula 2, Formula 3 and Formula 4 within the range of about 0.05-3%.

Patent publication No. WO 2012/073254 (“the ‘254 publication”) disclosed a process for preparation of pazopanib hydrochloride, which involves condensation of 2,4-dicMoropyrimidine of Formula B with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of a base like sodium bicarbonate and a solvent like ethanol to yield 5-(4-chloropyrimidm-2-yl-ammo)-2-memylbenzenesulfonamide The resultant compound was condensed with N-2,3-1rimethyl-2H-indazole-6-amine of Formula D in an alcoholic solvent like ethanol. WO ‘254 publication also discloses process for purification of pazopanib hydrochloride from alcoholic solvent and water. The process disclosed in the ‘254 publication is schematically represented as follows:

Patent publication No. IN 2505/CHE/2011 disclosed a process for preparation of pazopanib, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dichloropyrimidine of Formula B in presence of sodium bicarbonate and a phase transfer catalyst like tetrabutyl ammonium bromide in a solvent like methanol to obtain N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine of Formula II. The resultant compound was methylated in presence of methyl iodide, potassium carbonate in a solvent like dimethylformamide to obtain compound of Formula III. The obtained Formula III was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of dimethylformamide and concentrated HC1 to yield pazopanib hydrochloride.

Patent publication No. CN 103373989 (“the ‘989 publication”) disclosed a process for preparation of Pazopanib intermediate of Formula III by condensation of N-2,3-trimethyl-2H-indazole-6-amine of Formula D with 2,4-dicWoropyrimidine of Formula B in

Patent publication No. WO 2014/97152 (“the Ί52 publication”) disclosed a process for preparation of Pazopanib hydrochloride starting from 2,3-dimethyl-6-nitro-2H-indazole.

The processes for preparation of pazopanib described in the above literature have certain drawbacks as it involves: a) use of specific predefined particles of bases like sodium bicarbonate and potassium carbonate, which involves additional process steps like milling, grinding etc, b) use of expensive phase transfer catalysts and c) multiple steps making the process quite expensive, particularly on large scale.

European Medicines Agency (EMA) public assessment report disclosed that pazopanib hydrochloride is a white to slightly yellow, non-hygroscopic, crystalline substance and the manufacturing process consistently produces pazopanib hydrochloride Form 1. However, the EMEA does not describe any particular characterization data for the disclosed polymorph Form 1.

PCT Publication No. WO 2011/058179 (“the Ί79 publication”) discloses pazopanib base crystalline Forms such as Form-I and Form-II and a process for its preparation; also disclosed characterization data of Form-I and Form-II by XRD, IR and melting point. –

PCT Publication No. WO 2011/069053 (“the ‘053 publication”) discloses crystalline pazopanib base and crystalline pazopanib hydrochloride Forms such as Form-II, Form-Ill, Form-TV, Form-V, Form- VI, Form- VIII, Form-IX, Form-X, Form-XI, Form-XII, Form-XIII, Form-A, Form-G and also discloses crystalline Pazopanib dihydrochloride Forms such as Form-I, Form-XIV, Form-XV. The crystalline Forms reported in the PCT publication characterized by its XRD pattern.

IN Publication No. 3023/CHE/2010 discloses crystalline pazopanib dihydrochloride Form-I and crystalline pazopanib mono hydrochloride, process for it preparation and characterization by XRD of the same.

IN Publication No. 1535/CHE/2012 discloses crystalline pazopanib hydrochloride Form-SP and a process for its preparation; also disclosed characterization data, of Form-SP by XRD, DSC and TR.

PCT Publication No (s): WO 2007/143483, WO 2007/064753, WO 2006/20564 and WO 2005/105094 as well as US Publication No. US 2008/0293691 disclose anhydrous and hydrated Forms of pazopanib hydrochloride and their process for preparation thereof. ‘

IP. Com journal disclosure Number IPCOM000207426D discloses crystalline Form of pazopanib hydrochloride Form-R, which is characterized by XRD pattern.

Further, IP.Com journal disclosure Number IPCOM000193076D discloses crystalline Forms of N-(2-cUoropyrirnidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine of

Formula III such as Form I and Form II along with characteristic data of XRD pattern

PATENT

https://www.google.com/patents/WO2012073254A1?cl=en

Examples

Example 1:

Preparation of 5-(4-chloropyrimidin-2ylamino)-2-methyIbenzenesulfonamide

To a mixture of 5-amino-2-methylbenzenesulfonamide (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75°C and maintained for 13 hours. The reaction mass was then cooled to 10°C and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55°C to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide. Example 2:

Preparation of N,2,3-trimethyI-2H-indazol-6-amine

Sodium methoxide (19 gm) was dissolved in methanol (610 ml) and then added 2,3-dimethyl-2H-indazol-6-amine (13 gm). The reaction mixture was stirred for 15 minutes and then added paraformaldehyde (3.9 gm). The contents were heated to 60°C and stirred for 10 hours. The reaction mass was then cooled to room temperature and maintained for 4 hours 30 minutes. Sodium borohydride (2.8 gm) was added to the reaction mass slowly at room temperature and then heated to reflux. The reaction mass was maintained for 2 hours at reflux and then cooled to room temperature. The reaction mass was stirred for 14 hours at room temperature and then added sodium hydroxide solution (1M, 100 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with hydrochloric acid solution (40 ml) and then added ethyl acetate (400 ml). Then the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The combined organic layers were washed with sodium chloride solution and dried with sodium sulfate. The organic layer was treated with carbon and filtered through hi-flow bed. The solvent was distilled off under vacuum at below 50°C to obtain a residual mass. To the residual mass was added diisopropyl ether (75 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 10 gm of N,2,3-trimethyl-2H-indazol-6-amine.

Example 3:

Preparation of pazopanib hydrochloride

5-(4-Chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide (17 gm) as obtained in example 1, N,2,3-trimethyl-2H-indazol-6-amine (10 gm) as obtained in example 2 and ethanol (166 ml) were added at room temperature and then heated to reflux. The reaction mass was maintained for 3 hours at reflux and then added concentrated hydrochloric acid (1 ml). The reaction mass was maintained for 10 hours at reflux and then cooled to room temperature. The separated solid was filtered and dried to obtain 17 gm of pazopanib hydrochloride (HPLC Purity: 97.5%). Example 4:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (5 gm; HPLC Purity: 97.5%) as obtained in example 3 was dissolved in a mixture of methanol (100 ml) and water (10 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and filtered. The filtrate obtained was cooled to room temperature and maintained for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 3.5 gm of pazopanib hydrochloride (HPLC Purity: 99.9%). Example 5:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (22 gm; HPLC Purity: 98%), methanol (528 ml), water (55 ml) and concentrated hydrochloric acid (0.2 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. Take the filtrate and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents were further cooled to 0 to 5°C, stirred for 1 hour and filtered. The solid obtained was dried to give 19 gm of pazopanib hydrochloride (HPLC Purity: 99.85%).

Example 6:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (10 gm; HPLC Purity: 96%), methanol (250 ml), water (25 ml) and concentrated hydrochloric acid (0.1 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. The filtrate obtained was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents further cooled to 0 to 10°C and stirred for 1 hour. The separated solid was filtered and dried to obtain 6.6 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).

Example 7: Purification of pazopanib hydrochloride

Pazopanib hydrochloride (22 gm; HPLC Purity: 97%) was dissolved in a mixture of isopropanol (132 ml) and water (20 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 1 hour at reflux and then cooled to room temperature. The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried to give 18 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).

Paper

http://pubs.acs.org/doi/full/10.1021/op400139z

Assessment of Predictivity of Semiquantitative Risk Assessment Tool: Pazopanib Hydrochloride Genotoxic Impurities

David P. Elder*†, George Okafo†, and Michael McGuire‡

^† GlaxoSmithKline, Park Road, Ware, Hertfordshire, United Kingdom SG12 0DP

^‡ GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

Org. Process Res. Dev., 2013, 17 (8), pp 1036–1041

DOI: 10.1021/op400139z

Publication Date (Web): July 02, 2013

*E-mail: david.p.elder@gsk.com

Abstract

The recently developed semiquantitative assessment tool for the evaluation of carryover potential of mutagenic impurities (MIs) into the final API was applied to the five identified MIs within pazopanib hydrochloride (dimethyl sulfate (DMS) and compounds II, III, VI, and VIII). The theoretical and predicted purge factors were compared. The tool accurately predicted the purging capacity for the most reactive MI, DMS, giving a theoretical purge factor of 30000 versus an actual value of 29411 (for spiking at stage 1). For the other less reactive MIs, both measured and predicted values agreed reasonably well, and the high values for the purging factors were indicative of an effective process capability that could significantly reduce observed MI levels. The only exception was for compound VI, where although the measured and theoretical purge factors were in agreement, they were significantly lower (<200) than for the other MIs. In this case, a strategy was implemented including a requirement for control of this MI on API specification. The purge-factor assessment tool has the potential to play a key role in GRA (genotoxic risk assessment) processes and subsequent regulatory submissions. This tool could provide regulators with additional confidence to accept these purging arguments without resorting to testing. This could potentially significantly reduce the analytical testing burden for early clinical candidates.

PATENT

WO 2011058179

The compound 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino)pyrimidine-2- ylamino)-2-methylbenzenesulfonamide, also known as Pazopanib, is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals. Pazopanib has the following formula (I):

H CH,

NH₂

In WO 02/059110 the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride as well as the uses of this compound have been disclosed. In particular, this compound is an inhibitor of tyrosine kinase enzymes, namely vascular endothelial growth factor receptors, and can be used for the treatment and/or prevention of diseases which are associated with tyrosine kinase enzymes such as vascular endothelial growth factor receptors, such as cancer, particularly breast cancer and colon cancer.

Alternative methods for the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride are disclosed in WO 03/106416.

In WO 2007/064752 the use of Pazopanib for the treatment of age related macula degeneration is disclosed. WO 2007/064753 further discloses Pazopanib for the treatment of various types of cancer, e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.

Typically Pazopanib is administered orally, as this route provides great comfort and convenience of dosing. Although the hydrochloride form of Pazopanib is known in the art, as described above, this form is not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known form of Pazopanib hydrochloride is not optimal with regard to mechanical and chemical stability, which is in particular necessary for manufacturing tablets, as well as not optimal in regard to flow properties, compressibility, dissolution rate. Additionally, it is at least to some extent hygroscopic and shows electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions

PAPER

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 4, 15 February 2014, Pages 1108–1110

http://www.sciencedirect.com/science/article/pii/S0960894X14000225

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

doi:10.1016/j.bmcl.2014.01.003

Abstract

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7mdemonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.

Figure 1.

Chemical structure of pazopanib.

Patent

https://www.google.co.in/patents/WO2002059110A1?cl=en

Example 69

5-({4-[(2,3-dimethyl-2r/-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2- methylbenzenesulfonamide

To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and 5-amino-2- ethylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. HCI salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2- yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. Y\ NMR (400 MHz, deDMSO+NaHCOa) δ 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

Example 13

Preparation of Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine

To a stirred solution of the Intermediate 12 (7.37 g) in DMF (50 ml) was added CS2CO3 (7.44 g, 2 eqv.) and Mel (1.84 ml, 1.1 eqv.) at room temperature. Mixture was stirred at rt for overnight The reaction mixture was poured into ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air- dried to afford Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine as an off-white solid (6.43 g, 83%). ‘H NMR (400 MHz, dsDMSO) δ 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).

Intermediate Example 12 Preparation of Λ/-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

to a stirred solution of Intermediate Example 11 (2.97 g, .015 mol) and NaHCOs (5.05 g, .06 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.70 g, .045 mol) at room temperature. After the reaction was stirred for four hours at 85 °C, the suspension was cooled to rt, filtered and washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was triturated with ethyl acetate to yield 3.84 g (89 % yield) of Λ/-(2-chloropyrimidin-4-yl)- 2,3-dimethyl-2tf-indazol-6-amine. ¹H NMR (400 MHz, deDMSO) δ 7.28 (d, J = 9.0 Hz, 1 H), 6.42 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 5.18 (br s, 1 H), 3.84 (s, 3H), 2.43 (s, 3H). MS (ES+, m/z) 274 (M+H).

Intermediate Example 11

Preparation of 2,3-dimethyl-2r/-indazol-6-amine

To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7W-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2S0₄). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2r/-indazole as a yellow solid (15.85 g, 73 o/o). ¹H NMR (300 MHz, dβDMSO) δ 8.51 (s, I H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).

To a stirred solution of 2,3-dimethyl-6-nitro-2V-indazole (1.13 g) in 2- methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(ll) chloride in 8.9 ml of concentrated HCI dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 %), the HCI salt 2,3-dimethyl-2/7-indazol-6- amine. ¹H NMR (300 MHz, deDMSO) δ 7.77 (d, J = 8.9 Hz, 1 H), 7.18 (s, 1 H), 7.88 (m, 1 H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).

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Let’s Research !!!!!

https://ayurajan.blogspot.in/2014/12/pazopanib.html

WO2003106416A2 (same appears in Drug Future 2006, 31, 7, 585-589)

Pazopanib synthesis: J Med Chem 2008, 51, 4632-4640 (same appears in Beilstein J Org Chem 2011, 7, 442–495)

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LINK

PAPER

http://www.eurekaselect.com/97375

10.2174/157017812800233714

A Novel Practical Synthesis of Pazopanib: An Anticancer Drug

Author(s): YiCheng Mei, BaoWei Yang, Wei Chen, DanDan Huang, Ying Li, Xin Deng, BaoMing Liu, JingJie Wang, Hai Qian and WenLong Huang

Affiliation: Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, P.R. China.

Abstract:

This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.

PATENT

https://www.google.com/patents/WO2014097152A1?cl=en

Pazopanib is a tyrosine kinase inhibitor of Formula la.

Formula la

Pazopanib is marketed as the hydrochloride salt, with the chemical name 5-[[4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride, having the structure as depicted in Formula I:

Formula I

U.S. Patent No. 7,105,530 provides a process for the preparation of a hydrochloride salt of a compound of Formula II

Formula II involving the reduction of 2,3-dimethyl-6-nitro-2H-indazole with tin (II) chloride in concentrated hydrochloric acid in the presence of 2-methoxyethyl ether at 0°C. It also describes the preparation of a compound of Formula III

Formula III involving the reaction of a hydrochloride salt of compound of Formula II with 2,4- dichloropyrimidine in the presence of a base and solvent mixture of

tetrahydrofuran/ethanol followed by stirring for 4 hours at 85°C.

PCT Publication No. WO 2007/064752 provides a process for the preparation of a compound of Formula II comprising reducing 2,3-dimethyl-6-nitro-2H-indazole with 10% Palladium-carbon (50% wet) in the presence of methanol, followed by the addition of ammonium formate at a rate that ensures the reaction temperature is maintained at or between 25°C and 30°C. It also discloses the preparation of a compound of Formula III comprising heating the compound of Formula II with sodium bicarbonate in presence of tetrahydrofuran and ethanol at or between 75°C and 80°C followed by cooling to 20°C to

25°C.

The present invention provides a process for the preparation of a compound of Formula II which offers recycling of the Raney nickel catalyst used in the process, and an easy filtration work-up procedure. Further, the present invention offers selective reduction under mild conditions that is economical to use at an industrial scale.

The present invention also provides a process for the preparation of compound of Formula III which avoids the use of two or more solvents, and additionally, also circumvents heating and cooling procedures during the reaction. The aforesaid advantages yield a compound of Formula III with a lesser amount of N-(4-chloropyrimidin-2-yl)-2,3- dimethyl-2H-indazol-6-amine (CPDMI) impurity.

The compounds of Formula II and Formula III prepared by the present invention yield a compound of Formula la or its salts in comparable yield and suitable purity required for medicinal preparations.

EXAMPLES

Step 1: Synthesis of 2,3-dimcthyl-6-nitro-2H-indazole

Example 1 :

Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was stirred at 25 °C to 30°C for 16 hours. The solvent was recovered under reduced pressure. A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4: 1 mixture of dichloromethane:isopropyl alcohol (1080 mL x 5). The solvent was recovered under reduced pressure. Methyl fert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45 °C to 50°C. The reaction mixture was cooled to 25 °C to 30°C and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert- butyl ether (100 mL x 2), and dried in an air oven at 50°C for 12 hours to afford 2,3- dimethyl-6-nitro-2H-indazole as a yellow solid.

Yield: 82.4% w/w

Step 2: Synthesis of 2,3-dimethyl-2H-indazol-6-amine

Example 2a:

Raney nickel ( 12.50 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (50 g, 0.26 mol) in methanol (500 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm² – 4.0 kg/cm² at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (100 mL x 2). The filtrates were combined, and the solvent was recovered completely. «-Heptane (250 mL) and dichloromethane (50 mL) were added to the residue, and the reaction mixture was stirred for 1 hour at 25°C to 30°C. The solid was collected by filtration, washed with n-heptane (50 mL x 2), and dried under vacuum at 40°C to 45 °C to afford 2,3-dimethyl-2H-indazol-6-amine as a light brown solid.

Yield: 95% w/w

Example 2b:

Raney nickel (21.25 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (85 g, 0.45 mol) in methanol (850 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm² – 4.0 kg/cm² at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (85 mL x 3). The filtrates were combined, and the solvent was recovered up to the volume of 850 mL. The 2,3-dimethyl-2H-indazol-6-amine in methanol was used as such in the next step. Step 3: Synthesis of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

Example 3 :

Sodium bicarbonate ( 112 g, 1.34 mol) was added to a stirred solution of 2,3- dimethyl-2H-indazol-6-amine (as obtained from step 2; Examples 2a and 2b) in methanol. 2,4-Dichloropyrimidine (99.35 g, 0.67 mol) was added to the reaction mixture followed by stirring of the reaction mixture for 24 hours at 25°C to 30°C. De-ionized water (850 mL) was added to the reaction mixture followed by stirring of the reaction mixture at 25 °C to 30°C for 1 hour. The solid was filtered. The wet solid was washed with de-ionized water (170 mL x 2) to obtain a wet material. De-ionized water (850 mL) was added to the wet material to obtain a slurry, and the slurry was stirred at 25°C to 30°C for 30 minutes. The solid was filtered, then washed with de-ionized water (170 mL x 2). The wet material obtained was treated with ethyl acetate (340 mL) to obtain a slurry. The slurry was stirred at 35°C to 40°C for 30 minutes and then cooled to 0°C to 5°C. The slurry was further stirred at 0°C to 5°C for 30 minutes. The solid was collected by filtration, then washed with cold ethyl acetate (170 mL x 2). The solid was dried in an air oven at 50°C for 16 hours to afford N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine as an off- white solid.

Yield: 86.7% w/w

Step 4: Synthesis of pazopanib hydrochloride

Example 4a: Synthesis of N-(2-Chloropyrimidin-4-yl)-N.2.3-trimethyl-2H-indazol-6- amine

Cesium carbonate (238 g, 0.73 mol) and iodomethane (57 g, 0.40 mol) were added to a stirred suspension of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (lOOg, 0.37 mol) in N,N-dimethylformamide (300 mL) at 25°C to 30°C. The reaction mixture was further stirred at 25 °C to 30°C for 6 hours followed by cooling of the reaction mixture to 0°C to 5°C. De-ionized water (300 mL) was added drop-wise to the reaction mixture, then the reaction mixture was stirred at 5°C to 10°C for 30 minutes. The solid was collected by filtration, and washed with de-ionized water (100 mL x 2). The wet material so obtained was dried in an air oven at 50°C for 12 hours to obtain the title compound.

Yield: 90.4% w/w Example 4b: Synthesis of pazopanib hydrochloride

To a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6- amine (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol) in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for 10 hours to 12 hours. The reaction mixture was cooled to 25°C. The reaction mixture was further stirred at 25°C to 30°C for 30 minutes, then the solid was filtered. The wet solid was washed with isopropyl alcohol (180 mL x 2), and then dried under vacuum at 45 °C to 50°C for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6- yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown solid.

Yield: 97% w/w

PATENT

https://www.google.com/patents/CN104557881A?cl=en

pazopanib hydrochloride monohydrate prepared:

(1) chemical reaction formula

(2) Operation process

In the reaction flask pazopanib hydrochloride crude 100g, 700ml of acetonitrile was added under stirring and purified water 200ml, feeding is completed, begin heating to 75~80 ° C, until clear solvent filtration system, slowly dropped 10~20 ° C, keep stirring lh, filtered, and the filter cake washed with purified water and acetonitrile respectively, drained and the filter cake was dried at 60 ° C blast 5h, have pazopanib hydrochloride monohydrate solid 84g, yield 80.9%. For example, crystalline form pazopanib hydrochloride prepared the following examples.

pazopanib hydrochloride polymorph of preparation:

Example 1:

In the reaction flask pazopanib hydrochloride monohydrate 8. 0g, ethanol 50ml and purified water 0.Iml (the volume of water accounted for a mixed solution of 2% of the total volume of the square, ethanol – water mixture total volume was 6.26 times pazopanib hydrochloride monohydrate quality), heated to 75 ° C, stirred at reflux for about 5h, after cooling to 10~20 ° C, keep stirring lh, the filter cake washed with ethanol, then blast drying at 105 ° C 5h, to obtain ultrafine powder solid 6. 8g, yield of 81. 9%, HPLC purity was 99.8%, as measured crystal X- ray powder diffraction pattern of FIG. 1 the basic consistent, as measured with a DSC thermogram consistent FIG. 2, the particle size distribution measurement is basically the same as Fig 3 (D90 <10ym).

CLIP

Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) -α, -β, cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.

Processes by which pazopanib and its intermediates can be synthesized have been described in US Patent No. 7,105,530 as well as in the published PCT application WO03/106416.

U.S. patent no. 7,105,530 disclosed pyrimidineamines and their derivatives thereof. These compounds are antineoplastic agents, and are useful in the treatment of various cancers and renal cell carcinoma. Among them pazopanib hydrochloride, chemically 5-[4-[N-(2,3-Dimethyl-2H-indazol-6-yl)-N-methylamino]pyrimidin-2- ylamino]-2-methylbenzenesulfonamide hydrochloride. Pazopanib hydrochloride is represented by the following structure:
Pazopanib hydrochloride is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR (Vascular endothelial growth factor receptors)- 1, VEGFR-2, VEGFR-3, PDGFR (Platelet-derived growth factor receptors )-a/p, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib hydrochloride may also be active in ovarian cancer and soft tissue sarcoma. Pazopanib hydrochloride also appears effective in the treatment of non-small cell lung carcinoma. Pazopanib hydrochloride is marketed under the brand name Votrient® by Glaxosmithkline in the form of tablet.

Processes for the preparation of pazopanib hydrochloride and related compounds were disclosed in U.S. patent no. 7,105,530 and U.S. patent no. 7,262,203.

According to U.S. patent no. 7,105,530, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5- amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in isopropanol and ether.

U.S. patent application publication no. 2006/0252943 disclosed a process for the preparation of pazopanib hydrochloride. According to this patent, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3- trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in ethanol or methanol or tetrahydrofuran or acetonitrile and dioxane.

Drugs of the Future, 2006, 31 (7): 585-589
WO0306416

CLIP

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann

, Ian R. Baxendale

, Steven V. Ley

and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

Corresponding author email

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

Pazopanib (246, Votrient) is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late 2009. The indazole system is built up via diazotisation and spontaneous cyclisation of 2-ethyl-5-nitroaniline (247) using tert-butyl nitrite. The resulting indazole structure 249 can be methylated entirely regioselectively with either Meerwein’s salt, trimethyl orthoformate or dimethyl sulfate. A tin-mediated reduction of the nitro group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of 253. Methylation of the secondary amine function with methyl iodide prior to a second S_NAr reaction with a sulfonamide-derived aniline affords pazopanib .

Synthesis of pazopanib.

Pandite, A. N.; Whitehead, B. F.; Ho, P. T. C.; Suttle, A. B. Cancer Treatment Method. WO Patent 2007/064753, June 7, 2007.
Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., III; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. J. Med. Chem.2008,51,4632–4640. doi:10.1021/jm800566m

CLIP

Pazopanib hydrochloride (Votrient)
Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food
and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline. The
synthesis of pazopanib begins with methylation of 3-methyl-6-nitroindazole (82) with trimethyl orthoformate in the presence of BF3OEt to give indazole 83 in 65% yield (Scheme 14).65 Reduction of the nitro group was achieved via transfer hydrogenation to give 84 in 97% yield, and this was followed by coupling the aniline with 2,4-dichloropyrimidine in a THF-ethanol mixture at elevated
temperature to provide diarylamine 85 in 90% yield. The aniline nitrogen was then methylated using methyl iodide to give 86 in
83% yield prior to coupling with 5-amino-2-methylbenzenesulfonamide (87) and salt formation using an alcoholic solution of
HCl to furnish pazopanib hydrochloride (XIV) in 81% yield.

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3
Patent	7262203
Expiration	Dec 19, 2021
Applicant	NOVARTIS PHARMS CORP
Drug Application	N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE) N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

FDA Orange Book Patents: 2 of 3
Patent	8114885
Expiration	Dec 19, 2021
Applicant	NOVARTIS PHARMS CORP
Drug Application	N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE) N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

FDA Orange Book Patents: 3 of 3
Patent	7105530
Expiration	Oct 19, 2023
Applicant	NOVARTIS PHARMS CORP
Drug Application	N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE) N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C₂₁H₂₃N₇O₂S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:

VOTRIENT (pazopanib) Structural Formula Illustration

Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

Tablets of VOTRIENT are for oral administration. Each 200 mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base. The inactive ingredients of VOTRIENT are:Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.

FierceBiotech. 2008-09-15. Retrieved 2010-08-10.

Country	Patent Number	Approved	Expires (estimated)
United States	7105530	2009-10-19	2023-10-19
United States	7262203	2009-10-19	2021-12-19
United States	8114885	2009-10-19	2021-12-19

JUNE 4 2013 old article cut paste

GlaxoSmithKline’s (GSK) Votrient (pazopanib) has met the primary objective of a statistically significant improvement in the time to disease progression or death that is the progression-free survival (PFS) against placebo in Phase III ovarian cancer..

http://clinicaltrials.pharmaceutical-business-review.com/news/gsks-votrient-meets-primary-objective-in-phase-iii-ovarian-cancer-trial-030613

Pazopanib shrinks lung cancers before surgery

FORMULATION

https://www.google.co.in/patents/US20140255505

Pazopanib is an angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-α/-β, and c-Kit. The hydrochloride salt of pazopanib (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide) is marketed by GlaxoSmithKline as Votrient®, which is approved in the United States and other countries for the treatment of renal cell carcinoma (RCC).

Votrient® is currently prescribed to adults in the form of 200 mg tablets for oral administration, with each 200 mg tablet containing an amount of pazopanib hydrochloride equivalent to 200 mg of pazopanib free base.

Though the current tablets are acceptable of use in adults, the tablets are not preferred for use in potential future use for administering pazopanib to children. In pediatric populations, it is often desired that drug be available as a powder for reconstitution to an oral suspension. Manufacture of such a powder requires dry blending of various excipients with the active substance to provide good flow properties and content uniformity of the powder blend.

Several additional challenges exist concerning the use of pazopanib in a pediatric formulation. For instance, the nature of the drug substance favors conversion from the hydrochloride salt to the free base and hydrate forms in an aqueous environment such that standard formulations fail to provide adequate suspension stability at long term storage conditions of 25° C./65% RH or room temperature. Further, the drug has been found to have a bitter taste and, therefore, taste masking is critical.It is desired to invent a pediatric formulation of pazopanib hydrochloride suitable for administration to a pediatric population

References

“Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 27 January 2014.
“VOTRIENT (pazopanib hydrochloride) tablet, film coated [GlaxoSmithKline LLC]”(PDF). DailyMed. GlaxoSmithKline LLC. November 2013. Retrieved 27 January 2014.
“Votrient : EPAR – Product Information” (PDF). European Medicines Agency. Glaxo Group Ltd. 23 January 2014. Retrieved 27 January 2014.
“Votrient 200 mg and 400 mg film coated tablets – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. GlaxoSmithKline UK. 20 December 2013. Retrieved 27 January 2014.
“PRODUCT INFORMATION VOTRIENT® TABLETS” (PDF). TGA eBusiness Services. GlaxoSmithKline Australia Pty Ltd. 25 March 2013. Retrieved 27 January 2014.
“Pharmaceutical Benefits Scheme (PBS) – Pazopanib”. Pharmaceutical Benefits Scheme. Australian Government. Retrieved 27 January 2014.
“Pazopanib – Online Pharmaceutical Schedule”. Pharmaceutical Management Agency. Retrieved 9 June 2015.
^ “Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer”. FierceBiotech. 2008-09-15. Retrieved 2010-08-10.
“GSK pulls bid to extend use of kidney drug to ovarian cancer”. Reuters. 31 March 2014. Retrieved 7 April 2014.
“Regulatory update: Votrient (pazopanib) as maintenance therapy for advanced ovarian cancer in the EU”. GlaxoSmithKline. 31 March 2014. Retrieved 7 April 2014.
Zivi, A; Cerbone, L; Recine, F; Sternberg, CN (September 2012). “Safety and tolerability of pazopanib in the treatment of renal cell carcinoma”. Expert Opinion on Drug Safety. 11 (5): 851–859. doi:10.1517/14740338.2012.712108. PMID 22861374.
Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910.
Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11.doi:10.1515/dmdi-2014-0014. PMID 24807167.
Verweij, J; Sleijfer, S (May 2013). “Pazopanib, a new therapy for metastatic soft tissue sarcoma”. Expert Opinion on Pharmacotherapy. 14 (7): 929–935.doi:10.1517/14656566.2013.780030. PMID 23488774.
Schöffski, P (June 2012). “Pazopanib in the treatment of soft tissue sarcoma”. Expert Review of Anticancer Therapy. 12 (6): 711–723. doi:10.1586/era.12.41.PMID 22716487.
Pick, AM; Nystrom, KK (March 2012). “Pazopanib for the treatment of metastatic renal cell carcinoma”. Clinical Therapeutics. 34 (3): 511–520.doi:10.1016/j.clinthera.2012.01.014. PMID 22341567.
Rimel, BJ (April 2015). “Antiangiogenesis agents in ovarian cancer”. Contemporary Oncology. 7 (2): 16–19. PMID 21638926.

WO2003106416A2 *	Jun 17, 2003	Dec 24, 2003	Smithkline Beecham Corporation	Chemical process
WO2005054212A2 *	Nov 26, 2004	Jun 16, 2005	Ciba Specialty Chemicals Holding Inc.	Electroluminescent device
WO2007064752A2	Nov 29, 2006	Jun 7, 2007	Smithkline Beecham Corporation	Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema
WO2011069053A1	Dec 3, 2010	Jun 9, 2011	Teva Pharmaceutical Industries Ltd.	Process for the preparation of pazopanip hcl and crystalline forms of pazopanib hcl
WO2012051659A1 *	Oct 20, 2011	Apr 26, 2012	Biota Scientific Management Pty Ltd	Viral polymerase inhibitors
US7105530	Dec 19, 2001	Sep 12, 2006	Smithkline Beecham Corporation	Pyrimidineamines as angiogenesis modulators

Reference
1	*	DAVIES R R: “Indazole derivatives: the synthesis of various amino- and hydroxy-indazoles and derived sulphonic acids“, JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1955 (1955-01-01), pages 2412-2423, XP009176650, ISSN: 0368-1769, DOI: 10.1039/JR9550002412

US20060252943 *	Jun 17, 2003	Nov 9, 2006	Amogh Boloor	Chemical process
US20080269170 *	Jan 9, 2008	Oct 30, 2008	Sanofi-Aventis	Novel 2,4-Dianilinopyrimidine Derivatives, the Preparation Thereof, Their Use as Medicaments, Pharmaceutical Compositions and, in Particular, as IKK Inhibitors

Reference
1	*	LUO G. ET AL.: “Microwave-assisted synthesis of aminopyrimidines“, TETRAHEDRON LETTERS, vol. 43, no. 33, 2002, pages 5739 – 5742, XP004372432
2	*	See also references of EP2646431A4

Citing Patent	Filing date	Publication date	Applicant	Title
WO2014085373A1 *	Nov 26, 2013	Jun 5, 2014	Glaxosmithkline Llc	Combination
CN103232443A *	Feb 1, 2013	Aug 7, 2013	天津药物研究院	Indazole derivative crystal and its preparation method and use
CN104557881A *	Dec 30, 2014	Apr 29, 2015	山东博迈康药物研究有限公司	Preparation method of pazopanib hydrochloride crystal form

Boloor, A.; et. al. Pyrimidineamines as angiogenesis modulators. US7105530B2

2. Boloor, A.; Harris, P. A.; et. al. Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor. J Med Chem 2008, 51(15), 4632–4640.

3. Bhanushali, D. S.; et. al. Compositions and processes. WO2011050159A1

4. Boloor, A.; et. al. Chemical Process. WO2003106416A2

5. Pandite, A. M.; et. al. Cancer treatment method. WO2007064753A2

European Medicines Agency, “CHMP assessment report: Votrient“, pages 1, 5, 6 (2010).

Click to access 022465s000_ChemR.pdf

Pazopanib
Systematic (IUPAC) name


5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide
Clinical data
Trade names	Votrient
AHFS/Drugs.com	Monograph
MedlinePlus	a610013
License data	EU EMA: Votrient US FDA: Pazopanib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	>99%^[1]
Metabolism	Hepatic (CYP3A4, 1A2 and2C8-mediated)^[1]
Biological half-life	31.9 hours^[1]
Excretion	Faeces (primary), urine (<4%)^[1]
Identifiers
CAS Number	444731-52-6
ATC code	L01XE11 (WHO)
PubChem	CID 11525740
ChemSpider	9700526
UNII	7RN5DR86CK
ChEMBL	CHEMBL477772
Chemical data
Formula	C₂₁H₂₃N₇O₂S
Molar mass	437.517 g/mol

////////////PAZOPANIB, GW786034, Votrient, Armala, GW 786034, GW-786034, GW786034GW786034, VOTRIENT, Pazopanib hydrochloride, FDA 2009, Antineoplastic, Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors, Renal Cell Carcinoma Therpay, Soft Tissue Sarcoma Therapy, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид

O=S(=O)(N)c1c(ccc(c1)Nc2nccc(n2)N(c4ccc3c(nn(c3C)C)c4)C)C

FDA panel recommends AstraZeneca and BMS’ metreleptin for generalised lipodystrophy

December 17, 2013 3:24 am / 1 Comment on FDA panel recommends AstraZeneca and BMS’ metreleptin for generalised lipodystrophy

metreleptin
The US Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) has recommended AstraZeneca and Bristol-Myers Squibb’s (BMS) investigational medicine metreleptin for the treatment of paediatric and adult patients with generalised lipodystrophy (LD).

FDA panel recommends AstraZeneca and BMS’ metreleptin for generalised lipodystrophy click here for story

JAPAN
Metreleptin, an analog of the human hormone leptin, is a unique potential therapy for certain metabolic disorders in patients with rare forms of inherited or acquired lipodystrophy. Lipodystrophy is a very rare condition characterized by loss of subcutaneous fat.

Shionogi & Co., Ltd. today announced that it received marketing and manufacturing approval of recombinant human leptin, “METRELEPTIN for subcutaneous injection 11.25 mg ‘SHIONOGI’”

(generic name: metreleptin) for lipodystrophy on March 25,2013 in Japan.

Metreleptin was in-licensed by Shionogi from US-based AmylinPharmaceuticals, LLC., a subsidiary of Bristol-Myers Squibb Company currently.

Metreleptin is being studied as a potential therapy for certain metabolic disorders in patients with inherited or acquired lipodystrophy. Metreleptin is believed to work by reducing fat accumulation in organs, caused by the disease, thereby improving insulin sensitivity. Clinical studies have been conducted by investigators at the National Institutes of Health (NIH) and other academic institutions in the US, Europe, and Japan to determine whether metreleptin can improve glycemic control and hypertriglyceridemia in patients with lipodystrophy.

In April 2012, Amylin completed its Biologics License Application (BLA) for metreleptin to treat diabetes and/or hypertriglyceridemia (high levels of triglycerides in the bloodstream) in patients with rare forms of lipodystrophy and requested Priority Review by the FDA.

If approved, metreleptin would be the first therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with inherited or acquired lipodystrophy, and the first approved therapeutic use of a leptin analog.

About Lipodystrophy

Lipodystrophy is a life-threatening, “ultra orphan” rare disease that is estimated to impact a few thousand people worldwide, often with an early age of onset, for which there is a significant unmet medical need. There are currently no approved drugs that treat the underlying cause of the disease.

Fat tissue is a major endocrine organ producing important metabolic hormones such as leptin. People with lipodystrophy lack the required fat tissue for normal metabolic function. This can be partial, affecting select areas of the body, or generalized, affecting nearly the entire body. A lack of fat tissue can lead to relative deficiency of leptin.

Without adequate leptin function, the metabolic system, which regulates food intake and the storage and break-down of dietary fat and carbohydrates, falls out of balance. As a result, fat accumulates in the blood and organs such as liver and muscle, which can lead to life-threatening complications including insulin-resistant diabetes, hypertriglyceridemia (high levels of triglycerides in the bloodstream), acute pancreatitis, and hepatic steatosis or steatohepatitis, also known as fatty liver disease. There are no approved drugs that address the underlying relative leptin deficiency that is believed to contribute in large part to the metabolic abnormalities that occur in lipodystrophy. Currently available therapies for diabetes and hypertriglyceridemia are often rendered marginally effective due to the severity of the condition.

ELETRIPTAN

December 16, 2013 12:33 pm / 1 Comment on ELETRIPTAN

ELETRIPTAN

Eletriptan, UK-116044-04(HBr salt), UK-116044, Relpax

143322-58-1 CAS OF FREE BASE

143577-61-1 (hemisuccinate), 179041-30-6 (monofumarate), 177834-92-3 (monoHBr salt), 180637-87-0 (monosuccinate)


(R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)- 1H-indole

Eletriptan hydrobromide is a selective serotonin (5-HT₁) agonist, used for the acute treatment of the headache phase of migraine attacks.

RELPAX (eletriptan hydrobromide) tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan hydrobromide is chemically designated as (R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole monohydrobromide, and it has the following chemical structure:

RELPAX® (eletriptan hydrobromide) Structural Formula Illustration

The empirical formula is C₂₂H₂₆N₂O₂S . HBr, representing a molecular weight of 462.43. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water.

Each RELPAX Tablet for oral administration contains 24.2 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose NF, lactose monohydrate NF, croscarmellose sodium NF, magnesium stearate NF, titanium dioxide USP, hypromellose, triacetin USP and FD&C Yellow No. 6 aluminum lake.

Patents

Country	Patent Number	Approved	Expires (estimated)
United States	6110940	1997-08-29	2017-08-29
United States	5545644	1996-12-26	2016-12-26
Canada	2352392	2006-01-24	2019-11-01
Canada	2198599	2000-06-06	2015-05-17

EP 0592438; JP 1993507288; JP 1997003063; US 5545644; WO 9206973, EP 0776323; JP 1997512283; US 6110940; WO 9606842, EP 1088817

U.S. Pat. No. 5,545,644A1 describes a synthetic process for Eletriptan. 5-Bromoindole was acylated at the 3-position by reacting the magnesium salt of 5-bromoindole. This process results in a dimer formation in the final Pd/C reduction stage which poses problems in purification which further leads to decrease in yields.

U.S. Pat. No. 7,288,662B2 discloses methods to circumvent the problems associated with dimer formation described in U.S. Pat. No. 5,545,644A1. The indole-nitrogen was acetylated prior to hydrogenation and later deacetylated to give pure Eletriptan. However, this process introduced two additional steps into the synthesis which is time consuming and subsequently costly.

WO2005/103035A1 discloses Eletriptan synthesis by a Fischer Indole process. However, enantiomeric purity of the finished product depends on the purity of an acetal intermediate which might require asymmetric synthesis or optical resolution. Eletriptan obtained in the reported procedure had about 94% enantiomeric excess.

Eletriptan (trade name Relpax, used in the form of eletriptan hydrobromide) is a second generation triptan drug intended for treatment of migraine headaches. It is used as an abortive medication, blocking a migraine attack which is already in progress. Eletriptan is marketed and manufactured by Pfizer Inc. It is sold in the US and Canada under the brand name Relpax, and in several other countries under the brand name Relert.

Eletriptan was approved by the U.S. Food and Drug Administration (FDA) on December 26, 2002, for the acute treatment of migraine with or without aura in adults.^[1] It is available only by prescription in the United States and Canada. It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. It is available in 20 mg, 40 mg and 80 mg strengths.

Eletriptan is covered by U.S. Patent no. 5545644^[1]^[2] and U.S. Patent no. 6110940;^[1]^[3] the FDA lists the patents as scheduled for expiration on December 26, 2016, and August 29, 2017, respectively.^[1]

Eletriptan is believed to reduce swelling of the blood vessels surrounding the brain. This swelling is associated with the head pain of a migraine attack. Eletriptan blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of symptoms by eletriptan.

Eletriptan is a serotonin agonist. Specifically, it is a selective 5-hydroxytryptamine 1_B/1_D (5-HT_1B) receptor agonist.

Eletriptan binds with high affinity to the 5-HT_1B_, _1D_, _1F] receptors.

It has a modest affinity to the 5-HT_[1A_, _1E_, _2B_, _7] receptors.

And little to no affinity at the 5-HT_[2A_, _2C_, ₃_, ₄_, _5A_, _6] receptors.

Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha1, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors. Eletriptan could be efficiently co-administrated with nitric oxide synthase (NOS’s) inhibitors for the treatment of NOS-dependent diseases (US patent US 2007/0254940)

Two theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

Common side effects include hypertension, tachycardia, headache, dizzyness, and symptoms similar to angina pectoris. Severe allergic reactions are rare.^[4]

Eletriptan is contraindicated in patients with various diseases of the heart and circulatory system, such as angina pectoris, severe hypertension, and heart failure, as well as in patients that have had a stroke or heart attack. It is also contraindicated in severe renal or hepatic impairment.^[4]

The drug has a relatively low potential for interactions. Notably, it is unlikely to interact to a relevant extent with beta blockers, tricyclic antidepressants and SSRI type antidepressants. Strong inhibitors of the liver enzyme CYP3A4, such as erythromycin and ketoconazole, significantly increase blood plasma concentrations and half life of eletriptan. Ergot alkaloids add to the drug’s hypertensive effect.^[4]

Merck Index: 3-[[(2R)-1-Methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole
5-[2-(benzenesulfonyl)ethyl]-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole
(R)-5-[2-(phenylsulfonyl)ethyl]-3-[(1-methyl-2-pyrrolidinyl)methyl]-1H-indole

FDA AccessData entry for Eletriptan Hydrobromide, accessed March 10, 2010.
U.S. Patent no. 5545644, John E. Macor & Martin J. Wythes, Indole Derivatives, August 13, 1996.
U.S. Patent no. 6110940, Valerie Denise Harding, et al., Salts of an anti-migraine indole derivative, August 29, 2000.
Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 6984–8. ISBN 978-3-85200-181-4.

FDA label (December 2002)
Physicians’ Desk Reference entry for Relpax
Medline Plus Drug Information for Eletriptan
Pfizer Relpax site

3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-5-[2-(phenylsulfonyl)ethyl]-1H-indole or Eletriptan, currently available in the market as a hydrobromide salt, is an agonist of the 5-hydroxytryptamine (5-HT_1B/1D) receptor and it is used for treating migraine.

Various processes of synthesis of such molecule are known, but the one generally used is the synthesis shown in the diagram of FIG. 1, which provides for a Heck reaction (step 4 or 4b) between 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole and phenyl vinyl sulfone to obtain the 1-(3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole-1-yl)ethanone intermediate.

This reaction uses a palladium-based catalyst which is very sensitive to the impurities present in the reaction environment. It is thus essential that the 5-bromo-3{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole intermediate be thoroughly purified before being reacted with phenyl vinyl sulfone.

In prior art documents (EP 0 592 438, U.S. Pat. No. 5,545,644 and U.S. Pat. No. 6,100,291) purification of the 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole intermediate is performed by means of chromatographic column, a process almost exclusively implementable in a laboratory or at a high cost in any case with long processing times alongside being ecologically unadvisable due to the large amount of solvents used.

Furthermore, it is known that the crystallisation of 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole intermediate (WO 2008/150500 and U.S. Pat. No. 5,545,644) provides a purified intermediate with assay not exceeding 98% (established through the HPLC analysis).

US5545644A1 describes a synthetic process for Eletriptan. 5-Bromoindole was acylated at the 3-position by reacting the magnesium salt of 5-bromoindole. This process results in a dimer formation in the final Pd/C reduction stage which poses problems in purification which further leads to decrease in yields.

US7288662B2 discloses methods to circumvent the problems associated with dimer formation described in US5545644A1. The indole-nitrogen was acetylated prior to hydrogenation and later deacetylated to give pure Eletriptan. However, this process introduced two additional steps into the synthesis which is time consuming and subsequently costly. WO2005/103035A1 discloses Eletriptan synthesis by a Fischer Indole process. However, enantiomeric purity of the finished product depends on the purity of an acetal intermediate which might require asymmetric synthesis or optical resolution. Eletriptan obtained in the reported procedure had about 94% enantiomeric excess.

Eletriptan and intermediates thereof, including 5-bromo-3-[(i?)-l-methyl- pyrrolidin-2-ylmethyl]-lH-indole (“BIP”) are described in US 5,545,644. Also disclosed is the synthesis of ELT, which is illustrated by the following scheme:

In the described process, intermediate I, BIP, is obtained by reacting intermediate II with lithium aluminium hydride (“LAH”). LAH spontaneously reacts with water, including atmospheric humidity, and the pure material is pyrophoric. The LAH is known as very unstable, and air-exposed samples are almost always contaminated with aluminium metal and or a mixture of lithium hydroxide and aluminium hydroxide, thus affecting the reactivity of the LAH powder. This leads to the use of a large excess of reagent in order to obtain moderate conversion. Furthermore, the described process requires heating to reflux for a long period of time (39 hours in total, according to example 29 in patent US 5,545,644) followed by a time consuming recovery process. The recovery process consists of diluting of the reaction mixture with ethyl acetate, filtering through cellulose filtration bar, as described in patent US 5,545,644 example 27, and purifying the obtained oily like residue by silica gel chromatography, wherein, dichloromethane, ethanol and concentrated aqueous ammonia are used as a mobile phase. This process provides BIP, which is then converted to ELT.

Anhydrous alpha-and beta-hydrobromide salt forms of eietriptan are disclosed in WO-A-96/06842.

………………..

WO2010049952A2

Figure imgf000003_0001

5-Bromoindole under Heck reaction conditions is coupled with phenyl vinyl sulfone followed by acylation with Cbz-Proline acid chloride to obtain a compound of Formula IV which on reduction in presence of a hydride agent provide Eletriptan.

¹H NMR CDCI₃ δ= 8.10 (bs, NH), 7.92-7.99 5 (m, 2H), 7.62-7.69 (m, 1H), 7.53-7.61 (m, 2H), 7.30 (s, 1H), 7.22 (d, 1H), 7.03 (s, 1H), 6.93 (dd, 1 H), 3.38-3.45 (m, 2H), 3.09-3.21 (m, 4H), 2.45-2.55 (m, 2H), 2.45 (s, 3H), 2.20-2.30 (m, 1H), 1.50-1.90 (m, 4H).

ESI Mass (M+H) 383.69

………..

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-57

Eletriptan (87, Relpax) is yet another indole-containing antimigraine drug. A process route for the synthesis of eletriptan published by Pfizer starts from a preformed bromo-indole 88 [28] (Scheme 20). In order to perform the acylation of the indole ring on larger scale, ethylmagnesium bromide and the corresponding acid chloride 89 are added concurrently from two different sides of the reactor to stop these reagents reacting with each other. This method of adding the reagents circumvents the necessity to isolate the magnesium salt of the indole and increases the yield from 50 to 82%. The carbonyl group of the proline side chain is then reduced simultaneously with the complete reduction of the Cbz-group to a methyl group with lithium aluminium hydride. Finally, the sulfonate side chain is introduced via a Heck-type coupling similar to that of naratriptan (Scheme 15), followed by hydrogenation of the double bond to afford eletriptan (Scheme 20).

[1860-5397-7-57-i20]

A rather ingenious Mitsunobu coupling reaction has been used to create a highly functionalised substrate 96 for an intramolecular Heck reaction resulting in a very short and succinct synthesis of eletriptan and related analogues 97 [29] (Scheme 21).

Scheme 21: Heck coupling for the indole system in eletriptan.

Interestingly, it was found that the most obvious approach, the direct Fischer indole synthesis, to prepare the core of eletriptan as shown in Scheme 22 is not successful [30]. This is believed to be due to the instability of the phenyl hydrazine species 98 under the relatively harsh reaction conditions required to promote the cyclisation.

Scheme 22: Attempted Fischer indole synthesis of elatriptan.

However, this problem could be avoided by using an acid-labile oxalate protected hydrazine 104 as depicted in Scheme 23. The yield of this step can be further improved up to 84% if the corresponding calcium oxalate is used.

Scheme 23: Successful Fischer indole synthesis for eletriptan.

Macor, J. E.; Wythes, M. J. Indole Derivatives. U.S. Patent 5,545,644, Aug 13, 1996.
Perkins, J. F. Process for the Preparation of 3-Acylindoles. Eur. Patent 1088817A2, April 4, 2001.
Ashcroft, C. P. Modified Fischer Indole Synthesis for Eletriptan. WO Patent 2005/103035, Nov 3, 2005.
Bischler, A. Chem. Ber. 1892, 25, 2860–2879. doi:10.1002/cber.189202502123

…………

……………..

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

Suri Babu Madasu^1,2, Nagaji Ambabhai Vekariya¹, M. N. V. D. Hari Kiran¹, Badarinadh Gupta¹, Aminul Islam¹, Paul S. Douglas² and Korupolu Raghu Babu²

¹Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak Dist-502329, Andhra Pradesh, India
²Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India

Associate Editor: J. Aube

Beilstein J. Org. Chem. 2012, 8, 1400–1405.

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-8-162

Synthetic route of eletriptan hydrobromide. Reagents and conditions: (i) Acetic anhydride, TEA, DMF, 90–100 °C; (ii) palladium acetate, tri-(o-tolyl)phosphine, TEA, DMF, 90–100 °C; (iii) methanol, K₂CO₃, acetonitrile, H₂O, 5–10 °C; (iv) palladium on carbon, acetone, H₂O, aqueous hydrobromic acid, IPA, 25–30 °C.

………….

Org. Process Res. Dev., 2011, 15 (1), pp 98–103

DOI: 10.1021/op100251q

http://pubs.acs.org/doi/full/10.1021/op100251q

^aReagents and conditions: (a) EtMgBr, Et₂O. (b) 3, DCM, 50% from 1. (c) LiAlH₄, THF, 72%. (d) Ac₂O, TEA, DMF. (e) Phenyl vinyl sulfone (PVS), Pd(OAc)₂, P(°Tol)₃, TEA, DMF, 80% from 5. (f) H₂, Pd/C, MeSO₃H, acetone, 95%. (g) K₂CO₃, MeOH, 92%. (h) HBr, acetone 73%.

¹H NMR (CDCl₃): δ = 1.51−1.85 (m, 4H), 2.22−2.28 (m, 1H), 2.43−2.49 (m, 4H), 2.56−2.62 (m, 1H), 3.11−3.18 (m, 4H), 3.42−3.46 (m, 2H), 6.91−6.93 (s, 1H), 7.01 (s, 1H), 7.23−7.27 (d, 1H), 7.31 (s, 1H), 7.56−7.60 (m, 2H), 7.65−7.68 (m, 1H), 7.96−7.98 (d, 2H), 8.14 (s, 1H); LC/MS: R_t = 2.30 min; m/z 383 [MH]⁺

…………………………

ELETRIPTAN HYDROBROMIDE MONOHYDRATE

http://www.sumobrain.com/patents/wipo/Eletriptan-hydrobromide-monohydrate/WO2000032589.html

‘H-NMR (400MHz, ds-DMSO): delta = 10.90 (1H, d, J=2.2Hz), 9.35 (1 H, br s), 7.95 (2H, d, J=7.5Hz), 7.76 (1 H, t, J=7.5Hz), 7.66 (2H, t, J=7.5Hz), 7.38 (1 H, s), 7.24 (1 H, d, J=8.3Hz), 7.23 (1 H, d, J=2.2Hz), 6.92 (1 H, dd, J=8.3,1.4Hz), 3.63 (2H, m), 3.58 (2H, br m), 3.24 (1 H, m), 3.06 (1 H, m), 2.95 (2H, m), 2.86 (1 H, m), 2.83 (3H, s), 2.00 (1 H, m), 1.90 (2H, m), 1.70 (1 H, m).

Found: C, 54.85; H, 6.03; N, 5.76. C22H29N203SBr requires C, 54.87; H, 6.08; N, 5.82%.

UPDATED 29 MAR 2015

ELETRIPTAN

Eletriptan, UK-116044-04(HBr salt), UK-116044, Relpax

143322-58-1 CAS OF FREE BASE

143577-61-1 (hemisuccinate), 179041-30-6 (monofumarate), 177834-92-3 (monoHBr salt), 180637-87-0 (monosuccinate)


(R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)- 1H-indole

Eletriptan hydrobromide was first disclosed in U.S. patent 5,545,644 (1996), assigned to Pfizer, New York, claiming the product “eletriptan” and its pharmaceutically acceptable salts thereof. ].

However, a detailed study on the profile of the impurities present and their synthesis has not yet been cited anywhere, except for in the case of some metabolites . Eletriptan hydrobromide is a second-generation drug serotonin (5-HT1) agonist used in the management of sensations of tightness, pain, pressure and heaviness in the precordium, throat and jaws.

Eletriptan is more lipophilic than other triptans and absorbed more quickly than sumatriptan in the intestinal absorption. Eletriptan is more effective than sumatriptan in reducing the blood vessels surrounding the brain, which cause the swelling that is associated with the headache pain of a migraine attack, by blocking the release of substances from the nerve endings that causes more pain.

1H NMR PREDICT

………………..
13C NMR

(S)-3-((1-Methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole NMR spectra analysis, Chemical CAS NO. 177834-92-3 NMR spectral analysis, (S)-3-((1-Methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole C-NMR spectrum

………….

WO2010049952A2

1H NMR CDCI3 δ= 8.10 (bs, NH), 7.92-7.99 5 (m, 2H), 7.62-7.69 (m, 1H), 7.53-7.61 (m, 2H), 7.30 (s, 1H), 7.22 (d, 1H), 7.03 (s, 1H), 6.93 (dd, 1 H), 3.38-3.45 (m, 2H), 3.09-3.21 (m, 4H), 2.45-2.55 (m, 2H), 2.45 (s, 3H), 2.20-2.30 (m, 1H), 1.50-1.90 (m, 4H).

ESI Mass (M+H) 383.69

………..

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-57

Scheme 21: Heck coupling for the indole system in eletriptan.

Scheme 22: Attempted Fischer indole synthesis of elatriptan.

Scheme 23: Successful Fischer indole synthesis for eletriptan.

Macor, J. E.; Wythes, M. J. Indole Derivatives. U.S. Patent 5,545,644, Aug 13, 1996.
Perkins, J. F. Process for the Preparation of 3-Acylindoles. Eur. Patent 1088817A2, April 4, 2001.
Ashcroft, C. P. Modified Fischer Indole Synthesis for Eletriptan. WO Patent 2005/103035, Nov 3, 2005.
Bischler, A. Chem. Ber. 1892, 25, 2860–2879. doi:10.1002/cber.189202502123

…………

……………..

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

Suri Babu Madasu1,2, Nagaji Ambabhai Vekariya1, M. N. V. D. Hari Kiran1, Badarinadh Gupta1, Aminul Islam1, Paul S. Douglas2 and Korupolu Raghu Babu2

1Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak Dist-502329, Andhra Pradesh, India
2Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India

Associate Editor: J. Aube

Beilstein J. Org. Chem. 2012, 8, 1400–1405.

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-8-162

Synthetic route of eletriptan hydrobromide. Reagents and conditions: (i) Acetic anhydride, TEA, DMF, 90–100 °C; (ii) palladium acetate, tri-(o-tolyl)phosphine, TEA, DMF, 90–100 °C; (iii) methanol, K2CO3, acetonitrile, H2O, 5–10 °C; (iv) palladium on carbon, acetone, H2O, aqueous hydrobromic acid, IPA, 25–30 °C.

………….

Org. Process Res. Dev., 2011, 15 (1), pp 98–103

DOI: 10.1021/op100251q

http://pubs.acs.org/doi/full/10.1021/op100251q

aReagents and conditions: (a) EtMgBr, Et2O. (b) 3, DCM, 50% from 1. (c) LiAlH4, THF, 72%. (d) Ac2O, TEA, DMF. (e) Phenyl vinyl sulfone (PVS), Pd(OAc)2, P(°Tol)3, TEA, DMF, 80% from 5. (f) H2, Pd/C, MeSO3H, acetone, 95%. (g) K2CO3, MeOH, 92%. (h) HBr, acetone 73%.

1H NMR (CDCl3): δ = 1.51−1.85 (m, 4H), 2.22−2.28 (m, 1H), 2.43−2.49 (m, 4H), 2.56−2.62 (m, 1H), 3.11−3.18 (m, 4H), 3.42−3.46 (m, 2H), 6.91−6.93 (s, 1H), 7.01 (s, 1H), 7.23−7.27 (d, 1H), 7.31 (s, 1H), 7.56−7.60 (m, 2H), 7.65−7.68 (m, 1H), 7.96−7.98 (d, 2H), 8.14 (s, 1H); LC/MS: Rt = 2.30 min; m/z 383 [MH]+

…………………………

ELETRIPTAN HYDROBROMIDE MONOHYDRATE

http://www.sumobrain.com/patents/wipo/Eletriptan-hydrobromide-monohydrate/WO2000032589.html

Found: C, 54.85; H, 6.03; N, 5.76. C22H29N203SBr requires C, 54.87; H, 6.08; N, 5.82%.
1H NMR

13C PREDICT

COSYPREDICT

SYNTHESIS

Reference:

KANSAL, Vinod Kumar; MISTRY, Dhirenkumar N.; PATEL, Rakesh Ravjibhai; PANDEY, Saurabh Patent: US2009/299077 A1, 2009 ; Location in patent: Page/Page column 8 ;

USV Limited B.S.D. Mar Patent: US2012/71669 A1, 2012 ; Location in patent: Page/Page column 11 ;

US2012/71669 A1, ;

US2011/166364 A1, ;
WO2011/4391 A2, ;
WO2012/4811 A1, ;

US2008/287519 A1, ; Page/Page column 10 ;

WO2011/4391 A2, ; Page/Page column 19 ;
US2008/287519 A1, ; Page/Page column 8 ;

PITAVASTATIN » All About Drugs

December 16, 2013 12:30 pm / Leave a comment

PITAVASTATIN » All About Drugs

Top 10 Pharma – products in the pipeline

December 16, 2013 1:00 am / Leave a comment

Regulatory Affairs in Latin America

Did you know that you can consult which new innovations are in the pipelines of the top 10 pharma companies directly from their websites?

Have a look!

1- Johnson&Johnson

2- Pfizer

3- Novartis

4- Sanofi

5- Merck&Co

6- GlaxoSmithKline

7- Abbott

8- Roche

9- Bayer

10- AstraZeneca

View original post

RALTEGRAVIR

December 15, 2013 6:49 am / 1 Comment on RALTEGRAVIR

CAS No…….518048-05-0 (free acid)
871038-72-1 (monopotassium salt)IUPAC Name:- N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)

Organic Process Research and Development, 2011 , vol. 15, 1 pg. 73 – 83,

143 – 144.1 °C(free acid)

MW: 444.42

………………………………………………….

K SALT

C₂₀H₂₀FN₆O₅*K, 482.513

MP..275 – 277 °C

European Journal of Medicinal Chemistry, 2012 , vol. 50, pG. 361 – 369

Drug information:- Raltegravir is an Anti-microbial drug further classified as anti-viral agent of the class integrase inhibitor. It is used either signally or in combination with other drugs for the treatment of human immunodeficiency virus (HIV) and further clinical trials are in process.

Raltegravir (RAL, Isentress, formerly MK-0518) is an antiretroviral drug produced by Merck & Co., used to treat HIV infection.^[1] It received approval by the U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.^[2]^[3]

In December 2011, it received FDA approval for pediatric use in patients ages 2–18, taken in pill form orally twice a day by prescription with two other antiretroviral medications to form the cocktail (most anti-HIV drugs regimens for adults and children use these cocktails). Raltegravir is available in chewable form but- because the two tablet formulations are not interchangeable- the chewable pills are only approved for use in children two to 11. Older adolescents will use the adult formulation.^[4]

Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. The drug is metabolized away via glucuronidation.^[5]

Isentress tablets

Raltegravir is taken orally twice daily.^[3] Doses of 200, 400, and 600 mg have been studied.

At the 2007 Conference on Retroviruses and Opportunistic Infections, researchers presented Phase III data showing that 77% of patients taking the 400 mg dose of raltegravir plus other antiretroviral drugs reached HIV viral loads below 400 copies, nearly twice as many compared with a control group.

Raltegravir was initially approved only for use in individuals whose infection has proven resistant to otherHAART drugs.^[3] However, in July 2009, the FDA granted expanded approval for Raltegravir for use in all patients.^[6] As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy.

In a study of the drug as part of combination therapy, raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides.^[7]^[8]

Raltegravir significantly alters HIV viral dynamics and decay and further research in this area is ongoing. In clinical trials patients taking raltegravir achieved viral loads less than 50 copies per millitre sooner than those taking similarly potent Non-nucleoside Reverse Transcriptase Inhibitors orProtease Inhibitors. This statistically significant difference in viral load reduction has caused some HIV researchers to begin questioning long held paradigms about HIV viral dynamics and decay.^[9] Research into raltegravir’s ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.^[10]

Research results were published in the New England Journal of Medicine on July 24, 2008. The authors concluded that “raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks.” ^[11]

Research on human cytomegalovirus (HCMV) terminase proteins demonstrated that Raltegravir may block viral replication of the herpesviruses.^[12]

In January 2013, a Phase II trial was initiated to evaluate the therapeutic benefit of raltegravir in treating multiple sclerosis (MS).^[13] The drug is active against Human Endogenous Retroviruses(HERVs) and possibly Epstein-Barr Virus, which have been suggested in the pathogenesis of relapsing-remitting MS.

Raltegravir was generally well tolerated when used in combination with optimized background therapy regimens in treatment-experienced patients with HIV-1 infection in trials of up to 48 weeks’ duration.^[14]

Synthesis

^[15]

WO 2006060730

…………………………………………………

Savarino A (December 2006). “A historical sketch of the discovery and development of HIV-1 integrase inhibitors”. Expert Opin Investig Drugs 15 (12): 1507–22. doi:10.1517/13543784.15.12.1507.PMID 17107277.
“FDA approval of Isentress (raltegravir)”. U.S. Food and Drug Administration (FDA). June 25, 2009. Retrieved 2009-11-15.
“Isentress Drug Approval Package”. U.S. Food and Drug Administration (FDA). February 22, 2008. Retrieved 2009-11-15.
http://www.everydayhealth.com/hiv-aids/1222/fda-okays-raltegravir-for-kids-teens-with-hiv.aspx?xid=aol_eh-hiv_6_20111219_&aolcat=HLT&icid=maing-grid7%7Cmain5%7Cdl10%7Csec3_lnk2%26pLid%3D122480
HIV Antiretroviral Agents in Development
“UPDATE 2-FDA OKs widened use of Merck’s Isentress HIV drug”. Reuters. 2009-07-10.
Markowitz M, Nguyen BY, Gotuzzo E, et al. (2007). “Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study”. J. Acquir. Immune Defic. Syndr. 46 (2): 125–33. doi:10.1097/QAI.0b013e318157131c. PMID 17721395.
Stephenson J (2007). “Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus”. JAMA 297 (14): 1535–6. doi:10.1001/jama.297.14.1535. PMID 17426263.
Faster Viral Decay With Raltegravir
ClinicalTrials.gov NCT00554398 Impact of MK-0518 (Raltegravir) Intensification on HIV-1 Viral Latency in Patients With Previous Complete Viral Suppression
Steigbigel RT, Cooper DA, Kumar PN, et al. (July 2008). “Raltegravir with optimized background therapy for resistant HIV-1 infection”. N. Engl. J. Med. 359 (4): 339–54.doi:10.1056/NEJMoa0708975. PMID 18650512.
Drug against AIDS could be effective against herpesvirus
Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis (INSPIRE)
Croxtall JD, Keam SJ. (2009). “Raltegravir”. Drugs 69 (8): 1059–75. doi:10.2165/00003495-200969080-00007. PMID 19496631.
Belyk, K. M.; Morrison, H. G.; Jones, P.; Summa, V.; 2007, WO 2006060730

……………………………………………………………………………………………………………………………………………….

Raltegravir, also referred to as Raltegravir free-hydroxy, N-(2-(4-(4-fluorobenzyl- carbamoyl)-5-hydroxy-l-methyl-6-oxo-l ,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl- l ,3,4-oxadiazole-2-carboxamide, having the following structure;

is an antiretroviral drug used to treat HIV infection. Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Raltegravir potassium salt is marketed under the trade name ISENTRESS™ by Merck & Co.

The processes for preparing Raltegravir that are known in the art either require a protection step for the 5-hydroxy group prior to the methylation step, or lead to an impurity resulting from the methylation of the 5-hydroxy group.

U.S. Patent No. 7, 169,780 discloses Raltegravir and preparation thereof, as described in the following reaction scheme:

Scheme 1

J. Med. Chem. 2008, 51 , 5843-5855 discloses another process for preparing Raltegravir as described in the following reaction scheme:

RLT K-salt

Scheme 2 U.S. Publication No. US 2006/0122205 describes an alternative process for preparing Raltegravir, in which the alkylation step does not include a step for protecting the 5-hydroxy group. The process is described in the following reaction scheme:

Scheme 3

Provided herein is an industrially applicable process for preparing RLT-7′, RLT-8, RLT-9 and RLT-9-OP, intermediates in the synthesis of Raltegravir, as well as processes for preparing Raltegravir and crystalline forms thereof.

US Publication No. US 2006/0122205, WO 2010/1401 56 and WO 201 1 /

024192 describe the potassium salt of Raltegravir, including amorphous and crystalline forms I, II, III and H I , as well as amorphous and crystalline forms of Raltegravir free- hydroxy. PCT publication No. WO 201 1/123754 describes certain Raltegravir salts and polymorphs, including form V of Raltegravir potassium.

Conditions:-

i. Benzylchloroformate, N,N-diisopropylethylamine, Methyl tert-butyl ether, 20 – 25 °C, 16 h, ii. Hydroxyl amine, Water, 60 °C, 3 h, iii. Dimethyl acetylenedicarboxylate, methanol, Room temperature 2 h then Xylene 90 °C, 2 h, iv. Magnesium methoxide, dimethyl sulfoxide, Methyl iodide, 20 – 25 °C, 2 h, v. 4-fluorobenzyl amine, ethanol, 72 °C, 2 h, vi. 5% Pd/C, methanol, Molybdate sulfuric acid, Hydrogen gas, 50 °C, 3 h, vii. 5-methyl-1,3,4-oxadiazole-2-carbonylchloride, N-methylmorpholine, Tetrahydrofuran, 0 – 5 °C, 2 h

preparation of Raltegravir is described in US patent 2006122205A1 and also in WO2006060730. Accordingly, 2-amino-2-methyl-propanenitrile 1 was reacted with benzylchloroformate in presence of N,N-diisopropylethylamine using methyl tert-butyl ether as solvent at ambient temperature to give benzyl N-(1-cyano-1-methyl-ethyl)carbamate 2. Treatment of 2 with hydroxyl amine using water as solvent at elevated temperature give benzyl N-[(2Z)-2-amino-2-hydroxyimino-1,1-dimethyl-ethyl]carbamate 3. The compound 3 was further cyclized with dimethyl acetylenedicarboxylate using methanol as solvent at higher temperature to give methyl 2-(1-benzyloxycarbonylamino-1-methyl-ethyl)-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylate 4. Compound 4 was then methylated with methyl iodide in presence of magnesium methoxide as base and dimethyl sulfoxide as solvent at ambient temperature to give methyl 2-(1-benzyloxycarbonylamino-1-methyl-ethyl)-5-hydroxy-1-methyl-6-oxo-pyrimidine-4-carboxylate 5. Compound 5 on condensing with 4-fluorobenzyl amine using ethanol as solvent result in to benzyl N-[1-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxo-pyrimidin-2-yl]-1-methyl-ethyl]carbamate 6, which underwent benzyloxy-decarboxylation on hydrogenating with hydrogen gas in presence of 5% Palladium on carbon catalyst and molybdate sulfuric acid using methanol as solvent to give 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-6-oxo-pyrimidine-4-carboxamide 7. The final step involves condensation of 7 with 5-methyl-1,3,4-oxadiazole-2-carbonylchloride in presence of N-methylmorpholine as base using tetrahydrofuran as solvent at slightly lower temperature to afford N-[1-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxo-pyrimidin-2-yl]-1-methyl-ethyl]-5-methyl-1,3,4-oxadiazole-2-carboxamide also called Raltegravir 8.

The formation of the hydroxypyrimidone core (3.22) of raltegravir deserves further discussion as its unexpected mechanism was only recently fully elucidated in a joint effort between Merck process chemists and the Houk group at UCLA [91]. These studies combined B3LYP density functional theory with labelling studies and revealed that the most likely pathway involves the formation of a tightly bound polar radical pair 3.31 resulting from thermal homolysis of the N–O bond (Scheme 35). This species subsequently recombines under formation of a C–N bond and a C=O double bond (3.32) allowing for the final cyclocondensation to occur with liberation of methanol. Furthermore these studies were able to disprove a potential alternative [3,3]-sigmatropic rearrangement step by incorporating 15N enriched precursors leading to the formation of pyrimidone 3.22, which is only consistent with a formal [1,3]-sigmatropic rearrangement. Subsequent calculations demonstrated the high energy barrier for such a concerted [1,3]-shift, ultimately leading to the finding of the before-mentioned polar radical pair pathway which is about 8 kcal/mol lower in energy. This is consistent with the experimentally observed rate acceleration in case of the Z-isomer of 3.33 over the E-isomer which was also confirmed by calculations showing an energy gap of 3 kcal/mol.

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Marcus Baumann

and Ian R. Baxendale

Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK

Corresponding author email

Associate Editor: P. R. Hanson

Beilstein J. Org. Chem. 2013, 9, 2265–2319.

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265

check beilstein journals as per link above ……………

this publication allows free usage of data if given proper ref…………………..

any objections email me amcrasto@gmail.com or cal +91 9323115463

………………..

nmr

Imp roved synthesis of raltegravir

GUO D i2liang et al

Department ofM edicinal Chem istry, China PharmaceuticalUniversity, N anjing 210009;

Journal of China Pharmaceutical University　2009, 40 (4) : 297 – 301

http://star.sgst.cn/upload/attach/attach20091230100028d4masjzgcv.pdf

1H NMR (CD3OD) δ: 7.40 (m, 2H) , 7.04 (m , 2H) ,

4.56 (s, 2H ) , 3.46 ( s, 3H ) , 2.65 (s, 3H ) , 1.83 (s,

6H);

13C NMR (CD3OD ) δ: 168.4, 164.8, 163.2,

162.0, 161.9, 160.1, 155.3, 145.8, 136.0, 134.9,

131.0, 116.7, 116.6, 60.2, 43.8, 41.3, 34.8, 27.6,

11.4;

ESI2MS m /z 443 (M )-; LR2MS (EI) m /z 444(M )+; HR2MS ( E I) m /z C20 H21 FN6O5(M )+

calcd444, 155, 7, found 444, 154, 2

second set

WO2009088729 , US20100280244

lH NMR (399.87 MHz₅ CDCI3) δ 12.04 (s, IH), 8.45 (s, IH), 7.94 (t, J = 6.2 Hz, IH), 7.41-736 (m, 2H), 7.08-7.02 (m, 2H)₅ 4.61 (d, J – 6.2 Hz, 2H), 3.68 (s, 3H), 2.63 (s, 3H), 1.87 (s, 6H).

13C NMR (100.55 MHz, CDCI3) δ 168.3, 166.7, 162.6 (d, JCF=245.7 Hz), 159.6, 159.1, 152.O₅ 150.4, 147.2, 133.4 (d, JCP=3.2 Hz)₅ 129.9 (d, JcF=8.0 Hz), 124.1, 115.9 (d, JcF=21.7 Hz), 58.0, 42.7, 33.5, 26.7, 11.4.

…………………….

WO2011024192, WO2011024192A3

absorption bandsKBR (cm^“1) at 832, 1017, 1248, 1350, 1510, 1682, 2995, and 3374

……………….

K SALT

Org. Process Res. Dev., 2011, 15 (1), pp 73–83

DOI: 10.1021/op100257r

http://pubs.acs.org/doi/full/10.1021/op100257r

mp 274.2−275.2 °C. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.65 (t, J = 6.0 Hz, 1 H), 9.75 (s, 1 H), 7.36 (dd, J = 8.6, 5.7 Hz, 2 H), 7.14 (app. t, J = 8.6 Hz, 2 H), 4.48 (d, J = 6.0 Hz, 2 H), 3.43 (s, 3 H), 2.58 (s, 3 H), 1.73 (s, 6 H);

¹³C NMR (125 MHz, DMSO-d₆) δ: 168.7, 167.0, 166.6, 162.1 (d, J_CF = 243 Hz), 159.7, 158.3, 153.1, 139.6, 138.0 (d, J_CF = 3 Hz), 130.2 (d, J_CF = 8 Hz), 123.7, 116.0 (d, J_CF = 22), 58.4, 42.1, 33.3, 28.1 (2 C), 11.7.

……………………………

impurities

Org. Process Res. Dev., 2012, 16 (8), pp 1422–1429

DOI: 10.1021/op300077m

http://pubs.acs.org/doi/full/10.1021/op300077m

Abstract Image

…………………

intermediates

http://www.google.com/patents/WO2013098854A2

Figure imgf000016_0001

N-[(1Z)-1 -amino-1 -(hydroxyimino)-2-memylpropan-2-yl]-5-methyl-l ,3 ,4- oxadiazole-2-carboxamide (IVa) (198 gms) was suspended in methanol (1188 ml) and cooled to 15 to 25°C. Dimethyl acetyl enedicarboxylate (DMAD; 152.8 gms) was added and the reaction mass was stirred for 2 to 3 hours at 25°C. The reaction mass was concentrated under reduced pressure and xylene was added and stirred between 135°C and 125°C for 6 hour. After completion of reaction, the mixture was cooled to 60°C and methanol (170 ml) & methyl tert-butyl ether (MTBE) were added to the reaction mass and stirred for 1 hour. The resultant slurry was filtered and washed with a 9:1 mixture of methanol & methyl tert-butyl ether (MTBE) and dried to give methyl 2-(2-(5-methyl-l ,3,4-oxadiazole-2-carboxamido)propan-2-yl)-l ,6-dihydro-5- hydroxy-6-oxopyrimidine-4-carboxylate (V a).

Yield: 198 gms (66 %).

1H NMR (400 MHz, DMSO d⁶): δ 12.74 (s, 1H), 10.35 (s, 1H), 9.12 (s, 1 H), 3.81 (s, 3H), 2.58 (s, 3H), 1.59 (s, 6 H);

¹³C NMR (100 MHz, DMSO d⁶): δ 166.60, 166.15, 160.19, 159.23, 153.26, 152.87, 145.65, 128.30, 56.60, 52.91 , 26.26, 11.34;

retroviral drugs

elvitegravir

Å for chemical synthesis from carboxylic acids elvitegravir 1 starts, the NIS transformed into acid chloride iodide, 2 , and with 3 condensation 4 . 4 and amino alcohols 5 addition-elimination reaction occurs 6 , 6 in alkaline conditions Shimonoseki ring hydroxyl group protected with TBS after seven , seven and zinc reagent 8 occurred Negishi coupling get nine , the last ninehydrolysis and methoxylated get angstrom for elvitegravir.

Medicinal Chemistry International

December 15, 2013 3:35 am / Leave a comment

Medicinal Chemistry International

The US Food and Drug Administration (FDA) has granted a six-month Priority Review designation to Genzyme’s New Drug Application (NDA) for Cerdelga (eliglustat)

December 14, 2013 12:13 pm / 2 Comments on The US Food and Drug Administration (FDA) has granted a six-month Priority Review designation to Genzyme’s New Drug Application (NDA) for Cerdelga (eliglustat)

13 dec 2013

Genzyme’s Cerdelga NDA receives US FDA priority review designationpharmabiz.comThe US Food and Drug Administration (FDA) has granted a six-month Priority Review designation to Genzyme’s New Drug Application (NDA) for Cerdelga (eliglustat), an investigational oral therapy for adult patients with Gaucher disease

ELIGLUSTAT TARTRATE

THERAPEUTIC CLAIM Treatment of lysosomal storage disorders

CHEMICAL NAMES

1. Octanamide, N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-
pyrrolidinylmethyl)ethyl]-, (2R,3R)-2,3-dihydroxybutanedioate (2:1)

2. bis{N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(pyrrolidin-1-
ylmethyl)ethyl]octanamide} (2R,3R)-2,3-dihydroxybutanedioate

MOLECULAR FORMULA C23H36N2O4 . ½ C4H6O6

MOLECULAR WEIGHT 479.6

MANUFACTURER Genzyme Corp.

CODE DESIGNATION Genz-112638

CAS REGISTRY NUMBER 928659-70-5

old article cut paste

Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease

Eliglustat tartrate (USAN)

CAS:928659-70-5

February 15, 2013

Genzyme , a Sanofi company (EURONEXT: SAN and NYSE: SNY), today announced positive new data from the Phase 3 ENGAGE and ENCORE studies of eliglustat tartrate, its investigational oral therapy for Gaucher disease type 1. The results from the ENGAGE study were presented today at the 9th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. In conjunction with this meeting, Genzyme also released topline data from its second Phase 3 study, ENCORE. Both studies met their primary efficacy endpoints and together will form the basis of Genzyme’s registration package for eliglustat tartrateThe data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease”The company is developing eliglustat tartrate, a capsule taken orally, to provide a convenient treatment alternative for patients with Gaucher disease type 1 and to provide a broader range of treatment options for patients and physicians. Genzyme’s clinical development program for eliglustat tartrate represents the largest clinical program ever focused on Gaucher disease type 1 with approximately 400 patients treated in 30 countries.“The data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease,” said Genzyme’s Head of Rare Diseases, Rogerio Vivaldi MD. “We are excited about this therapy’s potential and are making excellent progress in our robust development plan for bringing eliglustat tartrate to the market.”ENGAGE Study Results:In ENGAGE, a Phase 3 trial to evaluate the safety and efficacy of eliglustat tartrate in 40 treatment-naïve patients with Gaucher disease type 1, improvements were observed across all primary and secondary efficacy endpoints over the 9-month study period. Results were reported today at the WORLD Symposium by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the trial.

The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).

http://www.wikigenes.org/e/ref/e/20439622.html

Eliglustat tartate (Genz-112638)

What is Eliglustat?

Eliglustat is a new investigational phase 3 compound from Genzyme Corporation that is being studied for type 1 Gaucher Disease.
Eliglustat works as a substrate reduction therapy by reducing glucocerebroside. formation.
This product is an oral agent (i.e. a pill) that is taken once or twice a day in contrast to an IV infusion for enzyme replacement therapy. Enzyme replacement therapy focuses on replenishing the enzyme that is deficient in Gaucher Disease and breaks down glucocerebroside that accumulates.
The clinical trials for eliglustat tartate are sponsored by Genzyme Corporation.

HOMEOPATHY…… ALLERGY TREATMENT, GRASS POLLEN

December 14, 2013 9:21 am / 1 Comment on HOMEOPATHY…… ALLERGY TREATMENT, GRASS POLLEN

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http://www.iherb.com/NatraBio-bioAllers-Allergy-Treatment-Grass-Pollen-1-fl-oz-30-ml/6660

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Pazopanib Hydrochloride

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Assessment of Predictivity of Semiquantitative Risk Assessment Tool: Pazopanib Hydrochloride Genotoxic Impurities

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Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

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About Lipodystrophy

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An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

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Synthesis

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

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13 dec 2013

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Eliglustat tartate (Genz-112638)

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