GIVINOSTAT

GIVINOSTAT, ITF2357, UNII-5P60F84FBH, ITF-2357, Gavinostat,

[6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate,

diethyl-[6-(4-hydroxycarbamoyl-phenylcarbamoyloxymethyl)-naphthalen-2-yl-methyl]-amine

4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]benzohydroxamic acid

CAS 497833-27-9 FREE BASE

199657-29-9 HCL SALT

Molecular Formula: C₂₄H₂₇N₃O₄

Molecular Weight: 421.48888 g/mol

PHASE 2  Italfarmaco (INNOVATOR)

Italfarmaco S.P.A.

DESCRIBED IN U.S. Pat. No. 6,034,096 or in U.S. Pat. No. 7,329,689.

GIVINOSTAT

Givinostat (INN^[1]) or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.^[2] It is a hydroxamate used in the form of its hydrochloride.

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),^[3] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis^[4] and polycythaemia vera.^[5]

In 2010, orphan drug designation was assigned in the E.U. for the treatment of systemic-onset juvenile idiopathic arthritis and for the treatment of polycythemia vera. In 2013, this designation was assigned by the FDA for the treatment of Duchenne's muscular dystrophy and for the treatment of Becker's muscular dystrophy.

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.^[6][7]

Givinostat hydrochloride, an orally active, synthetic inhibitor of histone deacetylase, is being evaluated in several early clinical studies at Italfarmaco, including studies for the treatment of myeloproliferative diseases, polycythemia vera, Duchenne's muscular dystrophy and periodic fever syndrome. The company was also conducting clinical trials for the treatment of Crohn's disease and chronic lymphocytic leukemia; however, the trials were terminated.

No recent development has been reported for research into the treatment of juvenile rheumatoid arthritis, for the treatment of multiple myeloma and for the treatment of Hodgkin's lymphoma.

Patent	Submitted	Granted
Monohydrate hydrochloride of the 4-hydroxycarbamoyl-phenyl)-carbamic acid (6-diethylaminomethyl-naphtalen-2-yl) ester [US7329689]	2005-11-03	2008-02-12

Adverse effects

In clinical trials of givinostat as a salvage therapy for advanced Hodgkin's lymphoma, the most common adverse reactions were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia (decreased platelet counts, seen in one third of patients), and mild leukopenia (a decrease in white blood cell levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment.^[8]

Mechanism of action

Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6.^[7]

It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera.^[9][10] In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease.^[5]

......................

PATENT

http://www.google.co.in/patents/US7329689

Hydrochloride of (6-diethylaminomethyl-naphthalen-2-yl)-methyl ester of (4-hydroxycarbamoylphenyl)-carbamic acid (II)

has been described in U.S. Pat. No. 6,034,096 as a derivative of hydroxamic acid having anti-inflammatory and immunosuppressive activity, probably owing to the ability thereof to inhibit the production of pro-inflammatory cytokines. This compound is obtained according to Example 12 of the above-mentioned patent as an anhydrous, amorphous, hygroscopic, deliquescent solid which is difficult to handle.

The 4-(6-diethylaminomethyl-naphthalen-2-ylmethoxycarbonylamino)-benzoic acid can be prepared as described in Example 12, point C, of U.S. Pat. No. 6,034,096.

The acid (1.22 kg, 3 moles) was suspended in THF (19 l) and the mixture was agitated under nitrogen over night at ambient temperature. The mixture was then cooled to 0° C. and thionyl chloride (0.657 l, 9 moles) was added slowly, still under nitrogen, with the temperature being maintained below 10° C. The reaction mixture was heated under reflux for 60 minutes, DMF (26 ml) was added and the mixture was further heated under reflux for 60 minutes.

The solvent was evaporated under vacuum, toluene was added to the residue and was then evaporated. This operation was repeated twice, then the residue was suspended in THF (11.5 l) and the mixture was cooled to 0° C.

The mixture was then poured into a cold solution of hydroxylamine (50% aq., 1.6 l, 264 moles) in 5.7 l of water. The mixture was then cooled to ambient temperature and agitated for 30 minutes. 6M HCl was added until pH 2 was reached and the mixture was partially evaporated under vacuum in order to eliminate most of the THF. The solid was filtered, washed repeatedly with water and dissolved in a solution of sodium bicarbonate (2.5%, 12.2 l). The solution was extracted with 18.6 l of a mixture of THF and ethyl acetate (2:1 v/v). 37% HCl (130 ml) were added to the organic layer in order to precipitate the monohydrate of the (6-diethylaminomethyl-naphthalen-2-yl)-methyl ester hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid. If necessary, this operation can be repeated several times to remove any residues of the original acid.

Finally, the solid was dried under vacuum (approximately 30 mbar, 50° C.), producing 0.85 kg (60%) of compound (I).

HPLC purity: 99.5%; water content (Karl Fischer method): 3.8%; (argentometric) assay: 99.8%.

	Elemental analysis
	C %	H %	Cl %	N %
	Calculated for	60.56	6.35	7.45	8.83
	C24H30ClN3O5
	Found	61.06	6.48	7.48	8.90

 

 

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PATENT

http://www.google.co.in/patents/US20120302633

.......................

http://www.google.com/patents/US6034096

EXAMPLE 12

4-[6-(Diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]-benzohydroxamic acid hydrochloride

A. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (22.2 g, 115 mmol) was added to a solution of 2,6-naphthalenedicarboxylic acid (25 g, 115 mmol) and hydroxybenzotriazole (15.6 g, 115 mmol) in dimethylformamide (1800 ml) and the mixture was stirred at room temperature for 2 hours. Diethyl amine (34.3 ml, 345 mmol) was added and the solution was stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the crude was treated with 1N HCl (500 ml) and ethyl acetate (500 ml), insoluble compounds were filtered off and the phases were separated. The organic phase was extracted with 5% sodium carbonate (3×200 ml) and the combined aqueous solutions were acidified with concentrated HCl and extracted with ethyl acetate (3×200 ml). The organic solution was then washed with 1N HCl (6×100 ml), dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure yielding 18.5 g (Yield 60%) of pure 6-(diethylaminocarbonyl)-2-naphthalenecarboxylic acid; m.p.=122-124° C.

¹ H-NMR d 8.67 (s, 1H), 8.25-8.00 (m, 4H), 7.56 (d, 1H), 3.60-3.20 (m, 4H), 1.30-1.00 (m, 6H).

B. A solution of 6-(diethylaminocarbonyl)-2- naphthalenecarboxylic acid (18 g, 66 mmol) in THF (200 ml) was slowly added to a refluxing suspension of lithium aluminium hydride (7.5 g, 199 mmol) in THF (500 ml). The mixture was refluxed for an hour, then cooled at room temperature and treated with a mixture of THF (25 ml) and water (3.5 ml), with 20% sodium hydroxide (8.5 ml) and finally with water (33 ml). The white solid was filtered off and the solvent was removed under reduced pressure. Crude was dissolved in diethyl ether (200 ml) and extracted with 1N HCl (3×100 ml). The aqueous solution was treated with 32% sodium hydroxide and extracted with diethyl ether (3×100 ml). The organic solution was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure yielding 12.7 g (79% yield) of pure 6-(diethylaminomethyl)-2-naphthalenemethanol as thick oil.

¹ H-NMR d 7.90-7.74 (m, 4H), 7.49 (m, 2H), 5.32 (t, 1H, exchange with D₂ O), 4.68 (d, 2H), 3.69 (s, 2H), 2.52 (q, 4H), 1.01 (t, 6H).

C. A solution of 6-(diethylaminomethyl)-2-naphthalene-methanol (12.5 g, 51 mmol) and N,N'-disuccinimidyl carbonate (13.2 g, 51 mmol) in acetonitrile (250 ml) was stirred at room temperature for 3 hours, then the solvent was removed and the crude was dissolved in THF (110 ml). This solution was added to a solution of 4-amino benzoic acid (7.1 g, 51 mmol) and sodium carbonate (5.5 g, 51 mmol) in water (200 ml) and THF (100 ml). The mixture was stirred overnight at room temperature, then THF was removed under reduced pressure and the solution was treated with 1N HCl (102 ml, 102 mmol). The precipitate was filtered, dried under reduced pressure, tritured in diethyl ether and filtered yielding 13.2 g (yield 64%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]-benzoic acid; m.p.=201-205° C. (dec.)

¹ H-NMR d 10.26 (s, 1H), 8.13 (s, 1H), 8.05-7.75 (m, 6H), 7.63 (m, 3H), 5.40 (s, 2H), 4.32 (s, 2H), 2.98 (q, 4H), 1.24 (t, 6H).

D. A solution of 4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]benzoic acid (13.1 g, 32 mmol) and thionyl chloride (7 ml, 96 mmol) in chloroform (300 ml) was refluxed for 4 hours, then the solvent and thionyl chloride were evaporated. Crude was dissolved in chloroform (100 ml) and evaporated to dryness three times. Crude was added as solid to a solution of hydroxylamine hydrochloride (2.7 g, 39 mmol) and sodium bicarbonate (5.4 g, 64 mmol) and 1N sodium hydroxide (39 ml, 39 mmol) in water (150 ml) and THF (50 ml). The mixture was stirred overnight at room temperature, then THF was removed under reduced pressure and the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. Crude was dissolved in THF and treated with a 1.5 N etheric solution of HCl. The solid product was filtered and dried yielding 6 g (yield 41%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]benzohydroxamic acid hydrochloride as white solid; m.p.=162-165° C., (dec.)

¹ H-NMR d 11.24 (s, 1H, exchange with D₂ O), 10.88 (s, 1H, exchange with D₂ O), 10.16 (s, 1H), 8.98 (bs, 1H, exchange with D₂ O), 8.21 (s, 1H), 8.10-7.97 (m, 3H), 7.89 (d, 1H), 7.80-7.55 (m, 5H), 5.39 (s, 2H), 4.48 (d, 2H), 3.09 (m, 4H), 1.30 (t, 6H).

http://www.molbase.com/

Some nmr predictions

CAS NO. 497833-27-9, [6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate H-NMR spectral analysis

13 C NMR PREDICTIONS

COSY NMR.....http://www.nmrdb.org/

HMBC /HSQC

NMR spectra of reference

· 1H NMR prediction

· 13C NMR prediction

· COSY prediction

· HSQC/HMBC prediction

· All predictions

References

 1

• World Health Organization (2010). "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63". WHO Drug Information 24 (1): 58–9.
• 2
• National Cancer Institute (2010). "Gavinostat". NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.
• 3
• "Search results for ITF2357". ClinicalTrials.gov.
• 4
• Committee for Orphan Medicinal Products (23 February 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis". European Medicines Agency. Retrieved 2010-09-15.
• 5
• Committee for Orphan Medicinal Products (3 March 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera". European Medicines Agency.
• 6
• WO patent application 1997/043251, "Compounds with anti-inflammatory and immunosuppressive activities", published 1997-11-20, assigned to Italfarmaco S.p.A.
• 7
• Leoni F, Fossati G. (2005). "The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo". Molecular Medicine 11: 1. doi:10.2119/2006-00005.Dinarello. PMID 16557334.
• 8
• Tan J, Cang S, Ma Y, Petrillo RL, Liu D (2010). "Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents". Journal of Hematology & Oncology 3: 5. doi:10.1186/1756-8722-3-5. PMID 20132536. Review.
• 9
• Vannucchi AM, Guglielmelli P, Pieri L, Antonioli E, Bosi A (2009). "Treatment options for essential thrombocythemia and polycythemia vera." Expert Review of Hematology 2 (1): 41–55. doi:10.1586/17474086.2.1.41. Review.
• 
  

10. Guerini V, Barbui V, Spinelli O, et al. (April 2008). "The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F)". Leukemia 22 (4): 740–7. doi:10.1038/sj.leu.2405049. PMID 18079739.

Further reading

• Job-Deslandre, C (January 2007). "Idiopathic juvenile-onset systemic arthritis". Orphanet. Orphan number: ORPHA85414.

US6034096

12 May 1997

7 Mar 2000

Italfarmaco S.P.A.

Compounds with anti-inflammatory and immunosuppressive activities

Citing Patent	Filing date	Publication date	Applicant	Title
US8518988 *	3 Dec 2010	27 Aug 2013	Chemi Spa	Polymorph of the hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphthalenyl) ester
US20120302633 *	3 Dec 2010	29 Nov 2012	Chemi Spa	Novel polymorph of the hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphthalenyl) ester
WO2011092556A1	3 Dec 2010	4 Aug 2011	Chemi Spa	Novel polymorph of the hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphtalenyl) ester

Givinostat

Systematic (IUPAC) name
{6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
Clinical data
Pregnancy category	—
Legal status	Investigational Orphan status in EU for sJIA
Routes	Oral
Identifiers
CAS number	497833-27-9
ATC code	None
PubChem	CID 9804992
ChemSpider	7980752
UNII	5P60F84FBH
Chemical data
Formula	C24H27N3O4
Molecular mass	421.489 g/mol

Map for Italfarmaco S.P.A.

 

Italfarmaco S.p.A.
Stato	Italia
Tipo	Società per azioni
Fondazione	1938 a Milano
Fondata da	Gastone De Santis
Sede principale	Milano
Filiali	Spagna -  Portogallo  Grecia -  Russia  Cile -  Brasile  Turchia
Persone chiave	Francesco De Santis, [Presidente Holding]
Settore	sanità
Prodotti	Farmaci
Fatturato	>500 milioni di Euro (gruppo) (2011)
Dipendenti	>1900 (gruppo) (2011)
Sito web	www.italfarmaco.com

MILAN ITALY



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AMPRENAVIR

AMPRENAVIR For the treatment of HIV-1 infection in combination with other antiretroviral agents.

Amprenavir

KVX-478, 141W94, VX-478,

DrugSyn.org

US5585397

(3S)-Tetrahydro-3-furanyl ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)carbamate

(3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulphonamido)-1-benzyl-2-hydroxypropyl] carbamate

CAS NO. 161814-49-9, [(3S)-oxolan-3-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate

161814-49-9
WEIGHT	505.224656557
CHEMICAL FORMULA	C25H35N3O6S

	Amprenavir is a protease inhibitor used to treat HIV infection.

Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIVinfection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.

Production of amprenavir was discontinued by the manufacturer December 31, 2004; aprodrug version (fosamprenavir) is available.

Amprenavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Amprenavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

HIV-1 Protease dimer with Amprenavir (sticks) bound in the active site. PDB entry3nu3 [1]

COUNTRY	PATENT NUMBER	APPROVED	EXPIRES (ESTIMATED)
United States	5585397	1993-12-17	2013-12-17
United States	6730679	1997-11-11	2017-11-11

Background

Research aimed at development of renin inhibitors as potential antihypertensive agents had led to the discovery of compounds that blocked the action of this peptide cleaving enzyme. The amino acid sequence cleaved by renin was found to be fortuitously the same as that required to produce the HIV peptide coat. Structure–activity studies on renin inhibitors proved to be of great value for developing HIV protease inhibitors. Incorporation of an amino alcohol moiety proved crucial to inhibitory activity for many of these agents. This unit is closely related to the one found in the statine, an unusual amino acid that forms part of thepepstatin, a fermentation product that inhibits protease enzymes.

Synthesis

[2]

R.D. Tung, M.A. Murcko, G.R. Bhisetti, U.S. Patent 5,558,397 (1996). The scheme shown here is partly based on that used to prepare darunavir and fosamprenavir due to difficulty in deciphering the patent.

AGENERASE (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV)protease. The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate. Amprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C25H35N3O6S and a molecular weight of 505.64. It has the following structural formula:

Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C.

AGENERASE Capsules (amprenavir capsules) are available for oral administration. Each 50- mg capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene glycol 19 mg. The capsule shell contains the inactive ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 50- mg AGENERASE Capsule contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin E in the recommended daily adult dose of AGENERASE is 1,744 IU.

………………………………

paper

Org. Biomol. Chem., 2004,2, 2061-2070

DOI: 10.1039/B404071F

http://pubs.rsc.org/en/content/articlelanding/2004/ob/b404071f#!divAbstract

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

……………

The reaction of N,N-dibenzyl-L-alaninal (I) with nitromethane, catalyzed by the chiral ammonium salt (II) and KF in THF gives the chiral nitroalcohol (III), which is reduced with NiCl2 and NaBH4 to yield the aminoalcohol (IV). The condensation of (IV) with isobutyraldehyde (V) affords the Schiff base (VI), which is reduced with NaBH4 to provide the secondary amine (VII). The reaction of (VII) with 4-nitrobenzenesulfonyl chloride (VIII) and TEA in dichloromethane furnishes the sulfonamide (IX), which is deprotected by hydrogenation with H2 over Pd/C in methanol, giving the diamino compound (X). Finally, this compound is condensed with 3(S)-tetrahydrofuryl (N-oxysuccinimidyl) carbonate (XI) by means of TEA in dichloromethane to afford the target carbamate.

Angew Chem. Int Ed Engl1999,38,(13-14):1931

……………………………………………………….

The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding the dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) (prepared by condensation of tetrahydrofuran-3(S)-ol (VIII) with phosgene and N-hydroxysuccinimide (IX)) and DIEA in acetonitrile to provide the corresponding carbamate (X). The deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide (XIII). Finally, the nitro group of (XIII) is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.

EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639

……………………………………………………………

Patent

 https://www.google.com/patents/WO1999048885A1?cl=ensynthesis of (3S)-tetrahydro-3-furyl N-[(1S,2R)-3(4-amino-N-isobutylbenzenesulphonamido)-1-benzyl-2-hydroxypropyl]carbamate, hereinafter referred to as the compound of formula (I), and to novel intermediates thereto.The compound of formula (I) has the following structure

and was first described in PCT patent publication number WO94/05639 at Example 168. Currently there is considerable interest in the compound of formula (I) as a new chemotherapeutic compound in the treatment of human immunodeficiency virus (HIV) infection and the associated conditions such as acquired immune deficiency syndrome (AIDS) and AIDS dementia.

There exists at the present time a need to produce large quantities of the compound of formula (I) for clinical investigation into the efficacy and safety of the compound as a chemotherapeutic agent in the treatment of HIV infections.

An ideal route for the synthesis of the compound should produce the compound of formula (I) in high yields at a reasonable speed and at low cost with minimum waste materials and in a manner that is of minimum impact to the environment in terms of disposing of waste-materials and energy consumption.

We have found a new process for the synthesis of the compound of formula (I) with many advantages over previously known routes of synthesis. Such advantages include lower cost, less waste and more efficient use of materials. The new process enables advantageous preparation of the compound of formula (I) on a manufacturing scale.

The route of synthesis of the compound of formula (I) described in the specification of WO94/05639 is specifically described therein in examples 39A, 51A, 51B, 51C, 51D, 167 and 168. The overall yield from these examples is 33.2% of theory.

Generally the route described in WO94/05639 involves protecting the amino alcohol of formula (A) (Ex.39)

wherein P is a protecting group to form a compound of formula (B);

wherein P and P′ are each independently a protecting group;

deprotecting the compound of formula (B) to form a compound of formula (C) (Ex 51A);

wherein P′ is a protecting group;

forming a hydrochloride salt of compound (C) (Ex 51B) then reacting with N-imidazolyl-(S)-tetrahydrofuryl carbamate to form the compound of formula (D) (Ex 51C);

wherein P′ is a protecting group;

deprotecting the compound of formula (D) (Ex 51D) wherein P′ is a protecting group to form the compound of formula (D) wherein P′ is H (Ex 51E); and coupling the resultant secondary amine on the compound of formula (D) to a p-nitrophenylsulphonyl group to form a compound of formula (E) (Ex 167);

the resultant compound of formula (E) is then reduced to form the compound of formula (I) (Ex 168).

In summary, the process disclosed in WO94/05639 for producing the compound of formula (I) from the compound of formula (A) comprises 6 distinct stages:

1) protecting,

2) deprotecting,

3) reacting the resultant compound with an activated tetrahydrofuranol group,

4) deprotecting,

5) coupling with a p-nitrophenylsulfonyl group, and

6) reducing the resultant compound to form a compound of formula (I).

Applicants have now found a process by which the compound of formula (I) may be prepared on a manufacturing scale from the same starting intermediate, the compound of formula (A), in only 4 distinct stages instead of 6. In addition to the associated benefits of fewer stages, such as savings in time and cost, the improved process reduces the number of waste products formed. Furthermore, product may be obtained in a higher yield, of approximately 50% of theory

.

EXAMPLESExample 1

(1S,2R)-tert-butyl N-[1-benzyl-2-hydroxy-3-(isobutylamino)propyl]carbamate (127.77 g, 379.7 mmol) was heated in toluene (888 ml) to 80° C. and triethylamine (42.6 g, 417.8 mmol) added. The mixture was heated to 90° C. and a solution of p-nitrobenzene sulphonyl chloride (94.3 g, 425.4 mmol) in toluene (250 ml) was added over 30 minutes then stirred for a further 2 hours. The resultant solution of the nosylated intermediate {(1S,2R)-tert-butyl N-[1-benzyl-2-hydroxy-3-(N-isobutyl- 4-nitrobenzenesulphonamido)propyl]carbamate } was then cooled to 80° C. The solution was maintained at approximately 80° C., and concentrated hydrochloric acid (31.4 ml, 376.8 mmol) was added over 20 minutes. The mixture was heated to reflux (approx 86° C.) and maintained at this temperature for an hour then a further quantity of concentrated hydrochloric acid (26.4 ml, 316.8 mmol) was added. Solvent (water and toluene mixture) was removed from the reaction mixture by azeotropic distillation (total volume of solvent removed approx 600 ml), and the resultant suspension was cooled to 70-75° C. Denatured ethanol (600 ml) was added, and the solution was cooled to 20° C. The mixture was further cooled to approximately −10° C. and the precipitate formed was isolated by filtration, washed with denatured ethanol (50 ml) and dried at approximately 50° C., under vacuum, for approximately 12 hours, to give (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene sulphonamide hydrochloride (160 g; 73% of theory yield corrected for assay). NMR: 1H NMR (300Mhz, dmso-d6): 8.37(2H, d, J=9 Hz), 8.16(NH3 +s), 8.06(2H, d, J=9 Hz), 7.31(5H, m), 5.65(1H, d, J=5 Hz), 3.95(1H, m), 3.39(2H, m), 2.95(5H, m), 1.90(1H, m), 0.77(6H, dd, J=21 Hz and 6 Hz).

1,1′-carbonyidiimidazole (27.66 kg, 170.58 mol) was added to ethyl acetate (314.3 kg) with stirring to give 3-(S)-tetrahydrofuryl imidazole-1-carboxylate. (S)-3-hydroxytetrahydrofuran (157 kg, 178.19 mol) was added over 30 minutes, washed in with ethyl acetate (9.95 kg), then the mixture was stirred for a further hour. (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene sulphonamide hydrochloride (65.08 kg, 142.10 mol) was added and the mixture heated to reflux for approximately 22 hours. The solution was cooled slightly, and denatured ethanol (98 l) was added. The solution was stirred at 60° C. for 10 minutes then cooled and the product allowed to crystallise. The mixture was cooled to <10° C. and stirred for 2 hours. The product was isolated by filtration, washed with denatured ethanol (33 l) and dried at approximately 50° C., under vacuum to give (3S)-tetrahydro-3-furyl N-[(1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzene sulphonamido)propyl]carbamate in a yield of 82% of theory.

NMR: 1H NMR (500 Mhz, dmso-d6): 8.38(2H, d, J=9Hz), 8.06(2H, d, J=9 Hz), 7.20(6H, m), 5.02(1H, d, J=5 Hz), 4.94(1H, m), 4.35(EtOH, broad s), 3.71(EtOH, q), 3.65(1H, m), 3.60(1H, m), 3.51(2H, broad m), 3.40(2H, m), 3.15(1H, dd, J=8 Hz and 14 Hz), 3.07(1H, dd, J=8 Hz and 15 Hz), 2.94(2H, m), 2.48(1H, m), 2.06(1H, m), 1.97(1H, m), 1.78(1H, m), 1.05(EtOH, t), 0.83(6H, dd, J=7 Hz and 16 Hz).

Product from the above stage (80.0 g, 149.4 mmol) was hydrogenated in isopropanol (880 ml) with 5% palladium on carbon (16 g, of a wet paste) and hydrogen pressure (approx 0.5 to 1.5 bar) at 25-50° C. for approximately 5 hours. The mixture was cooled and the catalyst removed by filtration. The solution was distilled to a volume of approximately 320 ml and water (80 ml) was added. This solution was divided into two for the crystallisation step.

To half of the above solution, decolourising charcoal (2 g) was added, the mixture stirred at approximately 32° C. for 4 hours, then filtered. The filtercake was washed with isopropanol (20 ml) then further water (40 ml) was added to the filtrate. The solution was seeded to induce crystallisation and stirred for 5 hours. Water (130 ml) was added slowly over 1 hour then the mixture was stirred for 4 hours. The resultant slurry was cooled to approximately 20° C. and the product was isolated by filtration and washed with a 1:4 mixture of isopropano/water (120 ml). The product was dried at approximately 50° C., under vacuum, for approximately 12 hours to give (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulphonamido)-1-benzyl-2-hydroxypropyl] carbamate (30.3 g; 80% of theory yield).

NMR: 1H NMR (300 Mhz, dmso-d6): 7.39(2H, d, J=9 Hz), 7.18(6H, m), 6.60(2H, d, J=9 Hz), 6.00(2H, s), 4.99(1H, d, J=6 Hz), 4.93(1H, ddt), 3.64(5H, m), 3.34(1H, m), 3.28(1H, dd, J=14 Hz and 3 Hz), 3.01(1H, m, J=14 Hz and 3 Hz), 2.91(1H, m), 2.66(2H, m), 2.50(1H, m), 2.05(1H, m), 1.94(1H, m), 1.78(1H, m), 0.81(6H, dd, J=16 Hz and 7 Hz). m/z: 506.2(M+H+)

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PATENT

http://www.google.com/patents/US20150011782

Example 11Synthesis of Amprenavir (1)To a solution of carbamate nitro derivative 15 (0.05 g, 0.09 mmol) in 2 mL of EtOAc was added SnCl2.2H2O (0.1 g, 0.5 mmol) at 70° C. The reaction mixture was heated for 1 h until starting material disappeared and the solution cooled to room temperature. It was then poured into saturated aq. NaHCO3 solution and extracted with EtOAc. The organic extract was dried over anhyd. Na2SO4 and concentrated under reduced pressure. It was purified over chromatography using petroleum ether:EtOAc (3:2) to give amprenavir 1 (0.04 g, 90%).IR: (CHCl3, cm−1): υmax 757, 1090, 1149, 1316, 1504, 1597, 1633, 1705, 2960, 3371; 1H NMR (200 MHz, CDC3): δ 0.86 (d, J=5.7 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.78-2.21 (m, 3H), 235-3.11 (m, 6H), 3.58-4.11 (m, 7H), 4.25 (s, 2H), 5.01 (br s, 1H), 5.07 (br s, 1H), 6.65 (d, J=8.4 Hz, 2H), 7.20-7.28 (m, 5H), 7.51 (d, J=8.4 Hz, 2H); 13C NMR (50 MHz, CDC3): δ 19.9, 20.2, 27.3, 32.8, 35.4, 35.7, 53.8, 55.0, 58.6, 66.8, 72.6, 73.2, 75.3, 114.0, 125.9, 126.5, 1280.4, 129.5, 137.7, 150.9, 155.9;

Anal. Calcd for C25H35N3O6S: C, 59.39; H, 6.98; N, 8.31; S, 6.34. Found: C, 59.36; H, 6.81; N, 8.25; S, 6.29%.

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NMR PREDICTIONS

1H NMR

13 C NMR

COSY PREDICTION

· COSY prediction

See also

• Fosamprenavir, a prodrug of amprenavir

External links

• Amprenavir bound to proteins in the PDB

• Shen, C. H.; Wang, Y. F.; Kovalevsky, A. Y.; Harrison, R. W.; Weber, I. T. (2010).“Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters”. FEBS Journal 277 (18): 3699–3714. doi:10.1111/j.1742-4658.2010.07771.x. PMC 2975871. PMID 20695887. edit

AMPRENAVIR

SYSTEMATIC (IUPAC) NAME
(3S)-oxolan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-1-phenylbutan-2-yl]carbamate
CLINICAL DATA
TRADE NAMES	Agenerase
AHFS/DRUGS.COM	monograph
MEDLINEPLUS	a699051
LICENCE DATA	EMA:Link, US FDA:link
PREGNANCY CATEGORY	US: C
LEGAL STATUS	?
ROUTES	oral
PHARMACOKINETIC DATA
PROTEIN BINDING	90%
METABOLISM	hepatic
HALF-LIFE	7.1-10.6 hours
EXCRETION	<3% renal
IDENTIFIERS
CAS NUMBER	161814-49-9
ATC CODE	J05AE05
PUBCHEM	CID 65016
DRUGBANK	DB00701
CHEMSPIDER	58532
UNII	5S0W860XNR
KEGG	D00894
CHEBI	CHEBI:40050
CHEMBL	CHEMBL116
NIAID CHEMDB	006080
CHEMICAL DATA
FORMULA	C25H35N3O6S
MOLECULAR MASS	505.628 g/mol

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