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MARIZOMIB, Salinosporamide A
MARIZOMIB
http://www.ama-assn.org/resources/doc/usan/marizomib.pdf
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-
cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-
2. (1R,4R,5S)-4-(2-chloroethyl)-1-{(S)-[(1S)-cyclohex-2-en-1-yl]hydroxymethyl}-5-methyl-
6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione
MOLECULAR FORMULA C15H20ClNO4
MOLECULAR WEIGHT 313.8
MANUFACTURER Nereus Pharmaceuticals, Inc.
NOTE….Nereus Pharmaceuticals was acquired by Triphase Research and Development in 2012.
CODE DESIGNATION NPI-0052
CAS REGISTRY NUMBER 437742-34-2
Scripps Institution of Oceanography (Originator)
mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C.
[α]23 D −73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357);
FTIR (film) νmax: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm−1;
1H NMR (CDCl3, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);
13C NMR (CDCl3, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00;
HRMS (ESI) calcd. for (M−H)− C15H19ClNO4 312.1003, found 312.1003.
Marizomib, a highly potent proteasome inhibitor, is in early clinical development at Triphase Research and Development I Corp for the treatment of relapsed or relapsed/refractory multiple myeloma. Phase I clinical trials have also been carried out for the treatment of solid tumors and lymphoma; however, no recent developments have been reported for these studies.
HDAC inhibitors halt tumor cell differentiation and growth, and when combined with marizomib in preclinical in vitro and in vivo studies, show additive and synergistic antitumor activities.
The compound was discovered from a new marine-obligate gram-positive actinomycete (Salinispora tropica). Preclinical studies suggest that this next-generation compound may be superior to other proteasome inhibitors, with broader target inhibition, faster onset and longer duration of action, higher potency, and oral and intravenous availability. By inhibiting proteasomes, marizomib prevents the breakdown of proteins involved in signal transduction, which blocks growth and induces apoptosis in cancer cells.
In 2013, orphan drug designation was assigned in the U.S. for the treatment of multiple myeloma.
The compound was originally developed by Nereus Pharmaceuticals, which was acquired by Triphase Research and Development in 2012.
marizomib is a naturally-occurring salinosporamide, isolated from the marine actinomycete Salinospora tropica, with potential antineoplastic activity. Marizomib irreversibly binds to and inhibits the 20S catalytic core subunit of the proteasome by covalently modifying its active site threonine residues; inhibition of ubiquitin-proteasome mediated proteolysis results in an accumulation of poly-ubiquitinated proteins, which may result in the disruption of cellular processes, cell cycle arrest, the induction of apoptosis, and the inhibition of tumor growth and angiogenesis. This agent more may more potent and selective than the proteasome inhibitor bortezomib
Marizomib (NPI-0052) is an oral, irreversible ββ-lactone derivative that binds selectively to the active proteasomal sites. In vivo studies with marizomib demonstrate reduced tumor growth without significant toxicity in myeloma xenograft models. A phase I trial in refractory and relapsed MM is under way.
Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery.[1][2] This novel marine natural product is produced by the recently described obligate marine bacteria Salinispora tropica and Salinispora arenicola, which are found in ocean sediment. Salinosporamide A belongs to a family of compounds, known collectively as salinosporamides, which possess a densely functionalized γ-lactam-β-lactone bicyclic core.
Salinosporamide A was discovered by William Fenical and Paul Jensen from Scripps Institution of Oceanography in La Jolla, CA. In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery.Salinospora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1. This compound also displayed potent and highly selective activity in the NCI’s 60-cell-line panel with a mean GI50 value (the concentration required to achieve 50% growth inhibition) of less than 10 nM and a greater than 4 log LC50 differential between resistant and susceptible cell lines. The greatest potency was observed against NCI-H226 non-small cell lung cancer, SF-539 CNS cancer, SK-MEL-28 melanoma, and MDA-MB-435 breast cancer (all with LC50 values less than 10 nM). Salinosporamide A was tested for its effects on proteasome function because of its structural relationship to omuralide. When tested against purified 20S proteasome, salinosporamide A inhibited proteasomal chymotrypsin-like proteolytic activity with an IC50 value of 1.3 nM.[3] This compound is approximately 35 times more potent than omuralide which was tested as a positive control in the same assay. Thus, the unique functionalization of the core bicyclic ring structure of salinosporamide A appears to have resulted in a molecule that is a significantly more potent proteasome inhibitor than omuralide.[1]
Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.
Biosynthesis
Salinosporamide A and B building blocks
Proposed biosynthesis of the nonproteinogenic amino-acid beta-hydroxycyclohex-2′-enylanine (3) (R = H or S~PCP) via a shunt in the phenylalanine biosynthetic pathway
Biosynthesis
It was originally hypothesized that salinosporamide B was a biosynthetic precursor to salinosporamide A due to their structural similarities.
It was thought that the halogenation of the unactivated methyl group was catalyzed by a non-heme iron halogenase.[4][5]Recent work using 13C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.[4][6]
While they share the biosynthetic precursors acetate and presumed β-hydroxycyclohex-2′-enylalanine (3), they differ in the origin of the four-carbon building block that gives rise to their structural differences involving the halogen atom. A hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway is most likely the biosynthetic mechanism in which acetyl-CoA and butyrate-derived ethylmalonyl-CoA condense to yield the β-ketothioester (4), which then reacts with (3) to generate the linear precursor (5).
The first stereoselective synthesis was reported by Rajender Reddy Leleti and E. J.Corey.[7] Later several routes to the total synthesis of salinosporamide A have been reported.[7][8][9][10]
In vitro studies using purified 20S proteasomes showed that salinosporamide A has lower EC50 for trypsin-like (T-L) activity than does Bortezomib. In vivo animal model studies show marked inhibition of T-L activity in response to salinosporamide A, whereas bortezomib enhances T-L proteasome activity.
Initial results from early-stage clinical trials of salinosporamide A in relapsed/refractory multiple myeloma patients were presented at the 2011 American Society of Hematology annual meeting.[11] Further early-stage trials of the drug in a number of different cancers are ongoing.[12]
- Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003). “Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora”. Angew. Chem. Int. Ed. Engl. 42 (3): 355–7.doi:10.1002/anie.200390115. PMID 12548698.
- Chauhan D, Catley L, Li G et al. (2005). “A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib”. Cancer Cell 8 (5): 407–19.doi:10.1016/j.ccr.2005.10.013. PMID 16286248.
- K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
- Beer LL, Moore BS (2007). “Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica”. Org. Lett. 9 (5): 845–8.doi:10.1021/ol063102o. PMID 17274624.
- Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT (2006). “Nature’s inventory of halogenation catalysts: oxidative strategies predominate”. Chem. Rev.106 (8): 3364–78. doi:10.1021/cr050313i.PMID 16895332.
- Tsueng G, McArthur KA, Potts BC, Lam KS (2007). “Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins”. Applied Microbiology and Biotechnology 75 (5): 999–1005. doi:10.1007/s00253-007-0899-7.PMID 17340108.
- Reddy LR, Saravanan P, Corey EJ (2004). “A simple stereocontrolled synthesis of salinosporamide A”. J. Am. Chem. Soc. 126 (20): 6230–1. doi:10.1021/ja048613p.PMID 15149210.
- Ling T, Macherla VR, Manam RR, McArthur KA, Potts BC (2007). “Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052)”.Org. Lett. 9 (12): 2289–92. doi:10.1021/ol0706051. PMID 17497868.
- Ma G, Nguyen H, Romo D (2007). “Concise Total Synthesis of (±)-Salinosporamide A, (±)-Cinnabaramide A, and Derivatives via a Bis-Cyclization Process: Implications for a Biosynthetic Pathway?”. Org. Lett. 9 (11): 2143–6. doi:10.1021/ol070616u. PMC 2518687.PMID 17477539.
- Endo A, Danishefsky SJ (2005). “Total synthesis of salinosporamide A”. J. Am. Chem. Soc. 127 (23): 8298–9.doi:10.1021/ja0522783. PMID 15941259.
- “Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011)”. The Myeloma Beacon. 2012-01-23. Retrieved 2012-06-10.
- ClinicalTrials.gov: Marizomib
……………………………………………………
IMPORTANT PAPERS
Total synthesis of salinosporamide A
Org Lett 2008, 10(19): 4239
Entry to heterocycles based on indium-catalyzed conia-ene reactions: Asymmetric synthesis of (-)-salinosporamide A
Angew Chem Int Ed 2008, 47(33): 6244
A concise and straightforward total synthesis of (+/-)-salinosporamide A, based on a biosynthesis model
Org Biomol Chem 2008, 6(15): 2782
Formal synthesis of salinosporamide A starting from D-glucose
Synthesis (Stuttgart) 2009, 2009(17): 2983
Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A
Tetrahedron 2012, 68(32): 6504
………………
Salinosporamide A(1) was recently discovered by Fenical et al. as a bioactive product of a marine microorganism that is widely distributed in ocean sediments. Feeling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W., Angew. Chem. Int. Ed., 2003, 42, 355–357.
Structurally Salinosporamide A closely resembles the terrestrial microbial product omuralide (2a) that was synthesized by Corey et al. several years ago and demonstrated to be a potent inhibitor of proteasome function. See, (a) Corey, E. J.; Li, W. D., Z. Chem. Pharm. Bull., 1999, 47, 1–10; (b) Corey, E. J., Reichard, G. A.; Kania, R., Tetrahedron Lett., 1993, 34, 6977–6980; (c) Corey, E. J.; Reichard, G. A., J. Am. Chem. Soc., 1992, 114, 10677–10678; (d) Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.; Schreiber, S. L., Proc. Natl. Acad. Sci. USA, 1994, 91, 3358–3362.
Omuralide is generated by β-lactonization of the N-acetylcysteine thiolester lactacystin (2b) that was first isolated by the Omura group as a result of microbial screening for nerve growth factor-like activity. See, Omura, S., Fujimoto, T., Otoguro, K., Matsuzaki, K., Moriguchi, R., Tanaka, H., Sasaki, Y., Antibiot., 1991, 44, 113–116; Omura, S., Matsuzaki, K., Fujimoto, T., Kosuge, K., Furuya, T., Fujita, S., Nakagawa, A., J. Antibiot., 1991, 44, 117–118.
Salinosporamide A, the first compound Fenical’s group isolated from Salinospora, not only had a never-before-seen chemical structure 1, but is also a highly selective and potent inhibitor of cancer-cell growth. The compound is an even more effective proteasome inhibitor than omuralide and, in addition, it displays surprisingly high in vitro cytotoxic activity against many tumor cell lines (IC50values of 10 nM or less). Fenical et al. first found the microbe, which they’ve dubbed Salinospora, off the coasts of the Bahamas and in the Red Sea. See,Appl. Environ. Microbiol., 68, 5005 (2002).
Fenical et al. have shown that Salinospora species requires a salt environment to live. Salinospora thrives in hostile ocean-bottom conditions: no light, low temperature, and high pressure. The Fenical group has now identified Salinosporain five oceans, and with 10,000 organisms per cm3 of sediment and several distinct strains in each sample; and according to press reports, they’ve been able to isolate 5,000 strains. See, Chemical & Engineering News, 81, 37 (2003).
A great percentage of the cultures Fenical et al. have tested are said to have shown both anticancer and antibiotic activity. Like omuralide 2a, salinosporamide A inhibits the proteasome, an intracellular enzyme complex that destroys proteins the cell no longer needs. Without the proteasome, proteins would build up and clog cellular machinery. Fast-growing cancer cells make especially heavy use of the proteasome, so thwarting its action is a compelling drug strategy. See, Fenical et al., U.S. Patent Publication No. 2003-0157695A1
PATENTS
WO 2005113558
http://www.google.com/patents/US7183417
Part I. Synthesis of the Salinosporamide A(1)
EXAMPLE 1
(4S, 5R) Methyl 4,5-dihydro-2 (4-methoxyphenyl)-5-methyloxazole-4-carboxylate (4)
A mixture of (2S, 3R)-methyl 2-(4-methoxybenzamido)-3-hydroxybutanoate (3) (35.0 g, 131 mmol) and p-TsOH.H2O (2.5 g, 13.1 mmol) in toluene (400 mL) was heated at reflux for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give crude oxazoline as yellow oil. Flash column chromatography on silica gel (eluent 15% EtOAc-Hexanes) afforded the pure oxazoline (26.1 g, 80%) as solid.
Rf=0.51 (50% ethyl acetate in hexanes), mp, 86–87° C.; [α]23 D+69.4 (c 2.0, CHCl3); FTIR (film) νmax: 2955, 1750, 1545, 1355, 1187, 1011, 810 cm−1; 1HNMR(CDCl3, 400 MHz): δ 7.87 (2H, d, J=9.2 Hz), 6.84 (2H, d, J=8.8 Hz), 4.90 (1H, m), 4.40 (1H, d, J=7.6 Hz), 3.79 (3H,s), 3.71 (3H, s), 1.49 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 171.93, 165.54, 162.64, 130.52, 119.80, 113.85, 78.91, 75.16, 55.51, 52.73, 21.14; HRMS (ESI) calcd for C13H16NO4 (M+H)+.250.1079, found 250.1084.
EXAMPLE 2
(4R, 5R)-Methyl 4-{(benzyloxy) methyl)}-4,5-dihydro-2-(4-methoxyphenyl)-5-methyloxazole-4-carboxylate (5)
To a solution of LDA (50 mmol, 1.0 M stock solution in THF) was added HMPA (24 mL, 215 mmol) at −78° C. and then oxazoline 4 (12.45 g, 50 mmol, in 20 mL THF) was added dropwise with stirring at −78° C. for 1 h to allow complete enolate formation. Benzyloxy chloromethyl ether (8.35 mL, 60 mmol) was added at this temperature and after stirring the mixture at −78° C. for 4 h, it was quenched with water (50 mL) and warmed to 23° C. for 30 min. Then the mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:4 then 1:3) to give the benzyl ether 5 (12.7 g, 69%).
Rf=0.59 (50% ethyl acetate in hexanes). [α]23 D−6.3 (c 1.0, CHCl3); FTIR (film) (νmax; 3050, 2975, 1724, 1642, 1607, 1252, 1027, 745, 697 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.96 (2H, d, J=9.2 Hz), 7.26 (5H, m), 6.90 (2H, J=8.8 Hz), 4.80 (1H, m), 4.61 (2H, s), 3.87 (3H, m), 3.81 (3H, s), 3.73 (3H, s), 1.34 (3H, d, J=6.8 Hz); 13C NMR (CDCl3, 100 MHZ): 6171.23, 165.47, 162.63, 138.25, 130.64, 128.52, 127.87, 127.77, 120.15, 113.87, 81.40, 79.92, 73.91, 73.43, 55.58, 52.45, 16.92; HRMS (ESI) calcd for C21H24O5 (M+H)+370.1654, found 370.1644.
EXAMPLE 3
(2R,3R)-Methyl 2-(4-methoxybenzylamino)-2-((benzyloxy)methyl)-3hydroxybutanoate (6)
To a solution of oxazoline 5 (18.45 g, 50 mmol) in AcOH (25 mL) at 23° C. was added in portions NaCNBH3 (9.3 g, 150 mmol). The reaction mixture was then stirred at 40° C. for 12 h to allow complete consumption of the starting material. The reaction mixture was diluted with water (100 mL), neutralized with solid Na2CO3 and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over NaSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give the N-PMB amino alcohol 6 (16.78 g, 90%).
Rf=0.50 (50% ethyl acetate in hexanes). [α]23 D−9.1(c 1.0, CHCl3); FTIR (film) νmax; 3354, 2949, 1731, 1511, 1242, 1070, 1030, 820, 736, 697 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.32 (7H, m), 6.87 (2H, d, J=8.8 Hz), 4.55 (2H, m), 4.10 (1H, q, J=6.4 Hz), 3.85 (2H, dd, J=17.2, 10.0 Hz), 3.81 (3H, s,), 3.77 (3H, s), 3. 69 (2H, dd, J=22.8, 11.6 Hz), 3.22 (2H, bs), 1.16 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 173.34, 159.03, 137.92, 132.51, 129.78, 128.67, 128.07, 127.98, 114.07, 73.80, 70.55, 69.82, 69.65, 55.51, 55.29, 47.68, 18.15; HRMS (ESI) calcd. for C21H28NO5 (M+H)+ 374.1967, found 374.1974.
EXAMPLE 4
(2R,3R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-hydroxybutanoate (7)
A solution of amino alcohol 6 (26.2 g, 68.5 mmol) in Et2O (200 mL) was treated with Et3N (14.2 mL, 102.8 mmol) and trimethylchlorosilane (10.4 mL, 82.2 mmol) at 23° C. and stirred for 12 h. After completion, the reaction mixture was diluted with ether (200 mL) and then resulting suspension was filtered through celite. The solvent was removed to furnish the crude product (31.2 g, 99%) in quantitative yield as viscous oil. A solution of this crude trimethylsilyl ether (31.1 g) in CH2Cl2 (200 mL) was charged with diisopropylethylamine (14.2 mL, 81.6 mmol) and then cooled to 0° C. Acryloyl chloride (6.64 mL, 82.2 mmol) was added dropwise with vigorous stirring and the reaction temperature was maintained at 0° C. until completion (1 h). The reaction mixture was then diluted with CH2Cl2 (100 mL) and the organic layer was washed with water and brine. The organic layer was separated and dried over Na2SO4. The solvent was removed to afford the crude acrylamide 7 as a viscous oil. The crude product was then dissolved in Et2O (200 mL) and stirred with 6N HCl (40 mL) at 23° C. for 1 h. The reaction mixture was diluted with water (100 mL) and concentrated to provide crude product. The residue was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:1) to give pure amide 7 (28.3 g, 96%) as colorless solid, mp 88–89° C.
Rf=0.40 (50% ethyl acetate in hexanes), [α]23 D−31.1 (c 0.45, CHCl3), FTIR (film) νmax; 3435, 2990, 1725, 1649, 1610, 1512, 1415, 1287, 1242, 1175, 1087, 1029, 732, 698 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.25 (5H, m), 7.15 (2H, d, J=6.0 Hz), 6.85 (2H, d, J=7.5 Hz), 6.38 (2H, d, J=6.0 Hz), 5.55 (1H, t, J=6.0 Hz), 4.81 (2H, s), 4.71 (1H, q, J=6.5 Hz), 4.35 (2H, s), 4.00 (1H, d, J=10.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.76 (3H, s), 3.75 (3H, s), 3.28 (1H, bs), 1.22 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 125 MHz): δ 171.87, 168.74, 158.81, 137.73, 131.04, 129.68, 128.58, 128.51, 127.94, 127.72, 127.20, 127.14, 114.21, 73.71, 70.42, 69.76, 67.65, 55.45, 52.52, 49.09, 18.88; HRMS (ESI) calcd. for C24H30NO6 (M+H)+428.2073, found 428.2073.
EXAMPLE 5
(R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-oxybutanoate (8)
To a solution of amide 7 (10.67 g, 25.0 mmol) in CH2Cl2 (100 mL) was added Dess-Martin periodinane reagent (12.75 g, 30.0 mmol, Aldrich Co.) at 23° C. After stirring for 1 h, the reaction mixture was quenched with aq NaHCO3—Na2S2O3 (1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude ketone. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes) to give pure keto amide 8 (10.2 g, 96%).
Rf=0.80 (50% ethyl acetate in hexanes), mp 85 to 86° C.; [α]23 D−12.8 (c 1.45, CHCl3); FTIR (film) νmax: 3030, 2995, 1733, 1717, 1510, 1256, 1178, 1088, 1027, 733, 697 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.30 (2H, d, J=8.0), 7.25 (3H, m), 7.11 (2H, m), 6.88 (2H, d, J=9.0 Hz), 6.38 (2H, m), 5.63 (1H, dd, J=8.5, 3.5 Hz), 4.93 (1H, d, J=18.5 Hz), 4.78 (1H, d, J=18.5, Hz), 4.27 (2H, m), 3.78 (3H, s), 3.76 (3H, s), 2.42 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 198.12, 169.23, 168.62, 158.01, 136.95, 130.64, 130.38, 128.63, 128.13, 127.77, 127.32, 114.33, 77.49, 73.97, 70.66, 55.49, 53.09, 49.03, 28.24; HRMS (ESI) calcd. for C24H28NO6 (M+H)+ 426.1916, found 426.1909.
EXAMPLE 6
(2R,3S)-Methyl-1-(4-methoxybenzyl)-2-((benzyloxy)methyl)-3-hydroxy-3-methyl-4-methylene-5-oxopyrrolidine-2-carboxylate (9+10)
A mixture of keto amide 8 (8.5 g, 20.0 mmol) and quinuclidine (2.22 g, 20.0 mmol) in DME (10 mL) was stirred for 5 h at 23° C. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) washed with 2N HCl, followed by water and dried over Na2SO4. The solvent was removed in vacuo to give the crude adduct (8.03 g, 94.5%, 3:1 ratio of 9 to 10 dr) as a viscous oil. The diastereomeric mixture was separated at the next step, although small amounts of 9 and 10 were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2) for analytical purposes.
Major Diastereomer (9).
[α]23 D−37.8 (c 0.51, CHCl3); FTIR (film) vmax: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808,734 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.29 (5H, m), 7.15 (2H, d, J=7.5 Hz), 6.74 (2H, d, J=8.5 Hz), 6.13 (1H, s), 5.57 (1H, s), 4.81 (1H, d, J=14.5 Hz), 4.45(1H, d, J=15.0 Hz), 4.20 (1H, d, J=12.0 Hz), 4.10 (1H, d, J=12.0 Hz) 3.75 (3H, s), 3.70 (1H, d, J=10.5 Hz), 3.64 (3H, s), 3.54 (1H, d, J=10.5 Hz), 2.55 (1H, bs, OH), 1.50 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 169.67, 168.42, 158.97, 145.96, 137.57, 130.19, 130.12, 128.53, 127.83, 127.44, 116.79, 113.71, 76.32, 76.00, 73.16, 68.29, 55.45, 52.63, 45.36, 22.64; HRMS (ESI) calcd. for C24H28NO6 (M+H)+ 426.1916, found 426.1915.
Minor Diastereomer (10).
[α]23 D−.50.1 (c 0.40, CHCl3); FTIR (film) νmax: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808, 734 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.29 (5H, m), 7.12 (2H, d, J=7.5 Hz), 6.73 (2H, d, J=8.5 Hz), 6.12 (1H, s), 5.57 (1H, s), 4.88 (1H, d, J=15.5 Hz), 4.31 (1H, d, J=15.0 Hz), 4.08 (3H, m), 3.99 (1H, d, J=12.0 Hz) 3.73 (3H, s), 3.62 (3H, s), 3.47 (1H, bs, OH), 3.43 (1H, d, J=10.0 Hz), 1.31 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 169.65, 167.89, 159.13, 147.19, 136.95, 130.29, 129.76, 128.74, 128.19, 127.55, 116.80, 113.82, 76.21, 75.66, 73.27, 68.02, 55.45, 52.52, 45.24, 25.25; HRMS (ESI) calcd. for (M+H)+ C24H28NO6 426.1916, found 426.1915.
EXAMPLE 7
Silylation of 9 and 10 and Purification of 11.
To a solution of lactams 9 and 10 (7.67 g, 18 mmol) in CH2Cl2 (25 ml) was added Et3N (7.54 ml, 54 mmol), and DMAP (2.2 g, 18 mmol) at 0° C., and then bromomethyl-dimethylchlorosilane (5.05 g, 27 mmol) (added dropwise). After stirring the mixture for 30 min at 0° C., it was quenched with aq NaHCO3 and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give a mixture of the silated derivatives of 9 and 10 (9.83 g, 95%). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:4) to give pure diastereomer 11 (7.4 g, 72%) and its diastereomer (2.4 g, 22%).
Silyl Ether (11).
Rf=0.80 (30% ethyl acetate in hexanes). [α]23 D−58.9 (c 0.55, CHCl3); FTIR (film) νmax; 3050, 2995, 1738, 1697, 1512, 1405, 1243, 1108, 1003, 809, 732 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.27 (5H, m), 7.05 (2H, d, J=7.0 Hz), 6.71 (2H, d, J=8.5 Hz), 6.18 (1H, s), 5.53 (1H, s), 4.95 (1H, d, J=15.5 Hz), 4.45 (1H, d, J=15.0 Hz), 4.02 (1H, J=12.0 Hz), 3.86 (1H, d, J=11.5 Hz) 3.72 (3H, s), 3.68 (3H, s), 3.65 (1H, d, J=10.5 Hz), 3.30 (1H, d, J=10.0 Hz), 2.34 (2H, d, J=2.0 Hz), 1.58 (3H, s), 0.19 (3H, s), 0.18 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 168.62, 168.12, 158.93, 145.24, 137.53, 130.32, 130.30, 128.49, 127.76,127.22, 117.26, 113.60, 78.55, 78.03, 72.89, 68.45, 55.43, 52.37, 45.74, 21.87, 17.32, −0.72, −0.80; HRMS (ESI) Calcd. for C27H35BrNO6Si (M+H)+ 576.1417, found 576.1407.
EXAMPLE 8
Conversion of (11) to (12).
To a solution of compound 11 (5.67 g 10 mmol) in benzene (250 mL) at 80° C. under nitrogen was added a mixture of tributyltin hydride (4.03 ml, 15 mmol) and AIBN (164 mg, 1 mmol) in 50 ml benzene by syringe pump over 4 h. After the addition was complete, the reaction mixture was stirred for an additional 4 h at 80° C. and the solvent was removed in vacuo. The residue was dissolved in hexanes (20 mL) and washed with saturated NaHCO3 (3×25 mL), water and dried over Na2SO4. The solvent was removed in vacuo to give crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to afford the pure 12 (4.42 g, 89%).
Rf=0.80 (30% ethyl acetate in hexanes). [α]23 D−38.8 (c 0.25, CHCl3); FTIR (film) νmax; 3025, 2985, 1756, 1692, 1513, 1247, 1177, 1059, 667 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.28 (5H, m), 7.09 (2H, d, J=7.0 Hz), 6.73 (2H, d, J=9.0 Hz), 4.96(1H, d, J=15.0 Hz), 4.35 (1H, d, J=15.5 Hz), 3.97 (1H, d, J=12.5 Hz), 3.86 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.72 (3H, s), 3.65 (3H, s), 3.27 (1H, d, J=10.5 Hz), 2.67 (1H, t, J=4.0 Hz), 2.41 (1H, m), 1.79 (1H, m), 1.46 (3H, s), 0.77 (1H, m), 0.46 (1H, m), 0.10 (3H, s), 0.19 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 175.48, 169.46, 158.76, 137.59, 131.04, 129.90, 128.58, 127.88, 127.52, 113.59, 113.60, 81.05, 78.88, 73.12, 69.03, 55.45, 51.94, 48.81, 45.50, 22.79, 17.06, 7.76, 0.54; HRMS (ESI) calcd. for (M+H)+ C27H36NO6Si 498.2312, found 498.2309.
EXAMPLE 9
Debenzylation of (12).
A solution of 12 (3.98 g, 8 mmol) in EtOH (50 ml) at 23° C. was treated with 10% Pd—C (˜1 g) under an argon atmosphere. The reaction mixture was evacuated and flushed with H2 gas (four times) and then stirred vigorously under an atmosphere of H2 (1 atm, H2 balloon) at 23° C. After 12 h, the reaction mixture was filtered through Celite and concentrated in vacuo to give the crude debenzylation product (3.08 g, 95%) which was used for the next step. A small amount crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:3) for analytical purposes. Rf=0.41 (50% ethyl acetate in hexanes).
mp, 45–47° C.; [α]23 D−30.9 (c 0.55, CHCl3); FTIR (film) νmax: 3432, 3020, 2926, 1735, 1692, 1512, 1244, 1174, 1094, 1024, 870, 795 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.36 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.16 (1H, d, J=15.0 Hz), 4.29 (1H, d, J=15.0 Hz), 3.92 (1H, m), 3.78 (3H, s), 3.68 (3H, s), 3.45 (1H, m), 2.53 (1H, t, J=4.0 Hz), 2.42 (1H, m), 1.82 (1H, m), 1.50 (3H, s), 1.28 (1H, m), 0.75 (1H, m), 0.47 (1H, m), 0.11 (3H, s), 0.02 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 175.82, 169.51, 159.32, 131.00, 129.72, 114.52, 80.79, 80.13, 61.85, 55.48, 51.99, 49.29, 45.06, 23.11, 17.03, 7.44, 0.54; HRMS (ESI) calcd. for C20H30NO6Si (M+H)+ 408.1842, found 408.1846.
EXAMPLE 10
Oxidation to Form Aldehyde (13).
To a solution of the above alcohol from debenzylation of 12 (2.84 g, 7 mmol) in CH2Cl2 (30 mL) was added Dess-Martin reagent (3.57 g, 8.4 mmol) at 23° C. After stirring for 1 h at 23° C., the reaction mixture was quenched with aq NaHCO3—Na2S2O3 (1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude aldehyde. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give pure aldehyde 13 (2.68 g, 95%). Rf=0.56 (50% ethyl acetate in hexanes).
mp, 54–56° C.; [α]23 D−16.5 (c 0.60, CHCl3); FTIR (film) νmax: 3015, 2925, 1702 1297, 1247, 1170, 1096, 987, 794 cm−1; 1H NMR (CDCl3, 500 MHz): δ 9.62 (1H, s), 7.07 (2H, d, J=8.0 Hz), 6.73 (2H, d, J=8.5 Hz), 4.49 (1H, quart, J=8.5 Hz), 3.70 (3H, s), 3.67 (3H, s), 2.36 (2H, m), 1.75 (1H, m), 1.37 (3H, s), 0.73 (1H, m), 0.48 (1H, m), 0.07 (3H, s), 0.004 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 197.26, 174.70, 167.36, 158.07, 130.49, 128.96, 113.81, 83.97, 82.36, 55.34, 52.43, 47.74, 46.32, 23.83, 16.90, 7.52, 0.56, 0.45; HRMS (ESD calcd. for C20H28NO6Si (M+H)+ 406.1686, found 406.1692.
EXAMPLE 11
Conversion of (13) to (14).
To a solution of freshly prepared cyclohexenyl zinc chloride (10 mL, 0.5 M solution in THF, 5 mmol) (see Example 15 below) at −78° C. under nitrogen was added a −78° C. solution of aldehyde 13 (1.01 g, in 3 ml of THF, 2.5 mmol). After stirring for 5 h at −78° C. reaction mixture was quenched with water (10 mL) then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4 and solvent was removed in vacuo to give crude product (20:1 dr). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2 affords the pure major diastereomer 14 (1.0 g, 83%) and a minor diastereomer (50 mg 5%). For 14: Rf=0.56 (50% ethyl acetate in hexanes).
mp, 79–81° C.; [a]23 D−28.5 (c 1.45, CHCl3); FTIR (film) νmax: 3267, 2927, 2894, 2829, 1742, 1667, 1509, 1248, 1164, 1024, 795 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.34 (2H, d, J=8.5 Hz), 6.81 (2H, d, J=9.0 Hz), 5.84 (1H, m), 5.73 (1H, m), 4.88 (1H, d, J=15.5 Hz), 4.39 (1H, d, J=14.5 Hz), 4.11 (1H, t, J=6.5 Hz), 3.77 (3H, s), 3.58 (3H, s), 3.00 (1H, m), 2.95 (1H, d, J=9.0 Hz), 2.83 (1H, t, J=3.5 Hz), 3.36 (1H, m), 2.27 (1H, m), 1.98 (2H, m), 1.74 (3H, m), 1.62 (3H, s), 1.14 (2H, m), 0.59 (1H, m), 0.39 (11H, m), 0.13 (3H, s), 0.03 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 176.80, 170.03, 158.27, 131.86, 131.34, 128.50, 126.15, 113.40, 83.96, 82.45, 77.17, 55.45, 51.46, 48.34, 48.29, 39.08, 28.34, 25.29, 22.45, 21.09, 17.30, 7.75, 0.39, 0.28; HRMS (ESI) calcd. for C26H38NO6Si (M+H)+ 488.2468, found 488.2477.
EXAMPLE 12
Tamao-Fleming Oxidation of (14) to (15).
To a solution of 14 (0.974 g, 2 mmol) in THF (5 mL) and MeOH (5 mL) at 23° C. was added KHCO3 (0.8 g, 8 mmol) and KF (0.348 g, 6 mmol). Hydrogen peroxide (30% in water, 5 mL) was then introduced to this mixture. The reaction mixture was vigorously stirred at 23° C. and additional hydrogen peroxide (2 ml) was added after 12 h. After 18 h, the reaction mixture was quenched carefully with NaHSO3 solution (15 mL). The mixture was extracted with ethyl acetate (3×25 mL) and the combined organic layers were washed with water and dried over Na2SO4. The solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate) to give the pure triol 15 (0.82 g, 92%).
Rf=0.15 (in ethyl acetate). mp, 83–84° C.; [α]23 D: +5.2 (c 0.60, CHCl3); FTIR (film) νmax; 3317, 2920, 2827, 1741, 1654, 1502, 1246, 1170, 1018, 802 cm−1; 1HNMR(CDCl3, 500 MHz): δ 7.77 (2H, d, J=8.0 Hz), 6.28 (2H, d, J=8.0 Hz), 5. 76 (1H, m), 5.63 (1H, d, J=10.0 Hz), 4.74 (1H, d, J=15.5 Hz), 4.54 (1H, d, J=15.0 Hz), 4.12 (1H, d, J=2.5 Hz), 3.80 (1H, m), 3.76 (3H, s), 3.72 (1H, m), 3.68 (3H, s), 3.00 (1H, m), 2.60 (1H, br), 2.20 (1H, m), 1.98 (2H, s), 1.87 (1H, m), 1.80 (1H, m), 1.71 (2H, m), 1.61 (3H, s), 1.14 (2H, m); 13C NMR (CDCl3, 125 MHz): δ 178.99, 170.12, 158.27, 131.30, 130.55, 128.13, 126.39, 113.74, 81.93, 80.75, 76.87, 61.61, 55.45, 51.97, 51.32, 48.07, 39.17, 27.71, 27.13, 25.22, 21.35, 21.22; HRMS (ESI) calcd. for C24H34NO7 (M+H)+ 448.2335, found 448.2334.
EXAMPLE 13
Deprotection of (15) to (16).
To a solution of 15 (0.670 g, 1.5 mmol) in acetonitrile (8 mL) at 0° C. was added a pre-cooled solution of ceric ammonium nitrate (CAN) (2.46 g 4.5 mmol in 2 mL H2O). After stirring for 1 h at 0° C. the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaCl solution (5 mL) and organic layers was dried over Na2SO4. The solvent was removed in vacuo to give the crude product which was purified by column chromatography (silica gel, ethyl acetate) to give the pure 16 (0.4 g, 83%).
Rf=0.10 (5% MeOH in ethyl acetate). mp, 138 to 140° C.; [α]23 D+14.5 (c 1.05, CHCl3); FTIR (film) νmax 3301, 2949, 2911, 2850, 1723, 1673, 1437, 1371, 1239, 1156, 1008, 689 cm−1; 1H NMR (CDCl3, 600 MHz): δ 8.48 (1H, br), 6.08 (1H, m), 5. 75 (1H, d, J=9.6 Hz), 5.29 (1H, br), 4.13 (1H, d, J=6.6 Hz), 3.83 (3H, m), 3.79 (1H, m), 3.72 (1H, m), 2.84 (1H, d, J=10.2 Hz), 2.20 (1H, m), 2.16 (1H, br), 1.98 (3H, m), 1.77 (3H, m), 1.59 (1H, m), 1.54 (3H, s), 1.25 (1H, m). 13C NMR (CDCl3, 125 MHz): δ 180.84, 172.95, 135.27, 123.75, 82.00, 80.11, 75.56, 62.39, 53.14, 51.78, 38.95, 28.79, 26.48, 25.04, 20.66, 19.99; HRMS (ESI) calcd. (M+H)+ for C16H26NO6 328.1760, found 328.1752.
EXAMPLE 14
Conversion of (16) to Salinosporamide A(1).
A solution of triol ester 16 (0.164 g, 0.5 mmol) in 3 N aq LiOH (3 mL) and THF (1 mL) was stirred at 5° C. for 4 days until hydrolysis was complete. The acid reaction mixture was acidified with phosphoric acid (to pH 3.5). The solvent was removed in vacuo and the residue was extracted with EtOAc, separated, and concentrated in vacuo to give the crude trihydroxy carboxylic acid 16a (not shown). The crude acid was suspended in dry CH2Cl2 (2 mL), treated with pyridine (0.5 mL) and stirred vigorously at 23° C. for 5 min. To this solution was added BOPCl (152 mg, 0.6 mmol) at 23° C. under argon, and stirring was continued for 1 h. The solvent was removed under high vacuum and the residue was suspended in dry CH3CN (1 mL) and treated with pyridine (1 mL). To this solution was added PPh3Cl2 (333 mg, 1.0 mmol) at 23° C. under argon with stirring. After 1 h the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate-CH2Cl2, 1:5) to give the pure β-lactone 1 (100 mg, 64%) as a colorless solid.
Rf=0.55 (50% ethyl acetate in hexane). mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C. [α]23 D −73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357); FTIR (film) νmax: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm−1; 1H NMR (CDCl3, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);13C NMR (CDCl3, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00; HRMS (ESI) calcd. for (M−H)− C15H19ClNO4 312.1003, found 312.1003.
| 544814 | Oct 1, 2007 | Jun 9, 2009 | Nereus Pharmaceuticals, Inc. | [3.2.0] Heterocyclic compounds and methods of using the same |
| US7579371 | Jun 15, 2006 | Aug 25, 2009 | Nereus Pharmaceuticals, Inc. | Methods of using [3.2.0] heterocyclic compounds and analogs thereof |
| US7824698 | Feb 4, 2008 | Nov 2, 2010 | Nereus Pharmaceuticals, Inc. | Lyophilized formulations of Salinosporamide A |
| US7842814 | Apr 6, 2007 | Nov 30, 2010 | Nereus Pharmaceuticals, Inc. | Total synthesis of salinosporamide A and analogs thereof |
| US7910616 | May 12, 2009 | Mar 22, 2011 | Nereus Pharmaceuticals, Inc. | Proteasome inhibitors |
| US8003802 | Mar 6, 2009 | Aug 23, 2011 | Nereus Pharmaceuticals, Inc. | Total synthesis of Salinosporamide A and analogs thereof |
| US8067616 | Oct 27, 2010 | Nov 29, 2011 | Nereus Pharmaceuticals, Inc. | Total synthesis of salinosporamide A and analogs thereof |
| US8168803 | Jun 10, 2008 | May 1, 2012 | Nereus Pharmaceuticals, Inc. | Methods of using [3.2.0] heterocyclic compounds and analogs thereof |
| US8217072 | Jun 18, 2004 | Jul 10, 2012 | The Regents Of The University Of California | Salinosporamides and methods for use thereof |
| US8222289 | Dec 15, 2009 | Jul 17, 2012 | The Regents Of The University Of California | Salinosporamides and methods for use thereof |
| US8227503 | Mar 21, 2011 | Jul 24, 2012 | Nereus Pharmaceuticals, Inc. | Proteasome inhibitors |
| US8314251 | Jul 15, 2011 | Nov 20, 2012 | Nereus Pharmaceuticals, Inc. | Total synthesis of salinosporamide A and analogs thereof |
| US8389564 | May 14, 2012 | Mar 5, 2013 | Venkat Rami Reddy Macherla | Proteasome inhibitors |
| US8394816 | Dec 5, 2008 | Mar 12, 2013 | Irene Ghobrial | Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom’s Macroglobulinemia |
| Name: | Marizomib | |
| Synonyms: | 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-; Other Names: (-)-Salinosporamide A; ML 858; Marizomib; NPI 0052; Salinosporamide A | |
| CAS Registry Number: | 437742-34-2 | |
| Molecular Formula: | C15H20ClNO4 | |
| Molecular Weight: | 313.1 | |
| Molecular Structure: |  |
RAMOSETRON
Ramosetron (INN),(1-methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl]methanone, 132036-88-5 cas no
| C17H17N3O | |
| 279.33 g/mol |
(1-methyl-1H-indol-3-yl)[(5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl]methanone
YM060
- Nasea
- Nor-YM 060
- Ramosetron
- UNII-7ZRO0SC54Y
…………………………………………………………………………………..
HYDROCHLORIDE SALT
hyrochloride salt, cas no 132907-72-3
(−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H+]
1H NMR (DMSO-d6, 30° C.): δ ppm (TMS internal standard): 1.82-1.95 (1H, m), 2.12-2.22 (1H, m), 2.66-2.94 (4H, m), 3.63-3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.0 Hz), 8.53 (1H, s), 8.90 (1H, s), 14.42 (1H, br)
…………………………………………………………………………………….
Ramosetron (INN) is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting.[1] Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”.[2] In India it is marketed under the brand name of“IBset”.
It is only licensed for use in Japan and selected Southeast Asian countries. In Japan it is sold under the tradename Iribo (イリボー). [3] Elsewhere it is commonly sold under the tradename Nasea and in India as Nozia (300 mcg/ml Inj. & 100 mcg Tab.) [4]
- Fujii Y, Saitoh Y, Tanaka H, Toyooka H (February 2000). “Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery”.Anesth. Analg. 90 (2): 472–5. doi:10.1097/00000539-200002000-00043.PMID 10648342.
- http://www.astellas.com/en/corporate/news/detail/astellas-launches-irribow-for.html
- Summary in Japanese. Retrieved on September 4, 2012.
- Abridged prescribing information – Nasea (MIMS Philippines). Retrieved on June 13, 2008.
- Synthesis and 5-HT3 antagonistic activities of 4,5,6, 7-tetrahydrobenzimidazole derivatives
200th ACS Natl Meet (August 26-31, Washington DC) 1990, Abst MEDI 39
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1-27-2010
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Process for producing ramosetron or its salt
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11-20-1996
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Intrabuccally dissolving compressed moldings and production process thereof
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3-6-1996
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5-substituted tetrahydrobenzimidazole compounds
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11-15-1995
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Intrabuccally disintegrating preparation and production thereof
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9-7-1994
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Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
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6-24-1994
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NEW USE OF 5-HT3 RECEPTOR ANTAGONISTS
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AU 9048890; EP 0381422; JP 1991223278; US 5344927
| CN1696128A | Nov 2, 2004 | Nov 16, 2005 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
| CN1765896A | Oct 28, 2004 | May 3, 2006 | 北京博尔达生物技术开发有限公司 | Novel preparation method of ramosetron hydrochloride |
| US5496942 * | 14 Feb 1994 | 5 Mar 1996 | Yamanouchi Pharmaceutical Co., Ltd. | 5-substituted tetrahydrobenzimidazole compounds |
| US5677326 * | 30 Sep 1994 | 14 Oct 1997 | Tokyo Tanabe Company Limited | Indoline compound and 5-HT.sub.3 receptor antagonist containing the same as active ingredient |
| US7358270 | 28 Jan 2005 | 15 Apr 2008 | Astellas Pharma Inc. | Treating agent for irritable bowel syndrome |
| US7683090 | 18 Oct 2006 | 23 Mar 2010 | Astellas Pharma Inc. | Treating agent for irritable bowel syndrome |
| US7794748 | 27 Aug 2004 | 14 Sep 2010 | Yamanouchi Pharmaceutical Co., Ltd. | Stable oral solid drug composition |
WO 2010024306
WO 2013005760
WO 2013100701
WO 2011001954
The chemical name of ramosetron is (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole, and it has the structure represented by the formula (II).
It is known that ramosetron or a salt thereof has a potent 5-HT3 receptor antagonism (Patent Reference 1, Non-patent references 1 and 2), and it is on the market as a preventive or therapeutic agent for digestive symptoms (nausea, emesis) caused by administration of an anti-malignant tumor agent (cisplatin or the like). In addition, a possibility has been reported that ramosetron or a salt thereof may be useful as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome (Patent Reference 1), and its clinical trials are now in progress as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome.
As a process for producing ramosetron or a salt thereof, the following production methods are known.
Patent Reference 1 describes a production method shown by the following Production method A, namely a method for producing a tetrahydrobenzimidazole derivative (V) by allowing a heterocyclic compound (III) to react with a carboxylic acid represented by a formula (IV) or its reactive derivative.
(Production Method A)
(In the formula, X2 is a single bond and binds to a carbon atom on the heterocyclic ring represented by Het.)
As an illustrative production method of ramosetron, Patent Reference 1 describes a production method (Production method A-1) in which racemic ramosetron are obtained by using 1-methyl-1H-indole as the compound (III), and N,N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide or N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine, which are acid amides, as the reactive derivative of compound (IV), and allowing them to undergo treatment with phosphorus oxychloride (Vilsmeyer reaction), and then their optical resolution is carried out by fractional crystallization using (+)-dibenzoyltartaric acid.
In addition, the Patent Reference 1 exemplifies an acid halide as one of the reactive derivatives of the compound (IV), and also describes another production method of the compound (V) (Production method A-2) in which the heterocyclic compound (III) is condensed with an acid halide of the compound (IV) by the Friedel-Crafts acylation reaction using a Lewis acid as the catalyst. However, illustrative production example of ramosetron by the Friedel-Crafts acylation reaction is not described therein.
Also, a method similar to the Production example A-1 is described in Non-patent References 1 and 2 as a production method of ramosetron.
In addition, Non-patent Reference 3 describes a method for producing ramosetron labeled with 11C, represented by a Production method B. However, it discloses only the methylation step, and does not disclose a production method of nor-YM060 as the starting material.
(Production Method B)
(In the formula, nor-YM060 means (R)-5-[(1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole which was provided by the present applicant, DMF means dimethylformamide.)
- Non-patent Reference 1: Chemical & Pharmaceutical Bulletin, 1996, vol. 44, no. 9, p. 1707-1716
- Non-patent Reference 2: Drugs of the Future, 1992, vol. 17, no. 1, p. 28-29
- Non-patent Reference 3: Applied Radiation and Isotopes, 1995, vol. 46, no. 9, p. 907-910
- Patent Reference 1: JP-B-6-25153
LIU Qing-wen, XU Hao, TIAN Hua, ZHENG Liang-yu, ZHANG Suo-qin
Chemoenzymatic Synthesis of Ramosetron Hydrochloride
2012 Vol. 28 (1): 70-72 [Abstract] ( 1143 ) [HTML 1KB] [PDF 206KB] ( 1052 )
doi:http://www.cjcu.jlu.edu.cn/hxyj/EN/abstract/abstract13356.shtml
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The Vilsmeier-type reaction of 1-methylindole (I) with 5 – (1-pyrrolidinocarbonyl) -4,5,6,7-1 H-tetrahydrobenzimidazole hydrochloride (II) and phosphorous oxychloride in 1,2-dichloroethane gives (-5? -. [(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazol e (III) Optical resolution of (III) with (+)-dibenzoyltartaric acid (DIBTA) in DMF -H2O, followed by exchange of the salt affords YM060.
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Ondansetron: 1,2,3 ,9-Tetrahydro-9-methyl-3-[(2-methyl1-H-imidazole-1-yl)methyl]-4H-carbazol-4-one
Granisetron: Endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide
Tropisetron: Endo-1H-indole-3-carbocylic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester
Dolasetron: 1H-Indole-3 -carboxylic acid (2a, 6a, 8a, 9up)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl Ester
Azasetron: (±)-N-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide
Alosetron: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one
Ramosetron
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Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor
J Med Chem 2009, 52(5): 1255
Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation
Synlett (Stuttgart) 2010, 2010(5): 796
| WO2003095441A1 * | 7 mei 2003 | 20 nov 2003 | Melwyn A Abreo | Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same |
| WO2006018725A1 * | 5 aug 2005 | 23 feb 2006 | Pfizer | Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same |
| US20050176701 * | 19 nov 2003 | 11 aug 2005 | Agouron Pharmaceuticals, Inc. | Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the sameWO2007023381A1 |
| CAS | 877130-28-4 |
| FILIBUVIR | |
| (R)-6-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one | |
| Filibuvir;Pf-00868554;Unii-198J479Y2l;(6R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl(1,2,4)triazolo(1,5-A)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-one;(R)-6-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;2H-Pyran-2-one, 6-cyclopentyl-6-(2-(2,6-diethyl-4-pyridinyl)ethyl)-3-((5,7-dimethyl(1,2,4)triazolo(1,5-A)pyrimidin-2-yl)methyl)-5,6-dihydro-4-hydroxy-, (6R)- | |
| MF | C29H37N5O3 |
| MW | 503.64 |
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Medicinal Chemistry International: NARLAPREVIR
Medicinal Chemistry International: NARLAPREVIR
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NARLAPREVIR
Formula: C36H61N5O7S
oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]
amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-, (1R,2S,5S)-
dimethylethyl)sulfonyl]methyl}cyclohexyl)carbamoyl]amino}-3,3-dimethylbutanoyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
valyl}-N-{(1S)-1-[(cyclopropylamino)(oxo)acetyl]pentyl}-6,6-dimethyl-3-
azabicyco[3.1.0]hexane-2-carboxamide
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TAVABOROLE, AN 2690, 他伐硼罗 Таваборол تافابورول
TAVABOROLE
- AN 2690
- AN-2690
- AN2690
- UNII-K124A4EUQ3
5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
5-Fluoro-2,1-benzoxaborol-1(3H)-ol;
1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole
MOLECULAR FORMULA C7H6BFO2
MOLECULAR WEIGHT 151.9
SPONSOR Anacor Pharmaceuticals, Inc.
CAS REGISTRY NUMBER 174671-46-6
Mp 118-120° C…..US20070265226
1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H)
FDA APPROVED JULY 2 2014………..“FDA Approves Anacor Pharmaceuticals’ KERYDIN™ (Tavaborole) Topical Solution, 5% for the Treatment of Onychomycosis of the Toenails”. Market Watch. July 8, 2014.
Has antifungal activity.
The US Food and Drug Administration (FDA) 2014 JULY 8 ratified the Anacor’s Kerydin (5% Tavaborole solution) for the topical treatment of nail fungal infections. Tavaboroleindications of toenail fungus Trichophyton rubrum or Trichophyton rubrum infections.Instructions recommended once a day for toenail infections, treatment for 48 weeks, on the recommendation of Anacor, and do not need to nail debridement.
I tis an oxaborole antifungal used topically, as a 5% w/w solution, for the treatment of onychomycosis of the toenails due to Trichophyton rubrumor T. mentagrophytes. It is applied to the affected toenail once daily for 48 weeks.
Ingrowing toenails and application site reactions including exfoliation, erythema, and dermatitis have been reported during use.
1H NMR FROM NET
CLICK ON IMAGE FOR CLEAR VIEW
COSY NMR PREDICT
Tavaborole (AN2690, trade name Kerydin) is a topical antifungal medication for the treatment of onychomycosis, a fungal infectionof the nail and nail bed. Tavaborole began its Phase 3 trials in December 2010[1] and was approved in July 2014.[2] Tavaborole inhibits an essential fungal enzyme, Leucyl-tRNA synthetase, or LeuRS, required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection. No treatment-related systemic side effects were observed in any of its clinical trials.
Tavaborole is the first oxygen boron used to treat toenail infections dioxolane (oxaborole) antifungal agents, located in Palo Alto, Anacor focuses on boron-based drug development and production, according to the latest news, Tavaborole future also be used to infect fingernails. Wedbush Securities analyst predicts that next year the drug sales in the United States for $ 16 million, by 2021 will reach peak sales of $ 347 million.
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism.
Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the benzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, is active against Gram-negative bacteria, including Enterobacteriaceaebearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
Anacor continued development on that drug, tavaborole, and filed for FDA approval in July. The FDA will review the phase 3 trial data and issue a decision on July 29, 2014.
If approved, Anacor hopes tavaborole’s ability to clear onychomycosis in 10% of treated patients will be enough to win market share away from generic Lamisil and generic topical Pentac. While Lamisil cleared the fungus in 38% of patients, it’s been associated with rare cases of liver failure. And Pentac requires frequent debridement of the nail and only clears the fungus in 5.5% to 8.5% of patients.
Tavaborole is a novel, topical antifungal medication being developed for the topical treatment of onychomycosis, a nail fungus infection, which affects seven to ten percent of the U.S. population. Early studies show AN-2690 penetrates the nail effectively and has robust activity against dermatophytes, which cause onychomycosis.
1H NMR PREDICT
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13 C NMR PREDICT
ARTICLE
Anacor Pharmaceuticals to Present Pivotal Phase 3 Data of Tavaborole for the Topical Treatment of Toenail Onychomycosis
Abstract Accepted for Oral Presentation at the 2013 American Podiatric Medical Association Annual Scientific Meeting
PALO ALTO, Calif.–(BUSINESS WIRE)– Anacor Pharmaceuticals (NASDAQ:ANAC) announced today that its abstract “Pivotal Phase 3 Safety and Efficacy Results of Tavaborole (Formerly AN2690), a Novel Boron-Based Molecule for the Topical Treatment of Toenail Onychomycosis” was accepted for oral presentation at the 2013 APMA Annual Scientific Meeting (The National) to be held in Las Vegas, Nevada. Max Weisfeld, DPM, will present the data from tavaborole’s Phase 3 studies on Monday, July 22, 2013 during the Evidence-Based Medicine and Oral Abstracts session.
As announced earlier this year, tavaborole achieved statistically significant and clinically meaningful results on all primary and secondary endpoints in two Phase 3 pivotal studies without concomitant debridement. Anacor is seeking approval for tavaborole from the Food and Drug Administration (FDA) and will file a New Drug Application imminently. Currently, there is only one FDA-approved topical treatment for onychomycosis, a fungal infection of the nail and nail bed, which affects approximately 35 million people in the United States.
“I’m impressed with tavaborole’s safety and efficacy data. There is no FDA-approved topical treatment for onychomycosis with tavaborole’s range of efficacy and ability to penetrate the nail to reach the site of the infection,” said Dr. Weisfeld. “Tavaborole’s Phase 3 results demonstrate its ability to clear the nail and eliminate the infection which is important to both patients and the physicians who treat them. In addition, tavaborole is easy to apply and dries quickly which makes it convenient for patients to use.”
“We are pleased to present these positive data at the APMA’s Annual Scientific Meeting, the leading annual meeting of podiatrists. As we seek FDAapproval for tavaborole, we look forward to developing relationships with podiatrists to potentially offer them a new treatment option for the large number of patients who seek treatment for onychomycosis,” said David Perry, Chief Executive Officer of Anacor Pharmaceuticals.
About the Studies
Anacor conducted two separate Phase 3 studies of tavaborole on patients with distal subungual onychomycosis affecting 20 to 60 percent of the target great toenail. Approximately 600 patients aged 18 years and older with no upper age limit (the oldest subject was 88 years old) were enrolled in each study and randomized two-to-one to receive either tavaborole or the vehicle control. Patients were instructed to apply tavaborole solution or the vehicle to the toenail once daily for 48 weeks.
A copy of the presentation will be available on Anacor’s website following the oral session.
About Anacor Pharmaceuticals
Anacor is a biopharmaceutical company focused on discovering, developing and commercializing novel small-molecule therapeutics derived from its boron chemistry platform. Anacor has discovered eight compounds that are currently in development. Its two lead product candidates are topically administered dermatologic compounds — tavaborole, a topical antifungal for the treatment of onychomycosis, and AN2728, a topical anti-inflammatory PDE-4 inhibitor for the treatment of atopic dermatitis and psoriasis. In addition to its two lead programs, Anacor has discovered three other wholly-owned clinical product candidates — AN2718 and AN2898, which are backup compounds to tavaborole and AN2728, respectively, and AN3365 an antibiotic for the treatment of infections caused by Gram-negative bacteria. We have discovered three other compounds that we have out-licensed for further development — two compounds for the treatment of animal health indications that are licensed to Eli Lilly and Company and AN5568, also referred to as SCYX-7158, for human African trypanosomiasis (HAT, or sleeping sickness), which is licensed to Drugs for Neglected Diseases initiative, or DNDi. We also have a pipeline of other internally discovered topical and systemic boron-based compounds in development. For more information, visit http://www.anacor.com.
Patents
WO 1995033754
WO 2004009578….
WO 2006089067
WO 2008025543
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SYNTHESIS
Reference:
ELI LILLY AND COMPANY Patent: WO2004/9578 A2, 2004 ; Location in patent: Page 36-37 ; WO 2004/009578 A2
PATENT
Anacor Pharmaceuticals Patent: US2007/265226 A1, 2007 ; Location in patent: Page/Page column 59 ;
http://www.google.com/patents/US20070265226
1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (19b)
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder:
mp 118-120° C.;
1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H);
ESI-MS m/z 151 (M−H)−;
HPLC purity 97.8%; Anal (C7H6BFO2) C, H.
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Gunasekera, Dinara S.; Gerold, Dennis J.; Aalderks, Nathan S.; Chandra, J. Subash; Maanu, Christiana A.; Kiprof, Paul; Zhdankin, Viktor V.; Reddy, M. Venkat Ram Tetrahedron, 2007 , vol. 63, # 38 p. 9401 – 9405
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Baker, Stephen J.; Zhang, Yong-Kang; Akama, Tsutomu; Lau, Agnes; Zhou, Huchen; Hernandez, Vincent; Mao, Weimin; Alley; Sanders, Virginia; Plattner, Jacob J. Journal of Medicinal Chemistry, 2006 , vol. 49, # 15 p. 4447 – 4450
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Ding, Charles Z.; Zhang, Yong-Kang; Li, Xianfeng; Liu, Yang; Zhang, Suoming; Zhou, Yasheen; Plattner, Jacob J.; Baker, Stephen J.; Liu, Liang; Duan, Maosheng; Jarvest, Richard L.; Ji, Jingjing; Kazmierski, Wieslaw M.; Tallant, Matthew D.; Wright, Lois L.; Smith, Gary K.; Crosby, Renae M.; Wang, Amy A.; Ni, Zhi-Jie; Zou, Wuxin; Wright, Jon Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 24 p. 7317 – 7322
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PATENT
PREPARATION 13 5-Fluoro-3H-benzo[c][1,2)oxaborol-1-ol
Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene(5.4 g, 19.5 mmol) in dry THF (100 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at −78° C. Upon complete addition, stir the reaction at −78° C. for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into 1N HCl (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compoud as a white solid.
1H NMR (d6-DMSO)
9.18 (s, 1H),
7.70 (dd, J=8.2, 5.8 Hz, 1H),
7.20 (dd, J=9.5, 2.7 Hz, 1H),
7.11 (m, 1H), 4.92 (s, 1H).
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SEE
http://jpet.aspetjournals.org/content/early/2012/11/28/jpet.112.200030.full.pdf
………………………………..
SEE
Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ.
J Med Chem. 2006 Jul 27;49(15):4447-50.
Boron-containing inhibitors of synthetases.
Baker SJ, Tomsho JW, Benkovic SJ.
Chem Soc Rev. 2011 Aug;40(8):4279-85. doi: 10.1039/c0cs00131g. Epub 2011 Feb 7. Review.
- Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.
Zhang YK, Plattner JJ, Freund YR, Easom EE, Zhou Y, Ye L, Zhou H, Waterson D, Gamo FJ, Sanz LM, Ge M, Li Z, Li L, Wang H, Cui H.
Bioorg Med Chem Lett. 2012 Feb 1;22(3):1299-307. doi: 10.1016/j.bmcl.2011.12.096. Epub 2011 Dec 28.
Tavaborole Market Opportunity
Anacor is developing tavaborole specifically to address the current limitations of existing treatment options for onychomycosis. This includes designed leaps forward in both the potential safety and efficacy profile aimed to make the drug a best-in-class therapy. Additionally, management has used the company’s expertise in medicinal chemistry to improve delivery of the compound through the nail plate to the nail bed, the site of onychomycosis infection. For example, preclinical studies indicate that tavaborole is able to penetrate the nail plate 250 times more effectively than ciclopirox.
Tavaborole novel mechanism of action inhibits an essential fungal enzyme, leucyl transfer RNA synthetase, or LeuRS required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection.
Likewise, the topical dosing was designed to eliminate systemic absorption. Previous preclinical and clinical data shows topical treatment with tavaborole resulted in little or no detectable levels of drug in the blood or urine. No treatment related systemic side effects have been observed in any clinical trials to date. Safety data from the company’s studies to date was recently presented at the 100th National APMA meeting in Washington, DC.
Anacor’s topical solution currently in two phase III trials for onychomycosis. Phase II data with tavaborole suggests efficacy superior to ciclopirox with little to no systemic exposure.
Data from an open-label phase 2 program with tavaborole showed 50% patients using a 7.5% solution saw 2 mm clear nail growth and negative fungal cultures after six months. Roughly 25% of the patients saw 5 mm clear nail growth and negative fungal cultures after six months.
Anacor and partner Merck (NYSE:MRK) met with the U.S. FDA in 2009 to discuss the phase II data. Merck has since returned the rights to tavaborole to Anacor. The original deal was with Schering-Plough in 2007. Merck most likely felt as though tavaborole clashed with existing products or did not have peak sales potential large enough to continue the partnership with Anacor. We see tavaborole as a specialty promoted product, into podiatrists and dermatologists. For a company like Anacor, it’s an attractive first product.
Anacor’s first phase III trial completed enrollment in November 2011. The second phase III trial completed enrollment in December 2011. Data from these trials are expected around the middle of January 2013. Data from the second study is expected six weeks later. Given the positive phase II data noted above, we think odds favor a positive outcome. A benchmark for the trial is the efficacy of Lamisil, which is a complete cure rate of around 35% to 40%, and a mycological cure of around 70% after a typical course of treatment.
I note that on Anacor’s third quarter conference call management noted that they are pleased with the conduct of the trial to date. Specifically, the compliance rate appears to better than management had expected. The trial was designed with a 20% drop-out rate. It looks as though the drop-out rate is only around 13%, at a minimum suggestive of good safety and tolerability, but potentially also a sign that the drug is working.
I see onychomycosis as a significant market opportunity for Anacor. An estimated 35 million Americans have nail fungus, with about 95% of the infections in the toenail. With efficacy similar to Lamisil, we think Anacor can capture 20% of the market. With a price per course of treatment at around $1,200, I think peak sales of tavaborole are $500 million.
Conclusion
I’ll note two more important pieces of information for investors. Firstly, besides optimism for tavaborole, Anacor has apipeline of anti-infectant drugs. For this article I discussed only tavaborole. A second article can be dedicated entirely to AN2728 for the treatment of psoriasis and atopic dermatitis. Anacor also has an animal health collaboration with Eli Lilly (NYSE:LLY).
The second important thing to note is Anacor’s cash position. The company reported financial results on November 7, 2012. The company held $36.6 million in cash on the balance sheet as of September 30, 2012. However, in October 2012, the company completed an underwritten public offering of 4.0 million shares of common stock at $6.00 per share to raise net proceeds of $22.7 million. I view the current cash position as sufficient to report data from both phase 3 trials and, if positive, file the new drug application (NDA) around the middle of 2013.
With phase 3 data expected in less than two months, good prior evidence of both safety and efficacy, and a solid cash position, I think Anacor could be an attractive investment at today’s price. The stock is down meaningfully over the past month and investors can buy sizably below the October offering.
SYNTHESIS
References
- Clinical trial number NCT01270971 at ClinicalTrials.gov
- “FDA Approves Anacor Pharmaceuticals’ KERYDIN™ (Tavaborole) Topical Solution, 5% for the Treatment of Onychomycosis of the Toenails”. Market Watch. July 8, 2014.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204427s000lbl.pdf
- http://www.molbase.com/en/hnmr_174671-46-6-moldata-1568017.html#tabs
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| Systematic (IUPAC) name | |
|---|---|
|
5-Fluoro-2,1-benzoxaborol-1(3H)-ol
|
|
| Clinical data | |
| Trade names | Kerydin |
| Legal status |
|
| Routes of administration |
Topical use only |
| Identifiers | |
| CAS Registry Number | 174671-46-6 |
| ATC code | None |
| PubChem | CID: 11499245 |
| ChemSpider | 9674047 |
| Synonyms | AN2690 |
| Chemical data | |
| Formula | C7H6BFO2 |
| Molecular mass | 151.93 g/mol |
NMR PREDICT
 CAS NO. 174671-46-6, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole H-NMR spectral analysis |
 CAS NO. 174671-46-6, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole C-NMR spectral analysis |
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Anacor
Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.
Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets………..https://pubs.acs.org/cen/coverstory/89/8912cover3.html
mp 118-120….http://www.syninnova.com/catalog/product/SL-264
antifugal AN2690 by Anacor
Tavaborole inhibits an essential fungal enzyme, Leucyl-tRNA synthetase, or LeuRS, required for protein synthesis.
Minimum Inhibitory Concentration: 1, 1, 0.5, 0.25, and 0.25 μg/mL for T.rubrum, T.mentagrophytes, C.albicans, C.neoformans, A.fumigatus, respectivley.
AN2690 is a new boron-containing antifungal agent for the potential treatment of onychomycosis. Onychomycosis is caused mainly by dermatophytes, a class of fungus that dwells on skin, hair, and nails and is the cause of other cutaneous fungal infections such as athlete’s foot.
In vitro: AN2690 showed the most active against fungi and especially against the dermatophytes T. rubrum and T. mentagrophytes, the primary fungal pathogens causing onychomycosis. In addition, AN2690 was identified as having a unique profile of in vitro antidermatophyte activity, maintenance of this activity in the presence of keratin, and exceedingly good penetration of human nails [1].
Ex vivo: AN2690 was found to have superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis [2].
Clinical trial: The efficacy of tavaborole as a topical treatment for onychomycosis has been evaluated in two identical randomised, double-blind phase III studies, NCT01270971 (301) and NCT01302119 (302), enrolling 593 and 601 patients, respectively. Completely or almost clear nail and negative mycology was achieved in 15.3 and 17.9 % of tavaborole recipients compared with 1.5 and 3.9 % of vehicle recipients [3]
References:
[1] Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem. 2006;49(15):4447-50.
[2] Hui X, Baker SJ, Wester RC, Barbadillo S, Cashmore AK, Sanders V, Hold KM, Akama T, Zhang YK, Plattner JJ, Maibach HI. In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007;96(10):2622-31.
[3] Markham A. Tavaborole: first global approval. Drugs. 2014;74(13):1555-8.
UPDATE
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EXAMPLE 23
Alternative Preparation of 4 from 3
A 22.0 L 3-neck flask was equipped with a stir motor, N2 inlet, addition funnel, heating mantle, and condenser. The flask was charged with 3500 g (17.1 moi) of 2-bromo-5-fluorobenzyl alcohol followed by the addition of 3556 g of tetrahydrofuran and 16.4 g (0.17 mol) of methanesulfonic acid. Next, 400 g (4.7 mol) of 3,4-dihydro-2H-pyran was added at 100C. This step is exothermic so no additional charges should be made until exotherm subsides. The temperature was increased to 27°C, stirred for 15 min and then charged with 400 g (4.7 mol) of 3,4-dihydro-2H- pyran at 240C. Again the temperature increased (24°C to 380C). The mixture was stirred for 15 min. Once the exotherm subsided, the flask was again charged with 40Og (4.7 mol) of 3,4-dihydro-2H-pyran at 350C. The temperature again increased to 470C over a 20 min period. Once the exotherm subsided, the mixture was stirred for 15 min. Finally the remaining 400 g (4.7 mol) of 3,4-dihydro-2H-pyran was added at 440C. The temperature increased to 510C. After stirring for one hour, a sample was removed to check for removal of starting material. Upon reaction completion, contents were cooled to 20 ± 5 0C.
EXAMPLE 24
Alternative Preparation of 5 from 4
To a 22.0 L 3-neck flask equipped with a stir motor, N2 inlet, addition funnel, cooling bath, and condenser was charged 436 g (17.96 mol) of magnesium turnings. 5334 g of tetrahydrofuran was then added followed by 291 g (0.51 mol) of diisobutylaluminum hydride (DIBAL) (25%wt) in toluene. The mixture was stirred for 60 min at 20 ± 5 0C. Some gas evolution was seen. Next, 260-430 g -3-5% (by weight if solution of 4 was dropped to drums) of 4 in THF was added. The mixture was stirred for 15-30 min at which time a slight exotherm should be seen (ΔT = 10- 150C). Once the exotherm was observed, the reaction mixture was cooled to 5 ± 5 0C. To this mixture, the remaining 8.22-8.39 kg of 4 in THF was added at a rate such that the temperature was kept below 300C (t = 3h). The reaction was stirred at 20-25 0C for 30 min, at which time an aliquot was removed, quench with 3 N HCl (10 mL), and analyzed.
Upon completion, the contents were cooled to -25 ± 5°C. A solution of trimethylborate in THF was prepared by mixing 2665 g (25.7 mol) of trimethyl borate and 6666 g of tetrahydrofuran. This solution can be prepared in a drum with stirring. [0618] Next, the 9331 g of trimethyl borate in THF was added at a rate such that the temperature was kept between -35 and -20 °C (t = 2.5h). The mixture became very thick so THF was added. After stirring at -25 ± 5°C for 10 min, 50 mL aliquot was removed, quenched with 25 mL of 3N HCl, and submitted for CoR. Stirring continued at -25 ± 50C for Ih, and then the mixture was allowed to warm to ambient temperature, where it was stirred for at least 12h. Pull two samples (one at 6h and the other at 12h).
Results:
1H-NMR (300 MHz, DMSO-d6) δ (ppm) 1.45-1.75 (m, 6H), 3.53 (s, 6H), 3.45 (m, IH), 3.75 (m, IH), 4.69 (t, J=3 Hz, IH), 4.97 (d, J=14.1 Hz, IH), 5.14 (d, J=14.1 Hz, IH), 7.03 ((td, J=8.4, 2.7 Hz, IH), 7.24 (dd, J=10.8, 2.1 Hz, IH), 7.89 (t, J=7.8 Hz, IH), 8.76 (s, IH).
EXAMPLE 25
Alternative Preparation of I from 5
To the reaction mixture above was added 5.3 kg of USP water. After stirring for 30 min, the mixture was charged 5.3 kg of acetic acid. Gas evolution was seen. After stirring for 30 min, an aliquot was removed for analysis. Mixture was then heated to reflux for 36-48 hours. During the reflux period, 12-13 L of THF were removed.
When the reaction was complete, the contents were cooled by the reactor to <40°C by setting jacket and by charging 10.5 kg of USP water. THF was removed until distillate did not remain. Contents of the reactor were transferred to Rosenmund filter dryer and allowed to cool to 20 ± 5°C. Reactor was rinsed with water, filtered, and then washed again with 10.5 kg of USP water. The flask was charged with 10.5 kg of 10% ACN in water (v/v) and agitated for Ih. After filtering, the cake was washed with 10.5 kg of 10% ACN in water (v/v), and then charged with 10.5 kg 10% ACN in water (v/v). The contents were agitated for Ih. The contents were subsequently washed with 10.5 kg of USP water, charged with 7.0 L of 5% Methyl t- Butyl Ether (MTBE)/Heptane (v/v), agitated for Ih, filtered, charged with 7.0 L of 5% MTBE/Heptanes (v/v) and again agitated for Ih. After filtering, the contents were charged again with 7.0 L of heptane and filtered. Solids were dried at <45°C to constant weight. Solids were recrystallized from toluene :heptane 75:25.
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Vedroprevir
GS 9451, GS-9451, 1098189-15-1 USAN ZZ-81
VEDROPREVIR THERAPEUTIC CLAIM Treatment of hepatitis C
CHEMICAL NAMES 1. Cyclopropanecarboxylic acid, N-[[(1α,3β,5α)-bicyclo[3.1.0]hex-3- yloxy]carbonyl]-3-methyl-L-valyl-(4R)-4-[[8-chloro-2-[2-[(1-methylethyl)amino]- 4-thiazolyl]-7-[2-(4-morpholinyl)ethoxy]-4-quinolinyl]oxy]-L-prolyl-1-amino-2- ethyl-, (1R,2R)-
2. N-{[(1R,3r,5S)-bicyclo[3.1.0]hex-3-yloxy]carbonyl}-3-methyl-L-valyl-(4R)-4-[(8- chloro-2-{2-[(1-methylethyl)amino]thiazol-4-yl}-7-[2-(morpholin-4- yl)ethoxy]quinolin-4-yl)oxy]-L-prolyl-(1R,2R)-1-amino-2- ethylcyclopropanecarboxylic acid
MOLECULAR FORMULA C45H60ClN7O9S
MOLECULAR WEIGHT 910.5 daltons
SPONSOR Gilead Sciences, Inc.
CODE DESIGNATION GS-9451
CAS REGISTRY NUMBER1098189-15-1
WHO NUMBER9745
GS-9451 is a NS3 protease inhibitor in phase II clinical trials at Gilead for the oral treatment of hepatitis C.
…………………………………………………………………………
Discovery of GS-9451: An acid inhibitor of the hepatitis C virus NS3/4A protease Bioorg Med Chem Lett 2012, 22(7): 2629 ……………………………………………………………
PATENTS WO 2012087596 WO 2009005676 WO 2013106631 WO2013101550 ……………………….
WO2012087596A1 Compound 3 can be prepared using synthetic methods and intermediates like those described in USSN 12/215,605 (US 20090257978 A1). Compound 3 can also be prepared described in the following Example. Example 3: Preparation of Compound 3
Compound 315 (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11g, 260 mmol) in H20 (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 hours. Upon completion of the reaction, 4 N HCI in H20 was added to adjust pH to 7 at 0 °C. The mixture was extracted with EtOAc (2 x 400 ml). The combined organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo to give compound 3 as a yellow solid (11 g, 93%). LC/MS = 911.52(M++1 ). 1H NMR (300MHz, CD3OD)57.95 (d, 1H), 7.90 (s, 1H), 7.48 (s, 1H), 7.31 (d, 1H), 5.42 (s, 1H), 4.37 (dd, 1H), 4.20 (m, 2H), 3.83-3.56 (m, 7H), 3.50 (m, 2H), 3.39 (m, 2H), 2.45 (m, 1H), 2.27(m, 1H), 1.62 (m, 2H), 1.50 (m, 1H), 1.33 (m, 2H), 1.18 (m, 1H), 1.05 (m, 8H), 0.90 (m, 3H), 0.76 (m, 11H), 0.14-0.04 (m, 2H) The intermediate compound 315 was prepared as follows.
301 302 a. Preparation of compound 301. To a dry, argon purged three-neck round bottom flask (1000 mL) were added anhydrous dichloromethane (100 mL) and Et2Zn (28 mL, 273 mmol) at 0 °C. (CAUTION: Source of argon can not be from needle. Use appropriate glass adapter only. A second bubbler can also be attached to the flask to prevent excessive pressure build up.) Cyclopenten-3-ol (10.0 mL, 119 mmol) was then added dropwise (large quantity of ethane gas was produced) to the flask and the reaction mixture was allowed to stir until the evolution of gas had ceased. Diiodomethane (22 mL, 242 mmol) was then added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature and continued to stir overnight under a positive flow of argon, at which point TLC analysis had indicated complete disappearance of the starting alcohol. The reaction was then diluted with CH2CI2 and quenched with 2M HCI (white precipitate should be completely dissolved). The biphasic mixture was poured into a separatory funnel and the organic layer was collected. The solvent was removed under reduced pressure until 100 mL of material containing compound 301 remained. b. Preparation of compound 302. Anhydrous dichloromethane (525 mL) was added to the flask followed by the dropwise addition of triethylamine (34 mL, 245 mmol). The reaction continued to stir at room temperature under a positive flow of nitrogen at which point, disuccinimidylcarbonate (40.7 g, 159 mmol) was added to the flask portion wise. The reaction was allowed to stir until TLC analysis indicated complete disappearance of the starting material (2-3 days). Upon completion, the reaction mixture was quenched with 1 M HCI (200 mL x 2) and washed with H20 (200 mL x 2). The desired material was extracted using CH2CI2and the combined organic layers were dried using anhydrous MgS0 and passed through a silica plug. The solvent was removed under reduced pressure and the crude material was purified using flash chromatography (Rf = 0.33, 1 :1 Hex/EtOAc) to provide compound 302 (22 g, 75%): 1H NMR (300 MHz, CDCI3): δ 5. 24 (t, 1 H), 3.82 (s, 4H), 2.24 (m, 2H), 2.03 (d, 2H), 1.38 (m, 2H), 0.48 (m, 1 H), 0.40 (m, 1 H).
c. Preparation of compound 304. N-i-Boc-cis-4-Hydroxy-L-Proline methyl ester 303 (100.0 g, 407.7 mmol) and DABCO (1.5eq, 68.6g, 61 1.6 mmol) were dissolved in anhydrous toluene (200 mL) in a 2 L three necked round bottom flask with a mechanical stirrer and an addition funnel. After cooling the solution to 0 °C under N2, A solution of 4-Bromo-benzenesulfonyl chloride (1.3eq, 135.6g, 530.0 mmol) in 300 mL of toluene was added through addition funnel over 60 minutes. The reaction mixture was stirred and warmed to room temperature overnight (16 hours). The mixture was slowly poured into 2L 1 M Na2C03 (aq.), and the product was extracted with EtOAc (2L). After the organic phase was washed by 0.5 N HCI (2L), H20 (1 L), and brine (1 L), it was dried (MgS04), concentrated to give 195.45 g of a yellow oily brosylate product. To a solution of the above brosylate (407.7 mmol) in dichloromethane (300 mL) was slowly added 4.0 M HCI in dioxane (500 mL, 5eq) and the resulting solution was allowed to stir at room temperature for 2 hours. After ether (500mL) was added to the reaction mixture, the mixture was stirred for 15 minutes and the white precipitate was collected by filtration. The solid was washed with ether and hexane and then dried under vacuum overnight to obtain 153.0 g of the HCI amine salt of compound 304, 381.8 mmol, in 94% yield for two steps. d. Preparation of compound 305. To a solution of Boc-fert-butyl-glycine (97.0g, 420.0 mmol) in DMF (200mL) and DCM (200mL) were added HATU (217.76g, 572.7 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of the previous HCI salt (153.0 g, 381.8 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3h, with monitoring by LCMS. The reaction mixture was concentrated to remove dichloromethane under reduced pressure and the white solid that formed was filtered off. The remaining DMF solution was diluted with ethyl acetate (1 L), washed successively with 3% LiCI (aq) (3x650mL), sat’d NH4CI (2x500mL), 0.5N HCI (aq) (2x600ml_), brine (500ml_), sat’d NaHC03 (3x500mL), and brine (500mL). The resulting organic fraction was dried (MgS04) and concentrated to afford compound 305 (111g). e. Preparation of compound 306. To a solution of the methyl ester 305 (120 g, 207.8 mmol) in THF (300 ml_), MeOH (75 mL) was added a solution of LiOH (26.18 g, 623.4 mmol) in H20 (150 ml_). The solution was allowed to stir at room temperature for 4 hours. The mixture was cooled in an ice-bath while acidifying with 3N HCI to pH about 5.5, stirred for 10minut.es, and the resulting white solids were collected by filtration. The solids were washed with more water, ether and hexane. The solids were dried under vacuum at 40°C overnight to give 95.78g (82%) of the acid 306. f. Preparation of compound 307. To a solution of the carboxylic acid 306 (81.4 g, 144.27 mmol) in DMF (200ml_) and dichloromethane (200mL) was added HATU (82.3g, 216.4 mmol) and Hunig’s base (47.5 mL, 432.8 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of amine (158.7 mmol) and Hunig’s base (47.5 mL, 1145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3 hours and monitored by LCMS. After the mixture was concentrated under reduced pressure to remove dichloromethane, the white solids that formed were filtered off. The remaining DMF solution was diluted with ethyl acetate (600mL) and successively washed with 3% LiCI (aq) (2x550mL), sat’d NH4CI (500mL), 1 N HCI (aq) (500mL), sat’d NaHC03(500mL), and brine (300mL). The resulting organic fraction was dried (Na2S04) and concentrated to afford compound 307 (111 g). g. Preparation of compound 308. Compound 307 was dissolved in 4N HCI in dioxane (300 mL) at room temperature and stirred for 2 hours. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2 x 200mL) to dryness. The residue was dissolved in EtOAc (600mL) and sat’d aq. NaHC03 (1 L). It was stirred vigorously. After 10 minutes, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester 302 (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 minutes, the organic layer was collected and washed with brine (500mL), dried (Na2S04), and concentrated. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.44 g (92%) of compound 308.
h. Preparation of compound 310.1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 309 (70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110 °C for 72 hours. After the mixture was cooled to 0 °C with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHC03 solution (-350 mL), filtered, washed with water, and dried under vacuum to give – 40 g (61%) of crude 310 as a dark brown solid. LC/MS = 186 (M++1). i. Preparation of compound 311. 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 310 (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65 °C for 24 hours. Upon cooling to room temperature, EtOAc (1 L) and H20 (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1 x 400 ml). The combined organic layer was washed with aqueous 3% LiCI solution (2 x 1 L), brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 311 as a white solid (39 g, 67%). j. Preparation of compound 312. To a mixture of 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone 311 ( 13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (12.64 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at -40 °C. The mixture was then stirred at 0 °C for 4 hours. Upon completion of the reaction, H20 (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0 °C for another 15 minutes. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHC03 aqueous solution. The organic layer was dried (Na2S04) and concentrated in vacuo. The residue was dissolved in CH2CI2, hexanes were added slowly to the solution, and a yellow solid started to crash out. More hexanes were added until not much product was left in the mother liquid to provide compound 312 (18 g, 85%). k. Preparation of compound 313. 2-lsopropylamino-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)- phenyl]-amide 312 (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while monitoring H2evolution. The mixture became a clear solution during heating to reflux. The reaction was complete after refluxing for 3 hours. The mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H20 (3 vol) was added to the mixture. After vigorous agitation for 1 hour at 0 °C, the solids were collected by filtration, rinsed forward with H20. The wet cake was dried under high vacuum to a constant weight to provide compound 313 ( 5 g, 86%). I. Preparation of compound 314. To a mixture of brosylate intermediate 303 (15 g, 35 mmol) and compound 313 (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65 °C for 5 hours. The reaction was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCI (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCI (1 x 600 ml), brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired methyl ester as a yellow solid (23.6 g, 75%). LC/MS = 900. 1 3(M++ 1 ) . m. Preparation of compound 315. Methyl ester 314 (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml), 1.4 N HCI in H20 (75 ml) was added to the solution. The mixture was stirred at 60 °C for 1 hour. Upon completion of the reaction, the mixture was concentrated to remove the solvents, coevaporated with toluene (x 2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHC03 aqueous solution (enough to neutralize the mixture) while monitoring C02 evolution. The organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used as is for the next step. The crude was dissolved in CH2CI2 (360 ml), morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0 °C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 minutes at 0 °C. Sat. NaHC03 aqueous solution was added to quench the reaction. After stirring for another 20 minutes, the organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired amine product 315 as a yellow solid (12 g, 50%). LC/MS = 924.63(M++ 1 )
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