AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

MK 5172, GRAZOPREVIR

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Jul 312015
 

GRAZOPREVIR

  • Grazoprevir hydrate
  • UNII-4O2AB118LA
  • MK 5172
THERAPEUTIC CLAIM Antiviral
Note……..drug is k salt
MF C38H49N6O9SK
MW804.99
CHEMICAL NAMES
1. Cyclopropanecarboxamide, N-[[[(1R,2R)-2-[5-(3-hydroxy-6-methoxy-2-
quinoxalinyl)pentyl]cyclopropyl]oxy]carbonyl]-3-methyl-L-valyl-(4R)-4-hydroxy-L-prolyl-1-
amino-N-(cyclopropylsulfonyl)-2-ethenyl-, cyclic (1→2)-ether, hydrate (1 :1) (1R,2S)-
2. (1aR,5S,8S,10R,22aR)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-
ethenylcyclopropyl}-5-(1,1-dimethylethyl)-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-
methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-
carboxamide hydrate
MOLECULAR FORMULA C38H50N6O9S.H2O
MOLECULAR WEIGHT 784.92
SPONSOR Merck Sharp & Dohme Corp.
CAS REGISTRY NUMBER 1350462-55-3  HYDRATE, 1350514-68-9 (anhydrous)
WHO NUMBER
9857
GRAZOPREVIR
MERCK
MK-5172 is in phase II clinical development at Merck & Co. for the oral treatment of chronic hepatitis C in combination with peginterferon and ribavirin and in combination with MK-8742. Phase I clinical trials are ongoing for the treatment of hepatitis C in patients with genotype 1 and genotype 3. In 2013, breakthrough therapy designation was assigned to the compound.
Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor
ACS Med Chem Lett 2012, 3(4): 332DOI: 10.1021/ml300017p
Development of a practical, asymmetric synthesis of the hepatitis c virus protease inhibitor MK-5172
Org Lett 2013, 15(16): 4174
WO2013142159
WO 2013106631
WO 2013101550
WO 2013028470
WO 2013028471
WO2013028465
WO 2010011566
Description:
IC50 Value: 7.4nM and 7nM for genotype1b and 1a respectively, in replicon system [1]
MK-5172 is a novel P2-P4 quinoxaline macrocyclic HCV NS3/4a protease inhibitor currently in clinical development.
in vitro: In biochemical assays, MK-5172 was effective against a panel of major genotypes and variants engineered with common resistant mutations observed in clinical studies with other NS3/4a protease inhibitors. In the replicon assay, MK-5172 demonstrated subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a [2].
in vivo: In rats, MK-5172 showed a plasma clearance of 28 ml/min/kg and plasma half-life of 1.4 hr. When dosed p.o. at 5 mg/kg, the plasma exposure of MK-5172 was good with an AUC of 0.7 uM.hr. The liver exposure of the compound was quite good (23 uM at 4 hr), and MK-5172 remained in liver 24 hr after a single p.o. 5 mg/kg dose. At 24 hr, the liver concentration of MK-5172 was 0.2 uM, which was over 25-fold higher than the IC50 in the replicon assay with 50% NHS. When dosed to dogs, MK-5172 showed low clearance of 5 ml/min/kg and a 3 hr half-life after i.v. 2 mg/kg dosing and had good plasma exposure (AUC=0.4 uM.hr) after a p.o. 1 mg/kg dose [1].
Clinical trial: Evaluation of Hepatic Pharmacokinetics for MK-5172 in Participants With Chronic Hepatitis C . Phase1
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein. NS4A provide a cofactor for NS3 activity.
Potential treatments for HCV infection have been discussed in the different references including Balsano, Mini Rev. Med. Chem. 8(4):307-318, 2008, Rönn et al., Current Topics in Medicinal Chemistry 8:533-562, 2008, Sheldon et al., Expert Opin. Investig. Drugs 16(8):1171-1181, 2007, and De Francesco et al., Antiviral Research 58:1-16, 2003
Different HCV inhibitors are described in different publications. Macrocyclic compounds useful as inhibitors the HCV protease inhibitors are described in WO 06/119061, WO 7/015785, WO 7/016441, WO 07/148,135, WO 08/051,475, WO 08/051,477, WO 08/051,514, WO 08/057,209. Additional HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116, WO 02/48172, British Patent No. GB 2 337 262, and U.S. Pat. No. 6,323,180.
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NMR
Figure US08080654-20111220-C00021
13C NMR (100 MHz, DMSO-d6) δ 172.32, 170.63, 169.04, 159.86, 156.95, 154.74, 148.10, 140.41, 133.55 (2 signals), 128.94, 118.21, 117.58, 105.89, 74.88, 59.75, 58.71, 55.68, 54.13, 54.01, 40.13, 34.49, 34.04, 33.76, 32.68, 30.71, 30.43, 28.55, 27.69, 27.28, 26.38, 21.98, 18.49, 10.67, 5.69, 5.46; MS (ES+) m/z 767 (M+H)+
(1aR,5S,8S,10R,22aR)-5-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide
………………….
NMR OF GRAZOPREVIR K SALT
Potassium {[(1R,2S)-1-({[(1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-
methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-
yl]carbonyl}amino)-2-ethenylcyclopropyl]carbonyl}(cyclopropylsulfonyl)azanide (15 K-salt).
1H NMR (400 MHz, DMSO-d6) δ 7.91 (br s, 1 H), 7.75 (d, J =
8.3 Hz, 1 H), 7.15 (m, 1 H), 7.04 (m, 1 H), 5.97 (m, 1 H), 5.73 (br s, 1 H), 4.96 (m, 1 H), 4.79 (apparent q, J = 9.3 Hz, 1 H), 4.26 (dd, J = 9.7, 7.7 Hz, 1 H), 4.20 (d, J = 11.3 Hz, 1 H), 4.14 (d, J = 8.8 Hz, 1 H), 3.90 (dd, J = 11.1, 3.2 Hz, 1 H), 3.86 (s, 3 H), 3.62 (m, 1 H), 2.86-2.60 (m, 3 H), 2.38 (m, 1 H), 2.21 (m, 1 H), 1.80-1.48 (m, 6 H), 1.42 (m, 5 H), 1.14 (m, 1 H), 0.95 (m, 10 H), 0.81 (m, 2 H), 0.72-0.50 (m, 3 H), 0.41 (m, 1 H) ppm.http://pubs.acs.org/doi/suppl/10.1021/ml300017p/suppl_file/ml300017p_si_001.pdf
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GRAZOPREVIR
(1aR,5S,8S,10R,22aR)-5-tert-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino] carbonyl}-2-
vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-
7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-
carboxamide (MK-5172, 15).
1H NMR (400 MHz, CD3
OD) δ 7.79 (dd, J = 9.6, 1.8 Hz, 1 H), 7.23 (s, 1 H), 7.22 (m, 1 H), 7.10 (d, J = 9.6 Hz, 1 H), 6.01 (apparent t, J = 3.6 Hz, 1 H), 5.74 (m, 1 H), 5.24 (dd, J = 17.0 Hz, 1.6 Hz, 1 H), 5.11 (dd, J = 10.4 Hz, 1.6 Hz, 1 H), 4.49 (d, J = 11.2 Hz, 1 H), 4.40 (m, 2 H), 4.13 (dd, J = 12.0 Hz, 4.0 Hz, 1 H), 3.92 (s, 3 H), 3.76 (m, 1 H), 2.92 (m, 2 H), 2.85 (m, 1 H), 2.55 (dd, J = 13.6 Hz, 6.4 Hz, 1 H), 2.28 (m, 1 H), 2.18 (apparent q, J =8.8 Hz, 1 H), 1.85 (dd, J = 8.0 Hz, 5.6 Hz, 1 H), 1.73 (m, 2 H), 1.5 (m, 2 H), 1.40 (dd, J = 9.6 Hz, 5.6 Hz, 1 H), 1.3 (m, 2 H), 1.23 (m, 4 H), 1.08 (s, 9 H), 0.99 (m, 2 H), 0.89 (m, 3 H), 0.73 (m, 1 H), 0.49 (m, 1 H) ppm; HRMS (ESI) m/z 767.3411 [(M+H)+; calcd for C38H51N6O9S: 767.3433].http://pubs.acs.org/doi/suppl/10.1021/ml300017p/suppl_file/ml300017p_si_001.pdf
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HPLC
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SYNTHESIS OF INTERMEDIATES Intermediates A
Intermediate # Structure Name Lit. Reference
A1 Figure US08080654-20111220-C00003 (1R,2S)-1-Amino-N- (cyclopropylsulfonyl)-2- vinylcyclopropanecarboxamide hydrochloride Wang et al., U.S. Pat. No. 6,995,174
Intermediate B1 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine
Figure US08080654-20111220-C00004
Step 1: [(1E)-hepta-1,6-dien-1-yloxy](trimethyl)silane
Figure US08080654-20111220-C00005
A solution (0.5 M) of butenyl magnesium bromide in THF (1.4 eq) was treated at −78° C. with Cu(I) Br.SMe2 (0.05 eq) and HMPA (2.4 eq). The mixture was stirred for 10 min, then a solution (1 M) of acrolein (1 eq) and TMSCl (2 eq) in THF was added over 1 h such that the internal temperature remained below −68° C. The resulting mixture was stirred at −78° C. for 2 h, then treated with excess Et3N and diluted with hexane. After reaching room temperature, the mixture was treated with a small portion of H2O and filtered through CELITE. The filtrate was washed 10 times with H2O and then with brine. The organic layer was dried, and the volatiles were removed to give a residue that was distilled under reduced pressure (20 mbar). The fraction collected at 80-86° C. contained the title compound (58%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 6.19 (d, J=11.6 Hz, 1H), 5.85-5.75 (m, 1H), 5.02-4.92 (m, 3H), 2.08-2.02 (m, 2H), 1.94-1.88 (m, 2H), 1.46-1.38 (m, 2H), 0.18 (s, 9H).
Step 2: trans-2-pent-4-en-1-ylcyclopropanol
Figure US08080654-20111220-C00006
A solution (0.45 M) of the preceding compound in hexane was treated with a solution (15%) of Et2Zn (1.2 eq) in toluene, and the resulting solution was cooled in an ice bath. Diiodomethane (1.2 eq) was added dropwise, then the solution was stirred for 1 h before being warmed to 20° C. Pyridine (6 eq) was added, and the slurry was stirred for 15 min then poured onto petroleum ether. The mixture was filtered repeatedly through CELITE until a transparent solution was obtained. This mixture was concentrated at 100 mbar, and the solution that remained (that contained trimethyl{[(trans)-2-pent-4-en-1-ylcyclopropyl]oxy}silane, toluene and pyridine) was further diluted with THF. The mixture was cooled to 0° C. then treated dropwise with a solution (1 M) of TBAF (1.2 eq) in THF. After 10 min, the mixture was allowed to warm to 20° C., and after a further 1 h was poured into H2O. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine then dried. Removal of the volatiles afforded a residue that was purified by flash chromatography (eluent 0-66% Et2O/petroleum ether) to furnish the title compound (71%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1H), 5.00 (dd, J=17.1, 1.6 Hz, 1H), 4.94 (br d, J=10.4 Hz, 1H), 3.20 (apparent dt, J=6.4, 2.5 Hz, 1H), 2.10-2.04 (m, 2H), 1.52-1.44 (m, 2H), 1.29-1.19 (m, 1H), 1.15-1.07 (m, 1H), 0.95-0.87 (m, 1H), 0.71-0.66 (m, 1H), 0.31 (apparent q, J=6.0 Hz, 1H).
Step 3: methyl 3-methyl-N-(oxomethylene)-L-valinate
Figure US08080654-20111220-C00007
A solution (0.39 M) of methyl 3-methyl-L-valinate in a 2:1 mixture of saturated aqueous NaHCO3 and CH2Cl2 was cooled in an ice bath and stirred rapidly. The mixture was treated with triphosgene (0.45 eq) in one portion, and the resulting mixture was stirred for 0.5 h. The reaction was diluted with CH2Cl2, and the layers were separated. The aqueous phase was extracted with CH2Cl2, then the combined organics were washed with brine and dried. Removal of the solvent gave the title compound as clear oil that was kept for 12 h under vacuum (0.1 mbar) then used directly in the subsequent step. 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 3.75 (s, 1H), 1.00 (s, 9H).
Step 4: methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate and methyl 3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate
Figure US08080654-20111220-C00008
A solution (0.45 M) of trans-2-pent-4-en-1-ylcyclopropanol in toluene was treated with methyl 3-methyl-N-(oxomethylene)-L-valinate (1.1 eq) and then DMAP (1 eq). The resulting mixture was heated under reflux for 12 h then cooled to 20° C. H2O and EtOAc were added, and the organic layer was separated and washed with 1N HCl, brine and dried. Removal of the volatiles afforded a residue that was purified twice by flash chromatography (eluent 0-30% Et2O/petroleum ether). The first fractions contained methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate (38%) as an oil. MS (ES+) m/z 298 (M+H)+
The later fractions contained methyl 3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate (28%) as an oil. MS (ES+) m/z 298 (M+H)+
Step 5: 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine
Figure US08080654-20111220-C00009
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate in 2:1 mixture of MeOH/H2O was treated with LiOH.H2O (4 eq) and then heated at 60° C. for 4 h. The mixture was cooled and concentrated to half volume, then diluted with EtOAc and acidified with aqueous HCl (1 N). The organic layer was separated and washed with brine then dried. Removal of the volatiles afforded the title compound (98%) as an oil. MS (ES+) m/z 284 (M+H)+
Intermediates C Intermediate C1 methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride
Figure US08080654-20111220-C00010
Step 1: 6-methoxyquinoxaline-2,3-diol
Figure US08080654-20111220-C00011
A suspension of 4-methoxybenzene-1,2-diamine dihydrochloride in diethyl oxalate (8 eq) was treated with Et3N (2 eq) and then heated at 150° C. for 2 h. The mixture was cooled and filtered, and then the collected solid was washed with H2O and EtOH. The residue was dried to give the title compound (69%). MS (ES+) m/z 193 (M+H)+
Step 2: 3-chloro-6-methoxyquinoxalin-2-ol
Figure US08080654-20111220-C00012
A solution (1.53 M) of 6-methoxyquinoxaline-2,3-diol in DMF was treated with SOCl2 (1 eq) and heated at 110° C. After 1.5 h, the reaction mixture was cooled and poured into aqueous HCl (1 N). The resulting precipitate was filtered and washed with H2O and Et2O. The dried solid contained predominantly the title compound as a mixture with 6-methoxyquinoxaline-2,3-diol and 2,3-dichloro-6-methoxyquinoxaline. This material was used directly in the subsequent step. MS (ES+) m/z 211 (M+H)+
Step 3: 1-tert-butyl 2-methyl (2S,4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
Figure US08080654-20111220-C00013
A solution (0.35 M) of 3-chloro-6-methoxyquinoxalin-2-ol in NMP was treated with Cs2CO3 (1.5 eq) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.1 eq). The resulting mixture was stirred at 50° C. for 18 h, then a further portion (0.1 eq) of 1-tert-butyl 2-methyl (25,45)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate was added. After stirring for 2 h, the mixture was cooled and diluted with H2O and EtOAc. The organic phases were washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine. The dried organic phase was concentrated to a residue that was purified by flash-chromatography (0-60% EtOAc/petroleum ether) to give the title compound (35% for two steps) as a solid. MS (ES+) m/z 438 (M+H)+
Step 4: methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride
Figure US08080654-20111220-C00014
A solution (0.62 M) of 1-tert-butyl 2-methyl (2S,4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate in CH2Cl2 was treated with a solution (4 M) of HCl in dioxane (5 eq). The mixture was stirred at 20° C. for 2 h, then treated with a solution (4 M) of HCl in dioxane (2 eq). After 5 h, the reaction was judged complete and the mixture was concentrated under reduced pressure. The residue was triturated with Et2O to give the title compound (95%) as a solid. MS (ES+) m/z 338 (M+H)+
Example 1 Potassium {[(1R,2S)-1-({[(1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-yl]carbonyl}amino)-2-vinylcyclopropyl]carbonyl}(cyclopropylsulfonyl)azanide
Figure US08080654-20111220-C00015
Step 1: methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate
Figure US08080654-20111220-C00016
A solution (0.2 M) of methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride in DMF was treated with 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine (1.1 eq), DIEA (5 eq) and HATU (1.2 eq). The resulting mixture was stirred at 20° C. for 5 h, then diluted with EtOAc. The organic layer was separated and washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine. The dried organic phase was concentrated under reduced pressure to give a residue that was purified by flash chromatography (eluent 10-30% EtOAc/petroleum ether) to furnish the title compound (96%) as an oil. MS (ES+) m/z 604 (M+H)+
Step 2: methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(7-methoxy-3-vinylquinoxalin-2-yl)oxy]-L-prolinate
Figure US08080654-20111220-C00017
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate in EtOH was treated with potassium trifluoro(vinyl)borate (1.5 eq) and triethylamine (1.5 eq). The resulting mixture was degassed, then PdCl2(dppf)-CH2Cl2 adduct (0.1 eq) was added. The mixture was heated under reflux for 1 h, then cooled to room temperature and diluted with H2O and EtOAc. The organic phase was separated, washed with H2O and brine then dried. Removal of the volatiles afforded a residue that was purified by flash chromatography (20-30% EtOAc/petroleum ether) to give the title compound as a yellow foam that was used directly in the subsequent step. MS (ES+) m/z 595 (M+H)+
Step 3: methyl (1aR,5S,8S,10R,18E,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate
Figure US08080654-20111220-C00018
A solution (0.02 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(7-methoxy-3-vinylquinoxalin-2-yl)oxy]-L-prolinate in DCE was heated to 80° C. then treated with Zhan 1 catalyst (0.15 eq). The resulting mixture was stirred at 80° C. for 1 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (20-50% EtOAc/petroleum ether) to give the title compound (25% for 2 steps) as a foam. MS (ES+) m/z 567 (M+H)+
Step 4: methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate
Figure US08080654-20111220-C00019
A solution (0.05 M) of methyl (1aR,5S,8S,10R,18E,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in MeOH/dioxane (1:1 ratio) was treated with Pd/C (8% in weight). The resulting mixture was stirred under atmosphere of hydrogen for 4 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (98%) as a solid. MS (ES+) m/z 569 (M+H)+
Step 5: (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid
Figure US08080654-20111220-C00020
A solution (0.1 M) of methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in a 1:1 mixture of H2O/THF was treated with LiOH.H2O (3 eq). The resulting mixture was stirred at 20° C. for 18 h, acidified with aqueous HCl (0.2 M) and diluted with EtOAc. The organic phase was separated, washed with aqueous HCl (0.2 M) and brine then dried. Removal of the volatiles afforded the title compound (98%) as a solid. MS (ES+) m/z 555 (M+H)+
Step 6: (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide
Figure US08080654-20111220-C00021
A solution (0.1 M) of (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid in CH2Cl2 was treated with (1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride (1.3 eq), DIEA (3 eq), DMAP (1.5 eq) and TBTU (1.45 eq). The resulting mixture was stirred at 20° C. for 18 h and then diluted with EtOAc. The solution was washed with aqueous HCl (0.2 M), saturated aqueous NaHCO3 and brine. The organic phases were dried and concentrated to give a residue that was purified by flash-chromatography (eluent 2.5% MeOH/CH2Cl2) to give the title compound (89%) as a solid. 13C NMR (100 MHz, DMSO-d6) δ 172.32, 170.63, 169.04, 159.86, 156.95, 154.74, 148.10, 140.41, 133.55 (2 signals), 128.94, 118.21, 117.58, 105.89, 74.88, 59.75, 58.71, 55.68, 54.13, 54.01, 40.13, 34.49, 34.04, 33.76, 32.68, 30.71, 30.43, 28.55, 27.69, 27.28, 26.38, 21.98, 18.49, 10.67, 5.69, 5.46; MS (ES+) m/z 767 (M+H)+
GRAZOPREVIR POTASSIUM
Step 7: potassium {[(1R,2S)-1-({[(1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxalin-8-yl]carbonyl}amino)-2-vinylcyclopropyl]carbonyl}(cyclopropylsulfonyl)azanide
Figure US08080654-20111220-C00022
The preceding material was taken up in EtOH and the resulting solution (0.025 M) was cooled to 0° C. A solution (0.02 M) of tert-BuOK (1.5 eq) in EtOH was added leading to the formation of a precipitate. The mixture was stirred at 20° C. for 18 h, then the solid was collected by filtration. This material was washed with EtOH and dried to give the title compound (93%) as a white crystalline solid. MS (ES+) m/z 767 (M+H)+http://www.google.nl/patents/US8080654
………………………..
PATENT
WO 2015095437

Step 1: Quinoxaline Hydroxyproline Methyl Ester HCl Salt

A 250-ml RB, equipped with magnetic stirrer and N2 bubbler, was charged with chloroquinoxaline BOC hydroxyproline adduct in MeOH (100 ml), and the mixture was cooled in an ice bath. Acetyl chloride (17.9 g) was then added, and the mixture was stirred at RT for 2 h. The batch was diluted with IP Ac (80 ml). Solids were filtered off and washed with IPAc (20 ml). The washed solids were dried under vacuum for 3 d, to provide 48.9 g (100% yield ). Part of this material was used in the next step.

…………………..
WO2015057611

Example 17: Preparation of Compound A, Method A

Macrocyclic acid hemihydrate, the product of Example 15 (10.16 g, 18.03 mmol) was dissolved in THF (50 mL to 90 mL). The solution was azetropically dried at a final volume of 100 mL. Sulfonamide pTSA salt (7.98 g, 1.983 mmol) followed by DMAc (15 mL) was added at RT. The batch was cooled to 0°C to 10°C, and pyridine (10 mL) was added dropwise. Then, EDC HCl (4.49 g, 23.44 mmol) was added in portions or one portion at 0°C to 10°C. The reaction mixture was aged at 0°C to 10°C for 1 h, and then warmed to 15°C to 20°C for 2 h to 4 h. MeOAc (100 mL) followed by 15 wt% citric acid in 5% NaCl in water (50 mL) was added, while the internal temperature was maintained to < 25°C with external cooling. The separated organic phase was washed with 15 wt% citric acid in 5% NaCl in water (50 mL) followed by 5% NaCl (50 mL). The organic phase was solvent-switched to acetone at a final volume of ~80 mL. Water (10 mL) was added dropwise at 35°C to 40°C. The batch was seeded with Compound A monohydrate form III (~10 mg) and aged for 0.5 h tol h at 35°C to 40°C. Additional water (22 mL) was added dropwise over 2 h to 4 h at 35°C to 40°C. The slurry was aged at 20°C for 2 h to 4 h before filtration. The wet cake was displacement washed with 60% acetone in water (2x 40 mL). Suction drying at RT gave Compound A monohydrate form III as a white solid.

XH NMR (400 MHz, CDC13) δ 9.95 (s, br, 1 H), 7.81 (d, J = 9.1 Hz, 1 H), 7.18 (dd, J = 9.1, 2.7 Hz, 1 H), 7.16 (s, br, 1 H), 7.13 (d, J = 2.7 Hz, 1 H), 5.96 (t, J = 3.8 Hz, 1 H), 5.72 (m, 1 H), 5.68 (d, J = 10.1 Hz, 1 H), 5.19 (d, J = 17.1 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 9.8 Hz, 1 H), 4.36 (d, J = 10.5, 6.9 Hz, 1 H), 4.05 (dd, J = 11.5, 3.9 Hz, 1 H), 3.93 (s, 3 H), 3.78 (m, 1 H), 2.90 (m, 1 H), 2.82 (tt, J = 8.0, 4.8 Hz, 1 H), 2.74 (dt, J = 13.2, 4.8 Hz, 1 H), 2.59 (dd, J = 14.0, 6.7 Hz, 1 H), 2.40 (ddd, J = 14.0, 10.6, 4.0 Hz, 1 H), 2.10 (dd, J = 17.7, 8.7 Hz, 1 H), 1.98 (2 H, mono hydrate H20), 1.88 (dd, J 8.2, 5.9 Hz, 1 HO, 1.74 (m, 3 H), 1.61 (m, 1 H), 1.50 (m, 3 H), 1.42 (dd, J = 9.6, 5.8 Hz, 1 H), 1.22 (m, 2 H), 1.07 (s, 9 H), 0.95 (m, 4 H), 0.69 (m, 1 H), 0.47 (m, 1 H).

1 C NMR (100 MHz, CDC13) δ 173.5, 172.1, 169.1, 160.4, 157.7, 154.9, 148.4, 141.0, 134.3, 132.7, 129.1, 118.8, 118.7, 106.5, 74.4, 59.6, 59.4, 55.8, 55.5, 54.9, 41.8, 35.4, 35.3, 35.2, 34.3,. 31.2, 30.7, 29.5, 28.6, 28.2, 26.6, 22.6, 18.7, 11.2, 6.31, 6.17.

HPLC conditions: Ascentis Express Column, 10 cm x 4.6 mm, 2.7 μηι; Column temperature of 40°C; Flow rate of 1.8 mL/min; and Wavelength of 215 nm.

Gradiant: mm 0.1% ¾PO4

0 20 80

5 55 45

15 55 45

25 95 5

27 95 5

27.1 20 80

32 20 80

Retention time: mm.

Compound A 14.50

Example 18: Preparation of Compound A, Method B

To a 50-L flask equipped with overhead stirring was added macrocyclic acid (1.06 kg crude, 1.00 eq), amine-pTSA (862 g crude, 1.12 eq) and MeCN (7.42 L) at 19°C. The slurry was cooled in a water bath, pyridine (2.12 L, 13.8 eq) was added, aged 15 min, and then added EDC (586 g, 1.60 eq) in one portion, aged 1.5 h, while it turned into a clear homogeneous solution.

The solution cooled in a water bath, then quenched with 2 N HC1 (1.7 L), and seeded (9.2 g), aged 15 min, and the rest of the aqueous HC1 was added over 2.5 h. A yellow slurry was formed. The slurry was aged overnight at RT, filtered, washed with MeCN/water (1 : 1 v/v, 8 L), to obtain Compound A (Hydrate II).

Compound A was dissolved in acetone (4 L) at RT, filtered and transferred to a

12-L round-bottom flask with overhead stirring, rinsed with extra acetone (1 L), heated to 50°C, water (0.9 L) was added, seeded with Compound A monohydrate form III (-10 mg), and aged 15 min, and then added water (0.8 L) over 2.5 h, extra water 3.3 v over 2.5 h was added, stopped heating, cooled to RT, aged at RT overnight, filtered, washed with water/acetone (1 : 1 v/v, 4 L), and dried in air under vacuum. Compound A Hydrate III, 670 g, was obtained as an off-white solid.

Example 19: Preparation of Compound A, Method C

Macrocyclic acid hemihydrate from Example 15 (10.16 g, 18.03 mmol) was dissolved in THF (50 ml to 90 mL). The solution was azetropically dried at a final volume of 100 mL. Sulfonamide pTSA salt (7.98 g, 19.83 mmol) was added, followed by DMAc (15 mL), at RT. The batch was cooled to 0° to 10°C, and pyridine (10 mL) was added dropwise. Then, EDC HC1 (4.49 g, 23.44 mmol) was added (in portions or one portion) at 0°C to 10°C. The reaction mixture was aged at 0°C to 10°C for 1 h, and then warmed to 15°C to 20°C for 2 h to 4 h. THF (50 mL) was added, followed by 15 wt% citric acid in 15 wt% aq. NaCl (50 mL), while the internal temperature was maintained at < 25°C with external cooling. The separated organic phase was washed with 15 wt% citric acid in 1 % aq. NaCl (40 mL), followed by 15% NaCl (40 mL). The organic phase was solvent-switched to acetone at a final volume of ~75 mL Water (1 1 mL to 12 mL) was added dropwise at 35°C to 40°C. The batch was seeded with Compound A monohydrate form III (~20 mg) and aged for 0.5 h to 1 h at 35°C to 40°C.

Additional water (22 mL) was added dropwise over 2 h to 4 h at 35°C to 40°C. The slurry was aged at 20°C for 2 h to 4 h before filtration. The wet cake was displacement washed with 60% acetone in water (40 mL x 2). Suction drying at RT or vacuum-oven drying at 45°C gave Compound A monohydrate form III as a white solid.

Example 20: Preparation of Compound A, Method D

Macrocyclic acid hemihydrate from Example 12 (10 g, 98.4wt%, 17.74 mmol) was dissolved in THF (70 mL). The solution was azetropically dried at a final volume of ~60 mL. Sulfonamide pTSA salt (7.53 g, 18.7 mmol) was added at RT. The batch was cooled to 0°C to 5°C, and pyridine (1 1.4 mL) was added dropwise. Then, EDC HC1 (4.26 g, 22.2 mmol) was added in portions at 0°C to 15°C. The reaction mixture was aged at 10°C to 15°C for 2 h to 4 h. 35 wt% Citric acid in 10 wt% aq. NaCl (80 mL) was added, while the internal temperature was maintained at < 25°C with external cooling. The separated organic phase was solvent-switched to acetone at a final volume of ~75 mL. Water (12 mL) was added dropwise at 50°C. The batch was seeded with Compound A monohydrate form III (-300 mg) and aged for 0.5 h to 1 h at 50°C. Additional water (25 mL) was added dropwise over 6 h at 35°C to 40°C. The slurry was aged at 20°C for 2 h to 4 h before filtration. The wet cake was displacement washed with 65%) acetone in water (40 mL). Suction drying at RT or vacuum-oven drying at 45°C gave Compound A monohydrate form III as a white solid.

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WO2015095430

Example 24: Ring Closing Metathesis

To a 50 mL 2-neck RB flask with reflux condenser and needle for N2 bubbling was charged the product of Example 20 (1.034 g, 0.869 mmol, 1.0 eq), toluene (20.68 ml, 20X), and the resulting solution was degassed with N2. Hoveyda-Grubbs 2nd generation catalyst (10.90 mg, 0.017 mmol) was charged to the pot, and the system was heated to 80°C with constant sparge of N2, with color change from green to reddish. The reaction was sampled (5 h) and assay by HPLC to be approximately 80% converted. The system was removed from the heat and allowed to stir at RT overnight under N2. The reaction was again assayed and deemed complete by HPLC. Toluene was removed by concentration and the resulting red oil was purified by gradient silica gel chromatography (50 g BlOTAGE SNAP Si gel column; loaded with DCM; eluted with 0 to 10% EtOAc in DCM over 10 column volumes; then 10 to 20% EtOAc in DCM over 3 column volumes; then hold; detect by TLC-UV) to yield a yellow solid, which was further slurried in EtOAc (3 mL) and hexanes (6 mL). The resulting slurry was filtered and washed with 25% EtOAc in hexanes (6 mL) to yield the product (445 mg, 0.754 mmol, 87% yield) as a white solid.

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http://anewmerckreviewed.wordpress.com/2013/04/23/okay-trivial-pursuit-will-the-real-mk-5172-please-stand-up/

Synthesis of MK-5172_NS3 protease inhibitor_Hepatitis C_Merck 默沙东丙型肝炎药物MK-5172的的化学合成

Merck reported interim data from the Phase 2 C-WORTHY study in April 2014 at the International Liver Congress (ILC) in London that evaluated the efficacy and safety of its two-drug regimen based on NS3/4A protease inhibitor MK-5172 and NS5A replication complex inhibitor MK-8742, given with or without ribavirin, in GT1 HCV patients with cirrhosis. The once-daily single pill (without ribavirin) showed a 98% SVR12 (12-week sustained virologic response) in genotype-1, treatment-naive patients. Merck will start the phase III clinical trials (NCT02105688, NCT02105662, NCT02105467 andNCT02105701) for the combination in June 2014.

 

MK-5172 is a novel, competitive inhibitor of the HCV NS3/4a protease with selective, potent in vitro activity against a broad range of HCV genotypes (GTs) and known viral variants that are resistant to other protease inhibitors in development.
MK-5172 is a Next Generation HCV NS3/4a Protease Inhibitor with a Broad HCV Genotypic Activity Spectrum and Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients. MK-5172 exhibits excellent selectivity over other serine proteases such as elastase and trypsin (no measurable inhibition), and shows only modest inhibitory potency with chymotrypsin (IC50 = 1.5 µM; 75,000-fold selective). In the genotype 1b replicon assay, MK-5172 potently inhibits viral replication (IC50 = 2 nM) and demonstrates a modest shift in the presence of 50% NHS (EC50 = 9.5 nM). In vitro, MK-5172 inhibits the NS3/4A enzyme from genotypes 1b, 2a, 2b, and 3a with Ki values of <0.02, 0.15, 0.02, and 0.7 nM, respectively. The genotype 2a replicon is also potently inhibited by MK 5172 (EC50 = 5 nM).
Kuethe J, * Zhong Y.-L, * Yasuda N, * Beutner G, Linn K, Kim M, Marcune B, Dreher SD, Humphrey G, Pei T. Merck Research Laboratories, Rahway, USA
Development of a Practical, Asymmetric Synthesis of the Hepatitis C Virus Protease Inhibitor MK-5172.Org. Lett. 2013;
15: 4174-4177
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MK-5172 is a hepatitis C virus protease inhibitor. Key steps in the synthesis depicted are (1) the regioselective SNAr reaction of dichloroquinoxaline A with prolinol derivative B and (2) construction of the 18-membered macrocycle ­using a macrolactamization (F → G).

Comment

The medicinal chemistry route to MK-5172 is based on a ring-closing metathesis strategy (S. Harper et al.ACS Med. Chem. Lett. 2012, 3, 332). The best regioselectivity (20:1) and minimization of double substitution in the SNAr reaction of A with B was achieved using 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU) as the base in polar solvents such as DMSO, NMP, or DMAc.

BELOW-TAKEN FROM THESIS

 

 

 

 

 

 

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Ozanimod, RPC1063

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Jul 292015
 

 

ChemSpider 2D Image | 5-(3-{(1S)-1-[(2-Hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile | C23H24N4O3

cas 1306760-87-1

Ozanimod, RPC1063

Receptos, Inc.  INNOVATOR

IUPAC/Chemical name: (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Benzonitrile, 5-(3-((1S)-2,3-dihydro-1-((2-hydroxyethyl)amino)-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-(1-methylethoxy)-

SMILES: N#CC1=CC(C2=NC(C3=CC=CC4=C3CC[C@@H]4NCCO)=NO2)=CC=C1OC(C)C

C23H24N4O3
Molecular Weight: 404.46
Elemental Analysis: C, 68.30; H, 5.98; N, 13.85; O, 11.87

Ozanimod is a selective sphingosine 1 phosphate receptor modulators and methods which may be useful in the treatment of S1P1-​associated diseases. ozanimod, a sphingosine-1-phosphate receptor 1 (S1P1) agonist in Phase III studies as a treatment for ulcerative colitis and multiple sclerosis (MS). Although Novartis’s S1P1 modulator Gilenya has been available to treat MS since 2010,

Relapsing multiple sclerosis (RMS) is a chronic autoimmune disorder of the central nervous system (CNS), characterized by recurrent acute exacerbations (relapses) of neurological dysfunction followed by variable degrees of recovery with clinical stability between relapses (remission). The CNS destruction caused by autoreactive lymphocytes can lead to the clinical symptoms, such as numbness, difficulty walking, visual loss, lack of coordination and muscle weakness, experienced by patients. The disease invariably results in progressive and permanent accumulation of disability and impairment, affecting adults during their most productive years. RMS disproportionately affects women, with its peak onset around age 30. In the past, the treatments for RMS were generally injectable agents with significant side effects. There is a substantial market opportunity for effective oral RMS therapies with improved safety and tolerability profiles.

RPC1063 is a novel, orally administered, once daily, specific and potent modulator of the sphingosine 1-phosphate 1 receptor (S1P1R) pathway. The S1P1R is expressed on white blood cells (lymphocytes), including those responsible for the development of disease. S1P1R modulation causes selective and reversible retention, or sequestration, of circulating lymphocytes in peripheral lymphoid tissue. This sequestration is achieved by modulating cell migration patterns (known as “lymphocyte trafficking”), specifically preventing migration of autoreactive lymphocytes to areas of disease inflammation, which is a major contributor to autoimmune disease. S1P1R modulation may also involve the reduction of lymphocyte migration into the central nervous system (CNS), where certain disease processes take place. This therapeutic approach diminishes the activity of autoreactive lymphocytes that are the underlying cause of many types of autoimmune disease.

O3

WO 2015066515

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015066515&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Scheme 3:

 

Reagents: (i) (a) MsCl, pyridine; (b) TsCl, pyridine; (c) NsCl, pyridine; (d) SOCl2, DCM; (e) SOCl2, pyridine, DCM; (f) NaN3, PPh3, CBr4; (ii) (a) DIEA, DMA, HNR’R”; (b) DIEA, NaBr or Nal, DMA, HNR’R”.

Enantiomerically enriched material can be prepared in the same manner outlined in Scheme 3 using the (R)- or (5)-indanols.

Scheme 4:

 

Reagents: (i) Zn(CN)2, Pd(PPh3)4, NMP; (ii) (i?)-2-methylpropane-2-sulfmamide, Ti(OEt)4, toluene; (iii) NaBH4, THF; (iv) 4M HCl in dioxane, MeOH; (v) Boc20, TEA, DCM; (vi) NH2OH HCl, TEA, EtOH; (vii) HOBt, EDC, substituted benzoic acid, DMF (viii) 4M HCl in dioxane; (ix) (a) R’-LG or R”-LG, where LG represents a leaving group, K2C03, CH3CN; (b) R -C02H or R2-C02H, HOBt, EDC, DMF or R -COCl or R2-COCl, TEA, DCM; (c) R -S02C1 or R3-S02C1, TEA, DCM (d) R2-CHO, HO Ac, NaBH4 or NaCNBH3 or Na(OAc)3BH, MeOH; (e) R -OCOCl or R2-OCOCl, DIEA, DMF; (f) HN(R5R5), CDI, TEA, DCM; (g) H2NS02NH2, Δ, dioxane; (h)

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2 ,3-dihydro- lH-inden- 1-yl)carbamate INT-16)

 

Prepared using General Procedure 9. To a flame-dried flask under N2 was added {R)-tert- vXy\ 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 (8.3 g, 32.1 mmol) in anhydrous DMF (240 mL). The reaction mixture was cooled to 0°C and sodium hydride (3.8 g, 60% in oil, 160.6 mmol) was added portionwise. After stirring at 0°C for 2.75 h, (2-bromoethoxy)(tert-butyl)dimethylsilane (16.9 mL, 70.7 mmol) was added. The ice bath was removed after 5 mins and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was quenched by the slow addition of sat. NaHC03 at 0°C. Once gas evolution was complete the reaction was extracted with EA. The organic layers were washed with water and brine, dried over MgS04 and concentrated. The product was purified by chromatography (EA / hexanes) to provide 10.76 g (80%) of {R)-tert-bvXy\ 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 as a colorless oil. LCMS-ESI (m/z) calculated for C23H36N203Si: 416.6; found 317.2 [M-Boc]+ and 439.0 [M+Na]+, tR = 4.04 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.46 (d, J = 7.6, 1H), 7.38- 7.32 (m, 1H), 7.33 – 7.18 (m, 1H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 3.70 (ddd, J = 48.8, 26.6, 22.9, 1.5 H), 3.50 – 3.37 (m, 1H), 3.17 (ddd, J = 16.7, 9.4, 2.2, 2H), 2.93 (m, 1.5 H), 2.45 (s, 1H), 2.21 (dd, J = 24.5, 14.5, 1H), 1.56 – 1.37 (bs, 4.5H), 1.22 (bs, 4.5H), 0.87 – 0.74 (m, 9H), -0.04 (dd, J = 26.6, 8.2, 6H). 13C NMR (101 MHz, CDC13) δ 155.03, 146.55, 145.54, 131.16, 130.76, [128.11, 127.03], 117.58, 109.20, 79.88, [63.93, 61.88], [61.44, 60.34], [49.73, 46.76], 30.30, 29.70, 28.44, 28.12, [25.87, 25.62], -5.43. (5)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro- 1 H-inden- 1 -yl)carbamate INT- 17 is prepared in an analogous fashion using INT-9.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate (INT-18)

 

 

Prepared using General Procedure 3. To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 (12.0 g, 28.9 mmol) in EtOH (120 mL), under an atmosphere of N2 was added hydroxylamine-HCl (6.0 g, 86.5 mmol) and triethylamine (13.4 mL, 9.7 g, 86.5 mmol). The reaction mixture was refluxed at 80°C for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness and then diluted with DCM (500 mL). The organic layer was washed with NaHC03, water, and brine. The combined organic layers were dried over MgSC^ and concentrated to produce 11.8 g of {R)-tert- vXy\ 2-(tert-butyldimethylsilyloxy) ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 as a white foamy solid, which was used without purification in the next experiment. LCMS-ESI (m/z) calculated for C23H39N304Si: 449.7; found 350.2 [M-Boc]+ and 472.2 [M+Na]+, tR = 1.79 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.32 (t, J= 7.3 Hz, 1H), 7.21 – 7.07 (m, 2H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 4.89 (s, 2H), 3.85 – 3.50 (m, 2H), 3.31 (ddd, J = 12.2, 9.2, 2.5 Hz, 2H), 3.28 – 3.03 (m, 2H), 3.03 – 2.70 (m, 1H), 2.29 (t, J= 23.6 Hz, 1H), 1.43 (bs, 4.5H), 1.28 (bs, 4.5H), 1.16 – 1.04 (m, 1H), 0.90 – 0.71 (m, 9H), 0.08 – -0.14 (m, 6H). 13C NMR (101 MHz, CDC13) δ 170.99, [156.20, 155.62], 152.38, [144.53, 143.57], [141.82, 141.21], 129.61, 126.78, [126.59, 126.25], [125.02, 124.77], [79.91, 79.68], 64.04, 61.88, [61.57, 61.23], [46.03, 45.76], 30.76, 30.21, [28.53, 28.28], 25.95, [25.66, 25.29], 25.13, [18.28, 17.94], 3.72, -5.34. (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate INT-19 is prepared in an analogous fashion using INT- 17.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl)carbamate and (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl) (2-hydroxethyl) carbamate

 

 

Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (4.5 g, 21.9 mmol) in anhydrous DMF (100 mL) was added HOBt (5.4 g, 40.0 mmol) and EDC (5.6 g, 29.6 mmol). After 1 h, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT- 18 (11.8 g, 26.3 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy) ethyl (4-(N-(3-cyano-4-isopropoxybenzoyloxy) carbamimidoyl)-2,3-dihydro-7H-inden-l-yl)carbamate INT-20. The reaction mixture was then heated to 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with EA (250 mL). NaHC03 (250 mL) and water (350 mL) were added until all the solids dissolved. The mixture was extracted with EA and the organic layers washed successively with water and brine. The organic layers were dried over MgS04 and concentrated to produce 15.3 g of a mixture of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5 -(3 -cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)- 2,3-dihydro-iH-inden-l-yl) carbamate INT-21, and the corresponding material without the TBS protecting group, {R)-tert-bvXy\ 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxy ethyl) carbamate INT-22. The mixture was a brown oil, which could used directly without further purification or purified by chromatography (EA/hexane). INT-21: LCMS-ESI (m/z) calculated for C34H46N405Si: 618.8; found 519.2 [M-Boc]+ and 641.3 [M+Na]+, tR = 7.30 min (Method 1). 1H NMR (400 MHz, CDC13) δ 8.43 (d, J =

2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.07 (d, J= 8.1, 1H), 7.46 – 7.26 (m, 2H), 7.12 (d, J = 9.0, 1H), 5.85 (s, 0.5H), 5.37 (s, 0.5H), 4.80 (dt, J = 12.2, 6.1, 1H), 3.92 – 3.32 (m, 3.5 H), 3.17 (s, 2H), 2.95 (s, 0.5 H), 2.62 – 2.39 (m, 1H), 2.38 – 2.05 (m, 1H), 1.53 (s, 4.5H), 1.48 (d, J = 6.1, 6H), 1.33 – 1.27 (m, 4.5H), 0.94 – 0.77 (m, 9H), 0.01 (d, J = 20.9, 6H). 13C NMR (101 MHz, DMSO) δ 173.02, 169.00, 162.75, [156.22, 155.52], [145.18, 144.12], [143.39, 142.76], 134.16, 133.89, 128.20, [128.01, 127.85], [127.04, 126.90], 126.43, 123.31, 116.93, 115.30, 113.55, 103.96, [79.95, 79.68], 72.73, 67.61, 63.42, [61.91, 61.77], 60.99, 46.11, 31.78, [30.47, 29.87], [28.55, 28.26], 25.93, 21.75, 18.30, 0.00, -5.37. INT-22: LCMS-ESI calculated for C28H32N405: 504.6; found 527.2 [M+Na]+, tR = 2.65 min (Method 1). 1H NMR (400 MHz, CDC13) δ 8.36 (d, J = 2.1, 1H), 8.27 (dd, J = 8.9, 2.2, 1H), 8.03 (d, J = 7.2, 1H), 7.35 – 7.26 (m, 2H), 7.06 (d, J = 9.0, 1H), 5.44 (s, 1H), 4.73 (dt, J= 12.2, 6.1, 1H), 3.64 (s, 2H), 3.44 (ddd, J= 17.5, 9.5,

3.2, 2H), 3.11 (dt, J = 17.4, 8.6, 3H), 2.54 – 2.38 (m, 1H), 2.04 (td, J = 17.6, 8.8, 1H), 1.50 – 1.24 (m, 15H).

(S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-23 and {S)-tert- vXy\ 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT-24 were made in an analogous fashion.

 (S) IS DESIRED CONFIGURATION

……………………………………

(S)-tert-Butanesulfinamide

(S)-(−)-2-Methyl-2-propanesulfinamide 97%CAS 343338-28-3

 

3-CYANO-4-ISOPROPOXYBENZOIC ACID Structure3-CYANO-4-ISOPROPOXYBENZOIC ACID;3-cyano-4-(propan-2-yloxy)benzoic acid;5-(1-hydroxyvinyl)-2-isopropoxybenzonitrile

cas 258273-31-3

 

(S)-1-Amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride

cas 1306763-57-4 HCl, 1213099-69-4 FREE BASE

 

4-bromo-2,3-dihydro-1H-inden-1-one

4-bromo-2,3-dihydro-1H-inden-1-one

cas 15115-60-3

 

O4S CONFIGURATION

Carbamic acid, N-​[(1S)​-​4-​cyano-​2,​3-​dihydro-​1H-​inden-​1-​yl]​-​, 1,​1-​dimethylethyl ester, cas 1306763-31-4

 

(S) IS DESIRED CONFIGURATION

……………….

 

O10

CAS 1306763-70-1, Carbamic acid, N-​[(1S)​-​2,​3-​dihydro-​4-​[(hydroxyamino)​iminomethyl]​-​1H-​inden-​1-​yl]​-​, 1,​1-​dimethylethyl ester

…………………

O11

CAS 1306763-71-2, Carbamic acid, N-​[(1S)​-​4-​[5-​[3-​cyano-​4-​(1-​methylethoxy)​phenyl]​-​1,​2,​4-​oxadiazol-​3-​yl]​-​2,​3-​dihydro-​1H-​inden-​1-​yl]​-​, 1,​1-​dimethylethyl ester

 

O12

1306760-73-5, Benzonitrile, 5-​[3-​[(1S)​-​1-​amino-​2,​3-​dihydro-​1H-​inden-​4-​yl]​-​1,​2,​4-​oxadiazol-​5-​yl]​-​2-​(1-​methylethoxy)​-

………………………..

O13

1306763-63-2,

………………….

86864-60-0, (2-Bromoethoxy)dimethyl-tert-butylsilane

 

Synthesis

O3

……………………………………

WO 2011060392

http://www.google.com/patents/WO2011060392A1?cl=en

(R)-N-(4-cyano-2,3-dihydro-lH-indene-l-ylidene)-2-methylpropane-^

(INT-4

Figure imgf000069_0001

[0304] To l-oxo-2,3-dihydro-/H-indene-4-carbonitrile INT-1 (42.5 g, 0.27 mol) and (R)-2- methylpropane-2-sulfmamide (36.0 g, 0.30 mol) in toluene (530 mL) was added titanium tetraethoxide (84.1 mL, 92.5 g, 0.40 mol) and the reaction mixture was heated at 60°C for 12 h under N2. The crude (R)-N-(4-cyano-2,3-dihydro-lH-indene-l-ylidene)-2-methylpropane- 2-sulfinamide INT-4 was used directly in the next experiment. LCMS-ESI (m/z) calculated for C14Hi6N2OS: 260.3; found 261.1 [M+H]+, tR= 3.19 min.

[0305] (R)-N'((R)-4-cyano-2,3-dihydro-lH nden-l-yl)-2-n thylprop ne-2-sulfirmmide

(INT-5)

Figure imgf000070_0001

[0306] To a flask containing the crude suspension of (R)-N-(4-cyano-2,3-dihydro-iH-indene- l-ylidene)-2-methylpropane-2-sulfrnaniide INT -4 under N2 was added THF (1.0 L) and the reaction mixture cooled to -78°C. Sodium borohydride (40.9 g, 1.08 mol) was added portion- wise over 30 mins. (The internal temperature did not rise during the addition). The reaction mixture was stirred at -78°C for 30 mins, half out of the bath for 30 mins, then warmed to 0°C over 1 h. The 0°C reaction mixture was placed in an ice bath and quenched with brine (100 mL) followed by saturated sodium potassium tartrate (420 mL) and the Ti salts precipitated. The reaction mixture was diluted with EA (1.5 L) and stirred at room temperature overnight. The organic layers were decanted and washed successively with saturated NH4CI, water, and brine. The organic layers were dried over MgS04 and filtered through a pad of MgS04. The filtrate was concentrated to produce 52.9 g of crude (R)-N-((/?)-4-cyano-2,3-dihydro-lH- inden-l-yl)-2-methylpropane-2-sulfmamide INT-5 as a brown oil, which was used directly in the next step. LCMS-ESI (m/z) calculated for C14H18 2OS: 262.3; found 263.1 [M+H]+, tR = 2.99 min. 1H NMR (400 MHz, CDC13) δ 7.89 (d, J = 7.7, 1H), 7.56 (t, J = 6.8, 1H), 7.36 (t, J = 7.7, 1H), 4.97 (q, J = 7.5, 1H), 3.50 (d, J = 7.6, 1H), 3.22 (ddd, J = 16.9, 8.8, 3.9, 1H), 3.01 (dt, J = 22.4, 6.9, 1H), 2.70 – 2.53 (m, 1H), 2.15 – 1.95 (m, 1H), 1.33 – 1.20 (m, 9H).

[0307] (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile (T^T-6)

Figure imgf000070_0002

[0308] To crude (R)-N-((R)-4-cyano-2,3-dihydro-iH-inden-l-yl)-2-methylpropane-2- sulfinamide INT-5 (52.9 g, 0.20 mol) in MeOH (200 mL) was added 4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid refluxed in acetonitrile (500 mL). The resulting white solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile INT-6. LCMS-ESI (m/z) calculated for Ci0H10N2: 158.2; found 142.0 [M-NH2]+, fR = 0.84 min. Ή NMR (400 MHz, DMSO) δ 8.61 (s, 3H), 7.96 (d, J = 7.7, 1H), 7.83 (d, J = 7.5, 1H), 7.52 (t, J = 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J = 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J = 16.6, 8.6, 6.3, 1H), 2.62 – 2.51 (m, 1H), 2.15 – 2.01 (m, 1H). 13C NMR (101 MHz, DMSO) δ 148.09, 141.15, 132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can be prepared by extraction with IN NaHC03and DCM. LCMS-ESI (m/z) calculated for Ci0H10N2: 158.2; found 142.0 [M-NH2]+, tR = 0.83 min. 1H NMR (400 MHz, CDC13) δ 7.52 – 7.38 (m, 2H), 7.23 (dd, 7 = 17.4, 9.8, 1H), 4.35 (t, J = 7.6, 1H), 3.11 (ddd, 7 = 16.8, 8.7, 3.2, 1H), 2.89 (dt, J = 16.9, 8.5, 1H), 2.53 (dddd, J = 12.8, 8.1, 7.3, 3.2, 1H), 1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). 13C NMR (101 MHz, DMSO) δ 150.16, 146.67, 130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, ¾ = 23.02 min. The (S)- enantiomer INT-7 was prepared in an analogous fashion using (5)-2-methylpropane-2- sulfinamide. tR for (S)-enantiomer = 20.17 min.

[0309] (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate (INT-8)

Figure imgf000071_0001

[0310] To ( ?)-l-amino-2,3-dihydro-/H-indene-l-yl)-4-carbonitrile HC1 INT-6 (11.6 g, 59.6 mmol) in DCM (100 mL) at 0°C was added TEA (12.0 mL, 131.0 mmol). To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgS04 and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through a pad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of (/?)-tert-butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 as an off-white solid. LCMS-ESI (m/z) calculated for C15H18N202: 258.3; found 281.1 [M+Na]+, tR = 3.45 min. Elemental Analysis determined for C^H^^O^ C calculated = 69.74%; found = 69.98%. H calculated = 7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. 1H NMR (400 MHz, CDC13) δ 7.64 – 7.49 (m, 2H), 7.34 (dt, / = 7.7, 3.8, 1H), 5.36 – 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J = 16.9, 8.9, 3.3, 1H), 3.02 (dt, J = 25.4, 8.4, 1H), 2.82 – 2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 – 1.44 (m, 9H). 13C NMR (101 MHz, DMSO) δ 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51, 107.76, 77.98, 55.09, 31.88, 29.11, 28.19. Chiral HPLC: (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate was eluted using 2.5% EtOH in hexanes: >99.9% ee, tR = 19.36 min. The (5)- enantiomer INT-9 was prepared in an analogous fashion using (S)-l-amino-2,3-dihydro-7H- indene-l-yl)-4-carbonitrile HC1. tR for (5)-enantiomer = 28.98 min.

General Procedure 3. Preparation oflndane Amide Oximes

[0311] To (R)- or (5)-tert-butyl 4-cyano-2,3-dihydro-7H-inden-l-ylcarbamate (1 eq) in EtOH

(0.56 M) was added hydroxylamine hydrochloride (3 eq) and TEA (3 eq) and the reaction mixture heated at 85°C for 1-2 h. The organic soluble amide oximes were isolated by removal of the solvent and partitioning between water and DCM. The water soluble amide oximes were chromatographed or used directly in the cyclization. Pure amide oximes can be obtained by recrystallization from alcoholic solvents.

[0312] (R)-tert-butyl 4-(N -hydroxy carbamimidoyl )-2, 3-dihydro-lH-inden-l -ylcarbamate

(INT-10)

Figure imgf000072_0001

[0313] Prepared using General Procedure 3. To (R)-tert-butyl 4-cyano-2,3-dihydro-iH- inden-1 -ylcarbamate INT-8 (15.0 g, 58.2 mmol) in EtOH (100 niL) was added hydroxylamine hydrochloride (12.1 g, 174.2 mmol) and TEA (17.6 mL, 174.2 mmol) and the reaction mixture heated at 85°C for 2 h. The solvents were removed and the resulting white solid was partitioned between water and DCM. The organic layers were dried over Na2S04, concentrated, and recrystallized from isopropanol (50 mL) to afford 14.4 g (85%) of (R)-tert- butyl 4-(N-hydroxycarbaniimidoyl)-2,3-dihydro-iH-inden-l-ylcarbamate INT-10 as white crystalline solid. LCMS-ESI (m/z) calculated for C15H21N303: 291.4; found 292.1 [M+H]+, ¾ = 2.04 min. 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.38 – 7.32 (m, 1H), 7.32 – 7.12 (m, 3H), 5.68 (s, 2H), 4.97 (q, J = 8.5, 1H), 3.07 (ddd, J = 16.6, 8.7, 2.6, 1H), 2.86 (dt, J = 16.8, 8.4, 1H), 2.30 (ddd, J = 12.6, 7.6, 3.6, 1H), 1.75 (dq, J = 12.3, 9.0, 1H), 1.44 (s, 9H). General Procedure 4. Cyclization to Indane Oxadiazole Amines

[0314] A solution of the appropriate acid (1 eq), HOBt (1.3 eq), and EDC (1.3 eq) in DMF

(0.08 M in acid) was stirred at room temperature under an atmosphere of N2. After the complete formation of the HOBt- acid complex (1-3 h), the (R)- or (5)-amide oxime (1.1 eq) was added to the mixture. After complete formation of the coupled intermediate (ca. 0.5- 2 h), the mixture was heated to 75-95°C until the cyclization was complete (8-12 h). The reaction mixture was diluted with saturated NaHC03 and extracted with EA. The combined organic extracts were dried, concentrated, and either purified by chromatography (EA/hexanes) or taken on directly. The oxadiazole was treated with HC1 (5N in dioxane, 5 eq) at 50-60°C for 0.5-6 h. The reaction mixture could be extracted (DCM /NaHC03), or the resulting HC1 salt concentrated, suspended in Et20, and collected. Pure indane amines can be obtained by recrystallization from alcoholic solvents or by chromatography.

( R)-tert-butyl 4-(5-( 3-cyano-4-isopropoxyphenyl)-l,2, 4-oxadiazol-3-yl )-2,3-dihydro-lH- inden-l-ylcarbamate (INT- 12)

Figure imgf000073_0001

[0315] Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (7.74 g, 37.7 mmol) in DMF (50 mL) was added HOBt (6.02 g, 44.6 mmol) and EDC (8.53 g, 44.6 mmol) at room temperature. The reaction was stirred for 2 h until complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3- dihydro-iH-inden-l-ylcarbamate INT-10 (10.0 g, 34.3 mmol) was added and the reaction mixture stirred at room temperature for 2 h until the formation of INT-11, (R)-tert-butyl 4- (N-(3-cyano-4-isopropoxybenzolyloxy) carbamimidoyl)-2,3-dihydro-iH-inden-l- ylcarbamate. The mixture was partitioned between EA and NaHC03 and the organic layer was collected and dried over MgS04. INT-11 (16.3 g, 34.0 mmol) was re-dissolved in DMF (50 mL) and the mixture was heated to 95°C for 12 hrs. The reaction was diluted with NaHC03 (200 mL) and extracted with EA (3 X 50 mL). The organic layer was dried over Na2S04and concentrated under reduced pressure to produce 12.8 g (81%) of (R)-tert-butyl 4- (5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden- 1-ylcarbamate INT-12 as a light brown solid and used without further purification in the next step. LCMS- ESI (m/z) calculated for C26H28N404: 460.5; found 483.2 [M+Na]+, tR = 4.25 min. Ή NMR (400 MHz, CDCI3) δ 8.43 (d, J = 2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.09 (d, J = 7.6, 1H), 7.51 (d, / = 7.5, 1H), 7.39 (t, J = 7.6, 1H), 7.12 (d, J = 9.0, 1H), 5.28 (d, J = 8.2, 1H), 4.80 (hept, J = 6.0, 1H), 3.47 (ddd, J = 17.4, 8.9, 3.5, 1H), 3.27 – 3.03 (m, 1H), 2.68 (d, J = 8.7, 1H), 1.87 (td, J = 16.7, 8.5, 1H), 1.53 – 1.43 (m, 15H). 13C NMR (101 MHz, CDC13) δ 173.00, 168.82, 162.70, 155.68, 145.31, 142.96, 134.05, 133.83, 128.25, 127.21, 126.79, 123.09, 116.78, 115.24, 113.52, 103.87, 79.52, 72.70, 55.72, 33.86, 31.47, 28.39, 21.70. Chiral HPLC: (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-lH-inden-l-ylcarbamate was eluted using 20% /-PrOH in hexanes: >99.9% ee, ?R = 13.33 min. The (5)-enantiomer INT-13 was prepared in an analogous fashion using (S)-tert- butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate using General Procedures 3 and 4 (tR for (Syenantiomer = 16.31 min).

 

( R )-5-( 3-(l -amino-2,3-dihydro-lH-inden-4-yl)-l,2, 4-oxadiazol-5-yl)-2-isopropoxy- benzonitrile h drochloride (Compound 49)

 

Figure imgf000074_0001

[0317] To (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-iH-inden-l-ylcarbamate(12.8 g, 27.8 mmol) in dioxane (200 mL) was added 4N HCl in dioxane (69 mL). The solution was heated to 55°C for 1 h, and product precipitated. Dioxane was removed and the resulting solid suspended in ether and collected. The material was recrystallized from MeOH (200 mL) to produce 8.11 g (81%) of (R)-5-(3-(l-amino-2,3- dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 as the HCl salt. LCMS-ESI (m/z): calcd for: C21H20N4O2: 360.4; found 383.2 [M+Na]+, tR = 2.49 min. Elemental Analysis and NMR spectra determined for C21H21N402C1 * 0.5 H20; C calculated = 62.14%; found = 62.25%. H calculated = 5.46%; found = 5.30%. N calculated = 13.80%; found = 13.84%. CI calculated = 8.73%; found = 8.34%. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 3H), 8.49 (d, J = 2.3, 1H), 8.39 (dd, J = 9.0, 2.3, 1H), 8.11 (d, J = 7.6, 1H), 7.91 (d, J = 7.6, 1H), 7.55 (t, J = 8.5, 2H), 4.97 (hept, J = 6.1, 1H), 4.80 (s, 1H), 3.47 (ddd, J = 17.4, 8.7, 5.3, 1H), 3.23 (ddd, 7 = 17.4, 8.6, 6.4, 1H), 2.55 (ddd, 7 = 13.7, 8.3, 3.2, 1H), 2.22 – 1.97 (m, 1H), 1.38 (d, J = 6.0, 6H). 13C NMR (101 MHz, CDC13) δ 173.28, 167.98, 162.53, 143.69, 141.29, 134.59, 133.80, 128.93, 128.11, 127.55, 122.72, 115.87, 115.24, 114.91, 102.46, 72.54, 54.38, 31.51, 29.91, 21.47. Chiral HPLC of the free base: (R)-5-(3-(l-amino-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile was eluted using 15% i‘-PrOH in hexanes plus 0.3% DEA: > 99.9% ee, tR = 30.80 min.

(S)- 5-(3-(l-amino-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy-benzonitrile 50 was prepared in an analogous fashion from (S)-tert-b tyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate: >99.9% ee, tR for (5)-enantiomer = 28.58 min.

 

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-lH-inden-l- yl)carbamate ( -16)

Figure imgf000087_0001

[0366] Prepared using General Procedure 9. To a flame-dried flask under N2 was added (R)- tert-butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 (8.3 g, 32.1 mmol) in anhydrous DMF (240 mL). The reaction mixture was cooled to 0°C and sodium hydride (3.8 g, 60% in oil, 160.6 mmol) was added portionwise. After stirring at 0°C for 2.75 h, (2- bromoethoxy)(½rt-butyl)dimethylsilane (16.9 mL, 70.7 mmol) was added. The ice bath was removed after 5 mins and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was quenched by the slow addition of sat. NaHC03at 0°C. Once gas evolution was complete the reaction was extracted with EA. The organic layers were washed with water and brine, dried over MgS04 and concentrated. The product was purified by chromatography (EA / hexanes) to provide 10.76 g (80%) of (R)-teri-butyl 2-(tert- butyldimemylsilyloxy)emyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 as a colorless oil. LCMS-ESI (m/z) calculated for C23H36N203Si: 416.6; found 317.2 [M-Boc]+ and 439.0 [M+Na]+, tR = 4.04 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.46 (d, J = 7.6, 1H), 7.38- 7.32 (m, 1H), 7.33 – 7.18 (m, 1H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 3.70 (ddd, J = 48.8, 26.6, 22.9, 1.5 H), 3.50 – 3.37 (m, 1H), 3.17 (ddd, J = 16.7, 9.4, 2.2, 2H), 2.93 (m, 1.5 H), 2.45 (s, 1H), 2.21 (dd, J = 24.5, 14.5, 1H), 1.56 – 1.37 (bs, 4.5H), 1.22 (bs, 4.5H), 0.87 – 0.74 (m, 9H), -0.04 (dd, J = 26.6, 8.2, 6H).13C NMR (101 MHz, CDC13) δ 155.03, 146.55, 145.54, 131.16, 130.76, [128.11, 127.03], 117.58, 109.20, 79.88, [63.93, 61.88], [61.44, 60.34], [49.73, 46.76], 30.30, 29.70, 28.44, 28.12, [25.87, 25.62], -5.43. (5)-tert-butyl 2-(tert- butyldimemylsilyloxy)emyl(4-cyano-2,3-dihydro-lH-inden-l-yl)carbamate INT-17 is prepared in an analogous fashion using INT -9. [0367] (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3- dihydro-1 H-inden-1 -yl)carbamate (INT-18)

Figure imgf000088_0001

[0368] Prepared using General Procedure 3. To a solution of (R)-iert-butyl 2-(tert- butyldimemylsilyloxy)ethyl(4-cyano-2,3-dmydro-/H-inden-l-yl)carbamate INT-16 (12.0 g, 28.9 mmol) in EtOH (120 mL), under an atmosphere of N2 was added hydroxylamine-HCl (6.0 g, 86.5 mmol) and triemylamine (13.4 mL, 9.7 g, 86.5 mmol). The reaction mixture was refluxed at 80°C for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness and then diluted with DCM (500 mL). The organic layer was washed with NaHC03, water, and brine. The combined organic layers were dried over MgS04 and concentrated to produce 11.8 g of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy) ethyl (4-(N- hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 as a white foamy solid, which was used without purification in the next experiment. LCMS-ESI (m/z) calculated for C23H39N304Si: 449.7; found 350.2 [M-Boc]+ and 472.2 [M+Na]+, ¾ = 1.79 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.32 (t, / = 7.3 Hz, 1H), 7.21 – 7.07 (m, 2H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 4.89 (s, 2H), 3.85 – 3.50 (m, 2H), 3.31 (ddd, / = 12.2, 9.2, 2.5 Hz, 2H), 3.28 – 3.03 (m, 2H), 3.03 – 2.70 (m, 1H), 2.29 (t, J = 23.6 Hz, 1H), 1.43 (bs, 4.5H), 1.28 (bs, 4.5H), 1.16 – 1.04 (m, 1H), 0.90 – 0.71 (m, 9H), 0.08 – -0.14 (m, 6H). 13C NMR (101 MHz, CDC13) 6 170.99, [156.20, 155.62], 152.38, [144.53, 143.57], [141.82, 141.21], 129.61, 126.78, [126.59, 126.25], [125.02, 124.77], [79.91, 79.68], 64.04, 61.88, [61.57, 61.23], [46.03, 45.76], 30.76, 30.21, [28.53, 28.28], 25.95, [25.66, 25.29], 25.13, [18.28, 17.94], 3.72, -5.34. ^-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N- hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate INT-19 is prepared in an analogous fashion using INT-17. [0369] (R)-tert-butyl 2-( tert-butyldimethylsilyloxy)ethyl( 4-( 5-( 3-cyano-4-isopropoxyphenyl)- l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl)carbamate and (R)-tert-butyl 4-(5-(3-cyano- 4-isopropoxyphenyl )-l,2, 4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl) (2-hydroxethyl) carbamate

Figure imgf000089_0001

[0370] Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (4.5 g, 21.9 mmol) in anhydrous DMF (100 mL) was added HOBt (5.4 g, 40.0 mmol) and EDC (5.6 g, 29.6 mmol). After 1 h, {R)-tert-buiy\ 2-(tert-butyldimethylsilyloxy)ethyl (4- (N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 (11.8 g, 26.3 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate, (R)-tert-b\xty\ 2-(tert- butyldimethylsilyloxy) ethyl (4-(N-(3-cyano-4-isopropoxybenzoyloxy) carbamimidoyl)-2,3- dihydro-7H-inden-l-yl)carbamate INT-20. The reaction mixture was then heated to 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with EA (250 mL). NaHC03 (250 mL) and water (350 mL) were added until all the solids dissolved. The mixture was extracted with EA and the organic layers washed successively with water and brine. The organic layers were dried over MgS04 and concentrated to produce 15.3 g of a mixture of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4- oxadiazol-3-yl)- 2,3-dihydro-iH-inden-l-yl) carbamate INT-21, and the corresponding material without the TBS protecting group, (R)-tert-butyl 4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT -22. The mixture was a brown oil, which could used directly without further purification or purified by chromatography (EA hexane). INT-21: LCMS-ESI (m/z) calculated for C34H46N4O5S1: 618.8; found 519.2 [M-Boc]+ and 641.3 [M+Na]+, tR = 7.30 min (Method 1). Ή NMR (400 MHz, CDC13) δ 8.43 (d, J = 2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.07 (d, J = 8.1, 1H), 7.46 – 7.26 (m, 2H), 7.12 (d, / = 9.0, 1H), 5.85 (s, 0.5H), 5.37 (s, 0.5H), 4.80 (dt, J = 12.2, 6.1, 1H), 3.92 – 3.32 (m, 3.5 H), 3.17 (s, 2H), 2.95 (s, 0.5 H), 2.62 – 2.39 (m, 1H), 2.38 – 2.05 (m, 1H), 1.53 (s, 4.5H), 1.48 (d, J = 6.1, 6H), 1.33 – 1.27 (m, 4.5H), 0.94 – 0.77 (m, 9H), 0.01 (d, J = 20.9, 6H). 1C NMR (101 MHz, DMSO) δ 173.02, 169.00, 162.75, [156.22, 155.52], [145.18, 144.12], [143.39, 142.76], 134.16, 133.89, 128.20, [128.01, 127.85], [127.04, 126.90], 126.43, 123.31, 116.93, 115.30, 113.55, 103.96, [79.95, 79.68], 72.73, 67.61, 63.42, [61.91, 61.77], 60.99, 46.11, 31.78, [30.47, 29.87], [28.55, 28.26], 25.93, 21.75, 18.30, 0.00, -5.37. INT-22: LCMS-ESI calculated for C28H32N4Os: 504.6; found 527.2 [M+Na]+, tR = 2.65 min (Method 1). Ή NMR (400 MHz, CDC13) δ 8.36 (d, J = 2.1, 1H), 8.27 (dd, / = 8.9, 2.2, 1H), 8.03 (d, / = 7.2, 1H), 7.35 – 7.26 (m, 2H), 7.06 (d, / = 9.0, 1H), 5.44 (s, 1H), 4.73 (dt, J = 12.2, 6.1, 1H), 3.64 (s, 2H), 3.44 (ddd, / = 17.5, 9.5, 3.2, 2H), 3.11 (dt, J = 17.4, 8.6, 3H), 2.54 – 2.38 (m, 1H), 2.04 (td, J = 17.6, 8.8, 1H), 1.50 – 1.24 (m, 15H). (5 -teri-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-23 and (S)-terf-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH- inden-l-yl) (2-hydroxyethyl) carbamate INT -24 were made in an analogous fashion.

[0371] (R)-5-(3-(l-(2-hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl)-l,2,4-oxadi zol-^ 2-isopropoxybenzonitrile (Compound 85)

Figure imgf000090_0001

[0372] To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-7H-inden-l-yl)carbamate INT-21 and (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro-iH- inden-l-yl) (2-hydroxethyl) carbamate INT-22 (13.9 g, 27.5 mmol) in dioxane (70 mL) at 0°C was added 4N HCl in dioxane (68.8 g, 275.4 mmol). The reaction mixture was warmed to room temperature and then heated to 50°C for 1 h. The resulting suspension was cooled to room temperature and Et20 (75 mL) was added. The precipitate was collected by filtration, washed with Et20 and dried to produce 10.5 g of an off-white solid. The HCl salt was recrystallized from MeOH (165 mL) to produce 5.98 g (56% overall yield from (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl) carbamate) of (R)-5- (3-(l-(2-hydroxyethylamino)-2,3-dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2- isopropoxybenzonitrile 85 as a white solid. LCMS-ESI (m/z) calculated for C23H24N403: 404.5; found 405.4 [M+H]+, tR = 2.44 min. Ή NMR (400 MHz, DMSO) 5 9.25 (s, 2H), 8.53 (d, J = 2.3, 1H), 8.42 (dd, J = 9.0, 2.3, 1H), 8.17 (d, J = 7.7, 1H), 7.97 (d, J = 7.6, 1H), 7.63 – 7.50 (m, 2H), 5.28 (t, J = 5.0, 1H), 4.99 (hept, J = 6.1, 1H), 4.92 (s, 1H), 3.72 (q, J = 5.2, 2H), 3.57 – 3.43 (m, 1H), 3.27 (ddd, J = 17.6, 9.1, 5.0, 1H), 3.15-2.85 (m, J = 24.2, 2H), 2.53 (dtd, J = 9.0, 5.5, 5.3, 3.6, 1H), 2.30 (ddd, J = 13.4, 8.9, 4.6, 1H), 1.39 (d, J = 6.0, 6H). 13C NMR (101 MHz, DMSO) 6 173.25, 167.86, 162.47, 144.56, 139.13, 134.53, 133.77, 129.30, 128.93, 127.45, 122.83, 115.79, 115.15, 114.84, 102.40, 72.46, 61.04, 56.51, 46.38, 31.53, 27.74, 21.37. Elemental analysis for C23H25N403C1: C calc. = 62.65%; found = 62.73%; H calc. = 5.71%; found = 5.60%; N calc. = 12.71%; found = 12.64%; CI calc. = 8.04%; found = 8.16%. Chiral HRLC of the free base: (R)-5-(3-(l-(2-hydroxyemylamino)-2,3-dihydro-iH- inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy – benzo-nitrile was eluted using 10% i‘-PrOH in hexanes plus 0.3% DEA: >99.9% ee, tR = 37.72 min.

(S)-5-(3-(l-(2-hydroxyethylamino)- 2,3-dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl) -2-isopropoxy benzonitrile 86 was obtained in analogous fashion from (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3- cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2, 3-dihydro-iH-inden- 1 -yl)carbamate INT-23 and (S)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT-24: >99.9% ee, tR for (5)- enantiomer = 35.86 min.

(S) IS DESIRED CONFIGURATION

 

THE SYNTHESIS IS SUMMARISED BELOW

O7

 

COSY PREDICT

COSY NMR prediction

 

 

1H NMR PREDICT

O8

 

O9

 

13C NMR PREDICT

Predict 13C GRAPH

 

13-C-NMR-VALUES

note——-(CH3 )2CH-O-AR appears at 72 ppm

 

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ROSAPROSTOL

 Uncategorized  Comments Off on ROSAPROSTOL
Jul 292015
 

 

Rosaprostol

Rosaprostol
CAS Registry Number: 56695-65-9
CAS Name: 2-Hexyl-5-hydroxycyclopentaneheptanoic acid
Additional Names: 9-hydroxy-19,20-bisnorprostanoic acid
Manufacturers’ Codes: C-83; IBI-C83
Trademarks: Rosal (IBI)
Molecular Formula: C18H34O3
Molecular Weight: 298.46
Percent Composition: C 72.44%, H 11.48%, O 16.08%

Rosal.png

Derivative Type: Sodium salt
CAS Registry Number: 56695-66-0
Molecular Formula: C18H33NaO3
Molecular Weight: 320.44
Percent Composition: C 67.47%, H 10.38%, Na 7.17%, O 14.98%
Properties: White solid. LD50 orally in mice: ~3000 mg/kg (Valcavi, 1978); orally in rats: >5 g/kg (Valcavi, 1982).
Toxicity data: LD50 orally in mice: ~3000 mg/kg (Valcavi, 1978); orally in rats: >5 g/kg (Valcavi, 1982)
Therap-Cat: Antiulcerative.

ROS1

 

ROS2

 

ROS3

ROS4

ROS5

ROS6

ROS7

ROS8

ROS9

ROS10ROS11

 

ROS101

J. Org. Chem. 1998, 63, 8894-8897

http://pubs.acs.org/doi/pdf/10.1021/jo981120g

Abstract Image

A total synthesis of racemic rosaprostol, an untiulcer drug, has been achieved in seven synthetic steps and in 42% overall yield starting from dimethyl methanephosphonate. The key steps include intramolecular carbenoid cyclization of dimethyl 1-diazo-2-oxoundecanephosphonate 4 leading to 2-dimethoxyphosphoryl-3-hexylcyclopentanone 5 and the Horner−Wittig reaction of the latter with methyl 5-formylpentanecarboxylate 6 employed for the introduction of the methoxycarbonylhexyl moiety at C(2) of the cyclopentanone ring

1 (0.076 g, 95%) as a mixture of trans-trans and trans-cis isomers: Rf ) 0.18 and 0.23 (petroleum ether/Et2O/ AcOH 8:8:0.1);

1H NMR δ 4.19-4.10 (m, 1H), 3.92-3.80 (m, 1H), 2.18 (t, J ) 7.3, 4H), 2.10-1.96 (m, 1H), 1.82-0.85 (m, 51H), 0.93 (t, J ) 6.6, 6H);

13C NMR δ 180.13, 79.93, 75.13, 55.09, 52.71, 45.71, 43.02, 37.15, 36.33, 35.23, 34.95, 34.71, 34.61, 33.03, 30.86, 30.77, 30.69, 30.48, 30.12, 30.03, 29.53, 29.48, 29.21, 28.79, 28.67, 25.68, 23.81, 15.06;

HRMS (CI) (M + H – H2O)+ calcd for C18H33O2 281.2480, obsd 281.2476.

 

ROS100

 

References: Prostaglandin analog. Prepn, hypolipemic, platelet aggregation inhibitory activity: U. Valcavi, DE 2535343,eidem, US 4073938 (1976, 1978 both to Ist. Biochim. Ital.).

Alternate process: V. Marotta, G. Zabban, EP 155392 (1985 to Ist. Biochim. Ital.).

Gastric antisecretory, cytoprotective activity: U. Valcavi et al., Arzneim.-Forsch. 32, 657 (1982).

Effect on mucus and gastrin secretion in duodenal ulcer: D. Foschi et al., Prostaglandins Leukotrienes Med. 15, 147 (1984). Comparison with cimetidine, q.v.: eidem, Drugs Exp. Clin. Res. 10, 427 (1984).

Clinical evaluation in treatment of ulcers: G. P. Tincani et al.,Minerva Med. 78, 847 (1987).

 

 

 

 

 

 

 

 

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Telescoping multistep reactions

 PROCESS, SYNTHESIS  Comments Off on Telescoping multistep reactions
Jul 292015
 

 

Telescoping multistep reactions

The synthesis of fine chemicals sometimes requires multiple reactions and tedious work-up between each step is often necessary. Purification may involve the addition of a quenching reagent, multiple aqueous and organic extractions, the addition of a drying agent, filtration, evaporation, and further purification by chromatography, distillation, or recrystallization. These operations all require significant input of energy and materials that ultimately end up as large amounts of waste. Methods and technologies that eliminate or simplify one or many of these steps can make a significant influence on the environmental impact of a multistep chemical synthesis. Continuous processing is particularly suitable for ‘telescoping’ reaction sequences, and many methods have been developed to facilitate this.1

One strategy utilizes solid supported reagents packed into columns which allow starting materials to flow in and product to be collected at the outlet without requiring separation of the spent reagent. Different columns may be linked in series, allowing multistep processes to take place. Extra operations may also be necessary, such as solvent changes or the removal of unwanted side products. Methods for automating these processes have also been developed. An example from the Ley group illustrates many of these technologies in the design of a single apparatus to continuously prepareImatinib (Gleevec) from simple starting materials (Scheme 1).2Acid chloride 5 and aniline 6 in DCM were flowed through a cartridge containing immobilized DMAP as a nucleophilic catalyst, followed by a basic cartridge to scavenge any remaining 5. The formation of the amide 7 was monitored by an in-line UV spectrometer and subsequently added to a vial containing piperazine 8 in DMF at 50 °C, which facilitated evaporation of the DCM. Once a particular amount of 7 was obtained, as indicated by the UV spectrometer, a connected autosampler would collect this solution and pump it through an immobilized base to induce a substitution reaction, followed by an immobilized isonitrile to scavenge any remaining 8. An immobilized acid was used to ‘catch’ amine 9 through protonation, allowing unreacted 7 to go to waste. ‘Release’ of 9 through deprotonation followed by the addition of aniline 10 and a palladium catalyst facilitated a cross-coupling reaction, furnishing the crude Imatinib, which was then evaporated onto a silica gel column for automated chromatography. Pure product was isolated in 32% overall yield and >95% purity. While not explicitly demonstrated, the possibility of using this apparatus to form analogs by using modified starting materials is proposed. The ability to perform multi-step synthesis of pharmaceuticals without handling of the intermediates is particularly interesting, as exposure to these species can be hazardous.

 

Multistep synthesis of Imatinib (Gleevec).49
Scheme 1 Multistep synthesis of Imatinib (Gleevec).

The above example utilizes packed cartridges of scavengers to effect purification. An alternative method is to more closely emulate typical batch purification operations such as distillation andextraction, but on a small, continuous scale. Several different ‘chip’ purification devices have been developed for this purpose.3-12 Some of these technologies were used together in a combined triflation/Heck reaction of phenols (Scheme2). After the initial triflation step in dichloromethane, the product is combined with a stream of aqueous HCl and passed on to a chip containing a membrane that allows the organic phase to pass through while the aqueous stream is passed to waste. The purified triflate then combines with a stream of DMF and the material enters a distillation device heated to 70 °C which allows the volatile dichloromethane to be carried out of the reactor with a stream of nitrogen gas. The product then enters a final reactor where it combines with a stream ofalkene and catalyst to form the Heck product. The whole reactor was operated continuously for 5.5 hours, generating approximately 32 mg of product per hour.

 

Triflation/Heck coupling facilitated by automated extraction and distillation.64
Scheme 2 Triflation/Heck coupling facilitated by automated extraction and distillation.

Integration of multiple reaction steps, separations, and purifications into one continuous process has great potential for avoiding energy intensive and wasteful intermediate purification. While great progress has been made, the development of a truly general set of reagents, methods, and devices still requires more research. Immobilized reagents can be wasteful to scale up, and there are significant limitations to current microreactor extraction and distillation technologies. Crystallization is another very important technique in pharmaceutical synthesis, and while there are an increasing number of methods for continuous crystallization,14 15 , it is yet to be used as an intermediate purification step in an automated multi-step synthesis. Lastly, large scale applications of such complex, streamlined processes are required before a thorough assessment of their environmental impact in comparison with traditional batch routes can be made.

 

 

  1. D. Webb and T. F. Jamison, Chem. Sci., 2010, 1, 675–680
  2. M. D. Hopkin, I. R. Baxendale and S. V. Ley, Chem. Commun., 2010, 46, 2450–2452
  3. J. G. Kralj, H. R. Sahoo and K. F. Jensen, Lab Chip, 2007, 7, 256–263
  4. R. L. Hartman, H. R. Sahoo, B. C. Yen and K. F. Jensen, Lab Chip, 2009, 9, 1843–1849
  5. M. O’Brien, P. Koss, D. L. Browne and S. V. Ley, Org. Biomol. Chem., 2012, 10, 7031–7036
  6. K. K. R. Tetala, J. W. Swarts, B. Chen, A. E. M. Janssen and T. A. van Beek, Lab Chip, 2009, 9, 2085–2092
  7. D. M. Fries, T. Voitl and P. R. von Rohr, Chem. Eng. Technol., 2008, 31, 1182–1187
  8. S. Aljbour, H. Yamada and T. Tagawa, Top. Catal., 2010, 53, 694–699
  9. A. Smirnova, K. Shimura, A. Hibara, M. A. Proskurnin and T. Kitamori, Anal. Sci., 2007, 23, 103–107
  10. R. C. R. Wootton and A. J. deMello, Chem. Commun., 2004, 266–267
  11. A. Hibara, K. Toshin, T. Tsukahara, K. Mawatari and T. Kitamora, Chem. Lett., 2008, 1064–1065
  12. Y. Zhang, S. Kato and T. Anazawa, Lab Chip, 2010, 10, 899–908
  13. R. L. Hartman, J. R. Naber, S. L. Buchwald and K. F. Jensen, Angew. Chem., Int. Ed., 2010, 49, 899–903
  14. S. Lawton, G. Steele, P. Shering, L. Zhao, I. Laird and X.-W. Ni, Org. Process Res. Dev., 2009, 13, 1357–1363
  15. H. Zhao, J.-X. Wang, Q.-A. Wang, J.-F. Chen and J. Yun, Ind. Eng. Chem. Res., 2007, 46, 8229–8235

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Heterogeneous catalysis and catalyst recycling

 MANUFACTURING, SYNTHESIS  1 Response »
Jul 282015
 

 

 

Heterogeneous catalysis and catalyst recycling

Heterogeneous catalysis is a type of catalysis in which the catalyst occupies a different phase from the reactants and products. This may refer to the physical phase — solid, liquid or gas — but also to immiscible fluids. Heterogeneous catalysts can be more easily recycled than homogeneous, but characterization of the catalyst and optimization of properties can be more difficult.

Heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a general, small scale batch reaction, the catalyst, reactants, and solvent are stirred together until completion of the reaction, after which the bulk liquid is separated by filtration. The catalyst can then be collected for either recycling or disposal. In a continuous process, the catalyst can be fixed in space and the reaction mixture allowed to flow over it. The reaction and separation are thus combined in a single step, and the catalyst remains in the reactor for easy recycling. Beyond facilitating separation, thecatalyst may have improved lifetime due to decreased exposure to the environment, and reaction rates and turnover numbers can be enhanced through the use of high concentrations of a catalyst with continuous recycling. The benefits of flow are seemingly obvious, yet it has only recently become a widely adopted method for bench-scale synthesis.1

Hydrogenation of ethene on a solid surface

The most common application of continuous heterogeneous catalysis is in hydrogenation reactions,2 where the handling and separation of solid precious metal catalysts is not only tedious but hazardous under batch conditions. Moreover, the mixing between the three phases in a hydrogenation is generally quite poor. The use of a flow reactor gives a higher interfacial area between phases and thus more efficient reactions. For example, Ley and co-workers found that the hydrogenation of alkene 1 to 2 was challenging in batch, requiring multiple days at 80 bar of H2 (Scheme 1).3 Using a commercially available H-Cube® reactor, the reaction time was shortened to 4 hours, the pressure reduced to 60 bar, and manual separation and recycling of the catalyst from the reaction was unnecessary. The increased efficiency is due to a combination of improved mixing of the three phases, as well as the continuous recycling and high local concentration of the catalyst. The H-Cube offers a further safety advantage because it generates hydrogen gas on demand from water, obviating the need for a high pressure H2 tank.

Hydrogenation with an immobilized heterogeneous catalyst.
Scheme 1 Hydrogenation with an immobilized heterogeneous catalyst.

Homogeneous catalysis has many advantages over heterogeneous catalysis, such as increased activity and selectivity, and mechanisms of action that are more easily understood. Unfortunately, the difficulty associated with separating homogeneous catalysts from the product is a significant hindrance to their large scale application. In an attempt to combine the high activity of homogeneous catalysis with the practical advantageous of heterogeneous catalysis, there has been much research into immobilizing homogeneous catalysts on solid supports.4 This is generally achieved by linking thecatalyst to the surface of an insoluble solid such as silica or polymer beads. As was the case in batch hydrogenation reactions, the process of separating and purifying the catalyst is inefficient, potentially dangerous, and may lead to degradation and loss of material. Performing these reactions in a flow system can help overcome these problems.5 A highly efficient example has been demonstrated by van Leeuwen and co-workers, who sought to immobilize a catalyst used in transfer hydrogenation reactions (Scheme 2).6Their test reaction was the asymmetric reduction of acetophenone; homogeneousreduction with ruthenium and ligand 3 provided 88% conversion and 95% enantioselectivity. The ligand was then covalently linked to silica gel through the benzyl group to form 4. Using this heterogenized system under batch conditions, conversion dropped to 38% on the same time scale, and a slight decrease in enantioselectivity occurred. A reduction in activity of a catalyst upon immobilization is common, so highly efficient recycling is required. Unfortunately, when attempting to re-use the catalyst after filtration, significant degradation and leaching occurred. The catalyst was then packed in a glass column for application in flow chemistry. After a short optimization of flow rate, 95% conversion and 90% ee were obtained. Importantly, the reaction could be run continuously for up to one week without significant degradation in conversion or enantioselectivity. The physical isolation of catalyst species on the solid support is suggested to contribute to the long catalystlifetime. Interestingly, the basic potassium tert-butoxide additive was only required initially to activate the catalyst, and the reaction could subsequently be run without additional base, allowing the product to be isolated completely free of additives. It is important to note, on top of the decreased activity due to modification, that leaching from cleavage off the solid support and the increased cost of the catalyst due to derivatization are all potential downsides of immobilization of catalysts. In some instances, a seemingly heterogeneous catalyst has been shown to leach active homogeneous species into solution.7 However, as can be seen above, robust systems can be developed which do combine the best features of both homogeneous and heterogeneous catalysis.

Immobilization of a homogeneous catalyst on a solid support.
Scheme 7 Immobilization of a homogeneous catalyst on a solid support.

Another important method for recycling expensive catalysts is through the use of liquid–liquid biphasic conditions where the catalyst and reactants can be separated by extraction upon completion of the reaction. Such processes have already been utilized on the medium and large scale in a continuous or semi-continuous fashion.8,9 Recycling on a small scale is typically done through batch liquid–liquid extractions, but examples using continuous methods are increasing.10-13 A recent automated small scale recycling of a biphasic catalyst system was demonstrated by the George group in the continuous oxidation of citronellol (Scheme 3).14A highly fluorinated porphyrin was used as the photocatalyst, and a combination of hydrofluoroether (HFE) and scCO2 was used as the solvent. Under high pressure flow conditions, a single phase was observed. Depressurization occurred after the reactor, resulting in two phases – the organic product in one, and the catalyst and HFE in the other. The denser, catalyst-containing fluorous phase was continuously pumped back through the reactor. With this method, the catalyst was recycled 10 times while maintaining 75% of its catalytic activity, giving an increase in TON of approximately 27-fold compared to previous batch conditions. Some leaching of the fluorinated catalyst into the organic product was observed, accounting for the decreased activity over time.

Automated recycling of a biphasic catalyst system.
Scheme 3 Automated recycling of a biphasic catalyst system.

Examples of heterogeneous catalysisThe hydrogenation of a carbon-carbon double bondThe simplest example of this is the reaction between ethene and hydrogen in the presence of a nickel catalyst.In practice, this is a pointless reaction, because you are converting the extremely useful ethene into the relatively useless ethane. However, the same reaction will happen with any compound containing a carbon-carbon double bond.One important industrial use is in the hydrogenation of vegetable oils to make margarine, which also involves reacting a carbon-carbon double bond in the vegetable oil with hydrogen in the presence of a nickel catalyst.Ethene molecules are adsorbed on the surface of the nickel. The double bond between the carbon atoms breaks and the electrons are used to bond it to the nickel surface.

Hydrogen molecules are also adsorbed on to the surface of the nickel. When this happens, the hydrogen molecules are broken into atoms. These can move around on the surface of the nickel.

If a hydrogen atom diffuses close to one of the bonded carbons, the bond between the carbon and the nickel is replaced by one between the carbon and hydrogen.

That end of the original ethene now breaks free of the surface, and eventually the same thing will happen at the other end.

As before, one of the hydrogen atoms forms a bond with the carbon, and that end also breaks free. There is now space on the surface of the nickel for new reactant molecules to go through the whole process again.



Catalytic converters


Catalytic converters change poisonous molecules like carbon monoxide and various nitrogen oxides in car exhausts into more harmless molecules like carbon dioxide and nitrogen. They use expensive metals like platinum, palladium and rhodium as the heterogeneous catalyst.


The metals are deposited as thin layers onto a ceramic honeycomb. This maximises the surface area and keeps the amount of metal used to a minimum.


Taking the reaction between carbon monoxide and nitrogen monoxide as typical:













Catalytic converters can be affected by catalyst poisoning. This happens when something which isn’t a part of the reaction gets very strongly adsorbed onto the surface of the catalyst, preventing the normal reactants from reaching it.Lead is a familiar catalyst poison for catalytic converters. It coats the honeycomb of expensive metals and stops it working.In the past, lead compounds were added to petrol (gasoline) to make it burn more smoothly in the engine. But you can’t use a catalytic converter if you are using leaded fuel. So catalytic converters have not only helped remove poisonous gases like carbon monoxide and nitrogen oxides, but have also forced the removal of poisonous lead compounds from petrol.




The use of vanadium(V) oxide in the Contact Process


During the Contact Process for manufacturing sulphuric acid, sulphur dioxide has to be converted into sulphur trioxide. This is done by passing sulphur dioxide and oxygen over a solid vanadium(V) oxide catalyst.













This example is slightly different from the previous ones because the gases actually react with the surface of the catalyst, temporarily changing it. It is a good example of the ability of transition metals and their compounds to act as catalysts because of their ability to change their oxidation state.










The sulphur dioxide is oxidised to sulphur trioxide by the vanadium(V) oxide. In the process, the vanadium(V) oxide is reduced to vanadium(IV) oxide.The vanadium(IV) oxide is then re-oxidised by the oxygen.This is a good example of the way that a catalyst can be changed during the course of a reaction. At the end of the reaction, though, it will be chemically the same as it started.








 


c1


 




    

  1. C. G. Frost and L. Mutton, Green Chem., 2010, 12, 1687–1703 .
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  2. M. Irfan, T. N. Glasnov and C. O. Kappe, ChemSusChem, 2011, 4, 300–316 
    

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  4. P. McMorn and G. J. Hutchings, Chem. Soc. Rev., 2004, 33, 108–122.
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  5. S. Ceylan and A. Kirschning, in Recoverable and Recyclable Catalysts, ed. M. Benaglia, John Wiley & Sons Ltd, 2009, pp. 379–410 .
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  6. A. J. Sandee, D. G. I. Petra, J. N. H. Reek, P. C. J. Kamer and P. W. N. M. Van Leeuwen, Chem.–Eur. J., 2001, 7, 1202–1208 
    

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  7. M. Pagliaro, V. Pandarus, R. Ciriminna, F. Belénd and P. D. Cerà, ChemCatChem, 2012, 4, 432–445 .
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  8. C. W. Kohlpaintner, R. W. Fischer and B. Cornils, Appl. Catal., A, 2001, 221, 219–225 
    

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  9. W. A. Herrmann, C. W. Kohlpaintner, H. Bahrmann and W. Konkol, J. Mol. Catal., 1992, 73, 191 
    

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  10. A. B. Theberge, G. Whyte, M. Frenzel, L. M. Fidalgo, R. C. R. Wootton and W. T. S. Huck, Chem. Commun., 2009, 6225–6227 .
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  11. A. Yoshida, X. Hao and J. Nishikido, Green Chem., 2003, 5, 554–557 .
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  12. E. Perperi, Y. Huang, P. Angeli, G. Manos, C. R. Mathison, D. J. Cole-Hamilton, D. J. Adams and E. G. Hope, Dalton Trans., 2004, 2062–2064 .
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  14. T. Fukuyama, M. T. Rahman, M. Sato and I. Ryu, Synlett, 2008, 151–163 
    

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  16. R. A. Bourne, X. Han, M. Poliakoff and M. W. George, Angew. Chem., Int. Ed., 2009, 48, 5322 
    

    17. 





 






 




 




 












 


 




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How flow chemistry can make processes greener…………Supercritical fluids

		

					 PROCESS, SYNTHESIS, Uncategorized
						 Comments Off on How flow chemistry can make processes greener…………Supercritical fluids
				

		

		
Jul 232015

	

	 	

		






Safe, small scale access to supercritical fluids


The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.


Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.


Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.




Continuous methods for utilizing supercritical fluids for extraction,1 chromatography,2 and as a reaction medium3 have all been commercialized, particularly for supercritical carbon dioxide (scCO2).4 Academic examples using scMeOH, scH2O, and scCO2 for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.5


A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).6 They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.




The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.


Thus, the total volume of scCO2 under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.










Small scale continuous use of supercritical fluids.





Scheme 1 Small scale continuous use of supercritical fluids.









Near- and supercritical water (scH2O) can be an interesting green solvent only obtainable at very high temperature (Tc = 374 °C) and pressure (Pc = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO2; however, it has also been shown to be an effective solvent for selective oxidations.7 Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.


Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.




The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH2O, a reaction carried out on industrial scale in acetic acid (Scheme 2).8 By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H2O2.


Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.9










Selective oxidation in supercritical water.





Scheme 2 Selective oxidation in supercritical water.






 




Schematic Diagram of sample Supercritical CO2 system



Table 1. Critical properties of various solvents (Reid et al., 1987)



Solvent
Molecular weight
Critical temperature
Critical pressure
Critical density




g/mol
K
MPa (atm)
g/cm3




Carbon dioxide (CO2)
44.01
304.1
7.38 (72.8)
0.469




Water (H2O) (acc. IAPWS)
18.015
647.096
22.064 (217.755)
0.322




Methane (CH4)
16.04
190.4
4.60 (45.4)
0.162




Ethane (C2H6)
30.07
305.3
4.87 (48.1)
0.203




Propane (C3H8)
44.09
369.8
4.25 (41.9)
0.217




Ethylene (C2H4)
28.05
282.4
5.04 (49.7)
0.215




Propylene (C3H6)
42.08
364.9
4.60 (45.4)
0.232




Methanol (CH3OH)
32.04
512.6
8.09 (79.8)
0.272




Ethanol (C2H5OH)
46.07
513.9
6.14 (60.6)
0.276




Acetone (C3H6O)
58.08
508.1
4.70 (46.4)
0.278




Nitrous oxide (N2O)
44.013
306.57
7.35 (72.5)
0.452






Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.



Comparison of Gases, Supercritical Fluids and Liquids






Density (kg/m3)
Viscosity (µPa∙s)
Diffusivity (mm²/s)




Gases
1
10
1–10




Supercritical Fluids
100–1000
50–100
0.01–0.1




Liquids
1000
500–1000
0.001






    

  1. F. Sahena, I. S. M. Zaidul, S. Jinap, A. A. Karim, K. A. Abbas, N. A. N. Norulaini and A. K. M. Omar, J. Food Eng., 2009, 95, 240–253
    2. 

  2. D. J. Dixon and K. P. Jhonston, in Encyclopedia of Separation Technology, ed. D. M. Ruthven, John Wiley, 1997, 1544–1569
    3. 

  3. P. Licence, J. Ke, M. Sokolova, S. K. Ross and M. Poliakoff, Green Chem., 2003, 5, 99–104
    4. 

  4. X. Han and M. Poliakoff, Chem. Soc. Rev., 2012, 41, 1428–1436
    5. 

  5. S. Marre, Y. Roig and C. Aymonier, J. Supercrit. Fluids, 2012, 66, 251–264
    6. 

  6. F. Benito-Lopez, R. M. Tiggelaar, K. Salbut, J. Huskens, R. J. M. Egberink, D. N. Reinhoudt, H. J. G. E. Gardeniers and W. Verboom, Lab Chip, 2007, 7, 1345–1351
    7. 

  7. R. Holliday, B. Y. M. Jong and J. W. Kolis, J. Supercrit. Fluids, 1998, 12, 255–260
    8. 

  8. P. A. Hamley, T. Ilkenhans, J. M. Webster, E. García-Verdugo, E. Vernardou, M. J. Clarke, R. Auerbach, W. B. Thomas, K. Whiston and M. Poliakoff, Green Chem., 2002, 4, 235–238
    9. 

  9. E. Pérez, J. Fraga-Dubreuil, E. García-Verdugo, P. A. Hamley, M. L. Thomas, C. Yan, W. B. Thomas, D. Housley, W. Partenheimer and M. Poliakoff, Green Chem., 2011, 13, 2397–2407
    10. 







Phase change - en.svg








 


 


सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027LIONEL MY SON


He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy




सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।


 


 




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Cyclopentene-1,3-dione derivative

		

					 PROCESS, spectroscopy, SYNTHESIS
						 Comments Off on Cyclopentene-1,3-dione derivative
				

		

		
Jul 202015

	

	 	

		




the isolated cyclopentenedione derivative may have structure 1a or 1b or even exist as an equilibrium mixture between these two enol forms showing average 1H and 13C NMR spectra due to a proposed rapid interconversion between 1a and 1b.


http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024




 


Synthetic results


Our approach to cyclopentenedione derivative (1) started with the preparation of furylmethylcarbinol (3) by the reduction of commercially available 2-acetylfuran (2) with NaBH4 (Scheme 2).5 Compound 3 was isolated in 98% yield and transformed into 4-hydroxy-5-methylcyclopenten-2-one (4) in 90% yield after treatment with ZnCl2-HCl (pH 6.0) under reflux in dioxane-H2O for 48 h.6 Upon treatment of 4-hydroxy-5-methylcyclopenten-2-one (4) with phosphate buffer (pH 8.0) in refluxing dioxane for 24 h, 4-hydroxy-2-methylcyclopenten-2-one (5) was obtained in 65% yield.7 By using this strategy we were able to prepare up to gram quantities of hydroxyketone 5.




 




 


Diketone 6 was obtained in almost quantitative yield by the smooth oxidation of hydroxyketone 5 with MnO2(Scheme 3).8,9 At this point, all that remained was to carry out the necessary acylation coupling. It was with some gratification that we observed that the reaction between lithium enolate of diketone 6 and cinnamic anhydride 7 gave a 57:43 mixture of cyclopentenediones 1a/1b in 22% yield, after purification by flash column chromatography, together with starting material and by-products arising from O-acylation (Scheme 3).




 




 


 






 


 


In order to try to improve the yields for formation of 1a/1b, we tested a new synthetic route (Scheme 4). Protection of the OH-functionality in 5 with TESCl and imidazole at room temperature gave ketone 8 in 85% yield. Treatment of 8 with LDA in THF at –78 ºC, followed by slow addition of cinnamaldehyde, gave aldol adduct 9 as a mixture of diastereoisomers. Oxidation of the OH-function at C9 in allylic alcohol 9 under standard Swern11 conditions followed by removal of the TES protecting group with TBAF in THF led to diol 10 in 60% overall yield. The last step involved treatment of diol 10 under standard Swern oxidation conditions, to give a 59:41 mixture of 1a/1b in 79% yield.11




 


The correct structure for the natural product was confirmed as being 1a by the heteronuclear long-range coupling (nJCH; n = 2,3,4) obtained by HMBC experiments in CDCl3 as solvent. Heteronuclear long-range coupling of C11 (dC 201.3) with H13 (dH 6.70, 3JCH) and H15 (dH 2.12, 3JCH), as well as between C14 (dC 191.8) with H13 (dH 6.70, 2JCH) and H15 (dH 2.12, 4JCH) for 1a, together with the long-range coupling of C11 (dC 200.7) with H12 (dH 6.61, 2JCH) and H15 (dH 2.11, 4JCH), as well as between C14 (dC 192.3) with H12 (dH 6.61, 3JCH) and H15 (dH 2.11 ppm, 3JCH) for 1b, unambiguously established the correct structure as being 1a (Figure 10).




 




 cyclopentenedione derivative (1) as a yellow solid. Rf 0.37 (30% EtOAc/Hexane); IR (film) nmax/cm-1: 3428, 2965, 1632, 1589, 1266, 1103, 1023, 803, 742, 699; (HRMS) Exact mass calc. for C15H12O3: 240.0786. Found: 240.0787.


Journal of the Brazilian Chemical Society


On-line version ISSN 1678-4790


J. Braz. Chem. Soc. vol.16 no.3a São Paulo May/June 2005


http://dx.doi.org/10.1590/S0103-50532005000300024




Short synthesis of a new cyclopentene-1,3-dione derivative isolated from Piper carniconnectivum


Luiz C. Dias*; Simone B. Shimokomaki; Robson T. Shiota


http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024


Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas – SP, Brazil


 


 


सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027LIONEL MY SON


He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy




सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।


 


 




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Flow chemistry can make processes greener….Swern oxidation

		

					 MANUFACTURING, PROCESS, SYNTHESIS
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Jul 202015

	

	 	

		


The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride,dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine.The reaction is known for its mild character and wide tolerance of functional groups.






The Swern oxidation.




The by-products are dimethyl sulfide (Me2S), carbon monoxide (CO), carbon dioxide (CO2) and — when triethylamine is used as base — triethylammonium chloride (Et3NHCl). Two of the by-products, dimethyl sulfide and carbon monoxide, are very toxic volatile compounds, so the reaction and the work-up needs to be performed in a fume hood.Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an extremely unpleasant odour.


The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a, formally as resonance contributor 1b, with oxalyl chloride, 2. The first intermediate, 3, quickly decomposes giving off CO2 and CO and producing chloro(dimethyl)sulfonium chloride, 4.




Dimethylchlorosulfonium chloride formation.




After addition of the alcohol 5, the chloro(dimethyl)sulfonium chloride 4 reacts with the alcohol to give the key alkoxysulfonium ion intermediate, 6. The addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. In a five-membered ring transition state, the sulfur ylide 7decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.




 


 


Dimethyl sulfide, a byproduct of the Swern oxidation, is one of the most foul odors known in organic chemistry. Human olfactory glands can detect this compound in concentrations as low as 0.02 to 0.1 parts per million. A simple remedy for this problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.


The reaction conditions allow oxidation of acid-sensitive compounds, which might decompose under the acidic conditions of a traditional method such as Jones oxidation. For example, in Thompson & Heathcock’s synthesis of the sesquiterpene isovelleral,the final step uses the Swern protocol, avoiding rearrangement of the acid-sensitive cyclopropanemethanol moiety.




IsovelleralPreparationViaSwernOxidation.png




Rapid, exothermic reactions are challenging to do in batch reactors. Reagents such as organometallics, strong bases, and highly active electrophiles are often added slowly to a reaction mixture under energy-intensive cryogenic conditions to prevent an uncontrollable exotherm. Quenching of these high-energy reagents may again require low temperature. This issue is scale dependent,1 and without proper precautions, both the likelihood and hazard of a runaway reaction increase with the size of a reactor.


The high surface area to volume ratio found in flow reactors makes heat transfer more efficient than in batch, allowing rapid removal of thermal energy given off. These features serve to give the chemist or engineer more control over reaction temperature and reduces the risk of thermal runaway.


Many instances have been reported of reactions being performed safely at 0 °C or room temperature in flow that would require cryogenic conditions in batch.2,3,4 This has a further benefit on the overall processing time, as the reaction will occur faster at the elevated temperature and inefficient cooling and warming steps are avoided. A remarkable example demonstrating these principles is the room temperature Swern oxidation reaction by Yoshida and co-workers .5


The Swern reaction is a reliable procedure for converting alcohols to ketones and aldehydes using DMSOactivated by an electrophile (typically COCl2 or TFAA) as the oxidant. In batch, the reaction takes place over three exothermic steps, each of which requires dropwise addition of reagents at cryogenic temperatures.6, 7


PROCESS TO FLOW


When converting the process to flow, the Yoshida group found that the Swern oxidation could be done at room temperature with good yields and purity. Moreover, instead of having reaction times on the order of minutes or hours, the whole process was completed in seconds. They attributed the success of their process to the precise temperature control that can be obtained in flow systems, as well as the ability to quickly transfer unstable intermediates to subsequent steps. Using only a series of syringe pumps, stainless steel tubing, and commercial micromixers, they could prepare over 10 grams of material per hour. Being able to perform reactions on species with very short lifetimes is another general advantage of performing reactions in flow.8


 








Room temperature Swern oxidation.





Scheme  Room temperature Swern oxidation.






 


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MORE……..




http://thalesnano.com/products/IceCube












 


…………………




 


The Swern oxidation. The center column (green background) shows the desired chemical path, with added reagents shown in black boxes. The outer columns (red background) show the potential chemical pathways for side-product formation (8 and 9).


http://www.mdpi.com/2227-9717/2/1/24/htm


REF


    

  1. R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem., Int. Ed., 2011, 50, 7502–7519 
    

    2. 

  2. V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld and B. Werner, Org. Process Res. Dev., 2004, 8, 511–523 Search PubMed.
    3. 

  3. A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto and J.-i. Yoshida, Chem.–Asian J., 2007, 2, 1513–1523 
    

    4. 

  4. T. Gustafsson, H. Sörensen and F. Pontén, Org. Process Res. Dev., 2012, 16, 925–929 Search PubMed.
    5. 

  5. T. Kawaguchi, H. Miyata, K. Ataka, K. Mae and J.-I. Yoshida, Angew. Chem., Int. Ed., 2005, 44, 2413–2416
    6. 

  6. A. K. Sharma and D. Swern, Tetrahedron Lett., 1974, 15, 1503–1506 Search PubMed.
    7. 

  7. A. K. Sharma, T. Ku, A. D. Dawson and D. Swern, J. Org. Chem., 1975, 40, 2758–2764 
    

    8. 

  8. J.-i. Yoshida, Chem. Rec., 2010, 10, 332–341 
    

    9. 



 


 


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सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

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ETC-159

		

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Jul 172015

	

	 	

		


 




ETC-159


Duke-NUS Graduate Medical School; Experimental Therapeutics Centre of Singapore


Cysteine palmitoyltransferase porcupine inhibitor


 





    

  • By Proffitt Kyle David; Madan Babita; Ke Zhiyuan; Pendharkar Vishal; Ding Lijun; Lee May Ann; Hannoush Rami N; Virshup David M
    • 





Cancer research (2013), 73(2), 502-7…..http://cancerres.aacrjournals.org/content/73/2/502.abstract


 


Ke, Z.; Madan, B.; Lim, S.Q.Y.; et al.


 A novel porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations

 106th Annu Meet Am Assoc Cancer Res (AACR) (April 18-22, Philadelphia) 2015, Abst 4449


 


Madan, B.; Ke, Z.; Lim, S.Q.Y.; et al.

 Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers

 25th EORTC-NCI-AACR Symp Mol Targets Cancer Ther (October 19-23, Boston) 2013, Abst C248




2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics


 







C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers

Tuesday, Oct 22, 2013, 12:30 PM – 3:00 PM

Babita Madan1, Zhiyuan Ke2, Shermaine Q.y. Lim2, Jenefer Alam2, Soo Yei Ho2, Duraiswamy A. Jeyaraj2, Kakaly Ghosh1, Yun Shan Chew2, Jamal Aliyev1, Li Jun Ding2, Vishal Pendharkar2, Sifang Wang2, Kanda Sangthongpitag2, Thomas Keller2, May Ann Lee2, David M. Virshup1. 1Duke-NUS Graduate Medical School, Singapore, Singapore; 2Experimental Therapeutics Center, A*STAR, Singapore, Singapore		






 






Abstract Number:
C248




Presentation Title:
Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers




Presentation Time:
Tuesday, Oct 22, 2013, 12:30 PM – 3:00 PM




Location:
Exhibit Hall C-D




Author Block:
Babita Madan1, Zhiyuan Ke2, Shermaine Q.y. Lim2, Jenefer Alam2, Soo Yei Ho2, Duraiswamy A. Jeyaraj2, Kakaly Ghosh1, Yun Shan Chew2, Jamal Aliyev1, Li Jun Ding2, Vishal Pendharkar2, Sifang Wang2, Kanda Sangthongpitag2, Thomas Keller2, May Ann Lee2, David M. Virshup1. 1Duke-NUS Graduate Medical School, Singapore, Singapore; 2Experimental Therapeutics Center, A*STAR, Singapore, Singapore




Abstract Body:
Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity






 


Abstract C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers.




    
















  1. David M. Virshup1
    2. 



+Author Affiliations


    

  1. 1Duke-NUS Graduate Medical School, Singapore, Singapore
    2. 

  2. 2Experimental Therapeutics Center, A*STAR, Singapore, Singapore
    3. 







Abstract


Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity.


Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C248.


Citation Format: Babita Madan, Zhiyuan Ke, Shermaine Q.y. Lim, Jenefer Alam, Soo Yei Ho, Duraiswamy A. Jeyaraj, Kakaly Ghosh, Yun Shan Chew, Jamal Aliyev, Li Jun Ding, Vishal Pendharkar, Sifang Wang, Kanda Sangthongpitag, Thomas Keller, May Ann Lee, David M. Virshup. Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C248.




 




Made-in-Singapore cancer drug advances to clinical trials on humans


The drug, ETC-159, was developed in a collaboration between A*STAR and Duke-NUS, and is expected to target a range of cancers, including colorectal, ovarian and pancreatic cancers.


    

  • POSTED: 16 Jul 2015 10:13
    • 















Prof David Virshup (centre, in blazer) and the rest of the research teams. (Photo: A*STAR, Duke-NUS)












SINGAPORE: A made-in-Singapore cancer drug is touted to be the first publicly-funded drug candidate discovered and developed in Singapore to make it to trials on humans.


In a statement on Thursday (Jul 16), The Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS), announced the start of the Phase I clinical trial of novel cancer drug candidate, ETC-159.


The Phase I clinical trial is meant to evaluate the safety and tolerability of ETC-159 in advanced solid tumours of up to 58 patients, and the first patient was dosed on Jun 18. The first two sites for the trial are the National Cancer Centre Singapore and the National University Hospital, and sites in the US will be added as the trial progresses.


The drug is expected to target a range of cancers, including colorectal, ovarian and pancreatic cancers. These cancers are linked to a group of cell signalling pathways known as Wnt signalling, which have been identified to promote cancer growth and spread, said the agencies. ETC-159 acts as an inhibitor of these pathways.


“This drug candidate therefore offers a promising novel and targeted cancer therapy that could shape future cancer therapeutic strategies,” said A*STAR and Duke-NUS.


ETC-159 was discovered and developed through a collaboration between A*STAR’s Experimental Therapeutics Centre (ETC), Drug Discovery and Development (D3) unit and Duke-NUS since 2009. It was based on the discovery work of Prof David Virshup from Duke-NUS.


Prof David Virshup, inaugural Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS, said: “As the drug candidate provides a targeted cancer therapy, it could potentially minimise side effects and make cancer treatments more bearable for cancer patients.”


He added: “It is fitting that Singaporeans might be the first to benefit from this Singapore-developed drug.”


http://www.channelnewsasia.com/news/singapore/made-in-singapore-cancer/1988090.html?cid=FBSG


 


 Duke-NUS Graduate Medical School, Singapore, Singapore




 


Map of duke nus




 






Babita MADAN


Assistant Professor


babita.madan@duke-nus.edu.sg












Kakaly GHOSH


Research Assistant


kakaly.ghosh@duke-nus.edu.sg
























David VIRSHUP










MD










Professor & Program Director










Cancer & Stem Cell Biology Program








Office no.:




+65 6516 6954








Lab no.:




+65 6516 1790









Administrative Support’s Email:







 


Experimental Therapeutics Center, A*STAR, Singapore, Singapore




Map of Experimental Therapeutic Centre (ETC)




A*STAR Scientist Alex Matter Awarded Prestigious Szent-Gyorgyi Prize For Progress In Cancer




… of the Programme in Cancer and Stem Cell Biology at Duke-NUS, and Professor Alex Matter, chief executive of A*Star’s Experimental Therapeutics Centre




Kanda Sangthongpitag, Ph.D.


Group Leader, Preclinical Pharmacology




Kanda Sangthongpitag obtained a Bachelor of Science (nursing and midwifery) from Mahidol University and worked as the registered nurse in the EENT theatre at the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand. She continued her studies and obtained a Master of Applied Science (Biotechnology) at the University of New South Wales, Sydney, Australia.


 


May Ann Lee, Ph.D.


Group Leader, Cell Based Assay Development




May Ann Lee completed her PhD in Molecular Biology in Epstein Barr Virus research from State University in New York at Buffalo. Molecular and Cell Biology Department, Roswell Park Cancer Institute in 1993. She did her postdoctoral training in HIV research in the Picower Institute of Medical Research in Manhasset, New York


Experimental Therapeutics Centre (ETC)


31 Biopolis Way

Nanos Level 3

Singapore 138669


Main: +65 6478 8767

Fax: +65 6478 8768

Enquiries: info@etc.a-star.edu.sg




////


सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027LIONEL MY SON


He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy




सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।


 


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Application in Febuxostat synthesis

		

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Jul 172015

	

	 	

		




………..


Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions


Abstract




Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr2, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions.




The nitrile moiety is an important group that is found in pharmaceuticals and agrochemicals. In addition the nitrile can serve as a stable intermediate for amides, carboxylic acids, ketones, aldehydes, etc. As a result, many methods to make nitriles have been reported. In a new publication Togo et al. report their development of a one-pot metal-cyanide-free protocol to make electron-rich aromatic nitriles ( Eur. J. Org. Chem. 2015, 2023). The reaction first reacts arenes with zinc bromide (ZnBr2) and dichloromethyl methyl ether to make in situ the (dichloromethyl)arene, that then reacts with aq. ammonia and iodine to make the nitrile. The electron-rich aromatic nitriles are formed in moderate-to-high yields (59–94%). They demonstrate usefulness of this reaction by synthesizing febuxostat.


 




Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions






    

  1. Toshiyuki Tamura,
    2. 

  2. Katsuhiko Moriyama and
    3. 

  3. Hideo Togo*
    4. 



Article first published online: 9 FEB 2015


Tamura, T., Moriyama, K. and Togo, H. (2015), Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions. Eur. J. Org. Chem., 2015: 2023–2029. doi: 10.1002/ejoc.201403672




Author Information


    

  1. Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan, http://reaction-2.chem.chiba-u.jp/index.html
    2. 



Email: Hideo Togo (togo@faculty.chiba-u.jp)


*Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan








Issue




European Journal of Organic Chemistry






European Journal of Organic Chemistry




Volume 2015, Issue 9, pages 2023–2029, March 2015








http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201403672/abstract


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