WO2016056031A1 - Novel diol compounds synthesis and its use for formal synthesis of (2r, 3 s)-3-hydroxypipecolic acid - Google Patents
Novel diol compounds synthesis and its use for formal synthesis of (2r, 3 s)-3-hydroxypipecolic acid Download PDFInfo
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- WO2016056031A1 WO2016056031A1 PCT/IN2015/050131 IN2015050131W WO2016056031A1 WO 2016056031 A1 WO2016056031 A1 WO 2016056031A1 IN 2015050131 W IN2015050131 W IN 2015050131W WO 2016056031 A1 WO2016056031 A1 WO 2016056031A1
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- glucose
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 47
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 45
- FDMYUQHVJYNDLI-CRCLSJGQSA-N (2r,3s)-3-hydroxypiperidine-2-carboxylic acid Chemical compound O[C@H]1CCCN[C@H]1C(O)=O FDMYUQHVJYNDLI-CRCLSJGQSA-N 0.000 title claims abstract description 13
- -1 diol compounds Chemical class 0.000 title claims description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 34
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 24
- 150000002009 diols Chemical class 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- LHEQEHGKCFLBFV-UHFFFAOYSA-N piperidine-2,6-diol Chemical compound OC1CCCC(O)N1 LHEQEHGKCFLBFV-UHFFFAOYSA-N 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 claims description 3
- 229960003868 paraldehyde Drugs 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 claims description 3
- 229940086542 triethylamine Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000003138 primary alcohols Chemical class 0.000 claims description 2
- PWSQTDGCHPNMMT-RTBURBONSA-N tert-butyl (2R,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylate Chemical compound [Si](C)(C)(C(C)(C)C)O[C@H]1[C@H](N(CCC1)C(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C PWSQTDGCHPNMMT-RTBURBONSA-N 0.000 claims description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 238000013459 approach Methods 0.000 abstract description 8
- 239000008103 glucose Substances 0.000 abstract description 7
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 230000000707 stereoselective effect Effects 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 150000000093 1,3-dioxanes Chemical class 0.000 description 3
- FDMYUQHVJYNDLI-UHFFFAOYSA-N 3-hydroxypiperidine-2-carboxylic acid Chemical compound OC1CCCNC1C(O)=O FDMYUQHVJYNDLI-UHFFFAOYSA-N 0.000 description 3
- 229910019891 RuCl3 Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 2
- MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-dihydropyridine Chemical compound C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 description 2
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical compound C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241001227713 Chiron Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000006894 reductive elimination reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- IVMWRPYVCWVKPQ-SFYZADRCSA-N (2s,3r)-3-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H]1C(O)=O IVMWRPYVCWVKPQ-SFYZADRCSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical class C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- KKXQWCWONCEHSQ-UHFFFAOYSA-N 1-hydroxypiperidine-2-carboxylic acid hydrochloride Chemical compound Cl.ON1CCCCC1C(O)=O KKXQWCWONCEHSQ-UHFFFAOYSA-N 0.000 description 1
- MVNJWFVAYSIJFB-UHFFFAOYSA-N 4-methyl-n-(2-oxopropyl)benzamide Chemical compound CC(=O)CNC(=O)C1=CC=C(C)C=C1 MVNJWFVAYSIJFB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- SEWARTPIJFHCRP-UHFFFAOYSA-N N-hydroxypipecolic acid Chemical compound ON1CCCCC1C(O)=O SEWARTPIJFHCRP-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- IMYPSTHZBIWMNA-NBEIKUQISA-N chembl270960 Chemical compound CC=1OC(C=2C=CC(C)=CC=2)=NC=1CCCC[C@H]1CO[C@@](C)(C(O)=O)OC1 IMYPSTHZBIWMNA-NBEIKUQISA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011905 homologation Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- NHVKSUKFAMAWSE-UHFFFAOYSA-N n-(2-hydroxypropyl)-4-methylbenzamide Chemical compound CC(O)CNC(=O)C1=CC=C(C)C=C1 NHVKSUKFAMAWSE-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Definitions
- the present invention relates to novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof. Further, the present invention relates to a process for the synthesis of (2R, 3S)-3-hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form.
- the 3-hydroxy pipecolic acid is a non proteinogenic cyclic a-amino acid. It is used in the preparation of conformationally restricted peptides and ligands binding studies. It is a constituent of many natural as well as synthetic biologically active compounds.
- the biological activities of piperidines vary with the position and nature of substituent on the ring. Both cis as well as trans isomers are structural units found in diverse natural products.
- the hydroxy pipecolic acid framework is target of several synthetic efforts. Synthetic chemists are interested in this structural motif because of its presence in compounds with diverse biological activities. They are of pivotal importance to medicinal chemistry and organic synthesis.
- US 6528538 B l discloses compounds having the following general formula for the treatment of dyslipidemia, atherosclerosis and diabetes;
- US 5594153 A discloses a process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibiting compounds.
- the 1,3 dioxane derivatives does not lead to diols but it gives acyclic hydroxyl compounds.
- US 5,103,024 discloses a process which starts with (4R-cis)-l,l-dimethylethyl 6- hydroxymethyl-2,2-dimethyl-l,3-dioxane-4-acetate and derives the desired substance therefrom by two steps, namely conversion to an arylsulfonate and cyanation.
- the starting material disclosed therein is expensive and a multistep synthetic process is required for the preparation of the startin material itself from commercially available materials.
- the key step in the overall synthesis is a highly regioselective reductive cleavage of benzylidene acetal leading to (2R,3S)-l-tert.-butoxycarbonyl-3- benzyloxypiperidine-2-methanol.
- This process involves the use of azide chemistry, hazardous and sensitive reagents like Lithium aluminium hydride, silyl hydride, diphenyl phosphoryl azide which makes it less preferable for scale up. Further, 13 steps are required to achieve final target compound with low overall yield.
- WO 2006030892 Al discloses a process for the production of NS-220 which is suitable for mass production on an industrial scale.
- the invention is constituted of (1) a process for the production of methyl cis-5-(4-chlorobutyl) -2-methyl-l,3-dioxane-2-carboxylate, characterized by hydrolyzing a cis/trans isomer mixture of methyl 5-(4- chlorobutyl)-2- methyl-l,3-dioxane-2-carboxylate in the presence of a base; (2) a process for the production of 4-methyl-N-(2-oxopropyl)benzamide, characterized by oxidizing 4-methyl-N-(2- hydroxypropyl)benzamide with 2,2,6, 6-tetra- methyl- 1-piperidinyloxyl radicals and sodium hypochlorite; and so on.
- the main object of present invention is to provide novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof.
- Another object of the present invention relates to a process for the synthesis of (2R, 3S)-3- hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form.
- the present invention provides novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof.
- the present invention provides a process for the synthesis of (2R, 3S)-3- hydroxypipecolic acid from D-glucose using chiral pool approach.
- the present invention provide novel diol derivatives of general formula I,
- R 2 OH, I I . N i l . I I
- R 3 I I . OH, I I . N i l ,
- R CH 2 Ph, A l ly l , I I . Hoc. CBz, COO Me
- the present invention provides chiral pool process for the synthesis of the compound of formula I from D glucose.
- the present invention provide a process for the synthesis of (2R, 35)-3-hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D- glucose used is in enantiomerically pure form.
- the D-glucose compound as used herein for the synthesis of (2R, 35)-3-hydroxypipecolic acid is prepared by below scheme 1 :
- the present invention provides a process for synthesis of (2R, 35)- 3-hydroxypipecolic acid from D-glucose, wherein said process comprises the following steps: a) Reacting D-glucose with paraldehyde to give mono acetal protected (17?)-(-)-4,6-0- ethylidene-D-glucose;
- step (b) Compound from step (a) is then subjected for cleavage with NaI0 4 to give (-)-2,4-0- ethylidene-D-erythrose;
- step (b) Stirring the compound of step (b) at room temperature with Ph 3 PCHCOOEt in presence of toluene to give a, ⁇ -unsaturated hydroxy ester;
- step (e) Reacting the compound of step (e) with methanesulphonyl chloride and triethyl amine to give obtain dimesylate compound;
- step (f) Cyclization of compound of step (f) is carried out by heating dimesylate compound in neat benzyl amine to give cyclized product;
- step (j) Treating compound of step (j) with acetic acid to afford the selectively deprotected free primary alcohol;
- the intermediate cis piperidine 2,6-diol used for the synthesis of (2R, 3S)-3- hydroxypipecolic acid is also prepared by using one pot synthesis from N-benzylated compound by carrying hydrogenation reaction in presence of dil.HCl followed by addition of boc anhydride to get this intermediate in good yields.
- the intermediate cis piperidine 2, 6-diol compound of formula 1 is prepared by one pot synthesis from N-benzylated compound by carrying hydrogenation reaction in presence of dil.HCl followed by addition of boc anh dride to get this intermediate in ood yields. Then (Boc)2°
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Abstract
The patent discloses novel diol derivatives of general formula I, [Formula should be inserted here] A chiral pool process for the synthesis of the compound of formula I from D glucose. Further, it discloses a process for the synthesis of (2R, 3S)-3-hydroxypipecolic acid from D- glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form.
Description
NOVEL DIOL COMPOUNDS SYNTHESIS AND ITS USE FOR FORMAL SYNTHESIS OF (2R, 35)-3-HYDROXYPIPECOLIC ACID
FIELD OF THE INVENTION
The present invention relates to novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof. Further, the present invention relates to a process for the synthesis of (2R, 3S)-3-hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form. BACKGROUND AND PRIOR ART OF THE INVENTION
The 3-hydroxy pipecolic acid is a non proteinogenic cyclic a-amino acid. It is used in the preparation of conformationally restricted peptides and ligands binding studies. It is a constituent of many natural as well as synthetic biologically active compounds. The biological activities of piperidines vary with the position and nature of substituent on the ring. Both cis as well as trans isomers are structural units found in diverse natural products. The hydroxy pipecolic acid framework is target of several synthetic efforts. Synthetic chemists are interested in this structural motif because of its presence in compounds with diverse biological activities. They are of pivotal importance to medicinal chemistry and organic synthesis.
In view of their great significance, a number of synthetic strategies have been devoted to the stereoselective synthesis of these chiral piperidines. These syntheses utilized both chiral pool and asymmetric routes. In chiral pool approaches, carbohydrates and non-carbohydrate sources are used for their syntheses. Carbohydrates are ideally suited to the preparation of single isomer of piperidines.
US 6528538 B l discloses compounds having the following general formula for the treatment of dyslipidemia, atherosclerosis and diabetes;
where X, Y=CH2, O, S, Ra (Ra=H, alkyl, aryl, etc.); R=H, alkyl, cycloalkyl, etc.;R =H, alkyl, hydroxyalkyl,— (CH2)t-COORc where t=0-6 & Rc represents H or alkyl group, etc.; R2 & R3=H, alkyl, cycloalkyl, (C6-Cio)aryl, (C6-Cio)aryl(Ci-C7)alkyl, 3-10 membered optionally
substituted heterocyclic group etc.; or R2 & R3 optionally form a chain— (CH2)ri(rl=2-5), etc.; R4-R7=H, alkyl, (un)substituted aryl, etc. It further relates to method for the synthesis of racemic compounds which is not useful in the synthesis of diols and pipecolic acids.
US 5594153 A discloses a process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibiting compounds. The 1,3 dioxane derivatives does not lead to diols but it gives acyclic hydroxyl compounds.
US 5,103,024 discloses a process which starts with (4R-cis)-l,l-dimethylethyl 6- hydroxymethyl-2,2-dimethyl-l,3-dioxane-4-acetate and derives the desired substance therefrom by two steps, namely conversion to an arylsulfonate and cyanation. However, the starting material disclosed therein is expensive and a multistep synthetic process is required for the preparation of the startin material itself from commercially available materials.
CH3
X
Article titled "Chiron Approach to the Synthesis of (25, 3 ?)-3-Hydroxypipecolic Acid and (2R, 3 ?)-3-Hydroxy-2-hydroxymethylpiperidine from D-Glucose" by Dilip D. Dhavale et al. in J. Org. Chem., 2008, 73 (9), pp 3619-3622 reports the first chiron approach from d- glucose for the total synthesis of (25, 3 ?)-3-hydroxypipecolic acid. This is a long synthetic route which involves azide chemistry wherein scalability is an issue, reaction conditions are sensitive and not practical on higher scale.
Article titled, "A regioselective reductive cleavage of benzylidene acetal: Stereoselective synthesis of N-Boc-protected cis-(2R,3S)-3-hydroxypipecolic acid" by Kumar, Ponminor Senthil; Baskaran, Sundarababu in Tetrahedron Letters (2009), 50(26), 3489-3492 reports a stereoselective synthesis of N-Boc-protected cis-(2R,3S)-3-hydroxypipecolic acid, starting
from D-glucose. The key step in the overall synthesis is a highly regioselective reductive cleavage of benzylidene acetal leading to (2R,3S)-l-tert.-butoxycarbonyl-3- benzyloxypiperidine-2-methanol. This process involves the use of azide chemistry, hazardous and sensitive reagents like Lithium aluminium hydride, silyl hydride, diphenyl phosphoryl azide which makes it less preferable for scale up. Further, 13 steps are required to achieve final target compound with low overall yield.
Article titled "An efficient stereoselective and stereodivergent synthesis of (2R,3R)- and (2 ?,35)-3-hydroxypipecolic acids" by Jourdant et al. in Tetrahedron Letters, 2000, 41 (36), pp 7033-7036 reports a synthetic route to both cis and trans isomers 15 and 13 linear steps respectively from L-serine.
Article titled, "A convenient formal synthesis of (25,35)-3-hydroxy pipecolic acid" by Subhash P. Chavan in Tetrahedron: Asymmetry Volume 22, Issue 5, 2011, 587-590 reports a convenient synthesis of (25,35)-3-hydroxy pipecolic acid starting from inexpensive and easily available l-(+)-tartaric acid.
Article titled, "Stereoselective Syntheses of 1-Pipecolic Acid and (25,35)-3-Hydroxypipecolic Acid from a Chiral N-Imino-2-phenyl-l,2-dihydropyridine Intermediate" by Alexandre Lemire and Andre B. Charette in J. Org. Chem., 2010, 75 (6), pp 2077-2080 reports a. stereoselective synthesis of 1-pipecolic acid and (25,35)-3-hydroxypipecolic acid were achieved from a chiral N-imino-2-phenyl-l,2-dihydropyridine intermediate. The 3-hydroxy substituent of the latter amino acid was introduced by hetero-Diels- Alder reaction of singlet oxygen with the 1,2-dihydropyridine.
Article titled,"m-Dioxanes and Other Cyclic Acetals" by CHRISTIAN S. RONDESTVEDT Jr. in . Org. Chem., 1961, 26 (7), pp 2247-2253 reports an extensive series of substituted m- Dioxanes.
WO 2006030892 Al discloses a process for the production of NS-220 which is suitable for mass production on an industrial scale. The invention is constituted of (1) a process for the production of methyl cis-5-(4-chlorobutyl) -2-methyl-l,3-dioxane-2-carboxylate, characterized by hydrolyzing a cis/trans isomer mixture of methyl 5-(4- chlorobutyl)-2- methyl-l,3-dioxane-2-carboxylate in the presence of a base; (2) a process for the production of 4-methyl-N-(2-oxopropyl)benzamide, characterized by oxidizing 4-methyl-N-(2- hydroxypropyl)benzamide with 2,2,6, 6-tetra- methyl- 1-piperidinyloxyl radicals and sodium hypochlorite; and so on.
In literature there are number of syntheses reported. These synthesis have various drawbacks such as use of costly harmful metals, expensive starting material, lengthy synthetic routes which reduces over all yield of 3-hydroxy pipecolic acid.
Therefore there is need to develop a process for the synthesis of 3-hydroxy pipecolic acid which is short, efficient, scalable and with minimum purifications required, which successfully over coming these drawbacks. OBJECTIVE OF THE INVENTION
The main object of present invention is to provide novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof.
Another object of the present invention relates to a process for the synthesis of (2R, 3S)-3- hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof.
Further, the present invention provides a process for the synthesis of (2R, 3S)-3- hydroxypipecolic acid from D-glucose using chiral pool approach.
In an aspect of present invention is to provides a simple reaction sequences, azide free, improved process for the synthesis of (2R, 3S)-3-hydroxypipecolic acid from D-glucose with over all yield in the range of 20-26 %. DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In an embodiment, the present invention provide novel diol derivatives of general formula I,
R2 = OH, I I . N i l . I I
R3 = I I . OH, I I . N i l ,
R , =R , = -CH2CH2CH2NR4
R ,= CH2Ph, A l ly l , I I . Hoc. CBz, COO Me
Formula I
In another embodiment, the present invention provides chiral pool process for the synthesis of the compound of formula I from D glucose.
In yet another embodiment, the present invention provide a process for the synthesis of (2R, 35)-3-hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D- glucose used is in enantiomerically pure form.
The D-glucose compound as used herein for the synthesis of (2R, 35)-3-hydroxypipecolic acid is prepared by below scheme 1 :
D glucose 4
Scheme: 1
In a preferred embodiment, the present invention provides a process for synthesis of (2R, 35)- 3-hydroxypipecolic acid from D-glucose, wherein said process comprises the following steps: a) Reacting D-glucose with paraldehyde to give mono acetal protected (17?)-(-)-4,6-0- ethylidene-D-glucose;
b) Compound from step (a) is then subjected for cleavage with NaI04 to give (-)-2,4-0- ethylidene-D-erythrose;
c) Stirring the compound of step (b) at room temperature with Ph3PCHCOOEt in presence of toluene to give a, ^-unsaturated hydroxy ester;
d) Reduction of a, ^-unsaturated hydroxy ester by treatment with LiBr or LiCl and NaBH4 in THF: Water (1: 1) at ambient temperature to give allyl alcohol;
e) Hydrogenation of allyl alcohol of step (d) with Pd/C in methanol in hydrogen atmosphere to give the saturated compound 1,5 diol;
f) Reacting the compound of step (e) with methanesulphonyl chloride and triethyl amine to give obtain dimesylate compound;
g) Cyclization of compound of step (f) is carried out by heating dimesylate compound in neat benzyl amine to give cyclized product;
h) Hydrogenation of compound of step (g) in the presence of Boc anhydride and Pd/C to give N-debenzylation-N-Boc formation;
i) The N-boc piperidine from step (h) deprotected with PTSA in methanol and purified by recrystalization to get the target intermediate cis piperidine 2,6-diol in quantitative yield;
j) Adding t-BuMe2SiCl and imidazole to a solution of compound of step (i) in DMF followed by stirring at 40°C for 12 h to obtain (2R,3R)-tert-Butyl 3-(tert- butyldimethylsilyloxy)-2- ((tert-butyldimethylsilyloxy)methyl)piperidine- 1 - carboxylate;
k) Treating compound of step (j) with acetic acid to afford the selectively deprotected free primary alcohol;
1) Adding solution mixture of NaI04 in CH3CN/CC14/H20 and RuCl3.H20 to a solution of compound of step (k) in CH3CN followed by stirring at room temperature for 30 min to obtain (2S,3R)-N-tert-Butoxycarbonyl-3-hydroxypipecolic Acid; m) Heating the compound of step (1) in HC1 at 70 °C for 2 h to obtain (2S,3R)-3-
Hydroxypipecolic Acid Hydrochloride.
The above process for the synthesis of (2R, 35)-3-hydroxypipecolic acid compound of formula 12 is shown below in scheme 2.
11 12
Scheme 2
Scheme2. Reagents and conditions a) Ref.
1 ; b) NaI04, Water, 3 h, 97%; c) Ph3PCHCOOEt DCM, rt, 6 h, 87%; d) i) NaBH4 , LiCl, THF:water (1: 1), 12 h, ii) H2, Pd/C, MeOH, 60 psi, 3 h, 96%; e) MsClJEA, DCM, 0 °C, 30 min; f) BnNH2, heat, 2 h, 90%; g) H2, Pd/C, Boc20, MeOH, 60 Psi, 6 h; h) PTSA, MeOH, 3
h, rt, 91%; i) TBSC1, TEA, DMAP, DCM, 12 h, 86%; j) AcOH:H20:THF, 94%; k) RuCl3 (Cat.), NaI04, MeCN:CCl4:H20; 1) 6N HC1, 70 °C, 2 h.
The intermediate cis piperidine 2,6-diol used for the synthesis of (2R, 3S)-3- hydroxypipecolic acid is also prepared by using one pot synthesis from N-benzylated compound by carrying hydrogenation reaction in presence of dil.HCl followed by addition of boc anhydride to get this intermediate in good yields.
The process for synthesis of intermediate cis piperidine 2,6 diol compound of formula 1 is as shown in scheme
Scheme: 3
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. EXAMPLES
Example 1:
Synthesis intermediate diol (1):
Synthesis of (2R, 35)-3-hydroxypipecolic acid began with mono acetal protection of glucose to obtain (17?)-(-)-4, 6-O-ethylidene-D-glucose in 65% yield which was then subjected for cleavage with NaI04 to afford (_)-2, 4-O-ethylidene-D-erythrose in almost quantitative yield. The two-carbon Wittig homologation of (-)-2,4-0-ethylidene-D-erythrose with Ph3PCHCOOEt by stirring in DCM afforded a, ?-unsaturated hydroxy ester in 7:3 trans/ cis ratio in good yield. Reduction of a, ^-unsaturated hydroxy ester by treatment with LiBr or LiCl and NaBH4 in THF: Water (1: 1) at ambient temperature. Allyl alcohol formed during reduction was hydrogenated with Pd/C in methanol in hydrogen atmosphere which give the saturated compound 1,5 diol in 96% yield. This 1, 5 diol compound is subjected for mesylation by treating it with methanesulphonyl chloride and triethyl amine in DCM at 0 °C for 0.5 h to obtain dimesylate compound. This mesylate derivative is used for further cycloamination without purification. Cyclization was carried out by heating dimesylate compound in neat benzyl amine at 90 °C for 2 h to afford cyclized product in 90% yield. This cyclized benzylated piperidine was hydrogenated with Pd/C in methanol at 60 psi and
concomitant boc protection which led to one-pot N-debenzylation-N-Boc formation. The N- boc piperidine was obtained in almost quantitative yield which is deprotected with PTSA in methanol and purified by recrystalization to get the target intermediate in quantitative yield. Example 2:
Ethyl (E)-3-((2R,45,5R)-5-hydroxy-2-methyl-l,3-dioxan-4-yl)acrylate (6):
The crude aldehyde 3 (1.12 g, 7.87 mmol) was dissolved in DCM (100 mL) and to this solution Ph3PCHC02Et (3 g, 8.66 mmol) was added. The reaction mixture was stirred at room temperature for 4
h. Completion of reaction was monitored on TLC. After completion of reaction, solvent was removed under reduced pressure and the crude product was purified using silica gel coloumn chromatography to furnish the a, ?-unsaturated ester 6 (1.7 g, 87% ) as a colorless solid. Rf (ethyl acetate: pet. ether/2:3): 0.3
Yield: 87%
Molecular formula: CioHi6Os;
Molecular weight: 216.2310
IR: 3453, 2988, 2932, 1718, 1662, 1447 cm"1
Optical rotation: [a] ^ : -41.45 ( c = 0.5, chloroform)
1H NMR (400 MHz, CDC13+CC14): δ 1.31 (t, / = 7.2 Hz, 3 H), 1.36 (d, = 5.0 Hz, 3 H), 2.68 (br. s., 1 H), 3.44 (q, = 10.5 Hz, 1 H), 3.48 - 3.55 (m, 1 H), 3.98 (ddd, = 9.0, 4.6, 1.5 Hz, 1 H), 4.13 (dd, = 10.4, 4.6 Hz, 1 H), 4.21 (q, = 7.2 Hz, 2 H), 4.73 (q, = 5.0 Hz, 1 H), 6.14 (dd, = 15.8, 1.6 Hz, 1 H), 7.08 (dd, = 15.8, 4.5 Hz, 1 H).
13C NMR (100 MHz, CDCI3+CCI4): δ 14.29, 20.45, 60.62, 65.23, 70.71, 80.04, 98.78, 122.19, 143.68, 166.50.
HRMS: calcd for Ci0Hi6O5Na 239.0895 found 239.0890 [M+Na]+.
(2R,45,5R)-4-(3-hydroxypropyl)-2-methyl-l,3-dioxan-5-ol (2):
addition by saturated NH4C1 solution at 0 °C and again stirred for 10 min. Evaporation of the solvent furnished a residue which was extracted with ethyl acetate (3x8 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude residue was dissolved in methanol. To this
solution catalytic Pd/C was added. This reaction mixture was stirred under hydrogen gas pressure. After 3 h, catalyst was filtered off. Methanol was eavaporated under reduced pressure. The residue was purified by a silica gel column chromatography using ethyl acetate/hexane (1: 1) as eluent furnished the reduced 1,5-diol compound 2 (790 mg, 97%) as a colorless liquid. Rf (ethyl acetate: pet. ether/3 :2): 0.2.
Molecular formula: Formula: C8Hi604
Molecular Weight: 176.21
Yield: 94%.
Optical rotation: [a]^ : -45.45 (c = 1.02, chloroform).
IR (CHC13): 3390, 2992; 1652 cm"1.
1H NMR (400 MHz, CDC13): δ 1.30 (d, J = 5.0 Hz, 3 H), 1.47 - 1.68 (m, 2 H), 1.69 - 1.83 (m, 1 H), 1.89 - 2.06 (m, 1 H), 3.26 - 3.48 (m, 3 H), 3.57 - 3.76 (m, 3 H), 4.05 (dd, J = 10.5, 5.0 Hz, 1 H), 4.29 (br. s., 1 H), 4.65 (q, = 5.0 Hz, 1 H).
13C NMR (100 MHz, CDC13): δ 20.39, 27.70, 28.03, 62.18, 65.12, 70.71, 81.15, 98.88.
HRMS: calcd for C8Hi604Na: 199.0946; found 199.0942 [M+Na]+.
(2R,4a5,8a5)-5-Benzyl-2-methylhexahydro-4H-[l,3]dioxino[5,4-b]pyridine(7)
A solution of 1,5-diol 2 (400 mg, 2.27 mmol) in dry CH2C12 (5 mL), and
Et3N (1.37g, 13.63 mmol) was cooled to 0 °C. Subsequently mesyl
chloride (780 mg, 6.81 mmol) was added and the mixture was stirred for 30 min at the same temperature. Progress of reaction was monitored by TLC. After completion of the reaction, it was quenched by addition of 5 mL of aqueous solution of NaHC03 and the organic layer was washed with water (2 x 5 mL), followed by brine (5 mL). The organic layer was dried over NaS04, filtered and concentrated in vacuo. The residue of dimesylate was used as such for further reaction witout purification.
The dimesylate (300 mg, 0.617 mmol) was dissolved in benzylamine (5 mL) and stirred at 90 °C for 2 h. After completion of reaction (monitored by TLC), 10 mL of IN HC1 was added and extracted with DCM (3 x 10 mL). The organic layer was washed with saturated aqueous NaHC03 (15 mL) and brine (10 mL), dried over NaS04, concentrated in vacuo and the crude product purified by silica gel column chromatography (Hexane-EtOAc = 9: 1) to yield 7 (215 mg, 90%) as a colorless oil. 7 (ethyl acetate: pet. ether/2:3): 0.5.
Chemical Formula: C15H21NO2
Molecular Weight: 247.33
Yield: 90%.
Optical rotation: [a] ^ : -37 (c=1.036, chloroform)
1H NMR (200 MHz, CDC13+CC14): δ 1.40 - 1.44 (m, 3 H), 1.88 - 2.23 (m, 6 H), 2.95 (dd, J = 10.6, 2.1 Hz, 1 H), 3.59 (d, J = 14.1 Hz, 1 H), 3.68 (dd, = 12.8, 2.3 Hz, 1 H), 3.79 - 3.90 (m, 1 H), 4.05 (d, J = 14.1 Hz, 1 H), 4.58 (dt, = 12.8, 0.7 Hz, 1 H), 4.80 (q, J = 5.1 Hz, 1 H), 7.15 - 7.44 (m, 5 H).
13C NMR (50 MHz, CDCI3+CCI4): δ 19.66, 20.91, 29.93, 51.84, 56.20, 57.05, 67.25, 73.44, 99.41, 126.96, 127.99, 129.30, 136.65.
HRMS: calcd for C15H22NO2: 248.1651 ; found: 248.1645 [M+Na]+.
tert-Butyl(2/f,4a5,8a5)-2-methylhexahydro-5H-[l,3]dioxino[5,4-b]pyridine-5- carboxylate (8):
To the solution of N-benzyl piperidine 7 (0.250 g, 0.546 mmol) in methanol (20 mL, 9: 1) was added boc anhydride (0.17 g, 0.65 mmol) and catalytic Pd/C. The reaction mixture was stirred under hydrogen gas atmoshphere at
60 psi pressure for 8 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered on celite. The solvent was removed under reduced pressure to afford crude N-boc protected compound 8. The residue was purified by flash silica gel column chromatography in 10% ethyl acetate in pet. ether to give compound 8 (0.118 g, 94%) as colorless thick syrup. 7 (ethyl acetate: pet. ether/l :3): 0.5.
Molecular formula: Ci3H23N04 Molecular weight: 257.32
Yield: 94%.
25
Optical rotation: [a] ^ : -32 ( c = 1.05, chloroform) IR (CHCI3): 2979, 1671, 757 cm"1.
1H NMR (500 MHz, CDCI3+CCI4): δ 1.31 (d, J = 4.9 Hz, 3 H), 1.44 (s, 9 H), 1.51 - 2.08 (m, 4 H), 3.36 (br. s., 1 H), 3.48 (td, = 12.5, 6.1 Hz, 1 H), 3.72 (dd, = 12.4, 2.3 Hz, 1 H), 3.94 (dd, = 13.1, 7.9 Hz, 1 H), 4.01 (q, = 3.4 Hz, 1 H), 4.25 (d, = 12.2 Hz, 1 H), 4.67 (q, = 5.0 Hz, 1 H).
13C NMR (125 MHz, CDCI3+CCI4): δ 18.75, 21.35, 24.17, 28.52, 38.10, 49.12, 70.50, 71.13, 79.37, 79.40, 98.36, 154.93. HRMS: calcd for Ci3H23N04Na: 280.1519; found: 280.1525 [M+Na]+.
tert-butyl (2S,3S)-3-hydroxy-2-(hydroxymethyl)piperidine-l-carboxylate(l)
To a solution of ieri-butyl (2 ?,4aS,8aS)-2-methylhexahydro-5H- [l,3]dioxino[5,4-b]pyridine-5-carboxylate 8 (1.7 g, 6.88 mmol) in MeOH
(20 mL) was added p-TSA (130 mg, 0.69 mmol) at 0 °C and the mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with NaHC03 and the organic layer and aqueous layers were separated. Aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to dryness under reduced pressure. Purification by column chromatography using petroleum ether: ethyl acetate (1: 1) as eluent afforded 1.55 g compound as a white solid in 96% yield. Purification can also be carried out by recrystalizing the compound 1 from pet ether by dissolving in it by addition of minimum amount of ethyl actetate. Rf (ethyl acetate: Pet. ether/2:3): 0.4.
Molecular formula: CnH2iN04 Molecular weight: 231.29 Yield: 96%.
MP: 115-117 °C Lit. 114-116 °C
Optical rotation: [<x]¾ : +24.2 (c: 1, MeOH); Lit.37 [<x]¾ : (c: 1.03, MeOH), [<x]¾ : +33.6 (c = 1.04, CHC13); Lit. [<x]¾ : +23.4 (c = 1, CHC13) IR (CHC13): I : 3407, 2935, 1668, 1423 cm"1
1H NMR (400 MHz, CDCI3+CCI4): δ 1.45 (s, 10 H), 1.55 - 1.77 (m, 2 H), 1.85 (d, 7 = 12.3 Hz, 1 H), 2.82 (br. s., 1 H), 3.36 (br. s, 2 H), 3.73 (dd, 7 = 11.2, 6.9 Hz, 1 H), 3.79 (br. s., 1 H), 3.87 - 3.96 (m, 1 H), 4.10 (dd, 7 = 11.2, 6.5 Hz, 1 H), 4.42 (q, 7 = 6.1 Hz, 1 H).
13C NMR (100 MHz, CDCI3+CCI4): δ 23.80, 28.34, 28.45, 39.76, 56.08, 59.26, 69.39, 80.26, 155.62.
HRMS: calcd for CnH2iN04Na: 254.1368; found:254.1363 [M+Na]+.
(25,35)-tert-Butyl3-((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy) methyl)piperidine- 1 -carboxylate (9) 15
To the solution of diol 1 (40 mg, 0.173 mmol ) in DCM (1 mL) TBDMSC1 (79 mg, 0.52 mmol), imidazole (71 mg, 0.10 mmol) and
DMAP (0.0173 mmol) was added under nitrogen. The mixture was stirred at room temperature for 12 h and diluted with DCM (3.0 mL). An aqueous solution saturated of NaHC03 (3.0 mL) was added and the product was extracted four times with DCM (3 mL). The organic layer was, dried over NaS04, filtered and concentrated in vacuo and the crude product purified by silica gel column chromatography (Hexane-EtOAc = 9: 1) to yield 9 (69 mg, 86%) as a colorless oil. 7 (ethyl acetate: Pet. ether/l:8): 0.3.
Molecular formula: C23H49N04Si2 Molecular weight: 459.81
Yield: 86%
Optical rotation: +14 (c 0.5, CHC13); ent-l: Lit. 15 -13:6 (c 0.5, CHC13); IR (CDC13): 2930, 1693, 756 cm"1.
1H NMR (400 MHz, CDCI3): δ 0.02 - 0.17 (m, 12 H), 0.79 - 1.00 (m, 18 H), 1.46 (s, 9 H), 1.53 - 1.86 (m, 4 H), 2.71 - 3.06 (m, 1 H), 3.58 - 4.09 (m, 4 H), 4.19 - 4.46 (m, 1 H).
13C NMR (100 MHz, CDC13): δ -5.4, -5.4, -5.0, -4.8, 18.1, 18.2, 24.2, 25.8, 25.9, 28.4, 29.6, 29.7, 37.3, 39.2, 55.8, 57.8, 58.1, 69.6, 79.1, 155.2.
Example 3:
Synthesis of (25,3/?)-N-tert-Butoxycarbonyl-3-hydroxypipecolic Acid (11):
To a suspension of NaI04 (235 mg, 1.1 mmol) in
(4.8 mL; 1: 1: 10) was added RuCl3,H20 (11.4 mg, 0.055 mmol) in small portions, and the mixture was stirred at room temperature for 45 min. The resulting solution was added to the alcohol 10 (191 mg, 0.55 mmol) dissolved in CH3CN (3 mL), followed by the addition of a second portion of NaI04 (118 mg, 0.55 mmol). The resulting mixture was stirred at room temperature for 30 min and filtered through Celite, and the Celite layer was washed thoroughly with EtOAc. The combined filtrate was dried over Na2S04 and concentrated. The crude product thus obtained was purified by flash column chromatography (MeOH/CHCl3) 5:95 to 20:80) to yield the pure acid 11 (97 mg, 72%) as a semisolid.
Example 4:
Synthesis of (25, 3/?)-3-Hydroxypipecolic acid hydrochloride (12):
The Boc-protected acid 11 (78 mg, 0.32 mmol) was taken in 6 N HCl (10 mL) and heated at 70 °C for 2 h. The reaction mixture was cooled to room temperature and extracted once with CH2CI2 (10 mL) to remove any organic soluble impurities. Concentration of the aqueous layer under high vacuum followed by overnight drying under high vacuum afforded the product 12 as a light yellow solid (57 mg, quantitative).
Example 5:
Synthesis of cis piperidine 2,6 diol (1):
The intermediate cis piperidine 2, 6-diol compound of formula 1 is prepared by one pot synthesis from N-benzylated compound by carrying hydrogenation reaction in presence of dil.HCl followed by addition of boc anh dride to get this intermediate in ood yields.
Then (Boc)2°
To the solution of N-benzyl piperidine 7 (0.250 g, 0.546 mmol) in methanol - dil. HCl (20 mL, 9: 1), was added catalytic Pd/C and the reaction mixture was stirred under hydrogen gas atmoshphere at 60 psi pressure for 4 h. After completion of the reaction (monitored by TLC), the boc anhydride (0.17 g, 0.65 mmol) was added to this reaction mixture and stirred further for 2 h. The reaction mixture was filtered on celite. The solvent was removed under reduced pressure to afford crude N-boc protected compound 8. The product was purified by recrystalization. ADVANTAGES OF THE PRESENT INVENTION
Simple reaction sequence which is good for industrial production.
1) Azide-free reaction makes the process cheaper.
2) Improved over all yield good for large scale synthesis.
3) Easily available cheap staring material decreases the cost.
Claims
1. Compounds of formula I,
R2 - OH, H, NH, H
R3 = H, OH, H, NH2
R1=R3 = -CH2CH2CH2NR4
R4= CH2Ph, Allyl, H, Boc, CBz, COOMe
2. A process for the synthesis of compound of formula I as claimed in claim 1, wherein said process comprises of:
a. Reacting D-glucose with paraldehyde to give mono acetal protected (l'R)-(-)- 4,6-O-ethylidene-D-glucose at room temperature ( temperature range 20 °C to 50 °C for 3 days) compound from step (a) is then subjected for cleavage with NaI04( temperature range 0 °C to 10 °C for 3 to 5 h) to give (-)-2,4-0- ethylidene-D-erythrose;
b. Stirring the compound of step (b) at room temperature with Ph3PCHCOOEt in the presence of toluene/DCM ( temperature range 20 °C to 110 °C for 4 to 10 h) to give a, ^-unsaturated hydroxy ester;
c. Reduction of a, ^-unsaturated hydroxy ester by treatment with LiBr or LiCl and NaBH4 in THF: Water (1 : 1) ( temperature range 0 °C to 40 °C/ room temperature for 12 to 18 h) to give allyl alcohol;
d. Hydrogenation of allyl alcohol of step (d) with Pd/C in methanol in hydrogen atmosphere at 60 psi ( temperature range 20 °C to 40 °C for 2 to 4 h) to give the saturated compound of formula I.
3. The process as claimed in claim 2, wherein said process is used for the synthesis of (2R, 35)-3-hydroxypipecolic acid from D-glucose.
4. The process as claimed in claim 3, wherein said process comprises the steps of:
a) Reacting D-glucose with paraldehyde to give mono acetal protected (l'R)-(-)- 4,6-O-ethylidene-D-glucose;
b) Compound from step (a) is then subjected for cleavage with NaI04 to give (-)- 2,4-O-ethylidene-D-erythrose;
c) Stirring the compound of step (b) at room temperature( temperature range 20 °C to 40 °C for 4 to 10 h) with Ph3PCHCOOEt in presence of toluene/DCM to give a, ^-unsaturated hydroxy ester;
d) Reduction of a, ^-unsaturated hydroxy ester by treatment with LiBr or LiCl and NaBH4 in THF:Water (1 : 1) at ambient temperature ( temperature range - from 0 °C allowed to attain room range 20 °C to 40 °C) to give allyl alcohol; e) Hydrogenation of allyl alcohol of step (d) with Pd/C in methanol in hydrogen atmosphere (60 psi pressure and temperature range 20 °C to 40 °C for 2 to 4 h) to give the saturated compound 1,5 diol;
f) Reacting the compound of step (e) with methanesulphonyl chloride and triethyl amine to give obtain dimesylate compound ( temperature range 20 °C to 10 °C for 30 min to 60 min);
g) Cyclization of compound of step (f) is carried out by heating dimesylate compound in neat benzyl amine to give cyclized product ( temperature range 85 °C to 95 °C for 2-4 hours);
h) Hydrogenation of compound of step (g) in the presence of Boc anhydride and Pd/C to give N-debenzylation-N-Boc formation (60 psi pressure and temperature range 27 °C to 40 °C);
i) The N-boc piperidine from step (h) deprotected with PTSA in methanol ( temperature range 20 °C to 40 °C);
j) and purified by recrystalization to get the target intermediate cis piperidine
2,6-diol in quantitative yield;
k) Adding t-BuMe2SiCl and imidazole to a solution of compound of step (i) in
DMF followed by stirring at 20-40°C for 10 to 18 h to obtain {2R,3R)-tert-
Butyl 3-(tert-butyldimethylsilyloxy)-2- ((tert- butyldimethylsilyloxy)methyl)piperidine- 1 -carboxylate;
1) Treating compound of step (j) with acetic acid to afford the selectively deprotected free primary alcohol;
m) Adding solution mixture of NaI04 in CH3CN/CC14/H20 and RuCl .H20 to a solution of compound of step (k) in CH3CN followed by stirring at room
temperature ( range- 20 °C to 40 °C) for 30 to 60 min to obtain 2S,3R)-N-tert- B utoxycarbonyl- 3 -hydroxypipecolic Acid ;
n) Heating the compound of step (1) in HC1 at temperature range 60-80 °C for 2 to 4 h to obtain (25, 3 ?)-3-Hydroxypipecolic Acid Hydrochloride.
5. The process as claimed in claim 3, wherein the D-glucose used is in enantiomerically pure form.
6. The process as claimed in claim 4, wherein the temperature is in the range of 0 to 110 °C and overall yield is in the range of 20 to 26 %.
7. A one pot process for the synthesis of the cis piperidine 2,6-diol intermediate as claimed in step (i) of claim 6, wherein the said process comprises carrying hydrogenation reaction of N-benzylated compound in presence of dil.HCl at temperature 20 °C to 40 °C followed by addition of boc anhydride to obtain the desired product in good yields.
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