UA64695C2 - 2-azabicyclo[2.2.1]heptane derivatives and a method for preparing the same - Google Patents
2-azabicyclo[2.2.1]heptane derivatives and a method for preparing the same Download PDFInfo
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- UA64695C2 UA64695C2 UA97115616A UA97115616A UA64695C2 UA 64695 C2 UA64695 C2 UA 64695C2 UA 97115616 A UA97115616 A UA 97115616A UA 97115616 A UA97115616 A UA 97115616A UA 64695 C2 UA64695 C2 UA 64695C2
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- general formula
- radical
- carbon atoms
- radicals
- hydrogen atom
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- GYLMCBOAXJVARF-UHFFFAOYSA-N 3-azabicyclo[2.2.1]heptane Chemical class C1C2CCC1NC2 GYLMCBOAXJVARF-UHFFFAOYSA-N 0.000 title claims abstract 3
- 238000000034 method Methods 0.000 title claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 52
- -1 alkyl radical Chemical class 0.000 claims description 42
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 32
- 150000003254 radicals Chemical class 0.000 claims description 28
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 229910052709 silver Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000012285 osmium tetroxide Substances 0.000 claims description 4
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 4
- FNWWXCLMWLVPJX-UHFFFAOYSA-N 4-hydroxy-3-methylmorpholine Chemical compound CC1COCCN1O FNWWXCLMWLVPJX-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- LFMTUFVYMCDPGY-UHFFFAOYSA-N n,n-diethylethanamine oxide Chemical compound CC[N+]([O-])(CC)CC LFMTUFVYMCDPGY-UHFFFAOYSA-N 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 238000010908 decantation Methods 0.000 description 3
- NGAZZOYFWWSOGK-UHFFFAOYSA-N ethyl-n-butyl-ketone Natural products CCCCC(=O)CC NGAZZOYFWWSOGK-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- USBJLGXPMPMTSL-UHFFFAOYSA-N heptan-3-one Chemical compound [CH2]CC(=O)CCCC USBJLGXPMPMTSL-UHFFFAOYSA-N 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 241000609240 Ambelania acida Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 238000006359 acetalization reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000010905 bagasse Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- KWUVPYOGESDCNX-UHFFFAOYSA-N n-ethylcyclopentanecarboxamide Chemical compound CCNC(=O)C1CCCC1 KWUVPYOGESDCNX-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229910001925 ruthenium oxide Inorganic materials 0.000 description 1
- WOCIAKWEIIZHES-UHFFFAOYSA-N ruthenium(iv) oxide Chemical compound O=[Ru]=O WOCIAKWEIIZHES-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Β -Β C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Β -Β C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
ΠΠ°Π½ΠΈΠΉ Π²ΠΈΠ½Π°Ρ ΡΠ΄ ΡΡΠΎΡΡΡΡΡΡΡ Π½ΠΎΠ²ΠΈΡ ΠΏΠΎΡ ΡΠ΄Π½ΠΈΡ 2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|)Π³Π΅ΠΏΡΠ°Π½Ρ Π· 1Π8- Π°Π±ΠΎ 15-ΠΊΠΎΠ½ΡΡΠ³ΡΡΠ°ΡΡΡΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Π°Π±ΠΎ (Π): Ρ . Π² Π Π½ΠΎ Π ΠΠΎ Π²ΠΎ ; Π½ΠΎ ΡΡ ΠΠ ΡΠΈ Π½ΠΈ 7 Ρ ΡΠΏΠΎΡΠΎΠ±Ρ ΡΡ ΠΎΡΡΠΈΠΌΠ°Π½Π½Ρ ΡΠ° ΡΡ Π·Π°ΡΡΠΎΡΡΠ²Π°Π½Π½Ρ.The present invention relates to new derivatives of 2-azabicyclo(2.2.1|)heptane with the 1A8- or 15-configuration of the general formula (I) or (I): x. in K no A Ko vo ; but yuyu AB shin ny 7 t method of their obtaining and their application.
Π£ Π·Π°Π³Π°Π»ΡΠ½ΠΈΡ ΡΠΎΡΠΌΡΠ»Π°Ρ (Π) Π°Π±ΠΎ (Π) Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ Π°Π±ΠΎ, Π²ΡΠ΄ΠΏΠΎΠ²ΡΠ΄Π½ΠΎ, ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π°Π±ΠΎ (ΠΠ):In the general formulas (I) or (I), A means a hydrogen atom or, respectively, a radical of the general formula (II) or (II):
Π Π² Π±Π΅ Π¨Π ΡΠ»Ρ ΠΡ Π§Π΅ Ρ . Ρ, Π΄Π΅ ΠΒ» ΠΎΠ·Π½Π°ΡΠ°Ρ Π°Π»ΠΊΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, Π° ΠΠ³ ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ΅Π½ΡΠ» Π°Π±ΠΎ Ρ- Π°Π±ΠΎ ΡΠ-Π½Π°ΡΡΠΈΠ», ΡΠΎ ΠΌΠΎΠΆΠ΅ Π±ΡΡΠΈ Π·Π°ΠΌΡΡΠ΅Π½ΠΈΠΌ ΠΎΠ΄Π½ΠΈΠΌ Π°Π±ΠΎ Π΄Π΅ΠΊΡΠ»ΡΠΊΠΎΠΌΠ°, ΠΎΠ΄Π½Π°ΠΊΠΎΠ²ΠΈΠΌΠΈ Π°Π±ΠΎ ΡΡΠ·Π½ΠΈΠΌΠΈ, Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π°Π±ΠΎ ΡΠ°Π΄ΠΈΠΊΠ°Π»Π°ΠΌΠΈ, ΡΠΎ ΠΎΠ±ΠΈΡΠ°ΡΡΡ ΡΠ΅ΡΠ΅Π΄ Π°ΡΠΎΠΌΡΠ² Π³Π°Π»ΠΎΠ³Π΅Π½Ρ ΡΠ° Π°Π»ΠΊΡΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, Π°Π»ΠΊΠΎΠΊΡΠΈΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ Π°Π±ΠΎ Π½ΡΡΡΠΎΠ³ΡΡΠΏΠΈ.Π Π² Π±Π΅ Π¨Π ΡΠ»Ρ ΠΡ Π§Π΅ Ρ . and, where B" means an alkyl radical with 1-4 carbon atoms, and Ag means phenyl or c- or p-naphthyl, which may be substituted by one or more, the same or different, atoms or radicals selected from halogen atoms and alkyl radicals with 1-4 carbon atoms, alkyl radicals with 1-4 carbon atoms or nitro groups.
ΠΠ΅ΡΠ΅Π²Π°ΠΆΠ½ΠΎ, ΠΡ ΠΎΠ·Π½Π°ΡΠ°Ρ ΠΌΠ΅ΡΠΈΠ»ΡΠ½ΠΈΠΉ Π°Π±ΠΎ Π΅ΡΠΈΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π° ΠΠ³ ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ΅Π½ΡΠ», ΠΌΠΎΠΆΠ»ΠΈΠ²ΠΎ Π·Π°ΠΌΡΡΠ΅Π½ΠΈΠΉ ΠΎΠ΄Π½ΠΈΠΌ Π°Π±ΠΎ Π΄Π΅ΠΊΡΠ»ΡΠΊΠΎΠΌΠ° ΠΌΠ΅ΡΠΈΠ»ΡΠ½ΠΈΠΌΠΈ Π°Π±ΠΎ ΠΌΠ΅ΡΠΎΠΊΡΠΈ-ΡΠ°Π΄ΠΈΠΊΠ°Π»Π°ΠΌΠΈ.Preferably, Bi represents a methyl or ethyl radical and Ag represents a phenyl, optionally substituted with one or more methyl or methoxy radicals.
ΠΠ΅ΡΠ΅Π²Π°ΠΆΠ½ΡΡΠ΅, ΠΠ: ΠΎΠ·Π½Π°ΡΠ°Ρ ΠΌΠ΅ΡΠΈΠ», Π° ΠΠ³ ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ΅Π½ΡΠ».Preferably, BA: stands for methyl and Ag stands for phenyl.
ΠΠ³ΡΠ΄Π½ΠΎ Π²ΠΈΠ½Π°Ρ ΠΎΠ΄Ρ, ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Π°Π±ΠΎ (Π), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π²ΡΠ΄ΠΏΠΎΠ²ΡΠ΄Π½ΠΎ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π°Π±ΠΎ (Π) ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ Π±ΡΡ-Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ»ΡΠ²Π°Π½Π½Ρ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Π°Π±ΠΎ (ΠΠΠ):According to the invention, compounds of the general formula (I) or (I), where A means, respectively, a radical of the general formula (II) or (I) can be obtained by bis-hydroxylation of a compound of the general formula (I) or (PII):
Π ΠΎΡ Ρ ΡΠ°ΠΉ Π’Π΅ΠΌ Π² Π― ΡΠ° ΡΠ΅ Π, ΠΎ ΡΠ° Ρ Π§ΠΠ Ρ ΠΉ -- ΡΡΡ: ΡΠΌ Π΄Ρ Π΄Π΅ ΠΡ ΡΠ° ΠΠ³ ΠΌΠ°ΡΡΡ Π²ΠΈΡΠ΅Π²ΠΊΠ°Π·Π°Π½Π΅ Π·Π½Π°ΡΠ΅Π½Π½Ρ.A oh h rai Tem v Ya rashe V, o ra r CHYN t y -- yati: tm du de Ni and Ag have the above meaning.
ΠΠ²ΠΈΡΠ°ΠΉΠ½ΠΎ Π±ΡΡ-Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ»ΡΠ²Π°Π½Π½Ρ Π·Π΄ΡΠΉΡΠ½ΡΡΡΡ, ΠΏΡΠ°ΡΡΡΡΠΈ Π² ΡΠΌΠΎΠ²Π°Ρ , ΡΠΎ ΠΎΠΏΠΈΡΠ°Π½Ρ Π.ΠΠ°ΠΏ ΠΠΏΠ΅ΡΠΏΠ΅ΠΏ Π΅Ρ ΡΠΎΡ).,Usually, bis-hydroxylation is carried out, working under the conditions described by M. Map Apeepep eyi soi).
Π’Π΅ΠΌΠ°ΠΏΠ΅Π΄ΡΠΎΠΏ ΠΠ΅ΠΉΡΠ΅Π³Π²5, 23, 1973-1976 (1976). ΠΠΎΠΊΡΠ΅ΠΌΠ°, ΠΎΠΊΠΈΡΠ»Π΅Π½Π½Ρ ΠΌΠΎΠΆΠ½Π° Π·Π΄ΡΠΉΡΠ½ΡΠ²Π°ΡΠΈ Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ ΠΏΠ΅ΡΠΌΠ°Π½Π³Π°Π½Π°ΡΡ ΠΊΠ°Π»ΡΡ Π°Π±ΠΎ ΡΠ΅ΡΡΠΎΠΊΡΠΈΠ΄Ρ ΠΎΡΠΌΡΡ Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ Π-ΠΌΠ΅ΡΠΈΠ»ΠΌΠΎΡΡΠΎΠ»ΡΠ½ΠΎΠΊΡΠΈΠ΄Ρ Π°Π±ΠΎ ΡΡΠΈΠ΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΡΠΈΠ΄Ρ, Π°Π±ΠΎ ΡΠ΅ΡΠΈΡΠΈΠ°Π½ΡΠ΄Ρ ΠΊΠ°Π»ΡΡ(ΠΠ·ΠΠ΅Π‘ΠΠ²). ΠΠ²ΠΈΡΠ°ΠΉΠ½ΠΎ ΠΏΡΠ°ΡΡΡΡΡ Ρ Π²ΠΎΠ΄Π½ΠΎ-ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠ΅ΡΠ΅Π΄ΠΎΠ²ΠΈΡΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ ΡΡΠΌΡΡ Π²ΠΎΠ΄ΠΈ Π· ΡΡΠ΅Ρ-Π±ΡΡΠ°Π½ΠΎΠ»ΠΎΠΌ Π°Π±ΠΎ Π²ΠΎΠ΄ΠΈ Π· Π°ΡΠ΅ΡΠΎΠ½ΠΎΠΌ.Temapedtop Ieitsegv5, 23, 1973-1976 (1976). In particular, oxidation can be carried out using potassium permanganate or osmium tetroxide in the presence of M-methylmorpholine oxide or triethylamine oxide, or potassium ferricyanide (KzBeSMv). They usually work in an aqueous-organic environment, such as a mixture of water with tert-butanol or water with acetone.
ΠΠ³ΡΠ΄Π½ΠΎ Π·Π°Π³Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΏΡΠ°Π²ΠΈΠ»Π°, ΠΎΠΊΠΈΡΠ½ΠΈΠΊ ΠΏΠΎΡΡΡΠ±Π½ΠΎ ΠΎΠ±ΠΈΡΠ°ΡΠΈ ΡΠ°ΠΊ, ΡΠΎΠ± Π²ΡΠ½ Π΄Π°Π²Π°Π² Π»ΠΈΡΠ΅ 5,6-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-ΠΏΠΎΡ ΡΠ΄Π½Π΅ Π² Π΅ΠΊΠ·ΠΎΡΠΎΡΠΌΡ.As a general rule, the oxidant should be chosen to give only the 5,6-dihydroxy derivative in the exoform.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π°Π±ΠΎ (ΠΠ) ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ ΡΠ΅Π°ΠΊΡΡΡ ΠΠΈΠ»ΡΡ-ΠΠ»ΡΠ΄Π΅ΡΠ° ΠΌΡΠΆ Π³ΠΎΠΌΠΎΡ ΡΡΠ°Π»ΡΠ½ΠΈΠΌ Π°ΠΌΡΠ½ΠΎΠΌ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π°Π±ΠΎ (ΠΠ): ΠΌ'Ρ Ρ Π΅ Π»Π΅Ρ, ΠΏΠ΅, Π΄Π΅ ΠΡ ΡΠ° ΠΠ³ ΠΌΠ°ΡΡΡ Π²ΠΈΡΠ΅Π²ΠΊΠ°Π·Π°Π½Ρ Π·Π½Π°ΡΠ΅Π½Π½Ρ, Ρ ΡΠΎΠΌΡ ΡΠΎΠ»Ρ, ΠΏΠ΅ΡΠ΅Π²Π°ΠΆΠ½ΠΎ Π· Π½Π΅ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΎΡ, ΡΠ°ΠΊΠΎΡ ΡΠΊ ΡΠΎΠ»ΡΠ½Π° ΠΊΠΈΡΠ»ΠΎΡΠ°, ΡΠΎΡΠΌΠ°Π»ΡΠ΄Π΅Π³ΡΠ΄ΠΎΠΌ ΡΠ° ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π΄ΡΡΠ½ΠΎΠΌ, ΠΏΡΠ°ΡΡΡΡΠΈ Π² ΡΠΌΠΎΠ²Π°Ρ , ΡΠΎ ΠΎΠΏΠΈΡΠ°Π½Ρ 5.0. Π Π°Π³Π²Π΅ΠΏ ΡΠ° Π .Π.A compound of the general formula (PP) or (PG) can be obtained by the Diels-Alder reaction between a homochiral amine of the general formula (IM) or (IM): ΠΌΡ Ρ Π΅ Π»Π΅Ρ, ΠΏΠ΅, where Ni and ΠΠ³ have the above values, in the form of a salt, preferably with an inorganic acid such as hydrochloric acid, formaldehyde and cyclopentadiene, working under the conditions described in 5.0. And Agvep and R.A.
Π‘ΡΡΠ΅ΡΠΎ, Ρ). ΠΡΠ΅Π³. Π‘ΠΏΠ΅Ρ. Π±ΠΎΡ, 107, 1768-1769 (1985).Scieso, u). Ateg. Spent boss, 107, 1768-1769 (1985).
ΠΠΈΡ ΠΎΠ΄ΡΡΠΈ Π· Π³ΠΎΠΌΠΎΡ ΡΡΠ°Π»ΡΠ½ΠΎΠ³ΠΎ Π°ΠΌΡΠ½Ρ Π² Π- Π°Π±ΠΎ 5-ΡΠΎΡΠΌΡ, Π·Π΄ΡΠΉΡΠ½Π΅Π½Π½Ρ ΡΠΏΠΎΡΠΎΠ±Ρ ΠΏΡΠΈΠ·Π²ΠΎΠ΄ΠΈΡΡ Π΄ΠΎ ΡΡΠ²ΠΎΡΠ΅Π½Π½Ρ ΡΡΠΌΡΡΡ Π΄Π²ΠΎΡ Π΄ΡΠ°ΡΡΠ΅ΡΠ΅ΠΎΡΠ·ΠΎΠΌΠ΅ΡΡΠ², ΡΠΎΠ·Π΄ΡΠ»Π΅Π½Π½Ρ ΡΠΊΠΈΡ Π½Π΅ Ρ Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΈΠΌ, ΠΎΡΠΊΡΠ»ΡΠΊΠΈ Π²ΠΎΠ½ΠΈ ΠΎΠ΄Π½Π°ΠΊΠΎΠ²ΠΎ ΡΠ΅Π°Π³ΡΡΡΡ Π½Π° Π½Π°ΡΡΡΠΏΠ½ΡΠΉ ΡΡΠ°Π΄ΡΡ Π±ΡΡ-Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ»ΡΠ²Π°Π½Π½Ρ.Based on the homochiral amine in the B- or 5-form, the implementation of the method leads to the formation of a mixture of two diastereoisomers, the separation of which is not necessary, since they react in the same way at the next stage of bis-hydroxylation.
ΠΠ³ΡΠ΄Π½ΠΎ Π²ΠΈΠ½Π°Ρ ΠΎΠ΄Ρ, ΡΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Π°Π±ΠΎ (Π), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ Π³ΡΠ΄ΡΠΎΠ³Π΅Π½ΠΎΠ»ΡΠ·Ρ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΡ) Π°Π±ΠΎ (Π), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΡ) Π°Π±ΠΎ (1), Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ Π²ΠΎΠ΄Π½Ρ Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΊΠ°ΡΠ°Π»ΡΠ·Π°ΡΠΎΡΠ°, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ ΠΏΠ°Π»Π°Π΄ΡΠΉ-Π½Π°-Π²ΡΠ³ΡΠ»Π»Ρ, ΠΏΡΠ°ΡΡΡΡΠΈ Π² ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠΎΠ·ΡΠΈΠ½Π½ΠΈΠΊΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ ΡΠΏΠΈΡΡ, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, ΠΌΠ΅ΡΠ°Π½ΠΎΠ».According to the invention, a compound of the general formula (I) or (I), where A represents a hydrogen atom, can be obtained by hydrogenolysis of a compound of the general formula (II) or (I), where A represents a radical of the general formula (II) or (1), by using hydrogen in the presence of a catalyst such as palladium-on-charcoal, working in an organic solvent such as an alcohol such as methanol.
ΠΠ·ΠΎΠΌΠ΅Ρ (18) Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΡ), ΠΌΠΎΠΆΠ½Π° Π²ΠΈΠ΄ΡΠ»ΠΈΡΠΈ ΡΠ· ΡΡΠΌΡΡΡ ΡΠΏΠΎΠ»ΡΠΊ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) ΡΠ° Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) ΡΠ»ΡΡ ΠΎΠΌ Π΄ΡΠ°ΡΡΠ΅ΡΠ΅ΠΎΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΠΎΡ ΠΊΡΠΈΡΡΠ°Π»ΡΠ·Π°ΡΡΡ Π· ΠΎΠΏΡΠΈΡΠ½ΠΎ Π°ΠΊΡΠΈΠ²Π½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΎΡ Ρ Π²ΡΠ΄ΠΏΠΎΠ²ΡΠ΄Π½ΠΎΠΌΡ ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠΎΠ·ΡΠΈΠ½Π½ΠΈΠΊΡ. ΠΠ°ΠΉΠΊΡΠ°ΡΠΈΠΌ Ρ Π²ΠΈΠΊΠΎΡΠΈΡΡΠ°Π½Π½Ρ |Π- Π΄ΠΈΠΌΠ΅ΡΠΎΠΊΡΠΈΠ±ΡΡΡΡΠΈΠ½ΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ Π² Π°Π»ΡΡΠ°ΡΠΈΡΠ½ΠΎΠΌΡ ΡΠΏΠΈΡΡΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ ΡΠ·ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ».Isomer (18) of the general formula (I), where A is a radical of the general formula (II), can be isolated from a mixture of compounds of the general formula (I) and the general formula (I) by diastereoselective crystallization with an optically active acid in a suitable organic solvent. It is best to use |I-dimethoxysuccinic acid in an aliphatic alcohol such as isopropanol.
ΠΠΎΠ²Ρ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Ρ ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ ΡΡΠΊΠ°Π²ΠΈΠΌΠΈ Π΄Π»Ρ ΠΎΡΡΠΈΠΌΠ°Π½Π½Ρ ΡΠΏΠΎΠ»ΡΠΊ, ΡΠΎ Ρ ΠΎΠ±ΡΠ΅ΠΊΡΠΎΠΌ Π²ΠΈΠ½Π°Ρ ΠΎΠ΄Ρ ΠΏΠ°ΡΠ΅Π½ΡΡ 5 5364862. ΠΠΎΠ½ΠΈ ΡΠ°ΠΊΠΎΠΆ Ρ Π°ΠΊΡΠΈΠ²Π½ΠΈΠΌΠΈ ΡΠ½Π³ΡΠ΅Π΄ΡΡΠ½ΡΠ°ΠΌΠΈ ΠΏΡΠΈ Π»ΡΠΊΡΠ²Π°Π½Π½Ρ ΡΠ΅ΡΡΠ΅Π²ΠΎ-ΡΡΠ΄ΠΈΠ½Π½ΠΈΡ Π·Π°Ρ Π²ΠΎΡΡΠ²Π°Π½Ρ, ΡΠ°ΠΊΠΈΡ ΡΠΊ Π³ΡΠΏΠ΅ΡΡΠΎΠ½ΡΡ ΡΠ° ΠΌΡΠΎΠΊΠΎΡΠ΄ΠΈΠ°Π»ΡΠ½Π° ΡΡΠ΅ΠΌΡΡ.New compounds of the general formula (I) are particularly interesting for obtaining compounds that are the subject of the invention of patent 5 5364862. They are also active ingredients in the treatment of cardiovascular diseases such as hypertension and myocardial ischemia.
ΠΠ°ΠΉΡΡΠΊΠ°Π²ΡΡΠΎΡ Ρ ΡΠΏΠΎΠ»ΡΠΊΠ° (1-5-1ΠΎ02Ρ,3Ρ.,40457)1)-4-(7-(Π¦2-(3-Ρ Π»ΠΎΡ-2-ΡΡΡΠ½ΡΠ»)-1-Π΅ΡΠΈΠ»|Π°ΠΌΡΠ½ΠΎ|-ΠΠ-ΡΠΌΡΠ΄Π°Π·ΠΎ-|4,5-The most interesting compound is (1-5-1ΠΎ02Ρ,3Ρ.,40457)1)-4-(7-(C2-(3-chloro-2-thienyl)-1-ethyl|amino|-ZH-imidazo-|4, 5-
Π|ΠΠΏΡΡΠΈΠ΄ΠΈΠ½-3-ΡΠ»|-Π-Π΅ΡΠΈΠ»-2,3-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½ΠΊΠ°ΡΠ±ΠΎΠΊΠ°ΠΌΡΠ΄ ΡΠΎΡΠΌΡΠ»ΠΈ:B|Ipyridin-3-yl|-M-ethyl-2,3-dihydroxycyclopentanecarboxamide of the formula:
Β«ΠΈ Ρ -Π΅ Π."and r -e M.
Π£Ρ ΡΠ΅ ΠUh re M
Π ΠΎΠ½ ΡΠΈΠ²ΠΈΠ½ΡΠ½Π½Ρ, ΡΠ΅ ΡΡ And he is graying, more of them
Π‘ΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Ρ ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ ΠΊΠΎΡΠΈΡΠ½ΠΈΠΌΠΈ Π΄Π»Ρ ΠΎΡΡΠΈΠΌΠ°Π½Π½Ρ ΠΊΠ°ΡΠ±ΠΎΡΡΠΊΡΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π): ΠΊΠΈΡ ΠΠ, ΠΌ ΠΉ ΠΏΡΠ½ Ρ.Compounds of the general formula (I) are especially useful for obtaining carbosugar of the general formula (M): kikh MH, m and ptn r.
ΠΠΎΠ΄ Π΄Π΅:Water where:
ΠΠ³ ΠΎΠ·Π½Π°ΡΠ°Ρ ΠΊΠ°ΡΠ±ΠΎΠΊΡΠΈΠ»; Π°Π»ΠΊΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ», Π°Π»ΠΊΡΠ»ΡΠ½Π° ΡΠ°ΡΡΠΈΠ½Π° ΡΠΊΠΎΠ³ΠΎ ΠΌΡΡΡΠΈΡΡ 1-4 Π°ΡΠΎΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ; Π- Π°Π»ΠΊΡΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ», Π°Π»ΠΊΡΠ»ΡΠ½Π° ΡΠ°ΡΡΠΈΠ½Π° ΡΠΊΠΎΠ³ΠΎ ΠΌΡΡΡΠΈΡΡ 1-4 Π°ΡΠΎΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ; Π°Π±ΠΎ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠΌΠ΅ΡΠΈΠ», Π°Π±ΠΎ Π°Π»ΠΊΠΎΠΊΡΠΈΠΌΠ΅ΡΠΈΠ»; ΡΠ°Ag means carboxyl; Alkoxycarbonyl, the alkyl part of which contains 1-4 carbon atoms; M- alkylaminocarbonyl, the alkyl part of which contains 1-4 carbon atoms; or hydroxymethyl or alkoxymethyl; and
Π ΡΠ° Π", ΠΎΠ΄Π½Π°ΠΊΠΎΠ²Ρ Π°Π±ΠΎ ΡΡΠ·Π½Ρ, ΠΎΠ·Π½Π°ΡΠ°ΡΡΡ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ Π°Π±ΠΎ Π·Π°Π»ΠΈΡΠΎΠΊ ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΡ Π°Π»ΡΡΠ°ΡΠΈΡΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ Π· 2-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΡΠ°ΠΊΠΈΠΉ ΡΠΊ Π°ΡΠ΅ΡΠΈΠ» Π°Π±ΠΎ ΠΏΡΠΎΠΏΡΠΎΠ½ΡΠ», Π°Π±ΠΎ Π·Π°Π»ΠΈΡΠΎΠΊ Π°ΡΠΎΠΌΠ°ΡΠΈΡΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ, ΡΠ°ΠΊΠΈΠΉ ΡΠΊ Π±Π΅Π½Π·ΠΎΡΠ»ΡΠ½ΠΈΠΉ Π·Π°Π»ΠΈΡΠΎΠΊ; Π°Π±ΠΎ Π" ΡΠ° Π" ΡΠ°Π·ΠΎΠΌ ΡΡΠ²ΠΎΡΡΡΡΡ ΠΌΠ΅ΡΠΈΠ»Π΅Π½ΠΎΠ²ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π°ΡΠΎΠΌ Π²ΡΠ³Π»Π΅ΡΡ ΡΠΊΠΎΠ³ΠΎ ΠΌΠΎΠΆΠ΅ Π±ΡΡΠΈ Π·Π°ΠΌΡΡΠ΅Π½ΠΈΠΌ ΠΎΠ΄Π½ΠΈΠΌ Π°Π±ΠΎ ΠΊΡΠ»ΡΠΊΠΎΠΌΠ°, ΠΎΠ΄Π½Π°ΠΊΠΎΠ²ΠΈΠΌΠΈ Π°Π±ΠΎ ΡΡΠ·Π½ΠΈΠΌΠΈ ΡΠ°Π΄ΠΈΠΊΠ°Π»Π°ΠΌΠΈ, ΡΠΎ ΠΎΠ±ΠΈΡΠ°ΡΡΡ ΡΠ΅ΡΠ΅Π΄ Π°Π»ΠΊΡΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΡΠΊΡ ΠΌΠΎΠΆΡΡΡ ΡΡΠ²ΠΎΡΡΠ²Π°ΡΠΈ ΡΠ°Π·ΠΎΠΌ Π°Π»ΡΡΠΈΠΊΠ»ΡΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π· 5-ΠΌΠ° Π°Π±ΠΎ 6Π±-ΠΌΠ° Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ; Π°Π±ΠΎ ΡΠ΅Π½ΡΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ²; ΡΠ°A and B", the same or different, mean a hydrogen atom or an organic aliphatic acid residue with 2-4 carbon atoms, such as acetyl or propionyl, or an aromatic acid residue, such as a benzoyl residue; or B" and B" together form a methylene radical , the carbon atom of which can be replaced by one or more, the same or different radicals, chosen among alkyl radicals with 1-4 carbon atoms, which can form together an alicyclic radical with 5 or 6 carbon atoms; or phenyl radicals; and
Π‘ΠΈ ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ Π°Π±ΠΎ Π·Π°Ρ ΠΈΡΠ½Ρ Π³ΡΡΠΏΡ Π‘2 Π΄Π»Ρ Π°ΠΌΡΠ½ΠΎ-ΡΡΠ½ΠΊΡΡΡ.Cy means a hydrogen atom or a C2 protecting group for the amino function.
ΠΡΠ»ΡΡ ΠΊΠΎΠ½ΠΊΡΠ΅ΡΠ½ΠΎ, Π2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π°Π±ΠΎ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠΌΠ΅ΡΠΈΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π° Π ΡΠ°More specifically, H2 means an ethylaminocarbonyl radical or a hydroxymethyl radical, and B and
Π" ΡΠ°Π·ΠΎΠΌ ΡΡΠ²ΠΎΡΡΡΡΡ ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½ΠΎΠ²ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π».A" together form an isopropylidene radical.
ΠΠ°ΡΠ±ΠΎΡΡΠΊΠΎΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Ρ ΠΎΠ΄Π½ΠΈΠΌ Π· Π΅Π»Π΅ΠΌΠ΅Π½ΡΡΠ² ΡΡΡΡΠΊΡΡΡΠΈ ΡΠΏΠΎΠ»ΡΠΊ, Π·Π°Ρ ΠΈΡΠ΅Π½ΠΈΡ Ρ ΠΏΠ°ΡΠ΅Π½ΡΡ Π5 5634862.Carbosugar of the general formula (M) is one of the elements of the structure of compounds protected in patent O5 5634862.
ΠΠ°ΡΠ±ΠΎΡΡΠΊΠΎΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ Π·Ρ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) ΡΠ°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ:Carbosugar of the general formula (M) can be obtained from the compound of the general formula (I) as follows:
ΠΡΠ΄ΡΠΎΠΊΡΠΈΠ»ΡΠ½Ρ ΡΡΠ½ΠΊΡΡΡ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ Π°Π±ΠΎ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), Π·Π°Ρ ΠΈΡΠ°ΡΡΡ Π· ΡΡΠ²ΠΎΡΠ΅Π½Π½ΡΠΌ ΡΠΊΠ»Π°Π΄Π½ΠΎΠ³ΠΎ Π΅ΡΡΡΡ Π°Π±ΠΎ Π°ΡΠ΅ΡΠ°Π»Ρ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ): Ρ The hydroxyl functions of the compound of the general formula (I), where A means a hydrogen atom or a radical of the general formula (II), are protected with the formation of an ester or acetal of the general formula (MI): x
ΠΠΊ ΠΠ₯Kk AH
ΠΡΠ°Ρ - Π²'Ρ -Π (ΠΠ,Isaiah - vya -E (WE,
ΠΠΈΠΉ ΠPiy J
ΠΠ΅:Where:
Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ Π°Π±ΠΎ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ); ΡΠ°A means a hydrogen atom or a radical of the general formula (II); and
ΠΠ³ ΡΠ° ΠΡ", ΠΎΠ΄Π½Π°ΠΊΠΎΠ²Ρ Π°Π±ΠΎ ΡΡΠ·Π½Ρ, ΠΎΠ·Π½Π°ΡΠ°ΡΡΡ Π·Π°Π»ΠΈΡΠΎΠΊ ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΡ Π°Π»ΡΡΠ°ΡΠΈΡΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ Π· 2-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΡΠ°ΠΊΠΈΠΉ ΡΠΊ Π°ΡΠ΅ΡΠΈΠ» Π°Π±ΠΎ ΠΏΡΠΎΠΏΡΠΎΠ½ΡΠ», Π°Π±ΠΎ Π·Π°Π»ΠΈΡΠΎΠΊ Π°ΡΠΎΠΌΠ°ΡΠΈΡΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ, ΡΠ°ΠΊΠΈΠΉ ΡΠΊ Π±Π΅Π½Π·ΠΎΡΠ»ΡΠ½ΠΈΠΉ Π·Π°Π»ΠΈΡΠΎΠΊ; Π°Π±ΠΎ ΠΠ³ ΡΠ° ΠΠ:Ρ" ΡΠ°Π·ΠΎΠΌ ΡΡΠ²ΠΎΡΡΡΡΡ ΠΌΠ΅ΡΠΈΠ»Π΅Π½ΠΎΠ²ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π°ΡΠΎΠΌ Π²ΡΠ³Π»Π΅ΡΡ ΡΠΊΠΎΠ³ΠΎ ΠΌΠΎΠΆΠ΅ Π±ΡΡΠΈ Π·Π°ΠΌΡΡΠ΅Π½ΠΈΠΌ ΠΎΠ΄Π½ΠΈΠΌ Π°Π±ΠΎ ΠΊΡΠ»ΡΠΊΠΎΠΌΠ°, ΠΎΠ΄Π½Π°ΠΊΠΎΠ²ΠΈΠΌΠΈ Π°Π±ΠΎ ΡΡΠ·Π½ΠΈΠΌΠΈ ΡΠ°Π΄ΠΈΠΊΠ°Π»Π°ΠΌΠΈ, ΡΠΎ ΠΎΠ±ΠΈΡΠ°ΡΡΡ ΡΠ΅ΡΠ΅Π΄ Π°Π»ΠΊΡΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΡΠΊΡ ΠΌΠΎΠΆΡΡΡ ΡΡΠ²ΠΎΡΡΠ²Π°ΡΠΈ ΡΠ°Π·ΠΎΠΌ Π°Π»ΡΡΠΈΠΊΠ»ΡΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π· 5-ΠΌΠ° Π°Π±ΠΎ Π±-ΠΌΠ° Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ; Π°Π±ΠΎ ΡΠ΅Π½ΡΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ².Ag and Bi", the same or different, mean an organic aliphatic acid residue with 2-4 carbon atoms, such as acetyl or propionyl, or an aromatic acid residue, such as a benzoyl residue; or Ag and AB:i" together form a methylene radical, atom whose carbon can be replaced by one or more, the same or different radicals, chosen from among alkyl radicals with 1-4 carbon atoms, which can form together an alicyclic radical with 5 or b carbon atoms; or phenyl radicals.
ΠΠ²ΠΈΡΠ°ΠΉΠ½ΠΎ, Π·Π°Ρ ΠΈΡΡ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ»ΡΠ½ΠΈΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π·Π΄ΡΠΉΡΠ½ΡΡΡΡ Ρ Π·Π²ΠΈΡΠ°ΠΉΠ½ΠΈΡ ΡΠΌΠΎΠ²Π°Ρ Π΅ΡΠ΅ΡΠΈΡΡΠΊΠ°ΡΡΡ Π°Π±ΠΎ Π°ΡΠ΅ΡΠ°Π»ΡΠ·Π°ΡΡΡ, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, ΠΏΡΠ΄ Π΄ΡΡΡ ΠΎΡΡΠΎΠ²ΠΎΡ Π°Π±ΠΎ ΠΏΡΠΎΠΏΡΠΎΠ½ΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΏ--ΠΎΠ»ΡΠΎΠ»ΡΡΠ»ΡΡΠΎΠΊΠΈΡΠ»ΠΎΡΠΈ, Π² ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠΎΠ·ΡΠΈΠ½Π½ΠΈΠΊΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ Π°ΡΠΎΠΌΠ°ΡΠΈΡΠ½ΠΈΠΉ Π²ΡΠ³Π»Π΅Π²ΠΎΠ΄Π΅Π½Ρ, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, Π±Π΅Π½Π·ΠΎΠ» Π°Π±ΠΎ ΡΠΎΠ»ΡΠΎΠ», Π²ΡΠ΄ΠΎΠΊΡΠ΅ΠΌΠ»ΡΡΡΠΈ Π²ΠΎΠ΄Ρ, ΠΊΠΎΠ»ΠΈ Π²ΠΎΠ½Π° ΡΡΠ²ΠΎΡΡΡΡΡΡΡ, Π°Π±ΠΎ ΠΏΡΠ΄ Π΄ΡΡΡ Π°Π»ΡΠ΄Π΅Π³ΡΠ΄Ρ Π°Π±ΠΎ ΠΊΠ΅ΡΠΎΠ½Ρ, ΠΌΠΎΠΆΠ»ΠΈΠ²ΠΎ Ρ ΡΠΎΡΠΌΡ Π°ΡΠ΅ΡΠ°Π»Ρ, Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ ΡΠ°ΠΊΠΎΡ ΡΠΊ ΡΡΠΈΡΡΠΎΡΠΎΡΡΠΎΠ²Π° ΠΊΠΈΡΠ»ΠΎΡΠ°, Π² ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠΎΠ·ΡΠΈΠ½Π½ΠΈΠΊΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ Π°ΡΠΎΠΌΠ°ΡΠΈΡΠ½ΠΈΠΉ Π²ΡΠ³Π»Π΅Π²ΠΎΠ΄Π΅Π½Ρ, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, Π±Π΅Π½Π·ΠΎΠ» Π°Π±ΠΎ ΡΠΎΠ»ΡΠΎΠ», ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π²ΡΠ΄ 50"Π‘ Π΄ΠΎ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΠΈ ΠΊΠΈΠΏΡΠ½Π½Ρ Π·Ρ Π·Π²ΠΎΡΠΎΡΠ½ΠΈΠΌ Ρ ΠΎΠ»ΠΎΠ΄ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠΌ ΡΠ΅Π°ΠΊΡΡΠΉΠ½ΠΎΡ ΡΡΠΌΡΡΡ.Of course, the protection of hydroxyl radicals is carried out under the usual conditions of esterification or acetalization, for example, under the action of acetic or propionic acid in the presence of p-toluenesulfonic acid, in an organic solvent such as an aromatic hydrocarbon, for example, benzene or toluene, separating the water when it is formed, or under the action of an aldehyde or ketone, possibly in acetal form, in the presence of an acid such as trifluoroacetic acid, in an organic solvent such as an aromatic hydrocarbon such as benzene or toluene, at a temperature of 50Β°C to the reflux temperature of the reaction mixture.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), ΠΌΠΎΠΆΠ½Π° ΠΏΠ΅ΡΠ΅ΡΠ²ΠΎΡΡΠ²Π°ΡΠΈ Π½Π° ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, ΡΠ»ΡΡ ΠΎΠΌ Π³ΡΠ΄ΡΠΎΠ³Π΅Π½Π΅ΠΎΠ»ΡΠ·Ρ.A compound of the general formula (MI), where A means a radical of the general formula (II), can be converted into compounds of the general formula (MI), where A means a hydrogen atom, by hydrogenolysis.
ΠΠ²ΠΈΡΠ°ΠΉΠ½ΠΎ Π³ΡΠ΄ΡΠΎΠ³Π΅Π½ΠΎΠ»ΡΠ· Π·Π΄ΡΠΉΡΠ½ΡΡΡΡ Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ Π²ΠΎΠ΄Π½Ρ, ΡΠΊΡΠΎ Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎ ΠΏΡΠ΄ ΡΠΈΡΠΊΠΎΠΌ, Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΊΠ°ΡΠ°Π»ΡΠ·Π°ΡΠΎΡΠ°, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ ΠΏΠ°Π»Π°Π΄ΡΠΉ-Π½Π°-Π²ΡΠ³ΡΠ»Π»Ρ, Π² ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠΎΠ·ΡΠΈΠ½Π½ΠΈΠΊΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ ΡΠΏΠΈΡΡ, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, ΠΌΠ΅ΡΠ°Π½ΠΎΠ», Π΅ΡΠ°Π½ΠΎΠ» Π°Π±ΠΎ ΡΠ·ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ», ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π²ΡΠ΄ 0 Π΄ΠΎ 507Π‘.Hydrogenolysis is usually carried out with hydrogen, if necessary under pressure, in the presence of a catalyst, such as palladium-on-charcoal, in an organic solvent, such as an alcohol, for example, methanol, ethanol or isopropanol, at a temperature of 0 to 507C.
Π‘ΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Ρ Π½ΠΎΠ²ΠΈΠΌΠΈ ΠΏΡΠΎΠ΄ΡΠΊΡΠ°ΠΌΠΈ ΡΠ° ΡΠΊΠ»Π°Π΄Π°ΡΡΡ ΡΠ½ΡΠΈΠΉ ΠΎΠ±ΡΠ΅ΠΊΡ Π΄Π°Π½ΠΎΠ³ΠΎ Π²ΠΈΠ½Π°Ρ ΠΎΠ΄Ρ.Compounds of the general formula (MI) are new products and constitute another object of this invention.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, ΠΌΠΎΠΆΠ½Π° ΠΏΠ΅ΡΠ΅ΡΠ²ΠΎΡΠΈΡΠΈ Π½Π° ΡΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ!):A compound of the general formula (MI), where A is a hydrogen atom, can be converted into a compound of the general formula (MI!):
Π.-ΠΎ Ρ Π²ΡΠΎ ΠΈ ΠΊΡ, (ΠΠΠ, Π΄ΠΈΡ Π¨Π΅ Π΄Π΅K.-o r vro i kyu, (MIV, child She de
ΠΠ³ ΡΠ° ΠΠ:" ΠΌΠ°ΡΡΡ Π²ΠΈΡΠ΅Π²ΠΊΠ°Π·Π°Π½Ρ Π·Π½Π°ΡΠ΅Π½Π½Ρ ΡΠ° (2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π·Π°Ρ ΠΈΡΠ½Ρ Π΄Π»Ρ Π°ΠΌΡΠ½ΠΎ-ΡΡΠ½ΠΊΡΡΡ Π³ΡΡΠΏΡ, Π΄ΡΡΡΠΈ Π²ΡΠ΄ΠΏΠΎΠ²ΡΠ΄Π½ΠΈΠΌ ΡΠ΅Π°Π³Π΅Π½ΡΠΎΠΌ, ΡΠΎ Π΄ΠΎΠ·Π²ΠΎΠ»ΡΡ ΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΠΎ Π²Π²ΠΎΠ΄ΠΈΡΠΈ Π·Π°Ρ ΠΈΡΠ½Ρ Π³ΡΡΠΏΡ.Ag and BA:" have the above values and (2) means a protective group for the amino function, acting as a suitable reagent, which allows the selective introduction of the protective group.
ΠΠ°Ρ ΠΈΡΠ½Ρ Π³ΡΡΠΏΠΈ ΠΎΠ±ΠΈΡΠ°ΡΡΡ Π· ΡΠ°ΠΊΠΈΡ Π³ΡΡΠΏ, ΡΠΎ Π² ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΠΌΡ ΠΌΠΎΠΆΡΡΡ Π±ΡΡΠΈ ΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΠΎ Π²ΠΈΠ΄Π°Π»Π΅Π½Ρ. Π Π½Π°ΠΉΠ±ΡΠ»ΡΡ ΠΏΡΠΈΠ΄Π°ΡΠ½ΠΈΡ Π·Π°Ρ ΠΈΡΠ½ΠΈΡ Π³ΡΡΠΏ ΠΌΠΎΠΆΠ½Π° Π½Π°Π·Π²Π°ΡΠΈ Ρ Π»ΠΎΡΠ°ΡΠ΅ΡΠΈΠ», ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠ΅ΡΠΈΠ», 2,2,2-ΡΡΠΈΡ Π»ΠΎΡΠ΅ΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ», ΡΡΠ΅Ρ- Π±ΡΡΠΈΠ», Π±Π΅Π½Π·ΠΈΠ», ΠΏ-Π½ΡΡΡΠΎΠ±Π΅Π½Π·ΠΈΠ», ΠΏ-ΠΌΠ΅ΡΠΎΠΊΡΠΈΠ±Π΅Π½Π·ΠΈΠ», Π΄ΠΈΡΠ΅Π½ΡΠ»ΠΌΠ΅ΡΠΈΠ», ΡΡΠΈΠ°Π»ΠΊΡΠ»ΡΠΈΠ»ΡΠ», Π°Π»ΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ», Π±Π΅Π½Π·ΠΈΠ»ΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ», Π² ΡΠΊΠΎΠΌΡ ΡΠ΅Π½ΡΠ»ΡΠ½Π΅ ΡΠ΄ΡΠΎ ΠΌΠΎΠΆΠ΅ Π±ΡΡΠΈ Π·Π°ΠΌΡΡΠ΅Π½ΠΈΠΌ Π°ΡΠΎΠΌΠΎΠΌ Π³Π°Π»ΠΎΠ³Π΅Π½Ρ Π°Π±ΠΎ Π°Π»ΠΊΡΠ»ΡΠ½ΠΈΠΌ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΠΎΠΌ Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, Π°Π±ΠΎ Π°Π»ΠΊΠΎΠΊΡΠΈ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΠΎΠΌ Π· 1-4 Π°ΡΠΎΠΌΠ°ΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ; Π°Π±ΠΎ ΡΡΠ΅Ρ- Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ». Π‘Π΅ΡΠ΅Π΄ ΡΠ½ΡΠΈΡ Π·Π°Ρ ΠΈΡΠ½ΠΈΡ Π³ΡΡΠΏ, ΡΠΊΡ ΡΠ°ΠΊΠΎΠΆ Ρ ΠΏΡΠΈΠ΄Π°ΡΠ½ΠΈΠΌΠΈ, ΠΌΠΎΠΆΠ½Π° Π½Π°Π·Π²Π°ΡΠΈ ΡΠ°ΠΊΡ, ΡΠΎ ΠΎΠΏΠΈΡΠ°Π½Ρ Π’. ΠΠ£.Protecting groups are chosen from groups that can be selectively removed later. The most suitable protective groups include chloroacetyl, methoxymethyl, 2,2,2-trichloroethoxycarbonyl, tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, alioxycarbonyl, benzyloxycarbonyl, in which the phenyl nucleus can be substituted by a halogen atom or an alkyl radical with 1-4 carbon atoms, or an alkoxy radical with 1-4 carbon atoms; or tert-butoxycarbonyl. Other protective groups that are also suitable include those described by T. MU.
Π‘ΡΠ΅ΡΠΏΠ΅ ΡΠ° Π . ΡΡ . Π. Π/ΡΡΠ² "Π Π³ΠΎΡΡΡΡΡΠΏΠ΄ Π‘Π³ΠΎΡΡΠ΅ ΡΠΏ ΠΠ³Π΄Π°ΠΏΡΡ ΠΡΠΏΡΠΏΠ΅Π²ΡΠ²", Π³Π»Π°Π²Π° 7, Π΄ΡΡΠ³Π΅ Π²ΠΈΠ΄Π°Π½Π½Ρ, Π΄ΠΎΠΏΠΏ Π£/ΡΡΡ Π°ΠΏΠ°Steepe and R. sch. M. M/tsiv "Rgoiesiipd Sgotsre ip Ogdapis Zupipeviv", chapter 7, second edition, supplement U/ieu apa
ΠΠΎΠΏΠ· (1991).Zopz (1991).
ΠΠ°ΠΉΠ±ΡΠ»ΡΡΠΈΠΉ ΡΠ½ΡΠ΅ΡΠ΅Ρ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΡ ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½Π° Π³ΡΡΠΏΠ°.The tert-butoxycarbonyl group is of greatest interest.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠΠ), Π΄Π΅ Π‘Π³ ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ Π±Π΅Π·ΠΏΠΎΡΠ΅ΡΠ΅Π΄Π½ΡΠΎ ΡΠ· ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ ΡΠ°Π΄ΠΈΠΊΠ°Π» Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), ΡΠ»ΡΡ ΠΎΠΌ ΠΎΠ΄Π½ΠΎΡΠ°ΡΠ½ΠΎΠ³ΠΎ Π³ΡΠ΄ΡΠΎΠ³Π΅Π½ΠΎΠ»ΡΠ·Ρ ΡΠ° ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ²Π°Π½Π½Ρ.The compound of the general formula (MII), where Cg represents the tert-butoxycarbonyl radical, can be obtained directly from the compound of the general formula (MI), where A represents the radical of the general formula (II), by simultaneous hydrogenolysis and tert-butoxycarbonylation.
ΠΠ²ΠΈΡΠ°ΠΉΠ½ΠΎ ΡΠ΅Π°ΠΊΡΡΡ ΠΏΡΠΎΠ²ΠΎΠ΄ΡΡΡ ΡΠ»ΡΡ ΠΎΠΌ ΠΎΠ΄Π½ΠΎΡΠ°ΡΠ½ΠΎΡ Π²Π·Π°ΡΠΌΠΎΠ΄ΡΡ Π²ΠΎΠ΄Π½Ρ, Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΊΠ°ΡΠ°Π»ΡΠ·Π°ΡΠΎΡΠ°, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ ΠΏΠ°Π»Π°Π΄ΡΠΉ-Π½Π°-Π²ΡΠ³ΡΠ»Π»Ρ, ΡΠ° Π΄ΠΈ-ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»Π΄ΠΈΠΊΠ°ΡΠ±ΠΎΠ½Π°ΡΡ ΡΠ· ΡΠΏΠΎΠ»ΡΠΊΠΎΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), ΠΏΡΠ°ΡΡΡΡΠΈ Π² ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠΎΠ·ΡΠΈΠ½Π½ΠΈΠΊΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ ΡΠΏΠΈΡΡ, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, ΠΌΠ΅ΡΠ°Π½ΠΎΠ», Π΅ΡΠ°Π½ΠΎΠ» Π°Π±ΠΎ ΡΠ·ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ», ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π²ΡΠ΄ Π Π΄ΠΎ 5070.Typically, the reaction is carried out by simultaneously reacting hydrogen, in the presence of a catalyst such as palladium-on-charcoal, and di-tert-butyldicarbonate with a compound of general formula (MI), working in an organic solvent such as an alcohol, for example methanol, ethanol or isopropanol , at a temperature from O to 5070.
Π‘ΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Ρ Π½ΠΎΠ²ΠΈΠΌΠΈ ΠΏΡΠΎΠ΄ΡΠΊΡΠ°ΠΌΠΈ, ΡΠΎ ΡΠΊΠ»Π°Π΄Π°ΡΡΡ Π½Π°ΡΡΡΠΏΠ½ΠΈΠΉ ΠΎΠ±ΡΠ΅ΠΊΡ Π΄Π°Π½ΠΎΠ³ΠΎ Π²ΠΈΠ½Π°Ρ ΠΎΠ΄Ρ.Compounds of the general formula (MI) are new products that make up the next object of this invention.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠΠ) ΠΏΠΎΡΡΠΌ ΠΎΠΊΠΈΡΠ»ΡΡΡΡ Π΄ΠΎ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠΠ): ΠΉ ΠΊΠΈΠ ΡΠ°The compound of the general formula (MII) is then oxidized to the compound of the general formula (MII):
ΠΠ Π "ΠΊΠΎ, Π£Π, ΡΠ΅ ΠΎ Π΄Π΅ Π, ΠΡ" ΡΠ° Π‘ΠΎ ΠΌΠ°ΡΡΡ Π²ΠΈΡΠ΅Π·Π³Π°Π΄Π°Π½Π΅ Π·Π½Π°ΡΠ΅Π½Π½Ρ.VZ Zh "ko, UM, she o de V, Vi" and So have the above-mentioned meaning.
ΠΠ²ΠΈΡΠ°ΠΉΠ½ΠΎ ΠΎΠΊΠΈΡΠ»Π΅Π½Π½Ρ Π·Π΄ΡΠΉΡΠ½ΡΡΡΡ Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ ΠΎΠΊΡΠΈΠ΄Ρ ΡΡΡΠ΅Π½ΡΡ(ΠΠΈΠΡΒ»), ΡΠΊΠΈΠΉ, ΡΠΊΡΠΎ Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎ, ΠΎΡΡΠΈΠΌΡΡΡΡ ΡΠΏ Π·ΠΉΡ Π· ΠΏΠΎΠΏΠ΅ΡΠ΅Π΄Π½ΠΈΠΊΠ°, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ ΠΠ: Π°Π±ΠΎ ΠΠΈΡΡ, Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΎΠΊΠΈΡΠ½ΠΈΠΊΠ°, ΡΠΎ ΠΎΠ±ΠΈΡΠ°ΡΡΡ ΡΠ΅ΡΠ΅Π΄ ΠΏΠ΅ΡΠΉΠΎΠ΄Π°ΡΡ, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ ΠΏΠ΅ΡΠΉΠΎΠ΄Π°Ρ Π½Π°ΡΡΡΡ; Π³ΡΠΏΠΎΡ Π»ΠΎΡΠΈΡΡ, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ Π³ΡΠΏΠΎΡ Π»ΠΎΡΠΈΡ Π°Π±ΠΎ Π³ΡΠΏΠΎΠ±ΡΠΎΠΌΡΠ΄ Π½Π°ΡΡΡΡ; Π±ΡΠΎΠΌΠ°ΡΡ, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ Π±ΡΠΎΠΌΠ°Ρ Π½Π°ΡΡΡΡ; Π°Π±ΠΎ ΠΎΠΊΡΠΈΠ΄Ρ ΡΡΠ΅ΡΠΈΠ½Π½ΠΎΠ³ΠΎ ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠ³ΠΎ Π°ΠΌΡΠ½Ρ, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ Π-ΠΌΠ΅ΡΠΈΠ»ΠΌΠΎΡΡΠΎΠ»ΡΠ½ΠΎΠΊΡΠΈΠ΄ Π°Π±ΠΎ ΡΡΠΈΠ΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΡΠΈΠ΄, ΠΏΡΠ°ΡΡΡΡΠΈ Ρ Π²ΠΎΠ΄Π½ΠΎΠΌΡ ΡΠ΅ΡΠ΅Π΄ΠΎΠ²ΠΈΡΡ Π°Π±ΠΎ Π³ΠΎΠΌΠΎΠ³Π΅Π½Π½ΠΎΠΌΡ Π°Π±ΠΎ Π³Π΅ΡΠ΅ΡΠΎΠ³Π΅Π½Π½ΠΎΠΌΡ Π²ΠΎΠ΄Π½ΠΎ- ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠΌΡ ΡΠ΅ΡΠ΅Π΄ΠΎΠ²ΠΈΡΡ, ΡΠ°ΠΊΠΎΠΌΡ ΡΠΊ ΡΡΠΌΡΡ Π²ΠΎΠ΄ΠΈ Π· Π΅ΡΠΈΠ»Π°ΡΠ΅ΡΠ°ΡΠΎΠΌ.Usually, oxidation is carried out with the help of ruthenium oxide (AlOi), which, if necessary, is obtained from a precursor, such as HO: or Vysi, in the presence of an oxidant selected from among periodate, such as sodium periodate; hypochlorite, such as hypochlorite or sodium hypobromide; a bromate such as sodium bromate; or tertiary organic amine oxide, such as M-methylmorpholine oxide or triethylamine oxide, working in an aqueous medium or a homogeneous or heterogeneous aqueous-organic medium, such as a mixture of water and ethyl acetate.
ΠΠΊΠΈΡΠ»Π΅Π½Π½Ρ ΡΠ°ΠΊΠΎΠΆ ΠΌΠΎΠΆΠ½Π° Π·Π΄ΡΠΉΡΠ½ΡΠ²Π°ΡΠΈ Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ Π»ΠΈΡΠ΅ Π³ΡΠΏΠΎΡ Π»ΠΎΡΠΈΡΡ Π½Π°ΡΡΡΡ(ΠΆΠ°Π²Π΅Π»Π΅Π²Π°Ρ Π²ΠΎΠ΄Π°) Π°Π±ΠΎ ΠΏΠ΅ΡΠΌΠ°Π½Π³Π°Π½Π°ΡΡ ΠΊΠ°Π»ΡΡ Π°Π±ΠΎ Π²ΠΎΠ»ΡΡΡΠ°ΠΌΠ°ΡΡ Π½Π°ΡΡΡΡ, Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΎΠΊΠΈΡΠ½ΠΈΠΊΠ°, ΡΠ°ΠΊΠΎΠ³ΠΎ ΡΠΊ Π³ΡΠΏΠΎΡ Π»ΠΎΡΠΈΡ Π½Π°ΡΡΡΡ, ΠΏΠ΅ΡΠΎΠΊΡΠΈΠ΄ Π²ΠΎΠ΄Π½Ρ, Π°Π±ΠΎ Π°Π»ΠΊΡΠ»Π³ΡΠ΄ΡΠΎΠΏΠ΅ΡΠΎΠΊΡΠΈΠ΄Ρ.Oxidation can also be carried out using only sodium hypochlorite (sour water) or potassium permanganate or sodium tungstate, in the presence of an oxidizer such as sodium hypochlorite, hydrogen peroxide, or alkyl hydroperoxide.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) ΠΌΠΎΠΆΠ½Π° ΡΠ°ΠΊΠΎΠΆ ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ ΠΎΠΊΠΈΡΠ»Π΅Π½Π½Ρ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ), Π΄Π΅ Π ΠΎΠ·Π½Π°ΡΠ°Ρ Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, Π² ΡΠΌΠΎΠ²Π°Ρ , ΡΠΎ ΠΎΠΏΠΈΡΠ°Π½Ρ Π²ΠΈΡΠ΅, Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΈΠΌ Π·Π°Ρ ΠΈΡΡΠΎΠΌ Π°ΡΠΎΠΌΠ° Π°Π·ΠΎΡΡ ΠΎΡΡΠΈΠΌΠ°Π½ΠΎΠ³ΠΎ Π»Π°ΠΊΡΠ°ΠΌΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ₯): ΠΊΠΈ, Π²ΠΎ ΠΠΈ Π°Ρ , ΡΡ Π ΠΎ Π΄Π΅:The compound of the general formula (MI) can also be obtained by oxidation of the compound of the general formula (MI), where A is a hydrogen atom, under the conditions described above, with subsequent protection of the nitrogen atom of the obtained lactam of the general formula (IX): ky, vo Ky ah, pcs W o where:
ΠΡ ΡΠ° ΠΡ" ΠΌΠ°ΡΡΡ Π²ΠΈΡΠ΅Π²ΠΊΠ°Π·Π°Π½Ρ Π·Π½Π°ΡΠ΅Π½Π½Ρ, Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ, ΡΠΎ Π²ΠΊΠ°Π·Π°Π½Π° Π²ΠΈΡΠ΅.B1 and B1" have the above meanings, with the help of the protecting group indicated above.
Π‘ΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Ρ Π½ΠΎΠ²ΠΈΠΌΠΈ ΠΏΡΠΎΠ΄ΡΠΊΡΠ°ΠΌΠΈ ΡΡΠ°Π½ΠΎΠ²Π»ΡΡΡ ΡΠ½ΡΠΈΠΉ ΠΎΠ±'ΡΠΊΡ Π²ΠΈΠ½Π°Ρ ΠΎΠ΄Ρ.Compounds of the general formula (MI) are new products and constitute another object of the invention.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) ΠΌΠΎΠΆΠ½Π° ΠΏΠ΅ΡΠ΅ΡΠ²ΠΎΡΡΠ²Π°ΡΠΈ Π½Π° Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) Π² ΡΠΌΠΎΠ²Π°Ρ , Π²ΡΠ΄ΠΏΠΎΠ²ΡΠ΄Π½ΠΈΡ ΠΏΡΠΈΡΠΎΠ΄Ρ Π·Π°ΠΌΡΡΠ½ΠΈΠΊΠ° ΠΒ», ΡΠΎ Π²Π²ΠΎΠ΄ΡΡΡ.The compound of the general formula (MI) can be converted to the general formula (M) under conditions corresponding to the nature of the substituent A" that is introduced.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ ΠΒ» ΠΎΠ·Π½Π°ΡΠ°Ρ ΠΊΠ°ΡΠ±ΠΎΠΊΡΠΈΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ ΠΎΠ±ΡΠΎΠ±ΠΊΠΈ Π½Π΅ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΡ ΠΎΡΠ½ΠΎΠ²ΠΎΡ, ΡΠ°ΠΊΠΎΡ ΡΠΊ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ΄ Π½Π°ΡΡΡΡ, ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ Π·Π°ΠΌΡΠ½ΠΎΡ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ Π‘Π³ Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.A compound of the general formula (M), where B" is a carboxyl radical, can be obtained by treating a compound of the general formula (MI) with an inorganic base, such as sodium hydroxide, followed by replacement of the protecting group Cg with a hydrogen atom and, if necessary, radicals B and B " per hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ ΠΒ» ΠΎΠ·Π½Π°ΡΠ°Ρ ΠΊΠ°ΡΠ±ΠΎΠΊΡΠΈΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ Π·Π°ΠΌΡΠ½ΠΈ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ (2 ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ ΠΎΠ±ΡΠΎΠ±ΠΊΠΎΡ Π½Π΅ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΡ ΠΎΡΠ½ΠΎΠ²ΠΎΡ, ΡΠ°ΠΊΠΎΡ ΡΠΊ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ΄ Π½Π°ΡΡΡΡ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.A compound of the general formula (M), where B" is a carboxyl radical, can be obtained by replacing the protecting group (2 of the compound of the general formula (MI) with a hydrogen atom, followed by treatment with an inorganic base such as sodium hydroxide and, if necessary, replacing the radicals B and Vi" per hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π°Π»ΠΊΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π°Π»ΠΊΡΠ»ΡΠ½Π° ΡΠ°ΡΡΠΈΠ½Π° ΡΠΊΠΎΠ³ΠΎ ΠΌΡΡΡΠΈΡΡ 1-4 Π°ΡΠΎΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ, Π΄ΡΡΡΠΈ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΡΠΎΠΌ Π»ΡΠΆΠ½ΠΎΠ³ΠΎ ΠΌΠ΅ΡΠ°Π»Ρ Π½Π° ΡΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ Π·Π°ΠΌΡΠ½ΠΎΡ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ (2 Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² ΠΠ: ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.A compound of the general formula (M), where B2 means an alkoxycarbonyl radical, the alkyl part of which contains 1-4 carbon atoms, can be obtained by acting with an alkali metal alcoholate on a compound of the general formula (MI) with subsequent replacement of the protective group (2 by a hydrogen atom and, according to necessary, by replacing the radicals BA: and Vi" with a hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π°Π»ΠΊΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π°Π»ΠΊΡΠ»ΡΠ½Π° ΡΠ°ΡΡΠΈΠ½Π° ΡΠΊΠΎΠ³ΠΎ ΠΌΡΡΡΠΈΡΡ 1-4 Π°ΡΠΎΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ Π·Π°ΠΌΡΠ½ΠΈ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ Π‘Π±2 ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ ΠΎΠ±ΡΠΎΠ±ΠΊΠΎΡ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΡΠΎΠΌ Π»ΡΠΆΠ½ΠΎΠ³ΠΎ ΠΌΠ΅ΡΠ°Π»Ρ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² ΠΠ: ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.A compound of the general formula (M), where B2 means an alkoxycarbonyl radical, the alkyl part of which contains 1-4 carbon atoms, can be obtained by replacing the protective group Π‘Π±2 of a compound of the general formula (MI) with a hydrogen atom, followed by treatment with an alkali metal alcoholate and, if necessary , by replacing the radicals BA: and Vi" with a hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π-Π°Π»ΠΊΡΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π°Π»ΠΊΡΠ»ΡΠ½Π° ΡΠ°ΡΡΠΈΠ½Π° ΡΠΊΠΎΠ³ΠΎ ΠΌΡΡΡΠΈΡΡ 1-4 Π°ΡΠΎΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ, Π΄ΡΡΡΠΈ Π°Π»ΠΊΡΠ»Π°ΠΌΡΠ½ΠΎΠΌ Π½Π° ΡΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠΠ) Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ Π·Π°ΠΌΡΠ½ΠΎΡ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ Π‘2 Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π: ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.A compound of the general formula (M), where B2 means an M-alkylaminocarbonyl radical, the alkyl part of which contains 1-4 carbon atoms, can be obtained by acting with an alkylamine on a compound of the general formula (MII) with subsequent replacement of the protective group C2 with a hydrogen atom and, if necessary , by replacing the radicals B: and Vi" with a hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π-Π°Π»ΠΊΡΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», Π°Π»ΠΊΡΠ»ΡΠ½Π° ΡΠ°ΡΡΠΈΠ½Π° ΡΠΊΠΎΠ³ΠΎ ΠΌΡΡΡΠΈΡΡ 1-4 Π°ΡΠΎΠΌΠΈ Π²ΡΠ³Π»Π΅ΡΡ, ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ Π·Π°ΠΌΡΠ½ΠΈ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ Π‘Π±2 ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ!) Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ ΠΎΠ±ΡΠΎΠ±ΠΊΠΎΡ Π°Π»ΠΊΡΠ»Π°ΠΌΡΠ½ΠΎΠΌ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ²The compound of the general formula (M), where B2 means the M-alkylaminocarbonyl radical, the alkyl part of which contains 1-4 carbon atoms, can be obtained by replacing the protective group Π‘Π±2 of the compound of the general formula (MI!) with a hydrogen atom, followed by treatment with an alkylamine and, according necessary, by replacing radicals
ΠΡ ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.Vi and Vi" per hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π2 ΠΎΠ·Π½Π°ΡΠ°Ρ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠΌΠ΅ΡΠΈΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π» ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ, Π΄ΡΡΡΠΈ Π²ΡΠ΄Π½ΠΎΠ²Π½ΠΈΠΊΠΎΠΌ, ΡΠ°ΠΊΠΈΠΌ ΡΠΊ Π±ΠΎΡΠ³ΡΠ΄ΡΠΈΠ΄, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, Π±ΠΎΡΠ³ΡΠ΄ΡΠΈΡ Π½Π°ΡΡΡΡ Π°Π±ΠΎ ΠΊΠ°Π»ΡΡ, Π½Π° ΡΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ Π·Π°ΠΌΡΠ½ΠΎΡ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ Π‘2 Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² Π: ΡΠ°A compound of the general formula (M), where B2 is a hydroxymethyl radical, can be obtained by treating a compound of the general formula (MI) with a reducing agent such as a borohydride, for example sodium or potassium borohydride, followed by replacement of the protecting group C2 with a hydrogen atom and, if necessary, by replacing radicals B: and
ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.Vi" per hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π), Π΄Π΅ Π: ΠΎΠ·Π½Π°ΡΠ°Ρ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠΌΠ΅ΡΠΈΠ»ΡΠ½ΠΈΠΉ ΡΠ°Π΄ΠΈΠΊΠ°Π», ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ»ΡΡ ΠΎΠΌ Π·Π°ΠΌΡΠ½ΠΈ Π·Π°Ρ ΠΈΡΠ½ΠΎΡ Π³ΡΡΠΏΠΈ (2 ΡΠΏΠΎΠ»ΡΠΊΠΈ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (ΠΠ) Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ, Π· ΠΏΠΎΠ΄Π°Π»ΡΡΠΎΡ ΠΎΠ±ΡΠΎΠ±ΠΊΠΎΡ Π²ΡΠ΄Π½ΠΎΠ²Π½ΠΈΠΊΠΎΠΌ, ΡΠ°ΠΊΠΈΠΌ ΡΠΊ Π±ΠΎΡΠ³ΡΠ΄ΡΠΈΠ΄, Π½Π°ΠΏΡΠΈΠΊΠ»Π°Π΄, Π±ΠΎΡΠ³ΡΠ΄ΡΠΈΡ Π½Π°ΡΡΡΡ Π°Π±ΠΎ ΠΊΠ°Π»ΡΡ, ΡΠ°, Π·Π° Π½Π΅ΠΎΠ±Ρ ΡΠ΄Π½ΠΎΡΡΡ, Π·Π°ΠΌΡΠ½ΠΎΡ ΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ² ΠΠ: ΡΠ° ΠΡ" Π½Π° Π°ΡΠΎΠΌ Π²ΠΎΠ΄Π½Ρ.A compound of general formula (M), where A: represents a hydroxymethyl radical, can be obtained by replacing the protecting group (2 of a compound of general formula (MI) with a hydrogen atom, followed by treatment with a reducing agent such as a borohydride, e.g. sodium or potassium borohydride, and if necessary, by replacing the radicals BA: and Vi" with a hydrogen atom.
Π‘ΠΏΠΎΠ»ΡΠΊΡ Π·Π°Π³Π°Π»ΡΠ½ΠΎΡ ΡΠΎΡΠΌΡΠ»ΠΈ (Π) ΠΌΠΎΠΆΠ½Π° Π²ΠΈΠΊΠΎΡΠΈΡΡΠΎΠ²ΡΠ²Π°ΡΠΈ Π² ΡΠΌΠΎΠ²Π°Ρ , ΠΎΠΏΠΈΡΠ°Π½ΠΈΡ Ρ ΠΏΠ°ΡΠ΅Π½ΡΡ 5 5364862, Π΄Π»Ρ ΠΎΡΡΠΈΠΌΠ°Π½Π½Ρ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ½ΠΎ Π°ΠΊΡΠΈΠ²Π½ΠΈΡ ΠΏΡΠΎΠ΄ΡΠΊΡΡΠ².The compound of the general formula (M) can be used under the conditions described in patent 5 5364862 to obtain therapeutically active products.
ΠΠ°ΡΡΡΠΏΠ½Ρ ΠΏΡΠΈΠΊΠ»Π°Π΄ΠΈ ΡΠ»ΡΡΡΡΡΡΡΡ Π΄Π°Π½ΠΈΠΉ Π²ΠΈΠ½Π°Ρ ΡΠ΄.The following examples illustrate the present invention.
ΠΡΠΈΠΊΠ»Π°Π΄ 1Example 1
ΠΠΎ ΠΊΠΎΠ»Π±ΠΈ Π· ΡΡΡΠΎΠΌΠ° ΡΠΈΠΉΠΊΠ°ΠΌΠΈ ΡΠΌΠ½ΡΡΡΡ 250ΡΠΌ3, ΡΠΎ ΠΎΠ±Π»Π°Π΄Π½Π°Π½Π° Ρ ΠΎΠ»ΠΎΠ΄ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠΌ ΡΠ° ΡΠΈΡΡΠ΅ΠΌΠΎΡ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΠ²Π°Π½Π½Ρ, Π² Π°ΡΠΌΠΎΡΡΠ΅ΡΡ Π°ΡΠ³ΠΎΠ½Ρ Π²Π²ΠΎΠ΄ΡΡΡ ΡΠΎΠ·ΡΠΈΠ½ 20Π³(165 ΠΌΠΎΠ»Ρ) ΠΎ-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»Π°ΠΌΡΠ½Ρ Π² Π±0ΡΠΌ3 Π²ΠΎΠ΄ΠΈ, Π·Π½Π°ΡΠ΅Π½Π½Ρ ΡΠ ΡΠΊΠΎΠ³ΠΎ Π΄ΠΎΠ²ΠΎΠ΄ΡΡΡ Π΄ΠΎ 6,10 ΡΠ»ΡΡ ΠΎΠΌ Π΄ΠΎΠ΄Π°Π²Π°Π½Π½Ρ 17ΡΠΌ3 3695-Π½ΠΎΡ(ΠΌΠ°ΡΠ°/ΠΎΠ±'ΡΠΌ) ΡΠΎΠ»ΡΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ. ΠΡΡΠ»Ρ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ Π΄ΠΎ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΠΈ 5"Π‘ Π΄ΠΎΠ΄Π°ΡΡΡ 20ΡΠΌ3 3795-Π½ΠΎΠ³ΠΎ(ΠΌΠ°ΡΠ°/ΠΎΠ±'ΡΠΌ) Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΡΠΎΠ·ΡΠΈΠ½Ρ ΡΠΎΡΠΌΠ°Π»ΡΠ΄Π΅Π³ΡΠ΄Ρ.A solution of 20 g (165 mol) of o-5-methylbenzylamine in 0 cm3 of water is introduced into a three-necked flask with a capacity of 250 cm3, equipped with a refrigerator and a stirring system, in an argon atmosphere, the pH of which is adjusted to 6.10 by adding 17 cm3 of 3695 (mass /volume) of hydrochloric acid. After cooling to a temperature of 5"C, add 20 cm3 of a 3795 (mass/volume) aqueous solution of formaldehyde.
ΠΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 5 Ρ Π²ΠΈΠ»ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 5"Π‘, ΠΏΡΡΠ»Ρ ΡΠΎΠ³ΠΎ Π΄ΠΎΠ΄Π°ΡΡΡ 21,8Π³(ΠΠΠΠΌΠΎΠ»Ρ) ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π΄ΡΡΠ½Ρ.Stir for 5 minutes at a temperature of 5"C, then add 21.8 g (30 mol) of cyclopentadiene.
ΠΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 16 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π²ΡΠ΄ -5"Π‘ Π΄ΠΎ 0"Π‘. ΠΠΎΠ΄Π½Ρ ΡΠ°Π·Ρ Π²ΡΠ΄Π΄ΡΠ»ΡΡΡΡ ΡΠ»ΡΡ ΠΎΠΌ Π΄Π΅ΠΊΠ°Π½ΡΠ°ΡΡΡ, ΠΏΠΎΡΡΠΌ ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ, Π²ΠΈΠΊΠΎΡΠΈΡΡΠΎΠ²ΡΡΡΠΈ 50ΡΠΌ3 ΠΏΠ΅Π½ΡΠ°Π½Ρ. ΠΠ΅ΠΉΡΡΠ°Π»ΡΠ·ΡΡΡΡ Π΄ΠΎ ΡΠ-8,0, Π΄ΠΎΠ΄Π°ΡΡΠΈ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΠΎΠ²Π°Π½ΠΈΠΉ ΡΠΎΠ·ΡΠΈΠ½ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ΄Ρ Π½Π°ΡΡΡΡ. ΠΡΡΠ»Ρ ΡΡΠΎΠ³ΠΎ Π΅ΠΊΡΡΡΠ°Π³ΡΡΡΡ Π΄Π²ΡΡΡ ΠΏΠΎ 70ΡΠΌ3 Π΅ΡΠΈΠ»Π°ΡΠ΅ΡΠ°ΡΠΎΠΌ. ΠΠΎΠ΄Π½Ρ ΡΠ°Π·Ρ Π΄ΠΎΠ²ΠΎΠ΄ΡΡΡ Π΄ΠΎ Π·Π½Π°ΡΠ΅Π½Π½Ρ ΡΠ-11, Π΄ΠΎΠ΄Π°ΡΡΠΈ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΠΎΠ²Π°Π½ΠΈΠΉ ΡΠΎΠ·ΡΠΈΠ½ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ΄Ρ Π½Π°ΡΡΡΡ, ΠΏΠΎΡΡΠΌ Π΅ΠΊΡΡΡΠ°Π³ΡΡΡΡ Π΄Π²ΡΡΡ ΠΏΠΎ 70ΡΠΌ3 Π΅ΡΠΈΠ»Π°ΡΠ΅ΡΠ°ΡΠΎΠΌ. ΠΡΠ³Π°Π½ΡΡΠ½Ρ ΡΠ°Π·ΠΈ Π·'ΡΠ΄Π½ΡΡΡΡ, ΠΏΠΎΡΡΠΌ ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ Π΄Π²ΡΡΡ ΠΏΠΎ 50ΡΠΌ3 Π²ΠΎΠ΄ΠΎΡ, ΠΏΡΡΠ»Ρ ΡΠΎΠ³ΠΎ ΡΡΡΠ°ΡΡ Π½Π°Π΄ ΡΡΠ»ΡΡΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡ. ΠΡΡΠ»Ρ ΡΡΠ»ΡΡΡΡΠ²Π°Π½Π½Ρ ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 33,10Π³ 2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡ-5-ΡΠ½Ρ Ρ Π²ΠΈΠ³Π»ΡΠ΄Ρ Π»Π΅Π΄Ρ ΠΆΠΎΠ²ΡΠΎΡ ΠΎΠ»ΡΡ.Stir for 16 hours at a temperature from -5"C to 0"C. The aqueous phase is separated by decantation, then washed using 50 cm3 of pentane. Neutralize to pH-8.0 by adding a concentrated solution of sodium hydroxide. After that, it is extracted twice with 70 cm3 of ethyl acetate. The aqueous phase is adjusted to pH-11 by adding a concentrated solution of sodium hydroxide, then extracted twice with 70 cm3 of ethyl acetate. The organic phases are combined, then washed twice with 50 cm3 of water, after which they are dried over sodium sulfate. After filtration and concentration to dryness under reduced pressure, 33.10 g of 2-(0-5-methylbenzyl)-2-azabicyclo(2.2.1|hept-5-ene) are obtained in the form of a pale yellow oil.
ΠΠΎ ΠΊΠΎΠ»Π±ΠΈ Π· ΡΡΡΠΎΠΌΠ° ΡΠΈΠΉΠΊΠ°ΠΌΠΈ ΡΠΌΠ½ΡΡΡΡ 500ΡΠΌ3, ΡΠΎ ΠΎΠ±Π»Π°Π΄Π½Π°Π½Π° Ρ ΠΎΠ»ΠΎΠ΄ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠΌ ΡΠ° ΡΠΈΡΡΠ΅ΠΌΠΎΡ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΠ²Π°Π½Π½Ρ, Π² ΡΠΊΡΠΉ ΠΌΡΡΡΠΈΡΡΡΡ ΡΠΎΠ·ΡΠΈΠ½ 20Π³(75,34 ΠΌΠΎΠ»Ρ) 2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.1|Π³Π΅ΠΏΡ-5-ΡΠ½Ρ Ρ 220ΡΠΌ3 ΡΡΠ΅Ρ-Π±ΡΡΠ°Π½ΠΎΠ»Ρ, Π΄ΠΎΠ΄Π°ΡΡΡ, ΠΏΡΠΈ ΡΠ΅ΠΌΠ΅ΠΏΡΠ°ΡΡΡΡ Π±Π»ΡΠ·ΡΠΊΠΎ 252Π‘, 12Π³ Π-ΠΌΠ΅ΡΠΈΠ»ΠΌΠΎΡΡΠΎΠ»ΡΠΎΠΊΡΠΈΠ΄Ρ Ρ 32ΡΠΌ3 Π²ΠΎΠ΄ΠΈ, ΠΏΠΎΡΡΠΌ ΠΏΠΎΠ²ΡΠ»ΡΠ½ΠΎ Π΄ΠΎΠ΄Π°ΡΡΡ ΡΠ΅ 6Π±,ΠΡΠΌ3 2,50-Π½ΠΎΠ³ΠΎ(ΠΌΠ°ΡΠ°/ΠΎΠ±'ΡΠΌ) ΡΠΎΠ·ΡΠΈΠ½Ρ ΡΠ΅ΡΡΠΎΠΊΡΠΈΠ΄Ρ ΠΎΡΠΌΡΡ (0) Ρ ΡΡΠ΅Ρ-Π±ΡΡΠ°Π½ΠΎΠ»Ρ.To a three-necked flask with a capacity of 500 cm3, equipped with a refrigerator and a stirring system, which contains a solution of 20 g (75.34 mol) of 2-(0-5-methylbenzyl)-2-azabicyclo|2.2.1|hept-5-ene in 220cm3 of tert-butanol, add, at a temperature of about 252C, 12g of M-methylmorphol oxide in 32cm3 of water, then slowly add another 6b,3cm3 of a 2.50 (mass/volume) solution of osmium tetroxide (0) in tert-butanol.
ΠΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ Π΄Π²ΠΎΡ Π³ΠΎΠ΄ΠΈΠ½, ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π±Π»ΠΈΠ·ΡΠΊΠΎ 207Π‘, ΠΏΠΎΡΡΠΌ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ ΡΡΡΠΎΡ Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 657Π‘. ΠΡΡΠ»Ρ Π²ΠΈΠΏΠ°ΡΡΠ²Π°Π½Π½Ρ ΡΡΠ΅Ρ-Π±ΡΡΠ°Π½ΠΎΠ»Ρ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ Π·Π°Π»ΠΈΡΠΎΠΊ ΠΎΠ±ΡΠΎΠ±Π»ΡΡΡΡ Π·Π° Π΄ΠΎΠΏΠΎΠΌΠΎΠ³ΠΎΡ 350ΡΠΌ3 ΡΠ·ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ»Ρ. ΠΡΡΠ»Ρ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 24Π³ ΡΠΈΡ- 5,6-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ (2.2.1|)Π³Π΅ΠΏΡΠ°Π½Ρ Ρ Π²ΠΈΠ³Π»ΡΠ΄Ρ ΠΎΠ»ΡΡ. Π¨Π»ΡΡ ΠΎΠΌ ΠΊΡΠΈΡΡΠ°Π»ΡΠ·Π°ΡΡΡ Π· ΡΠ΅ΠΊΠ»ΠΎΠ³Π΅ΠΊΡΠ°Π½Ρ ΠΎΡΡΠΈΠΌΡΡΡΡ 14Π³ 58,65-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡΠ°Π½Ρ, ΡΠ·ΠΎΠΌΠ΅ΡΠ½Π° ΡΠΈΡΡΠΎΡΠ° ΡΠΊΠΎΠ³ΠΎ Π±ΡΠ»ΡΡΠ΅ 9595.Stir for two hours at a temperature of about 207C, then for three hours at a temperature of 657C. After evaporation of tert-butanol under reduced pressure, the residue is treated with 350 cm3 of isopropanol. After concentration to dryness under reduced pressure, 24 g of cis-5,6-dihydroxy-2-(0-5-methylbenzyl)-2-azabicyclo (2.2.1|)heptane are obtained as an oil. By crystallization from cyclohexane, 14 g of 58,65-dihydroxy-2-(0-5-methylbenzyl)-2-azabicyclo(2.2.1|heptane) is obtained, the isomeric purity of which is more than 9595.
Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡ, ΡΠΎ Π·Π½ΡΡΠΎ Π² Π΄Π΅ΠΉΡΠ΅ΡΠΎΠ²Π°Π½ΠΎΠΌΡ Ρ Π»ΠΎΡΠΎΡΠΎΡΠΌΡ, Π²ΠΈΡΠ²Π»ΡΡ ΡΠ°ΠΊΡ Ρ ΡΠΌΡΡΠ½Ρ Π·ΡΡΠ²ΠΈ (Π±): 1,21 (ΠΠ, Π΄); 1,38 (Π΄, 1Π); 1,59 (Π΄, 1Π); 2,22 (ΠΌ, 2Π); 2,45 (Π΄Π΄, 1Π); 2,95 (1Π, Ρ); 3,39 (ΠΊ, 1Π); 3,78 (Π΄, 1Π); 3,90 (Π΄, 1Π); 7,28 (5Π, ΠΌ).The NMR spectrum recorded in deuterated chloroform reveals the following chemical shifts (b): 1.21 (ZH, d); 1.38 (d, 1H); 1.59 (d, 1H); 2.22 (m, 2H); 2.45 (dd, 1H); 2.95 (1H, s); 3.39 (k, 1H); 3.78 (d, 1H); 3.90 (d, 1H); 7.28 (5H, m).
ΠΡΠΈΠΊΠ»Π°Π΄ 2Example 2
ΠΠΎ ΠΊΠΎΠ»Π±ΠΈ Π· ΡΡΡΠΎΠΌΠ° ΡΠΈΠΉΠΊΠ°ΠΌΠΈ ΡΠΌΠ½ΡΡΡΡ 500ΡΠΌ3, ΡΠΎ ΠΎΠ±Π»Π°Π΄Π½Π°Π½Π° Ρ ΠΎΠ»ΠΎΠ΄ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠΌ ΡΠ° ΡΠΈΡΡΠ΅ΠΌΠΎΡ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΠ²Π°Π½Π½Ρ, Π² ΡΠΊΡΠΉ ΠΌΡΡΡΠΈΡΡΡΡ ΡΠΎΠ·ΡΠΈΠ½ 18,4Π³(76 ΠΌΠΎΠ»Ρ) 58,65-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ (2.2.1|Π³Π΅ΠΏΡΠ°Π½Ρ Ρ 130ΡΠΌ3 ΡΠΎΠ»ΡΠΎΠ»Ρ, Π΄ΠΎΠ΄Π°ΡΡΡ 31,7Π³ 2,2-Π΄ΠΈΠΌΠ΅ΡΠΎΠΊΡΠΈΠΏΡΠΎΠ»Π°Π½Ρ(3Π04ΠΌΠΎΠ»Ρ), ΠΏΠΎΡΡΠΌ ΠΏΠΎΠ²ΡΠ»ΡΠ½ΠΎ Π΄ΠΎΠ΄Π°ΡΡΡ 13Π³(114ΠΌΠΎΠ»Ρ) ΡΡΠΈΡΡΠΎΡΠΎΡΡΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ. Π‘ΡΠΌΡΡ Π½Π°Π³ΡΡΠ²Π°ΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 4 Π³ΠΎΠ΄ΠΈΠ½ 10 Ρ Π²ΠΈΠ»ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 65"Π‘. ΠΡΡΠ»Ρ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ Π΄ΠΎ 30"Π‘ ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Ρ ΡΠΎΡΠΎΡΠ½ΠΎΠΌΡ Π²ΠΈΠΏΠ°ΡΡΠ²Π°ΡΡ Π΄Π»Ρ Π²ΠΈΠ΄Π°Π»Π΅Π½Π½Ρ ΡΠΎΠ»ΡΠΎΠ»Ρ, Π½Π°Π΄Π»ΠΈΡΠΊΡ 2,2-Π΄ΠΈΠΌΠ΅ΡΠΎΠΊΡΠΈΠΏΡΠΎΠ»Π°Π½Ρ ΡΠ° ΡΠ°ΡΡΠΊΠΎΠ²ΠΎ ΡΡΠΈΡΡΠΎΡΠΎΡΡΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ, ΡΠ΅Π°ΠΊΡΡΠΉΠ½Ρ ΡΡΠΌΡΡ ΠΎΠ±ΡΠΎΠ±Π»ΡΡΡΡ Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½ΠΎΠΌ, ΠΏΠΎΡΡΠΌ Π½Π΅ΠΉΡΡΠ°Π»ΡΠ·ΡΡΡΡ, Π΄ΠΎΠ΄Π°ΡΡΠΈ 100ΡΠΌ3 2Π½ ΡΠΎΠ·ΡΠΈΠ½Ρ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ΄Ρ Π½Π°ΡΡΡΡ. ΠΡΡΠ»Ρ Π΄Π΅ΠΊΠ°Π½ΡΠ°ΡΡΡ, Π²ΠΈΡΡΡΡΠ²Π°Π½Π½Ρ ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΡ ΡΠ°Π·ΠΈ Π½Π°Π΄ ΡΡΠ»ΡΡΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡ, ΡΡΠ»ΡΡΡΡΠ²Π°Π½Π½Ρ, ΠΎΠ±ΡΠΎΠ±ΠΊΠΈ Π·Π½Π΅Π±Π°ΡΠ²Π»ΡΡΡΠΈΠΌ Π²ΡΠ³ΡΠ»Π»ΡΠΌ(Π0Π³) ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 30 Ρ Π²ΠΈΠ»ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ ΠΊΠΈΠΏΡΠ½Π½Ρ Π·Ρ Π·Π²ΠΎΡΠΎΡΠ½ΡΠΌ Ρ ΠΎΠ»ΠΎΠ΄ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠΌ Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½Ρ, ΡΡΠ»ΡΡΡΡΠ²Π°Π½Π½Ρ Π½Π° "ΡΡΠ°Π³ΡΠ΅!" Π· ΠΌΠ΅ΡΠΎΡ ΠΏΡΠΎΡΠ²ΡΡΠ»Π΅Π½Π½Ρ ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 18,8Π³ 58,65- ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΠΎ--5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡΠ°Π½Ρ, ΡΡΡΡΠΊΡΡΡΠ° ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΡΡΡΡΡΡ "ΠTo a three-necked flask with a capacity of 500 cm3, equipped with a refrigerator and a stirring system, which contains a solution of 18.4 g (76 mol) of 58,65-dihydroxy-2-(0-5-methylbenzyl)-2-azabicyclo (2.2.1| of heptane in 130 cm3 of toluene, add 31.7 g of 2,2-dimethoxyprolane (3304 mol), then slowly add 13 g (114 mol) of trifluoroacetic acid. The mixture is heated for 4 hours and 10 minutes at a temperature of 65"C. After cooling to 30"C and concentrating in rotary evaporator to remove toluene, excess 2,2-dimethoxyprolane and partially trifluoroacetic acid, the reaction mixture is treated with dichloromethane, then neutralized by adding 100 cm3 of 2N sodium hydroxide solution. After decantation, drying of the organic phase over sodium sulfate, filtration, treatment with decolorizing carbon (30g) for 30 minutes at the reflux temperature of dichloromethane, filtering on "siagse" for the purpose of clarification and concentration to dryness under reduced pressure, 18.8 g of 58.65-isopropylidenedioxy-2-(o--5-m) are obtained ethylbenzyl)-2-azabicyclo(2.2.1|heptane, the structure of which is confirmed by "H
Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡΠΎΠΌ, ΡΠΎ Π·Π½ΡΡΠΎ Π² Π΄Π΅ΠΉΡΠ΅ΡΠΎΡ Π»ΠΎΡΠΎΡΠΎΡΠΌΡ, ΡΠΊΠΈΠΉ Π²ΠΈΡΠ²Π»ΡΡ ΡΠ°ΠΊΡ Ρ ΡΠΌΡΡΠ½Ρ Π·ΡΡΠ²ΠΈ (Π±): 1,22 (Π΄, ΠΠ); 1,23 (Ρ, 6Π);NMR spectrum recorded in deuterochloroform, which reveals the following chemical shifts (b): 1.22 (d, ΠΠ); 1.23 (c, 6H);
1,91 (Π΄, 1Π); 1,57 (Π΄, 1Π); 2,08 (Π΄, 1Π); 2,34 (ΡΡ.Ρ, 1Π); 2,45 (Π΄Π΄, 1Π); 3,06 (Ρ, 1Π); 3,40 (ΠΊ, 1Π); 4,09 (Π΄, 1Π); 4,19 (Π΄, 1Π); 7,26 (ΠΌ, 5Π).1.91 (d, 1H); 1.57 (d, 1H); 2.08 (d, 1H); 2.34 (ush.s, 1H); 2.45 (dd, 1H); 3.06 (c, 1H); 3.40 (k, 1H); 4.09 (d, 1H); 4.19 (d, 1H); 7.26 (m, 5H).
ΠΠΎ ΠΊΠΎΠ»Π±ΠΈ Π· ΡΡΡΠΎΠΌΠ° ΡΠΈΠΉΠΊΠ°ΠΌΠΈ ΡΠΌΠ½ΡΡΡΡ 250ΡΠΌ3, ΡΠΎ ΠΎΠ±Π»Π°Π΄Π½Π°Π½Π° ΡΠΈΡΡΠ΅ΠΌΠΎΡ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΠ²Π°Π½Π½Ρ, Π²Π²ΠΎΠ΄ΡΡΡ 0,5Π³ 5ΠΌΠ°Ρ.96-Π½ΠΎΠ³ΠΎ ΠΏΠ°Π»Π°Π΄ΡΡ-Π½Π°-Π²ΡΠ³ΡΠ»Π»Ρ, 5Π³ 5ΠΠ,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.11 Π³Π΅ΠΏΡΠ°Π½Ρ, 3,98Π³ Π΄ΠΈ-ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»Π΄ΠΈΠΊΠ°ΡΠ±ΠΎΠ½Π°ΡΡ ΡΠ° ΠΠ±ΡΠΌ3 ΠΌΠ΅ΡΠ°Π½ΠΎΠ»Ρ. ΠΠΏΠ°ΡΠ°Ρ ΠΏΡΠΎΠ΄ΡΠ²Π°ΡΡΡ Π°ΡΠ³ΠΎΠ½ΠΎΠΌ, ΠΏΠΎΡΡΠΌ Π²ΠΎΠ΄Π½Π΅ΠΌ, ΠΏΡΡΠ»Ρ ΡΠΎΠ³ΠΎ ΡΡΠ²ΠΎΡΡΡΡΡ Π°ΡΠΌΠΎΡΡΠ΅ΡΡ Π²ΠΎΠ΄Π½Ρ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 25"Π‘. Π Π΅Π°ΠΊΡΡΡ ΠΏΡΠΎΠ΄ΠΎΠ²ΠΆΡΡΡΡ ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΡΠΈ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ Π³ΠΎΠ΄ΠΈΠ½, Π·Π΄ΡΠΉΡΠ½ΡΡΡΠΈ ΠΏΠΎΠ΄ΡΠ²Π°Π½Π½Ρ Π²ΠΎΠ΄Π½Π΅ΠΌ ΠΊΠΎΠΆΠ½Ρ 15 Ρ Π²ΠΈΠ»ΠΈΠ½, Π΄Π»Ρ Π²ΠΈΠ΄Π°Π»Π΅Π½Π½Ρ Π΄ΡΠΎΠΊΡΠΈΠ΄Ρ Π²ΡΠ³Π»Π΅ΡΡ, ΡΠΎ Π²ΠΈΠ΄ΡΠ»ΡΡΡΡΡΡ.0.5 g of 5 wt.96 palladium-on-charcoal, 5 g of 5ΠΠ,65-isopropylidenedioxy-2-(0-5-methylbenzyl)-2-azabicyclo|2.2 are introduced into a 250 cm3 three-necked flask equipped with a stirring system .11 of heptane, 3.98 g of di-tert-butyl dicarbonate and Zbsm3 of methanol. The apparatus is purged with argon, then with hydrogen, after which a hydrogen atmosphere is created at a temperature of 25"C. The reaction is continued for hours, blowing with hydrogen every 15 minutes to remove the released carbon dioxide.
ΠΡΡΠ»Ρ ΡΡΠ»ΡΡΡΡΠ²Π°Π½Π½Ρ Π· ΠΌΠ΅ΡΠΎΡ ΠΏΡΠΎΡΠ²ΡΡΠ»Π΅Π½Π½Ρ(Π½Π° ΡΠ°Π³ΡΠ΅Ρ) ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 4,84Π³ 5Π,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|(2.2.1) Π³Π΅ΠΏΡΠ°Π½Ρ, ΡΡΡΡΠΊΡΡΡΠ° ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΡΡΡΡΡΡ "Π-Π―ΠΠ -ΡΠ»Π΅ΠΊΡΡΠΎΠΌ, ΡΠΎ Π·Π½ΡΡΠΎ Π² Π΄Π΅ΠΉΡΠ΅ΡΠΎΠ²Π°Π½ΠΎΠΌΡ Π΄ΠΈΠΌΠ΅ΡΠΈΠ»ΡΡΠ»ΡΡΠΎΠΊΡΠΈΠ΄Ρ, ΡΠΊΠΈΠΉ Π²ΠΈΡΠ²Π»ΡΡ ΡΠ°ΠΊΡ Ρ ΡΠΌΡΡΠ½Ρ Π·ΡΡΠ²ΠΈ (6): 1,16 (Ρ, ΠΠ); 1,28 (Ρ, ΠΠ); 1,32 (Ρ, 1Π); 1,34 (Ρ, ΠΠ); 1,65 (Π΄, 1Π); 2,38 (ΠΌ, 1Π); 2,65 (Π΄, 1Π); 2,99 (ΠΌ, 1Π); 3,84 (ΠΌ, 1Π); 3,94 (ΠΌ, 1Π); 4,16 (Π΄, 1Π).After filtration for the purpose of clarification (on bagasse) and concentration to dryness under reduced pressure, 4.84 g of 5H,65-isopropylidenedioxy-2-(tert-butoxycarbonyl)-2-azabicyclo|(2.2.1) heptane are obtained, the structure of which is confirmed by "H- NMR spectrometer recorded in deuterated dimethylsulfoxide, which reveals the following chemical shifts (6): 1.16 (s, 3H); 1.28 (s, 3H); 1.32 (s, 1H); 1.34 ( c, ZN); 1.65 (d, 1H); 2.38 (m, 1H); 2.65 (d, 1H); 2.99 (m, 1H); 3.84 (m, 1H); 3.94 (m, 1H); 4.16 (d, 1H).
ΠΠΎ ΠΏΡΠΎΠ±ΡΡΠΊΠΈ ΡΠΌΠ½ΡΡΡΡ ΠΠΡΠΌ3 Π²Π²ΠΎΠ΄ΡΡΡ 270ΠΌΠ³(1 ΠΌΠΎΠ»Ρ) 58,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»)- 2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(|2.2.1| Π³Π΅ΠΏΡΠ°Π½Ρ ΡΠ° 40ΠΌΠ³(0,3 Π΅ΠΊΠ²ΡΠ²Π°Π»Π΅Π½ΡΠ°) ΠΠΈΠΒ».ΠΠ³Π. ΠΠΎΠ΄Π°ΡΡΡ 10ΡΠΌ3 Π΅ΡΠΈΠ»Π°ΡΠ΅ΡΠ°ΡΡ ΡΠ° 720ΠΌΠ³(40 Π΅ΠΊΠ²ΡΠ²Π°Π»Π΅Π½ΡΡΠ²) Π²ΠΎΠ΄ΠΈ. ΠΠΎΡΡΠΌ Π΄ΠΎΠ΄Π°ΡΡΡ 2,14Π³(10 Π΅ΠΊΠ²ΡΠ²Π°Π»Π΅Π½ΡΡΠ²) ΠΏΠ΅ΡΠΉΠΎΠ΄Π°ΡΡ Π½Π°ΡΡΡΡ, ΡΠ° ΠΏΡΠΎΠ±ΡΡΠΊΡ Π³Π΅ΡΠΌΠ΅ΡΠΈΡΠ½ΠΎ Π·Π°ΠΊΡΠΈΠ²Π°ΡΡΡ. ΠΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 16 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 50"Π‘. Π Π΅Π°ΠΊΡΡΠΉΠ½Ρ ΡΡΠΌΡΡ Π²ΡΠ΄ΡΡΠ»ΡΡΡΠΎΠ²ΡΡΡΡ Π΄Π»Ρ ΠΏΡΠΎΡΠ²ΡΡΠ»Π΅Π½Π½Ρ(Π½Π° ΡΠ³Π°ΡΠ΅Ρ), ΠΏΠΎΡΡΠΌ Π΅ΠΊΡΡΡΠ°Π³ΡΡΡΡ Π΄Π²ΡΡΡ ΠΏΠΎ 20ΡΠΌ3 Π΅ΡΠΈΠ»Π°ΡΠ΅ΡΠ°ΡΠΎΠΌ. ΠΡΠ³Π°Π½ΡΡΠ½Ρ ΡΠ°Π·ΠΈ Π²ΠΈΡΡΡΡΡΡΡ Π½Π°Π΄ ΡΡΠ»ΡΡΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡ. ΠΡΡΠ»Ρ ΡΡΠ»ΡΡΡΡΠ²Π°Π½Π½Ρ ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΎΡΡΠΈΠΌΡΡΡΡ 245ΠΌΠ³ ΡΠ²Π΅ΡΠ΄ΠΎΡ ΡΠ΅ΡΠΎΠ²ΠΈΠ½ΠΈ, ΡΠΎ ΠΌΡΡΡΠΈΡΡ 6595 5Π8,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|ΠΠ³Π΅ΠΏΡΠ°Π½-Π-ΠΎΠ½Ρ ΡΠ° 3295 Π²ΠΈΡ ΡΠ΄Π½ΠΎΡ ΡΠ΅ΡΠΎΠ²ΠΈΠ½ΠΈ. Π‘ΡΡΡΠΊΡΡΡΡ ΠΎΡΡΠΈΠΌΠ°Π½ΠΎΠ³ΠΎ ΠΏΡΠΎΠ΄ΡΠΊΡΡ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΠ΅Π½ΠΎ "Π-Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡΠΎΠΌ, ΡΠΊΠΈΠΉ Π±ΡΠ»ΠΎ Π·Π½ΡΡΠΎ Π² Π΄Π΅ΠΉΡΠ΅ΡΠΎΠ²Π°Π½ΠΎΠΌΡ Π΄ΠΈΠΌΠ΅ΡΠΈΠ»ΡΡΠ»ΡΡΠΎΠΊΡΠΈΠ΄Ρ. Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡ Π²ΠΈΡΠ²Π»ΡΡ ΡΠ°ΠΊΡ Ρ ΡΠΌΡΡΠ½Ρ Π·ΡΡΠ²ΠΈ (Π±): 1,38 (Ρ, 9Π); 1,23 (Ρ, ΠΠ); 1,33 (Ρ, ΠΠ); 1,85 (Π΄, 1Π); 1,93 (Π΄, 1Π); 2,69 (Ρ, 1Π); 4,24 (Ρ, 1Π); 4,Π1 (Π΄, 1Π); 4,51 (Π΄, 1Π).270 mg (1 mol) of 58,65-isopropylidenedioxy-2-(tert-butoxycarbonyl)-2-azabicyclo(|2.2.1| heptane and 40 mg (0.3 equivalents) ViOΒ»HgO are introduced into a test tube with a capacity of 30 cm3. Add 10 cm3 of ethyl acetate and 720 mg (40 equivalents) of water. Then 2.14 g (10 equivalents) of sodium periodate are added, and the test tube is hermetically closed. It is stirred for 16 hours at a temperature of 50 "C. The reaction mixture is filtered for clarification (on quenching), then extracted twice with 20 cm3 ethyl acetate. The organic phases are dried over sodium sulfate. After filtration and concentration to dryness, 245 mg of a solid containing 6595 5H8,65-isopropylidenedioxy-2-(tert-butoxycarbonyl)-2-azabicyclo(2.2.1|Heptan-3-one and 3295 of the starting substance. The structure of the obtained product was confirmed by the H-NMR spectrum, which was recorded in deuterated dimethyl sulfoxide. The NMR spectrum reveals the following chemical shifts (b): 1.38 (s, 9H); 1.23 (s, Π) ; 1.33 (c, ΠΠ); 1.85 (d, 1H); 1.93 (d, 1H); 2.69 (c, 1H); 4.24 (c, 1H); 4.A1 ( d, 1H); 4.51 (d, 1H).
ΠΡΠΈΠΊΠ»Π°Π΄ ΠExample C
ΠΠΎ ΠΎΠ°Π²ΡΠΎΠΊΠ»Π°Π²Ρ ΡΠΌΠ½ΡΡΡΡ 25ΡΠΌ3, ΡΠΊΠΈΠΉ ΠΎΠ±Π»Π°Π΄Π½Π°Π½ΠΎ ΠΌΠ°Π³Π½ΡΡΠ½ΠΎΡ ΠΌΡΡΠ°Π»ΠΊΠΎΡ, Π²Π²ΠΎΠ΄ΡΡΡ 1,47Π³ 5Π,65- ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.1|)Π³Π΅ΠΏΡΠ°Π½-Π-ΠΎΠ½Ρ Ρ Π²ΠΈΠ³Π»ΡΠ΄Ρ ΡΠΎΠ·ΡΠΈΠ½Ρ Π² 10ΡΠΌ3 Π±Π΅Π·Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΡΠΎΠ»ΡΠΎΠ»Ρ, ΠΏΠΎΡΡΠΌ Π±Π»ΠΈΠ·ΡΠΊΠΎ 0,7ΡΠΌ? Π΅ΡΠΈΠ»Π°ΠΌΡΠ½Ρ. ΠΠ²ΡΠΎΠΊΠ»Π°Π² Π·Π°ΡΠΈΠ½ΡΡΡΡ, ΠΏΠΎΡΡΠΌ Π½Π°Π³ΡΡΠ²Π°ΡΡΡ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π² ΠΌΠ΅ΠΆΠ°Ρ Π²ΡΠ΄ 907 Π΄ΠΎ 100"Π‘ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 21 Π³ΠΎΠ΄ΠΈΠ½ΠΈ. ΠΡΡΠ»Ρ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ ΡΠΎΠ»ΡΠΎΠ» Π²ΠΈΠΏΠ°ΡΡΡΡΡ ΡΠ° Π·Π°Π»ΠΈΡΠΎΠΊ ΠΎΠ±ΡΠΎΠ±Π»ΡΡΡΡ, Π²ΠΈΠΊΠΎΡΠΈΡΡΠΎΠ²ΡΡΡΠΈ 10ΡΠΌ3 Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½Ρ ΡΠ° 10ΡΠΌ3 Π²ΠΎΠ΄ΠΈ. ΠΡΡΠ»Ρ Π΄Π΅ΠΊΠ°Π½ΡΠ°ΡΡΡ ΠΎΡΠ³Π°Π½ΡΡΠ½Ρ ΡΠ°Π·Ρ ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ 10ΡΠΌ3 Π²ΠΎΠ΄ΠΈ. ΠΠΎΡΠ΄Π½Π°Π½Ρ Π²ΠΎΠ΄Π½Ρ ΡΠ°ΡΠΈ ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ 10ΡΠΌ? Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½Ρ. ΠΠΎΡΠ΄Π½Π°Π½Ρ ΠΎΡΠ³Π°Π½ΡΡΠ½Ρ ΡΠ°Π·ΠΈ ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ 10ΡΠΌ3 Π½Π°ΡΠΈΡΠ΅Π½ΠΎΠ³ΠΎ ΡΠΎΠ·ΡΠΈΠ½Ρ Ρ Π»ΠΎΡΠΈΠ΄Ρ Π½Π°ΡΡΡΡ, ΠΏΠΎΡΡΠΌ Π²ΠΈΡΡΡΡΡΡΡ Π½Π°Π΄ ΡΡΠ»ΡΡΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡ. ΠΡΡΠ»Ρ ΡΡΠ»ΡΡΡΡΠ²Π°Π½Π½Ρ ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 1,58Π³ ΠΏΡΠΎΠ΄ΡΠΊΡΡ, ΡΠΎ ΠΌΡΡΡΠΈΡΡ 9595 28,35-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4Π-ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»Π°ΠΌΡΠ½ΠΎ-15-Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½Ρ, ΡΡΡΡΠΊΡΡΡΡ ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΠ΅Π½ΠΎΡΡΠ³. "Π-'Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡΠΎΠΌ,ΡΠΎ Π·Π½ΡΡΠΎ Π² Π΄Π΅ΠΉΡΠ΅ΡΠΎΠ²Π°Π½ΠΎΠΌΡ Π΄ΠΈΠΌΠ΅ΡΠΈΠ»ΡΡΠ»ΡΡΠΎΠΊΡΠΈΠ΄Ρ. Π‘ΠΏΠ΅ΠΊΡΡ Π²ΠΈΡΠ²Π»ΡΡ ΡΠ°ΠΊΡ Ρ ΡΠΌΡΡΠ½Ρ Π·ΡΡΠ²ΠΈ (Π±): 0,95 (Ρ, ΠΠ); 1,14 (Ρ, ΠΠ); 1,31 (Ρ, 12Π); 1,55 (ΠΌ, 1Π); 2,11 (ΠΌ, 1Π); 2,64 (ΠΌ, 1Π); 3,00 (ΠΊΠ²ΡΠ½ΡΠ΅Ρ, 2Π); 3,77 (ΠΌ, 1Π); 4,23 (ΠΌ, 1Π); 4,54 (ΠΌ, 1Π); 7,07 (Π΄, 1Π); 8,12 (Ρ, 1Π).1.47 g of 5B,65-isopropylidenedioxy-2-(tert-butoxycarbonyl)-2-azabicyclo|2.2.1|)heptan-Z-one in the form of a solution in 10 cm3 of anhydrous toluene is introduced into an autoclave with a capacity of 25 cm3, which is equipped with a magnetic stirrer. then about 0.7 cm? ethylamine The autoclave is closed, then heated at a temperature ranging from 907 to 100Β°C for 21 hours. After cooling, the toluene is evaporated and the residue is treated using 10 cm3 of dichloromethane and 10 cm3 of water. After decantation, the organic phase is washed with 10 cm3 of water. The combined aqueous layers are washed with 10 cm3 of dichloromethane. The combined organic phases are washed with 10 cm3 of saturated sodium chloride solution, then dried over sodium sulfate. After filtration and concentration to dryness under reduced pressure, 1.58 g of product containing 9595 28,35-isopropylidenedioxy-4A-tert-butoxycarbonylamino-15-ethylaminocarbonylcyclopentane, structure which is confirmed by the H-NMR spectrum recorded in deuterated dimethylsulfoxide. The spectrum reveals the following chemical shifts (b): 0.95 (t, ZN); 1.14 (c, ZN); 1.31 (c, 12H); 1.55 (m, 1H); 2.11 (m, 1H); 2.64 (m, 1H); 3.00 (quintet, 2H); 3.77 (m, 1H); 4.23 (m, 1H); 4.54 (m, 1H); 7.07 (d, 1H); 8.12 (t, 1H).
ΠΠΎ ΠΊΠΎΠ»Π±ΠΈ ΡΠΌΠ½ΡΡΡΡ 25ΡΠΌ3 Π²Π²ΠΎΠ΄ΡΡΡ 1,22Π³ 28,35-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4Π-ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»Π°ΠΌΡΠ½ΠΎ-15- Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½Ρ ΡΠ° 10ΡΠΌ3 Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½Ρ. ΠΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π±Π»ΠΈΠ·ΡΠΊΠΎ 25"Π‘, ΠΏΠ΅ΡΠΌΡΡΡΡΡΠΈ ΡΡΡΠΌΡΡ ΠΌΠ°Π³Π½ΡΡΠ½ΠΎΡ ΠΌΡΡΠ°Π»ΠΊΠΎΡ, Π΄ΠΎΠ΄Π°ΡΡΡ 0,85Π³ ΡΡΡΡΠΎΡΠΎΡΡΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ. ΠΡΡΠ»Ρ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΠ²Π°Π½Π½Ρ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 6 Π³ΠΎΠ΄ΠΈΠ½ ΡΠ° ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΎΡΡΠΈΠΌΡΡΡΡ 1,16Π³ ΡΡΠΈΡΡΠΎΡΠ°ΡΠ΅ΡΠ°ΡΡ 2ΠΠ,35-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4Π-Π°ΠΌΡΠ½ΠΎ-15- Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½Ρ ΡΡΡΡΠΊΡΡΡΡ ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΠ΅Π½ΠΎ 'Π-Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡΠΎΠΌ, ΡΠΎ Π·Π½ΡΡΠΎ Π² Π΄Π΅ΠΉΡΠ΅ΡΠΎΠ²Π°Π½ΠΎΠΌΡ Π΄ΠΈΠΌΠ΅ΡΠΈΠ»ΡΡΠ»ΡΡΠΎΠΊΡΠΈΠ΄Ρ. Π‘ΠΏΠ΅ΠΊΡΡ Π²ΠΈΡΠ²Π»ΡΡ ΡΠ°ΠΊΡ Ρ ΡΠΌΡΡΠ½Ρ Π·ΡΡΠ²ΠΈ (Π±): 0,79 (Ρ, ΠΠ); 1,03 (Ρ, ΠΠ); 1,19 (Ρ,1.22 g of 28,35-isopropylidenedioxy-4B-tert-butoxycarbonylamino-15-ethylaminocarbonylcyclopentane and 10 cm3 of dichloromethane are introduced into a 25 cm3 flask. At a temperature of about 25"C, stirring the mixture with a magnetic stirrer, add 0.85 g of trifluoroacetic acid. After stirring for 6 hours and concentrating to dryness, 1.16 g of trifluoroacetate 2ΠΠ,35-isopropylidenedioxy-4B-amino-15-ethylaminocarbonylcyclopentane is obtained, the structure of which is confirmed by - NMR spectrum recorded in deuterated dimethylsulfoxide. The spectrum reveals the following chemical shifts (b): 0.79 (t, ΠΠ); 1.03 (s, ΠΠ); 1.19 (Ρ,
ΠΠ); 1,42 (ΠΌ, 1Π); 2,05 (ΠΌ, 1Π); 2,52 (ΠΌ, 1Π); 2,89 (ΠΊΠ²ΡΠ½ΡΠ΅Ρ, 2Π); 3,04 (ΠΌ, 1Π); 4,16 (ΠΌ, 1Π).ZN); 1.42 (m, 1H); 2.05 (m, 1H); 2.52 (m, 1H); 2.89 (quintet, 2H); 3.04 (m, 1H); 4.16 (m, 1H).
ΠΡΠΈΠΊΠ»Π°Π΄ 4Example 4
Π ΠΎΠ·ΡΠΈΠ½ 0,5ΠΌΠΌΠΎΠ»Ρ ΡΡΠΌΡΡΡ(78:22 Π² ΠΌΠΎΠ»ΡΠ½ΠΎΠΌΡ ΡΠΏΡΠ²Π²ΡΠ΄Π½ΠΎΡΠ΅Π½Π½Ρ) 5Π,65-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2- Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.1| Π³Π΅ΠΏΡΠ°Π½Ρ ΡΠ° 55,6Π-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|(2.2.1| Π³Π΅ΠΏΡΠ°Π½Ρ ΡΠ° Π,5ΠΌΠΌΠΎΠ»ΡA solution of 0.5 mmol of the mixture (78:22 in the molar ratio) 5A,65-dihydroxy-2-(0-5-methylbenzyl)-2-azabicyclo|2.2.1| of heptane and 55.6V-dihydroxy-2-(0-5-methylbenzyl)-2-azabicyclo|(2.2.1| heptane and 0.5 mmol
Π-Π΄ΠΈΠΌΠ΅ΡΠΎΠΊΡΠΈΠ±ΡΡΡΡΠΈΠ½ΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ Π² 1ΡΠΌ3 ΡΠ·ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ»Ρ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 24 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ, ΡΠΎ Π·ΠΌΡΠ½ΡΡΡΡΡΡ Π²ΡΠ΄ ΠΏΠΎΡΠ°ΡΠΊΠΎΠ²ΠΎΡ 257Π‘ Π΄ΠΎ 57"Π‘. ΠΡΡΠΈΠΌΠ°Π½Ρ ΠΊΡΠΈΡΡΠ°Π»ΠΈ Π²ΡΠ΄ΡΡΠ»ΡΡΡΠΎΠ²ΡΡΡΡ ΡΠ° Π²ΠΈΡΡΡΡΡΡΡ. Π’Π°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ ΠΎΡΡΠΈΠΌΡΡΡΡ 110ΠΌΠ³ 5ΠΠ,65-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.1| Π³Π΅ΠΏΡΠ°Π½Ρ Π· Π΅Π½Π°Π½ΡΡΠΎΠΌΠ΅ΡΠ½ΠΈΠΌ Π½Π°Π΄Π»ΠΈΡΠΊΠΎΠΌ 9795.1-dimethoxysuccinic acid in 1 cm3 of isopropanol is stirred for 24 hours at a temperature varying from the initial 257C to 57"C. The resulting crystals are filtered and dried. In this way, 110 mg of 5ΠΠ,65-dihydroxy-2-(0-5-methylbenzyl)- 2-azabicyclo|2.2.1|heptane with an enantiomeric excess of 9795.
Π‘ΡΠΌΡΡ(78:22 Π² ΠΌΠΎΠ»ΡΠ½ΠΎΠΌΡ ΡΠΏΡΠ²Π²ΡΠ΄Π½ΠΎΡΠ΅Π½Π½Ρ) 58,65-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2- Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|(2.2.1|1Π³Π΅ΠΏΡΠ°Π½Ρ /55,6Π-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(0-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.11) Π³Π΅ΠΏΡΠ°Π½Ρ ΠΌΠΎΠΆΠ½Π° ΠΎΡΡΠΈΠΌΠ°ΡΠΈ ΡΠ°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ:Mixture (78:22 in molar ratio) 58,65-dihydroxy-2-(0-5-methylbenzyl)-2-azabicyclo|(2.2.1|1heptane/55,6B-dihydroxy-2-(0-5-methylbenzyl) )-2-azabicyclo|2.2.11) heptane can be obtained as follows:
ΠΠΎ ΠΊΠΎΠ»Π±ΠΈ Π· ΡΡΡΠΎΠΌΠ° ΡΠΈΠΉΠΊΠ°ΠΌΠΈ ΡΠΌΠ½ΡΡΡΡ 250ΡΠΌ?3, ΡΠΎ ΠΎΠ±Π»Π°Π΄Π½Π°Π½ΠΎ Ρ ΠΎΠ»ΠΎΠ΄ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠΌ ΡΠ° ΡΠΈΡΡΠ΅ΠΌΠΎΡ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΠ²Π°Π½Π½Ρ, Π² ΡΠΊΡΠΉ ΠΌΡΡΡΠΈΡΡΡΡ 7Π³(Π5ΠΌΠΎΠ»Ρ) 2-(-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|)Π³Π΅ΠΏΡ-5-ΡΠ½Ρ Π² 70ΡΠΌ3 ΡΡΠ΅Ρ- Π±ΡΡΠ°Π½ΠΎΠ»Ρ, ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π±Π»ΠΈΠ·ΡΠΊΠΎ 25"Π‘ Π΄ΠΎΠ΄Π°ΡΡΡ 4,12Π³ Π-ΠΌΠ΅ΡΠΈΠ»ΠΌΠΎΡΡΠΎΠ»ΡΠΎΠΊΡΠΈΠ΄Ρ Π² 11ΡΠΌ3 Π²ΠΎΠ΄ΠΈ, ΠΏΠΎΡΡΠΌ ΠΏΠΎΠ²ΡΠ»ΡΠ½ΠΎ Π΄ΠΎΠ΄Π°ΡΡΡ ΠΠ±ΠΎΠΌΠΊΠ» 2,595-Π½ΠΎΠ³ΠΎ(ΠΌΠ°ΡΠ°/ΠΎΠ±'ΡΠΌ) ΡΠΎΠ·ΡΠΈΠ½Ρ ΡΠ΅ΡΡΠΎΠΊΡΠΈΠ΄Ρ ΠΎΡΠΌΡΡ Π² ΡΡΠ΅Ρ-Π±ΡΡΠ°Π½ΠΎΠ»Ρ. ΠΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 1 Π³ΠΎΠ΄ΠΈΠ½ΠΈ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π±Π»ΠΈΠ·ΡΠΊΠΎ 20"Π‘, ΠΏΠΎΡΡΠΌ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 4 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ 65"Π‘. ΠΡΡΠ»Ρ Π²ΠΈΠΏΠ°ΡΡΠ²Π°Π½Π½Ρ ΡΡΠ΅Ρ-Π±ΡΡΠ°Π½ΠΎΠ»Ρ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ Π·Π°Π»ΠΈΡΠΎΠΊ ΠΎΠ±ΡΠΎΠ±Π»ΡΡΡΡ 150ΡΠΌ3 ΡΠ·ΠΎΠΏΡΠΎΠΏΠ°Π½ΠΎΠ»Ρ. ΠΡΡΠ»Ρ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΠ²Π°Π½Π½Ρ Π΄ΠΎΡΡΡ Π° ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 8,27Π³ ΠΏΡΠΎΠ΄ΡΠΊΡΡ, Π-Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡ ΡΠΊΠΎΠ³ΠΎ ΠΏΠΎΠΊΠ°Π·ΡΡ, ΡΠΎ ΠΉΠΎΠ³ΠΎ ΡΡΠ²ΠΎΡΠ΅Π½ΠΎ ΡΡΠΌΡΡΡΡ(78:22 Π² ΠΌΠΎΠ»ΡΠ½ΠΎΠΌΡ ΡΠΏΡΠ²Π²ΡΠ΄Π½ΠΎΡΠ΅Π½Π½Ρ) 58,65-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2- Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ|2.2.1|Π³Π΅ΠΏΡΠ°Π½Ρ ΡΠ° 55,6Π-Π΄ΠΈΠ³ΡΠ΄ΡΠΎΠΊΡΠΈ-2-(-5-ΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·ΠΈΠ»)-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡΠ°Π½Ρ.To a 250 cm3 three-necked flask, equipped with a refrigerator and a stirring system, containing 7 g (35 mol) of 2-(-5-methylbenzyl)-2-azabicyclo(2.2.1|)hept-5-ene in 70 cm3 of tert - butanol, at a temperature of about 25"C, add 4.12 g of M-methylmorphol oxide to 11 cm3 of water, then slowly add Zbomkl of a 2.595 (mass/volume) solution of osmium tetroxide in tert-butanol. Stir for 1 hour at a temperature of about 20 "C, then for 4 hours at 65"C. After evaporation of tert-butanol under reduced pressure, the residue is treated with 150 cm3 of isopropanol. After concentration to dryness under reduced pressure, 8.27 g of product is obtained, the H-NMR spectrum of which shows that it was formed by a mixture ( 78:22 in the molar ratio) of 58,65-dihydroxy-2-(-5-methylbenzyl)-2-azabicyclo|2.2.1|heptane and 55,6B-dihydroxy-2-(-5-methylbenzyl)-2-azabicyclo (2.2.1|heptane.
ΠΡΠΈΠΊΠ»Π°Π΄ 5Example 5
ΠΠΎ ΠΏΡΠΎΠ±ΡΡΠΊΠΈ ΠΠ΅ΡΠ³ΠΎΡΠ° Π²Π²ΠΎΠ΄ΡΡΡ 56Π±8ΠΌΠ³ 5Π,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ½Π΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»)-2- Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡΠ°Π½-Π3-ΠΎΠ½Ρ ΡΠ° 7ΠΡΠΌ? Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ 7ΠΠΌΠ°Ρ.Π£ΠΎ-Π½ΠΎΠ³ΠΎ ΡΠΎΠ·ΡΠΈΠ½Ρ Π΅ΡΠΈΠ»Π°ΠΌΡΠ½Ρ. Π‘ΡΠΌΡΡ Π½Π°Π³ΡΡΠ²Π°ΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 4 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 60"Π‘, ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΡΡΠΈ. ΠΡΡΠ»Ρ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ Π²ΠΈΠ΄Π°Π»ΡΡΡΡ Π½Π°Π΄Π»ΠΈΡΠΎΠΊ ΡΡΠΈΠ΅ΡΠΈΠ»Π°ΠΌΡΠ½Ρ ΡΠ° Π²ΠΎΠ΄ΠΈ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ. Π’Π°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ, ΠΏΡΡΠ»Ρ Π²ΠΈΡΡΡΡΠ²Π°Π½Π½Ρ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ, ΠΎΡΡΠΈΠΌΡΡΡΡ Π±5ΠΠΌΠ³ 28,35-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4Π-ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»Π°ΠΌΡΠ½ΠΎ-15-56b8mg of 5H,65-isopropylenedioxy-2-(tert-butoxycarbonyl)-2-azabicyclo(2.2.1|heptan-Z3-one and 7Osm? of an aqueous 7Oms.Uo solution of ethylamine are introduced into a Berghoff test tube. The mixture is heated for 4 hours at at a temperature of 60"C, stirring. After cooling, excess triethylamine and water are removed under reduced pressure. Thus, after drying under reduced pressure, b5Omg of 28,35-isopropylidenedioxy-4B-tert-butoxycarbonylamino-15-
Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½Ρ, Π²ΠΈΡ ΡΠ΄ ΡΠΊΠΎΠ³ΠΎ ΡΡΠ°Π½ΠΎΠ²ΠΈΡΡ 9895. Π‘ΡΡΡΠΊΡΡΡΡ ΠΏΡΠΎΠ΄ΡΠΊΡΡ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΡΡ Π-Π―ΠΠ - ΡΠΏΠ΅ΠΊΡΡ. ΠΠ±Π΅ΡΡΠ°Π»ΡΠ½Π° Π·Π΄Π°ΡΠ½ΡΡΡΡ ΠΏΡΠΎΠ΄ΡΠΊΡΡ ΡΠΊΠ»Π°Π΄Π°Ρ (ΠΎΠ³ΠΎ - 15,02(Ρ-1, ΠΌΠ΅ΡΠ°Π½ΠΎΠ»).of ethylaminocarbonylcyclopentane, the yield of which is 9895. The structure of the product is confirmed by the H-NMR spectrum. The rotational capacity of the product is 15.02 (s-1, methanol).
ΠΠΎ ΡΠΎΠ·ΡΠΈΠ½Ρ 200ΠΌΠ³ 28,35-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4Π-ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»Π°ΠΌΡΠ½ΠΎ-15- Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½Ρ Π² 1,6ΡΠΌ3 Π±Π΅Π·Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½Ρ Π΄ΠΎΠ΄Π°ΡΡΡ 275ΠΌΠΊΠ» ΡΡΠΈΡΡΠΎΡΠΎΡΡΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ. Π‘ΡΠΌΡΡ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ ΠΎΠ΄Π½ΡΡΡ Π½ΠΎΡΡ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π±Π»ΠΈΠ·ΡΠΊΠΎ -57Π‘. Π Π΅Π°ΠΊΡΡΠΉΠ½Ρ ΡΡΠΌΡΡ Π²ΠΈΠ»ΠΈΠ²Π°ΡΡΡ Π΄ΠΎ 4ΡΠΌ3 2,5Π½ ΡΠΎΠ·ΡΠΈΠ½Ρ Π³ΡΠ΄ΡΠΎΠΊΡΠΈΠ΄Ρ Π½Π°ΡΡΡΡ. ΠΡΠ³Π°Π½ΡΡΠ½ΠΈΠΉ ΡΠ°Ρ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΡΡΡ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ Π½ΠΈΠΆΡΠ΅ 25"Π‘. Π’Π°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ ΠΎΡΡΠΈΠΌΡΡΡΡ 125ΠΌΠ³ ΠΏΡΠΎΠ΄ΡΠΊΡΡ, ΡΠΊΠΈΠΉ ΡΠΎΠ·ΡΠΈΠ½ΡΡΡΡ Π² 0,5ΡΠΌ3 ΡΠ΅ΡΡΠ°Π³ΡΠ΄ΡΠΎΡΡΡΠ°Π½Ρ. ΠΠΎΡΡΠΎΠ³ΠΎ ΡΠΎΠ·ΡΠΈΠ½Ρ Π΄ΠΎΠ΄Π°ΡΡΡ 7ΠΠΌΠ³ Π±Π΅Π½Π·ΠΎΠΉΠ½ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ. ΠΠ½Π°ΡΠ»ΡΠ΄ΠΎΠΊ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ ΠΎΡΡΠΈΠΌΠ°Π½ΠΎΠ³ΠΎ ΡΠΎΠ·ΡΠΈΠ½Ρ Π΄ΠΎ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΠΈ Π±Π»ΠΈΠ·ΡΠΊΠΎ 0"Π‘ ΡΡΠ²ΠΎΡΡΡΡΡΡΡ ΠΊΡΠΈΡΡΠ°Π»ΠΈ, ΡΠΊΡ Π²ΡΠ΄ΡΡΠ»ΡΡΡΠΎΠ²ΡΡΡΡ ΡΠ° ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ ΠΏΠ΅Π½ΡΠ°Π½ΠΎΠΌ.To a solution of 200 mg of 28,35-isopropylidenedioxy-4B-tert-butoxycarbonylamino-15-ethylaminocarbonylcyclopentane in 1.6 cm3 of anhydrous dichloromethane, add 275 ΞΌl of trifluoroacetic acid. The mixture is stirred overnight at a temperature of about -57C. The reaction mixture is poured into 4cm3 of 2.5N sodium hydroxide solution. The organic layer is concentrated under reduced pressure at a temperature below 25Β°C. In this way, 125 mg of the product is obtained, which is dissolved in 0.5 cm3 of tetrahydrofuran. To this solution, 7 mg of benzoic acid is added. As a result of cooling the obtained solution to a temperature of about 0Β°C, crystals are formed, which are filtered and washed with pentane.
Π’Π°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ ΠΎΡΡΠΈΠΌΡΡΡΡ 138ΠΌΠ³ 28,35-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4ΠΠ-Π°ΠΌΡΠ½ΠΎ-15- Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½Π±Π΅Π½Π·ΠΎΠ°ΡΡ.In this way, 138 mg of 28,35-isopropylidenedioxy-4ΠΠ-amino-15-ethylaminocarbonylcyclopentanebenzoate are obtained.
ΠΡΠΈΠΊΠ»Π°Π΄ 6Example 6
ΠΠΎ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½ΠΎΠ³ΠΎ Π΄ΠΎ 0"Π‘ ΡΠΎΠ·ΡΠΈΠ½Ρ 167ΠΌΠ³ 5Π,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ½Π΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-(ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»)-2- Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|)Π³Π΅ΠΏΡΠ°Π½-Π-ΠΎΠ½Ρ Π² ΡΡΠΌ3 Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½Ρ, Π΄ΠΎΠ΄Π°ΡΡΡ 9ΠΠΌΠΊΠ» ΡΡΠΈΡΡΠΎΡΠΎΡΡΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ. ΠΠ°ΡΡΡ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ ΠΏΡΠ΄Π²ΠΈΡΠΈΡΠΈΡΡ Π΄ΠΎ 23"Π‘ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 40 Ρ Π²ΠΈΠ»ΠΈΠ½, ΠΏΠΎΡΡΠΌ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΡΡΠΌΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 22 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΡΠΉ ΡΠ΅ΠΌΠ΅ΠΏΡΠ°ΡΡΡΡ. ΠΠ½ΠΎΠ²Ρ Π΄ΠΎΠ΄Π°ΡΡΡ 9Π0ΠΌΠΊΠ» ΡΡΠΈΡΡΠΎΡΠΎΡΡΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ, ΠΏΠΎΡΡΠΌ ΠΏΠ΅ΡΠ΅ΠΌΡΡΡΡΡΡ ΡΡΠΌΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 1 Π³ΠΎΠ΄ΠΈΠ½ΠΈ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 23Π‘. ΠΡΡΠ»Ρ Π²ΠΈΠΏΠ°ΡΡΠ²Π°Π½Π½Ρ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ ΠΎΡΡΠΈΠΌΡΡΡΡ 123ΠΌΠ³ 5Π,65- ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ½Π΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡΠ°Π½-Π-ΠΎΠ½Ρ. Π§ΠΈΡΡΠΎΡΡ ΠΏΡΠΎΠ΄ΡΠΊΡΡ Π²ΠΈΠ·Π½Π°ΡΠ°ΡΡΡ ΡΠ»ΡΡ ΠΎΠΌ Π²ΠΈΡΠΎΠΊΠΎΠ΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡ ΡΡΠ΄ΠΈΠ½Π½ΠΎΡ Ρ ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΡΡ Π²ΠΎΠ½Π° Π±ΠΈΠ·ΡΠΊΠ° Π΄ΠΎ 9295. Π‘ΡΡΡΠΊΡΡΡΡ ΠΏΡΠΎΠ΄ΡΠΊΡΡ ΠΏΡΠ΄ΡΠ²Π΅ΡΠ΄ΠΆΡΡΡΡ "Π-Π―ΠΠ - ΡΠΏΠ΅ΠΊΡΡΠΎΠΌ.To a solution of 167 mg of 5H,65-isopropylenedioxy-2-(tert-butoxycarbonyl)-2-azabicyclo(2.2.1|)heptan-3-one in 1 cm3 of dichloromethane, cooled to 0Β°C, add 9 ΞΌl of trifluoroacetic acid. Allow the temperature to rise to 23 C for 40 minutes, then the mixture is stirred for 22 hours at this temperature. Add 9O0ΞΌl of trifluoroacetic acid again, then stir the mixture for 1 hour at a temperature of 23C. After evaporation under reduced pressure, 123 mg of 5H,65-isopropylenedioxy-2-azabicyclo(2.2.1|heptan-3-one) are obtained. The purity of the product is determined by high-performance liquid chromatography, it is high up to 9295. The structure of the product is confirmed by the H-NMR spectrum.
Π ΠΎΠ·ΡΠΈΠ½ 10Π³ 58,65-ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ½Π΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-2-Π°Π·Π°Π±ΡΡΠΈΠΊΠ»ΠΎ(2.2.1|Π³Π΅ΠΏΡΠ°Π½-Π-ΠΎΠ½Ρ Π² 100ΡΠΌ3 Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ 7095-Π½ΠΎΠ³ΠΎ(Π·Π° ΠΌΠ°ΡΠΎΡ) ΡΠΎΠ·ΡΠΈΠ½Ρ ΡΡΠΈΠ΅ΡΠΈΠ»Π°ΠΌΡΠ½Ρ Π½Π°Π³ΡΡΠ²Π°ΡΡΡ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 20 Π³ΠΎΠ΄ΠΈΠ½ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 110"Π‘ ΠΏΡΠΈ ΡΠΈΡΠΊΡ, ΡΠΎ ΡΡΠ²ΠΎΡΡΡΡΡΡΡ ΠΏΡΠ΄ ΡΠ°Ρ ΡΡΠΎΠ³ΠΎ ΠΏΡΠΎΡΠ΅ΡΡ. ΠΡΡΠ»Ρ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ Π½Π°Π΄Π»ΠΈΡΠΎΠΊ ΡΡΠΈΠ΅ΡΠΈΠ»Π°ΠΌΡΠ½Ρ Π²ΠΈΠ΄Π°Π»ΡΡΡΡ ΠΏΡΠΈ Π·Π½ΠΈΠΆΠ΅Π½ΠΎΠΌΡ ΡΠΈΡΠΊΡ, ΠΏΠΎΡΡΠΌ Π·Π°Π»ΠΈΡΠΎΠΊ ΠΏΡΠΎΠΌΠΈΠ²Π°ΡΡΡ Π΄ΠΈΡ Π»ΠΎΡΠΌΠ΅ΡΠ°Π½ΠΎΠΌ Π· ΠΌΠ΅ΡΠΎΡ Π²ΠΈΠ΄Π°Π»Π΅Π½Π½Ρ Π²ΠΈΡ ΡΠ΄Π½ΠΎΡ ΡΠ΅ΡΠΎΠ²ΠΈΠ½ΠΈ, ΡΠΎ Π½Π΅ ΠΏΡΠΎΡΠ΅Π°Π³ΡΠ²Π°Π»Π°. ΠΠΎΠ΄Π½ΠΈΠΉ ΡΠ°Ρ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΡΡΡΡ ΡΠ° Π²ΠΈΡΡΡΡΡΡΡ. Π’Π°ΠΊΠΈΠΌ ΡΠΈΠ½ΠΎΠΌ ΠΎΡΡΠΈΠΌΡΡΡΡ 10,54Π³ 2ΠΠ8,35- ΡΠ·ΠΎΠΏΡΠΎΠΏΡΠ»ΡΠ΄Π΅Π½Π΄ΠΈΠΎΠΊΡΠΈ-4Π-Π°ΠΌΡΠ½ΠΎ-15-Π΅ΡΠΈΠ»Π°ΠΌΡΠ½ΠΎ-ΠΊΠ°ΡΠ±ΠΎΠ½ΡΠ»ΡΠΈΠΊΠ»ΠΎΠΏΠ΅Π½ΡΠ°Π½-Π±Π΅Π½Π·ΠΎΠ°ΡΡ.A solution of 10 g of 58,65-isopropylenedioxy-2-azabicyclo(2.2.1|heptan-Z-one in 100 cm3 of an aqueous 7095% (by mass) solution of triethylamine is heated for 20 hours at a temperature of 110"C under the pressure created during this process. After cooling, the excess triethylamine is removed under reduced pressure, then the residue is washed with dichloromethane to remove the unreacted starting material. The aqueous layer is concentrated and dried. Thus, 10.54 g of 2ΠΠ8,35-isopropylidenedioxy-4Π-amino-15-ethylamino is obtained -carbonylcyclopentane-benzoate.
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| FR9506353A FR2734822B1 (en) | 1995-05-30 | 1995-05-30 | NEW 2-AZABICYCLO (2.2.1) HEPTANE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION |
| PCT/FR1996/000793 WO1996038447A1 (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo[2.2.1]heptane derivatives, preparation and application thereof |
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