HRP960141A2 - Pyrrolidinyl hydroxamic acid compounds and their production process - Google Patents
Pyrrolidinyl hydroxamic acid compounds and their production process Download PDFInfo
- Publication number
- HRP960141A2 HRP960141A2 HRPCT/JP95/631A HRP960141A HRP960141A2 HR P960141 A2 HRP960141 A2 HR P960141A2 HR P960141 A HRP960141 A HR P960141A HR P960141 A2 HRP960141 A2 HR P960141A2
- Authority
- HR
- Croatia
- Prior art keywords
- hydroxy
- compound
- acetamide
- hydroxypyrrolidin
- formula
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 128
- -1 Pyrrolidinyl hydroxamic Chemical compound 0.000 title claims description 21
- 239000002253 acid Substances 0.000 title description 9
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims description 70
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 125000006239 protecting group Chemical group 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 239000000730 antalgic agent Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- 229940127240 opiate Drugs 0.000 claims description 6
- 208000004998 Abdominal Pain Diseases 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 5
- 230000001270 agonistic effect Effects 0.000 claims description 5
- 230000003444 anaesthetic effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000002934 diuretic Substances 0.000 claims description 5
- 230000001882 diuretic effect Effects 0.000 claims description 5
- 239000003193 general anesthetic agent Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 102000048260 kappa Opioid Receptors Human genes 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- 239000004090 neuroprotective agent Substances 0.000 claims description 5
- 108020001588 κ-opioid receptors Proteins 0.000 claims description 5
- HOGIAGOSNJXVGR-LJQANCHMSA-N 2-(3,4-dichlorophenyl)-n-hydroxy-n-[(1s)-1-phenyl-2-pyrrolidin-1-ylethyl]acetamide Chemical group C([C@@H](N(O)C(=O)CC=1C=C(Cl)C(Cl)=CC=1)C=1C=CC=CC=1)N1CCCC1 HOGIAGOSNJXVGR-LJQANCHMSA-N 0.000 claims description 4
- 230000000202 analgesic effect Effects 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 208000028774 intestinal disease Diseases 0.000 claims description 4
- GCJKQYAPGBMXGO-RBUKOAKNSA-N 2-(4-chlorophenyl)-n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=CC=C(Cl)C=C1 GCJKQYAPGBMXGO-RBUKOAKNSA-N 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 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 3
- LTWLIAPKBJYWFN-GOSISDBHSA-N n-hydroxy-n-[(1s)-1-phenyl-2-pyrrolidin-1-ylethyl]-2-(2,3,6-trichlorophenyl)acetamide Chemical compound C([C@@H](N(O)C(=O)CC=1C(=C(Cl)C=CC=1Cl)Cl)C=1C=CC=CC=1)N1CCCC1 LTWLIAPKBJYWFN-GOSISDBHSA-N 0.000 claims description 3
- ZJCHKZRCGMEKBN-JOCHJYFZSA-N n-hydroxy-n-[(1s)-1-phenyl-2-pyrrolidin-1-ylethyl]-2-(2,4,6-trimethylphenyl)acetamide Chemical compound CC1=CC(C)=CC(C)=C1CC(=O)N(O)[C@@H](C=1C=CC=CC=1)CN1CCCC1 ZJCHKZRCGMEKBN-JOCHJYFZSA-N 0.000 claims description 3
- QTEPVPGNPIHYTL-LJQANCHMSA-N n-hydroxy-n-[(1s)-1-phenyl-2-pyrrolidin-1-ylethyl]-2-[4-(trifluoromethyl)phenyl]acetamide Chemical compound C([C@@H](N(O)C(=O)CC=1C=CC(=CC=1)C(F)(F)F)C=1C=CC=CC=1)N1CCCC1 QTEPVPGNPIHYTL-LJQANCHMSA-N 0.000 claims description 3
- NJPBQRWPNXDMEA-KBXCAEBGSA-N n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-2-(2,3,6-trichlorophenyl)acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=C(Cl)C=CC(Cl)=C1Cl NJPBQRWPNXDMEA-KBXCAEBGSA-N 0.000 claims description 3
- JRAKCMZRAZMQCS-RBUKOAKNSA-N n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-2-[4-(trifluoromethyl)phenyl]acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=CC=C(C(F)(F)F)C=C1 JRAKCMZRAZMQCS-RBUKOAKNSA-N 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- YUZQPRVLDUFZKA-PKOBYXMFSA-N 2-(2,4-dichlorophenyl)-n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=CC=C(Cl)C=C1Cl YUZQPRVLDUFZKA-PKOBYXMFSA-N 0.000 claims description 2
- OZAKEAQVNFXLLC-HNAYVOBHSA-N 2-(2,6-dichlorophenyl)-n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=C(Cl)C=CC=C1Cl OZAKEAQVNFXLLC-HNAYVOBHSA-N 0.000 claims description 2
- LMPBXMBUTBQPJJ-QFBILLFUSA-N 2-(3,4-dichlorophenyl)-n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=CC=C(Cl)C(Cl)=C1 LMPBXMBUTBQPJJ-QFBILLFUSA-N 0.000 claims description 2
- JFOKVTUCFJZORN-RBUKOAKNSA-N 2-(4-bromophenyl)-n-hydroxy-n-[(1s)-2-[(3s)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]acetamide Chemical compound C1[C@@H](O)CCN1C[C@H](C=1C=CC=CC=1)N(O)C(=O)CC1=CC=C(Br)C=C1 JFOKVTUCFJZORN-RBUKOAKNSA-N 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 239000004305 biphenyl Chemical group 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims 1
- 229940031098 ethanolamine Drugs 0.000 claims 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 238000005160 1H NMR spectroscopy Methods 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 238000002360 preparation method Methods 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 238000004458 analytical method Methods 0.000 description 46
- 239000003921 oil Substances 0.000 description 42
- 235000019198 oils Nutrition 0.000 description 42
- 239000007787 solid Substances 0.000 description 41
- 150000003840 hydrochlorides Chemical class 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- JVWZVGMSJISZQR-PYNWJHIZSA-N (2r)-2-[(3s)-3-(oxan-2-yloxy)pyrrolidin-1-yl]-2-phenylethanol Chemical compound O([C@H]1CCN(C1)[C@@H](CO)C=1C=CC=CC=1)C1CCCCO1 JVWZVGMSJISZQR-PYNWJHIZSA-N 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000002632 kappa opiate receptor agonist Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- CNONYXFNOHXTLC-KBPBESRZSA-N (2r)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-2-phenylethanol Chemical compound C1[C@@H](OCOC)CCN1[C@@H](CO)C1=CC=CC=C1 CNONYXFNOHXTLC-KBPBESRZSA-N 0.000 description 10
- 239000000284 extract Substances 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000010561 standard procedure Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- ZOUPGSMSNQLUNW-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C(Cl)=C1 ZOUPGSMSNQLUNW-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- MWGPNRQVCPJJBW-LURJTMIESA-N (3s)-3-(methoxymethoxy)pyrrolidine Chemical compound COCO[C@H]1CCNC1 MWGPNRQVCPJJBW-LURJTMIESA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 229940035676 analgesics Drugs 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- JCZDMBKPCOKANB-VEDVMXKPSA-N (3r)-3-(oxan-2-yloxy)pyrrolidine Chemical compound C1NCC[C@H]1OC1OCCCC1 JCZDMBKPCOKANB-VEDVMXKPSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 102000003840 Opioid Receptors Human genes 0.000 description 3
- 108090000137 Opioid Receptors Proteins 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 3
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
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- CYRLHHDBZGNKEA-SNVBAGLBSA-N (1s)-1-[3-(methoxymethoxy)phenyl]ethane-1,2-diol Chemical compound COCOC1=CC=CC([C@H](O)CO)=C1 CYRLHHDBZGNKEA-SNVBAGLBSA-N 0.000 description 2
- UZCBDOLPPICICR-YNPPLXCJSA-N (1s)-2-[(3r)-3-(oxan-2-yloxy)pyrrolidin-1-yl]-1-phenylethanol Chemical compound O([C@@H]1CCN(C1)C[C@@H](O)C=1C=CC=CC=1)C1CCCCO1 UZCBDOLPPICICR-YNPPLXCJSA-N 0.000 description 2
- RCPWHIUMQKNAHD-LSDHHAIUSA-N (1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-(3-methylphenyl)ethanol Chemical compound C1[C@@H](OCOC)CCN1C[C@@H](O)C1=CC=CC(C)=C1 RCPWHIUMQKNAHD-LSDHHAIUSA-N 0.000 description 2
- CDLHNMKWIQZIOI-LSDHHAIUSA-N (1s)-2-[(3s)-3-(methoxymethoxy)pyrrolidin-1-yl]-1-(4-methylphenyl)ethanol Chemical compound C1[C@@H](OCOC)CCN1C[C@@H](O)C1=CC=C(C)C=C1 CDLHNMKWIQZIOI-LSDHHAIUSA-N 0.000 description 2
- IWWIUDASVBIUQU-PYNWJHIZSA-N (2r)-2-(4-fluorophenyl)-2-[(3s)-3-(oxan-2-yloxy)pyrrolidin-1-yl]ethanol Chemical compound O([C@H]1CCN(C1)[C@@H](CO)C=1C=CC(F)=CC=1)C1CCCCO1 IWWIUDASVBIUQU-PYNWJHIZSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Description
Područje izuma
Izum je iz područja farmaceutske kemije.
Stanje tehnike
Ovaj izum se odnosi na nove derivate hidroksamske kiseline i njihove farmaceutski prihvatljive soli, te na farmaceutske kompozite koji ih sadrže. Ovi spojevi i kompoziti su korisni kao analgetički, antiupalni, diuretički, anestetički ili neuro-protektivni agensi, ili kao agens za liječenje inzulta ili funkcionalnih crijevnih bolesti kao što je abdominalna bol, u liječenju sisavaca, poglavito ljudi.
Opijatski analgetici kao što je morfij su terapeutski korisni, ali je njihova uporaba strogo ograničena zbog njihovih nuspojava kao što je ovisnost. Prema tome, poželjni su analgetici koji su visoko učinkoviti i smanjene sklonosti stvaranja ovisnosti. Provedena su odgovarajuća istraživanja da se pronađu opijatni peptidi i opijatni receptori, te je otkriće podtipova opijatskih receptora kao što su μ, δ i κ u perifernim živcima različitih vrsta, uključujući ljude, utrlo put sintezi novih analgetika. Pošto se misli da opijatski analgetici kao što je morfij djeluju kao agonisti μ-receptora, proučeno je odvajanje djelovanja koje se zasniva na agonistima κ-receptora od djelovanja koje se zasniva na agonistima μ-receptora. Nedavno su u tom smislu prikazani radovi o κ-selektivnim agonistima, primjerice EMD-60400: A. Barber et al., Naunyn-Schmled. Arch. Pharmacol., 345 (Suppl.): Abst 456. Neki od njih su ispitani u kliničkim istraživanjima (Med. Res. Rev., 12, 525 (1992)).
Međutim čak i kada se koristi selektivni agonist κ-receptora, primjena visokih doza može izazvati nuspojave kao što je seciranje. Prema tome, poželjno je da se pronađu spojevi koji će pokazivati bolju agonističku aktivnost prema opijatskim κ-receptorima, posebice oni koji će biti slabog sedativnog djelovanja.
Opis tehničkog rješenja s primjerima izvođenja
Ovaj izum omogućava dobivanje spoja sljedeće formule:
[image]
i njegov1H soli, gdje
A je vodik, hidroksi ili OY, gdje Y je hidroksi zaštitna grupa;
Ar je fenil proizvoljno supstituiran s jednim ili više (poželjno do tri) supstituenta odabranih između halo, hidroksi, C1-C4 alkil, C1-C4 alkoksi, CF3, C1-C4 alkoksi- C1-C4 alkiloksi, te karboksi- C1-C4 alkiloksi;
X je fenil, naftil, bifenil, indanil, benzofuranil, benzotiofenil, 1-tetralon-6-il, C1-C4 alkilendioksi, piridil, furil i tienil, ove grupe mogu proizvoljno biti supstituirane sa do tri supstituenta odabran1H između halo, C1-C4 alkil, C1-C4 alkoksi, hidroksi, NO2, CF3 i SO2CH3; i
R je vodik, C1-C4 alkil ili hidroksi zaštitna grupa.
Derivati hidroksamske kiseline ovoga izuma formule (I), gdje A je vodik ili hidroksi i R je vodik ili C1-C4alkil, pokazuju značajnu agonističku aktivnost prema opijatnim κ-receptorima. Ovi κ agonisti su dakle osobito korisni kao analgetički agensi u sisavaca, posebice ljudi. Oni su također korisni kao antiupalni, diuretički, anestetički ili neuropretektivni agensi, ili kao agens za liječenje inzulta ili funkcionalnih crijevnih bolesti kao što je abdominalna bol, za liječenje sisavaca, poglavito ljudi.
Ovim izumom dobivaju se farmaceutski kompoziti koji su korisni kao analgetički, diuretički, anestetički ili neuroprotektivni agensi ili kao agens za liječenje inzulta ili funkcionalnih crijevnih bolesti kao što je abdominalna bol, za liječenje sisavaca, poglavito ljudi, što uključuje terapeutski djelotvornu količinu hidroksamičke kiseline formule (I), gdje je A vodik ili hidroksi i R je vodik ili C1-C4 alkil, ili njegova farmaceutski prihvatljiva sol zajedno s prihvatljivim nosačem.
Spojevi formule (I), gdje jedan ili oba OY ili OR predstavljaju zaštitnu hidrok-silnu grupu, korisni su kao kemijski intermedijati prema κagonistu formule (I).
Tipične hidroksi zaštitne grupe su benzil, trifenilmetil, tetrahidroksipiranil, metoksi-metil i R1R2R3Si, gdje svaki R1, R2 i R3 su C1-C6 alkil ili fenil.
Poželjna grupa κ agonističkih spojeva ovoga izuma sastoji se od spojeva formule (I), gdje je A vodik ili hidroksi, Ar je fenil, X je fenil supstituiran sa do tri supstituenta odabranih između kloro, metil ili CF3, poželjnije 3,4-diklorofenil, dok je R vodik. Poželjna konfiguracija ugljikova atoma na koji je spojena grupa Ar je (S).
Poželjni pojedinačni spojevi ovoga izuma su:
2-(3,4-diklorofenil)-N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil)acetamid;
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(2,3,6-triklorofenil)acetamid;
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(4-trifluorometilfenil)acetamid;
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(2,4,6-trimetilfenil)acetamid;
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(4-bromofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(4-trifluorometilfenil)acetamid;
2-(4-klorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-1-(S)-feniletil]acetamid;
2-(2,3-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil)acetamid;
2-(2,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(2,5-diklorofenil)-N-hidroksi-N-(2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(2,6-Diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]-2-(2,3,6-triklorofenil)acetamid;
2-(3,4-diklorofenil)-N-[2-(3-(S)-hidroksipirolidinl-il)-1-(S)-feniletil)acetamid; i
2-(3,4-dimetilfenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil)acetamid.
Ovim izumom se nadalje dobiva spoj formule:
[image]
i njegove soli, gdje
A je vodik, hidroksi ili OY, gdje Y je hidroksi zaštitna grupa;
Ar je fenil proizvoljno supstituiran s jednim ili više supstituenata odabranih između halo, hidroksi, C1-C4 alkil, C1-C4 alkoksi, CF3, C1-C4 alkoksi- C1-C4 alkiloksi, i karboksi- C1-C4 alkiloksi;
R je vodik, C1-C4 alkil ili hidroksi zaštitna grupa.
Ovis pojevi formule (II) mogu se koristiti kao intermedijati u priređivanju spojeva formule (I).
Ovim se izumom, nadalje, definiraju postupci za proizvodnju hidroksamsk1H spojeva formule (I) i njihovih intermedijatnih spojeva formule (II).
Opis tehničkog rješenja s primjerima izvođenja
κagonisti formule (I) ovoga izuma mogu se prirediti većim brojem metoda. Primjerice, mogu se jednostavno dobiti sukladno postupku koji je prikazan shemom (I).
[image]
κ agonistički spojevi formule (I), gdje A je vodik ili hidroksi i R je vodik, mogu se prirediti reakcijom spoja formule (VI) s karboksilnom kiselinom formule XCH2COOH, nakon čega slijedi uklanjanje zaštitne grupe P i zaštitine grupe u A1, ako je potrebno. To je uobičajena reakcija aciliranja, koja se može provesti standardnim metodama, koje su dobro poznate stručnjacima u ovome području.
Međutim, pogodan način aciliranja spoja formule (VI) s kiselinom formule XCH2COOH obuhvaća vezanje dva spoja u prisutnosti karbodiimidnog spoja. Osobito pogodan karbodiimidni spoj je 1-etil-3-(3-dimetilaminopropil)karbodiimid hidro-klorid, koji se ponekad označava kao u vodi topljivi karbodiimid, ili WSC. Ova reakcija se provodi dovođenjem u dodir ekvivalentnih količina kiseline i amida s malim suviškom karbodiimida u pogodnom otapalu pri temperaturi u području od -30 do 100°C, obično od 0 do 30°C. Pogodna otapala su neaktivni aromatski ugljikovodici, eteri, halogenirani ugljikovodici, osobito diklorometan. Reakcijsko vrijeme je od oko 30 minuta do 24 sata, obično 30 minuta do 3 sata na sobnoj temperaturi. Produkt se može odvojiti i pročistiti standardnim tehnikama.
Zaštitna grupa P i zaštitna grupa u A1 uklanjaju se odgovarajućom metodom za određenu odabranu zaštitnu grupu. Tipična zaštitna grupa je benzil. Ona se može ukloniti katalitičkim hidrogeniranjem. Odgovarajući katalizatori za hidrogeniranje su Pd/C, Pearlmanov katalizator, crni Pd ili Pd/BaSO4, odobito 10% Pd/C.
Druge pogodne zaštitine grupe za P i A1 su tetrahidropiranil grupa (THP). Ona se može ukloniti kiselo-kataliziranom hidrolizom. Odgovarajući kiseli katalizatori su organske kiseline, anorganske kiseline ili Lewisove kiseline kao AcOH, p-TsOH, HCl, ME2AlCl itd., osobito HCl.
κ agonistički spojevi formule (I), gdje je R C1-C4 alkilna grupa, mogu se prirediti alkiliranjem odgovarajućih spojeva formule (I), gdje je R hidroksi. Ovo se alkiliranje kože provesti standardnim metodama. Osobito pogodna metoda uključuje bazo-katalizirano alkiliranje pomoću alkil-halida u prisutnosti faznog prijenosnog katalizatora kao što je tetra-n-butilamonij hidrogen sulfat. Intermedijatni hidroksilamin formule (VI) može se prirediti iz alkohola (V), tretiranjem sa metansulfonil kloridom u prisutnosti baze kao što je trietilamin, na što slijedi dodatak zaštićenog hidroksilamina (NH2OP).
Alkohol (V) dobiva se iz odgovarajućeg etanoaminskog spoja (III) i odgovarajućeg etanskog spoja formule (IV).
Spojevi formule (III) i (IV) su ili poznati spojevi, koji se mogu dobiti poznatim metodama, ili su analozi poznatih spojeva, koji se mogu prirediti metodama analognim poznatim metodama.
Intermedijatni spojevi formule (II) gdje je Ar supstituirani fenil mogu se prirediti sukladno postupcima u sljedećoj shemi 2.
[image]
U gornjoj shemi 2, spoj (VII) može reagirati sa supstituiranim stiren-oksidom (VIII) da nastane smjesa spojeva (IX) i (X). Ova se reakcija može provesti u prisutnosti ili odsutnosti reakcijski inertnog otapala (npr. metanol (MeOH), etanol (EtOH), izopropilni alkohol, tetrahidrofuran (THF), dioksan, dimetilformamid (DMF), dimetilsulfoksid (DMSO), metilen klorid (CH2Cl2) voda, benzen, toluen, n-heksan, cikloheksan) na temperaturi od -78°C do temperature refluksa otapala, poželjno od 0°C do 25°C tijekom od 5 minuta do 48 sati, poželjno od 0,5 do 12 sati. Spoj (II’) može se prirediti iz smjese spoja (IX) i spoja (X) u istim uvjetima kao što je već opisano uz shemu 1.
Sukladno gornjim postupcima, R, S konfiguracija spojeva (IX) i (X) može se selektivno odrediti. Nadalje, u gornjim postupcima, 1-supstituiranifenil-1,2-etandiol 2-tozilat može se koristiti umjesto supstituirani-stiren oksida (VIII).
Spojevi formule - (I) ovoga izuma su bazični, pa prema tome oni stvaraju kisele adicijske soli. Sve takve soli su obuhvaćene dosegom ovoga izuma. Međutim, potrebno je koristiti kiselu adicijsku sol koja je farmaceutski prihvatljiva za primjenu sisavcima.
Kisele adicijske soli mogu se pripraviti standardnim metodama, npr. sjedinjavanjem kiselih i bazičnih spojeva u ehvivalentnim odnosima u vidi ili organskom otapalu kao što je etanol ili metanol, ili njihova smjesa. Soli se mogu izolirati isparavanjem otapala. Tipične soli koje se mogu dobiti su hidroklorid, nitrat, sulfat, bisulfat, fosfat, acetat, laktat, citrat, tartarat, sukcinat, maleat, fumarat, glukonat, saharat, benzoat, metansulfonat, p-toluensulfonat, oksalat i pamoat (1,1'-metilen-bis-(2-hidroksi-3-naftoat)) soli.
Spojevi formule (I) ovoga izuma, gdje je R vodik, su kisele i sve one stvaraju bazične soli. Sve talve soli su unutar dosega ovoga izuma. Potrebno je, međutim, koristiti bazičnu sol koja je farmaceutski prihvatljiva za primjenu sisavcima. Ove soli mogu se pripraviti standardnim metodama, npr. sjedinjavanjem kiselih i bazičnih spojeva u ekvivalentnim odnosima u vodi ili organskom otapalu kao što je metanol ili etanol, ili njihova smjesa. Soli se mogu izolirati isparavanjem otapala. Tipične bazične soli koje mogu nastati su soli natrija, kalija, kalcija i magnezija, te također amonijeve soli i amini, kao što su etilamin, dietilamin, trietilamin, cikloheksilamin, piperidin i morfolin.
Ovim su izumom također obuhvaćeni biološki prekursori (poznati pod imenom pro-lijekovi) κagonističkih spojeva formule (I). Bioprekursor kapa agonista formule (I) je njegov kemijski derivat koji se lako konvertira natrag u matični spoj formule (I) u biološkim sustavima. Osobito, bioprekursor κ agonista formule (I) se konvertira natrag u matični spoj formule (I) nakon što je bioprekursor primijenjen i adsorbiran u tijelu sisavca, npr. čovjeka. Na primjer, moguće je načiniti bioprekursor κ agonista ovoga izuma formule (I) u kojem su jedan ili oba A ili OR hidroksi grupe tako da se načini ester hidroksi grupe. Kada je samo jedan od A ili OR hidroksi grupa, mogući su samo mono-esteri. Kada su oba A i OR hidroksi, mogu se načiniti mono- i di-esteri (koji mogu biti isti ili različiti). Tipični esteri su jednostavni alkanoatni esteri, kao što su acetat, propionat, butirat itd. Nadalje, kada je A ili OR hidroksi grupa, bioprekursori se mogu prirediti konverzijom hidroksi grupe u aciloksimetilni derivat (npr. pivaloksimetil derivat) reakcijom s aciloksimetilni halidom (npr. pivaloksimetil klorid).
Spojevi κ agonista ovoga izuma formule (I) pokazuju značajnu agonističku aktivnost prema opijatskim κ-receptorima pa su korisni kao analgetski, antiupalni, diu-retički, anestetički ili neuroprotektivni agensi, ili agensi za liječenje inzulta ili funkcionalnih trbušnih bolesti kao što je abdominalna bol, u liječenju sisavaca, posebice ljudi.
Aktivnost κ-agonističkih spojeva formule (I) ovoga izuma se pokazuje kao vezana aktivnost opijatnih receptora. Takva aktivnost može se odrediti u homogenatima mozga guinea svinja, kao što je opisao Regina A. et al. u J. Receptor Res. 12: 171-180, 1992. Ukratko, homogenati tkiva su inkubirani na 25°C tijekom 30 minuta u prisutnosti obilježenog liganda i test spojeva, μ-mjesta su obilježena za 1nM (3H)-[D-Ala2, MePhe4, Gly-o15] enkefalin (DAMGO), 8-mjesta sa InM (3H)-[D-Pen2,5)enkephalin] (DPDPE) i κ-mjesta sa 0,5 nM (3H)-CI-977. Nespecifično vezanje je mjereno pomoću 1mM CI-911 (κ), 1 mM (DAMGO) (μ), ImM (DPDPE) (5). Podaci su prikazani u obliku IC50 vrijednosti koje su dobivene programom za nelinearnu regresiju korištenjem jednadžbe Chenga i Prusoffa. Neki spojevi priređeni u primjerima dali su niske IC50 vrijednosti u području od 0,01 do 100nM.
Aktivnost κ-agonističkih spojeva može se također pokazati formalinskim testom kojega su opisali Wheeler-Aceto H. et al. u Psychopharmacology 104: 35-44, 1991. U ovom testu, muški SD štakori (80-100 g) su injicirani s.d. sa testiranim spojem koji je otopljen u 0,1% metil celulozi u fiziološkoj otopini ili slijepom probom. Nakon 30 minuta, 50 ml 2% formalina je injicirano u stražnju šapu. Broj udara injicirane šape za opservacijsko vrijeme mjeren je 15-30 min. nakon injekcije formalina i izražen kao % inhibicije u odnosu na grupu sa slijepom probom.
Aktivnost κ-agonista može se također pokazati Rotarod testom kojega su opisali Hayes A.G. et al. u Br. J. Pharmacol. 79: 731-736, 1983. U ovom testu grupa od 6-10 muških SD štakora (100-120 g) odabrana je sposobnošću da balansira na rotirajućem štapu (promjer 9 cm, brzina okretanja 5 okretaja u minuti). Odabranim štakorima injiciran je s.c. sa testiranim spojem otopljenim u 0,1% metil celulozi u fizološkoj otopini. Životinje su testirane ponovo nakon 30 minuta od primjene: štakor koji je pao sa štapa više od dva puta u 150 sekundi uzeto je da ima motoričko oštećenje te je zabilježen rezultat (tj. vrijeme provedeno na štapu). Vrijednost ED50, koja je definirana kao doza lijeka koja prepolavlja postignuto vrijeme, određena je u kontrolnoj grupi.
κ-agonistički spojevi formule (I) ovoga izuma mogu se sisavcima aplicirati bilo oralno, parenteralno ili lokalno. Općenito, ovi spojevi se najpoželjnije primjenjuju ljudima u dozama koje se kreću od 0,01 mg do 50 mg na dan, premda su varijacije neophodne što zavisi o težini i stanju osobe koja se liječi, stanju bolesti koja se liječi i odabranom načinu aplikacije. Razina doze koja je u području od 0,01 mg do l mg po kilogramu tjelesne težine po danu, jednokratno ili razdijeljeno, najčešće se koristi u ljudi za tretman boli nakon operacije.
Spojevi ovoga izuma mogu se aplicirati sami ili u kombinaciji sa farmaceutski prihvatljivim nosačima ili diluensima bilo kojim od navedenih načina primjene, te se takva doza može dati jednokratno ili višekratno. Novi terapeutski agensi ovog izuma mogu se aplicirati u velikom broju dozirajućih oblika, tj. mogu se kombinirati s različitim farmaceutski prihvatljivim nosačima u obliku tableta, kapsula, lozenga, pastila, bombona, prašaka, sprejeva, krema, salveta, supozitorija, želea, pasta, losiona, pomasti, vodenih suspenzija, otopina za injiciranje, eliksira, sirupa i slično. Takvi nosači uključuju krute diluense ili punila, sterilni vodeni medij i različita netoksična organska otapala i dr. Oralni farmaceutski kompoziti mogu biti zaslađeni i/ili poboljšanog okusa. Općenito, terapeutski djelotvorni spojevi ovoga izuma su u dozirajućim blicima prisutni u koncentracijama koje se kreću od 5% do 70% (tež.), poželjno od 10% do 50% (tež.).
Za oralnu primjenu, tablete koje sadrže različite ekcipijente kao što su mikro-kristalinična celuloza, natrij citrat, kalcij karbonat, dinatrij fosfat i glicin mogu se koristiti zajedno s različitim disintegrantima kao što su škrob i poželjno kukuruzni, krumpirov ili tapioka škrob, alginska kiselina i određeni složeni silikati, zajedno s granulacijskim vezivima kao što je pilivnilpirolidon, saharoza, želatina i akacija. Dodatno, za potrebe tabletiranja mogu s erabiti lubrikanti kao što su magnezij stearat, natrij lauril sulfat i talk. Krute komponente sličnog tipa mogu se koristiti kao punila u želatinskim kapsulama; poželjne tvari s svezi s ovim također su lak-toza ili mliječni šećer kao i visokomolekularni polietilen glikoli. Kada su za oralnu primjenu poželjne vodene suspenzije i/ili eliksiri, aktivna tvar može se kombinirati s različitim sladilima ili tvarima za poboljšanje okusa, obojenim tvarima ili bojama, te, ako je potrebno, agensima za emulgiranje i/ili suspendiranje, zajedno s takvim diluentima kao što je voda, etanol, propilen glikol, glicerin i različite nj1Hove kombinacije.
Za parenteralnu primjenu, mogu se koristiti otopine spoja ovoga izuma u sezamo-vom ili lješnikovom ulju ili u vodenoj otopini propilen glikola. Vodene otopine valja ako je potrebno odgovarajuće puferirati (poželjno pH>8) i tekući diluens zadržati izotoničnim. Za intravenske injekcije pogodne su vodene otopine. Priparavk svih ovih otopina vrši se u aseptičkim uvjetima standardnim farmaceutskim tehnikama koje su poznate znalcima u ovom području. Spojeve ovoga izuma također je moguće primijeniti lokalno kada se vrši liječenje upalnih stanja kože i to se može poželjno provesti pomoću krema, želea, gelova, pasta, pomada i slično, sukladno standardnim farmaceutskim postupcima.
Primjeri i pripravci
Ovaj izum je ilustriran sljedećim primjerima i pripravcima. Međutim, valja imati na umu da izum nije ograničen specifičnim pojedinostima ovih primjera i pripravaka. Tališta su određena Buchi-evim aparatom za mikro-određivanje tališta i nisu korigirana. Infracrveni apsorpcijski spektri (IR) su izmjereni Shimazu infracrvenim spektrometrom (IR-470). 1H i 13C spektri nuklearne magnetske rezonance (NMR) su mjereni u CDCl3 sa JEOL NMR spektrometrom (JNM-GX270, 270MHz) ako nije drugačije navedeno i položaji peakova su izraženi u dijelovima na milijun (ppm) prema tetrametilsilanu. Oblici peakova su označeni na sljedeći način: s, singlet; d, dublet; t, triplet; m, multiplet; br, široki.
Pripravak 1
S-N-benziloksi-1-fenil-2-pirolidinoetilamin
Uz miješanje otopini (R)-2-fenil-2-pirolidinoetanola (E. Brown et al, Tetrahedron: Asymmetry, 1991, 2, 339; 4,78g, 25mmol) i trietilamina (3,95ml, 28mmol) u CH2Cl2 (50ml) dodan je kap po kap metansulfonil klorid (2ml, 26mmol) na 0°C (ledena kupelj). Nakon 3h miješanja na 0°C do sobne temperature (rt), reakcijska smjesa je isprana zasićenom NaHCO3 vodenom otopinom, osušena (Na2SO4) i koncentrirana da se dobije 5,88g smjese žute krutine i smeđeg viskoznog ulja. Ovoj smjesi je dodan O-benzilhidroksilamin (ovaj spoj je priređen iz O-benzil-hidroksilamin hidroklorida 5,99g (37,5mmol) zaluženjem) i etanol (6ml) i ova je smjesa miješana na 80°C tijekom 1h. Otapalo je ispareno da se dobije 9,47g bijele krutine koja je sakupljena filtriranjem i isprana etanol/eterom da se dobije 6,96g (83,7%) hidrokloridne soli željenog produkta kao bijele kristalinične krutine, tt 161-162°C.
1H NMR (270MHz, CDCl3) δ 7,44-7,25 (10H, m), 6,40 (1H, br, s), 4,68 (1H, d, J=11,7Hz), 4,68-4,62 (1H, m), 4,63 (1H, d, J=11,7Hz), 3,90-3,70 (1H, m), 3,60 (1H, dd, J=7,7, 13,2Hz), 3,55-3,40 (1H, m), 3,05 (1H, dd, J=5,5, 13,2Hz), 2,80-2,65 (1H, m), 2,65-2,45 (1H, m), 2,25-2,05 (2H, m), 2,05-1,80 (3H, m).
Analiza izračunata za C19H24N2O-HCl: C, 68,56; H, 7,57; N, 8,42; Cl, 10,65.
Nađeno: C, 68,36; H, 7,70; N, 8,39; Cl, 11,13.
Ova hidrokloridna sol je zalužena (80mg) otopinom amonij-hidroksida, ekstrahirana sa CH2Cl2, osušena (Na2SO4) i koncentrirana da se dobije 67mg slobodnog amin-skog derivata kao bezbojnog ulja.
1H NMR (270MHz, CDCl3) § 7,46-7,12 (10H, m), 6,53 (1H, br, s), 4,53 (1H, d, J=11,OHz), 4,45 (1H, d, J=11,4Hz), 4,20 (1H, dd, J=3,7, 11,4Hz), 2,90 (1H, dd, J=11,4, 12,5Hz), 2,70-2,60 (2H, m), 2,50-2,35 (2H, m), 2,28 (1H, dd, J=4,0, 12,5Hz), 1,80-1,70 (4H, m).
IR(čisti): 3250 cm1.
[a]n= +44.6(c=0,67, MeOH).
Primjer 1
N-benziloksi-2-(3,4-diklorofenil)-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamid
Uz miješanje otopini (S)-1-(2-O-benzilhidroksilamino-2-fenil-etil)pirolidin hidroklorida (2,88g, 8,65mmol) i 3,4-diklorofeniloctene kiseline (2.05g, 10 mmol) u CH2Cl2 (30ml) dodan je 1-etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida (2,30g, 12mmol) na sobnoj temperaturi. Nakon miješanja 1H, reakcijska smjesa je isprana vodom i zasićenom NaHCO3 aqueous solution, osušena (Na2SO4) koncentrirana da se dobije 4,44g svijetlo smeđeg viskoznog ulja. Ovom ulju je dodan metanol (2ml) i ostavljeno je 1H. Bijela kristalinična krutina je sakupljena filtriranjem da se dobije l,60g bijelog praška. Filtrat je koncentriran da se dobije 2,84g smjese ulja i krutine, koja je pročišćena krornatografijom na koloni (silika-gel; 100 g, CH2Cl2/MeOH: 40/1) da se dobije 0,82g čistog žutog viskoznog ulja, koje je kristaliziralo dodatkom metanola (0,2ml).
Ukupni prinos je 2,42g (57,9%). tt 88,5-90°C.
1H NMR (270MHz, CDCl3) δ 7,46-7,21 (12H, m), 6,98 (1H, dd, J=2,2, 8,4Hz), 5,80-5,65 (1H, m), 4,73 (1H, d, J=10,3Hz), 4,43 (1H, d, J=10,6Hz), 3,77 (1H, d, J=15,8Hz), 3,61-3,51 (2H, m, uklj. 1H, d, J=15,4Hz na 3,54ppm), 2,75-2,60 (3H, m), 2,55-2,40 (2H, m), 1,80-1,50 (4H,m).
IR(Nujol): 1670cm-1.
Primjer 2
2-(3,4-diklofenil)-N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamid
(1-pirolidinil)etil)acetamid (1,60g, 3,3mmol), 10% paladij na ugljenu (0,16g) i meta-nol zasićen plinovitim HCl (20ml) miješani su u metanolu (20ml) u atmosferi vodika na sobnoj temperaturi tijekom 13 h. Nakon uklanjanja katalizatora filtriranjem kroz Celite, filtrat je koncentriran da se dobije 1,63g ljubičasto obojenog viskoznog ulja koje je zaluženo sa NH4OH i ekstrahirano sa CH2Cl2 (20mlx3). Sjedinjeni ekstrakti su osušeni (Na2SO4) i koncentrirani da se dobije smeđe obojena krista-linična krutina koja je sakupljena filtriranjem i isprana etanol/heksanom da se dobije 1,04g (80%) blijedožute krutine. tt 118-120°C.
1H NMR (270MHz, CDC13) δ 7,44 (1H, d, J=l,8Hz), 7,37-7,24 (6H, m, uklj. 1H, d, J=8,4Hz na 7,36ppm), 7,17 (1H, dd, J=1,8, 8,4Hz), 5,56 (1H, dd, J=5,9, 10,3Hz), 3,90 (1H, d, J=14,3Hz), 3,70 (1H, d, J=13,9Hz), 3,31 (1H, dd, J=10,6, 12,5Hz), 2,73 (1H, dd, J=5,9, 12,5Hz), 2,60-2,45 (4H, m), 1,80-1,55 (4H, m).
IR(CH2Cl2): 3450, 1650cm-1.
MS m/z: 394 (M++2, 0,48), 392(M+,1,1), 211(4,8), 173(3,1), 149(12,9), 132(12,8), 99(28,8), 84(100).
925mg ove krutine je otopljeno u CH2Cl2 (10 ml). Ovoj otopini je dodan eter zasićen plinovitim HCl (10 ml) na sobnoj temperaturi. Smjesa je koncentrirana da se dobije bijela krutina koja je sakupljena filtriranjem i isprana eterom da se dobije 971mg HCl soli kao bijelog praška.
tt 161-162°C.
[a]o= + 119.8(c=0,884, MeOH).
Analiza izračunata za C20H22Cl2N2O2-HCl-0,5H2O: C, 54,75; 5,51; N, 6,38.
Nađeno: C, 54,96; H, 5,49; N, 6,44.
Primjer 3
2-(3,4-diklofenil)-N-metoksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamid
Smjesa 2-(3,4-diklorofenil)-N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamida (598mg, 1,5 mmol), tetrabutilamonij hidrogen sulfata (10 mg), 50% vodene otopine NaOH (Iml) i jodometana (0,12ml, 2mmol) u toluenu (4ml) miješana je na sobnoj temperaturi tijekom 3h. Smjesa je ekstrahirana etil acetatom (20mlx2). Sjedinjeni ekstrakti su isprani slanom otopinom, osušeni (Na2SO4) i koncentrirani da se dobije 1,06g smeđeg viskoznog ulja koje je pročišćeno kromatografijom na koloni (silika-gel 60g, CH2Cl2/MeOH: 20/1) da se dobije 304mg (49,8%) žutog viskoznog ulja.
1H NMR (270MHz, CDCl3) δ 7,41-7,26 (7H, m), 7,09 (1H, dd, J=l,8, 8,1 Hz), 5,70-5,60 (1H, m), 3,83 (1H, d, J=15,4Hz), 3,65 (1H, d, J=15,4Hz), 3,50 (3H, s), 3,50 (1H, dd, J=9,9, 12,5Hz), 2,75-2,57 (3H, m, uklj. 1H, dd, J=4,8, 12,5Hz na 2,60ppm), 2,55-2,40 (2H, m), 1,70 (4H, m).
IR(čisti): 1670cm-1.
304mg ove kristalinične krutine je otopljeno u MeOH (5ml). Ovoj otopini je dodan eter zasićen plinovitim HCl (5ml) na sobnoj temperaturi. Smjesa je koncentrirana da se dobije bijela krutina koja je sakupljena filtriranjem i isprana eterom da se dobije 277mg HC1 soli kao bijelog praška.
tt 165-166°C
Analiza izračunata za C21H24Cl2N2O2-HCl-0,5H2O: C, 55,70; 5,79; N, 6,19.
Nađeno: C, 55,53; H, 5,80; N, 6,19.
Primjer 4
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(2,3,6-triklorfenil)acetamid
Ovaj spoj je priređen iz (S)-l-(2-O-benzilhidroksilamino-2-feniletil)pirolidina s prinosom 68% sukladno postupku sličnom onom koji je opisan u primjerima 2 i 3.
tt 217-218,5°C (HC1 sol)
1H NMR (270MHz, slobodni amin, CDCl3) δ 7,44-7,20 (8H, m), 5,61 (1H, dd, 3=5,9, 10,6Hz), 4,36 (1H, d, J=16,9Hz), 4,26 (1H, d, J=17,2Hz), 3,40 (1H, dd, J=10,6, 12,5Hz), 2,80 (1H, dd, J=5,9, 12,5Hz), 2,76-2,55 (4H, m), 1,90-1,70 (4H, m).
IR(čisti, slobodni amin): 1650cm-1.
Analiza izračunata za C20H21Cl3N2O2-HCl-0,5H2O: C, 50,76; 4,90; N, 5,92.
Nađeno: C, 50,58; H, 4,65; N, 5,83.
Primjer 5
N-hidroksi-N-[1-(S)fenil-2-(1-pirolidinil)etil]-2-(4-trifluorometilfenil)acetamid
Ovaj spoj je priređen iz (S)-1-(2-O-benzilhidroksilamino-2-feniletil)pirolidina s prinosom 66,6% sukladno postupku sličnom onom koji je opisan u primjerima 2 i 3.
tt 172,8-177°C (HCl sol)
1H NMR (270MHz, slobodni amin, CDCl3) δ 7,55 (2H, d, J=8,4Hz), 7,45 (2H, d, J=8,lHz), 7,40-7,20 (6H, m), 5,57 (1H, dd, J=5,9, 10,3Hz), 4,00 (1H, d, J=13,9Hz), 3,81 (1H, d, J=13,9Hz), 3,30 (1H, dd, J =10,6, 12,5Hz), 2,71 (1H, dd, J=5,9, 12,5Hz), 2,60-2,40 (4H, m), 1,80-1,50 (4H, m).
IR(čisti, slobodni amin): 3150, 1650 cm-1.
Analiza izračunata za C21H23F3N2O2-HCl-H2O: C, 56,44; 5,86; N, 6,27.
Nađeno: C, 56,16; H, 5,77; N, 6,76.
Primjer 6
N-hidroksi-2-(1-naftil)-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamid
Ovaj spoj je priređen iz (S)-1-(2-O-benzilhidroksilamino-2-feniletil)pirolidina s prinosom 65,1% sukladno postupku sličnom onom koji je opisan u primjerima 2 i 3.
tt 81,0-83,5°C (HCl sol)
1H NMR (270MHz, slobodni amin, CDCl3) δ 7,55-7,20 (13H, m), 5,59 (1H, dd, J=5,9, 10,3Hz), 4,43 (1H, d, J=14,7Hz), 4,10 (1H, d, J=15,OHz), 3,31 (1H, dd, J=11,0, 12,lHz), 2,65 (1H, dd, J=5,9, 12,5Hz), 2,55-2,35 (4H, m), 1,60-1,35 (4H, m).
IR(čisti, slobodni amin) : 3150, 1650 cm-1.
Analiza izračunata za C24H26N2O2-HCl-1,2H2O: C, 66,64; 6,85; N, 6,48.
Nađeno: C, 66,93; H, 6,50; N,6,02.
Primjer 7
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(2,4,6-trimetilfenil)acetamid
Ovaj spoj je priređen iz (S)-1-(2-O-benzilhidroksilamino-2-feniletil)pirolidina s prinosom 58,9% sukladno postupku sličnom onom koji je opisan u primjerima 2 i 3.
tt 186-187,2°C (HC1 sol).
1H NMR (270MHz, slobodni amin, CDCl3) δ 7,42-7,24 (6H, m), 6,82 (2H, s), 5,70-5,55 (1H, m), 3,86 (2H, br, s), 3,38 (1H, dd, J=10,6, 12,1Hz), 2,74 (1H, dd, J=5,9, 12,5Hz), 2,70-2,55 (4H, m), 2,22 (9H, s), 1,85-1,75 (4H, m).
IR(čisti, slobodni amin): 3220, 1640 cm-1.
Analiza izračunata za C23H30N2O2-HCM,3H2O: C, 64,79; 7,94; N, 6,57.
Nađeno: C, 64,51; H, 7,48; N, 6,31.
Primjer 8
N-hidroksi-2-(4-piridil)-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamid
Ovaj spoj je priređen iz (S)-1-(2-O-benzilhidroksilamino-2-feniletil)pirolidina s prinosom 67,9% sukladno postupku sličnom onom koji je opisan u primjerima 2 i 3.
1H NMR (270MHz, slobodni amin, CDCl3) δ 8,46 (2H, d, J=5,9Hz), 7,40-7,18 (8H, m), 5,61 (1H, dd, J=5,5, 10,6Hz), 3,91 (1H, d, J=14,3Hz), 3,77 (1H, d, J=13,9Hz), 3,33 (1H, dd, J=11,0, 12,1Hz), 2,68 (1H, dd, J=5,5, 12,5Hz), 2,57-2,40 (4H, m), 1,80-1,55 (4H, m).
IR(čisti, slobodni amin): 1640cm-1.
Primjer 9
2-(benzo[b]furan-4-il)-N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]acetamid
Ovaj spoj je priređen iz (S)-1-(2-O-benzilhidroksilamino-2-feniletil)pirolidina s prinosom 73,5% sukladno postupku sličnom onom koji je opisan u primjerima 2 i 3.
1H NMR (270MHz, CDCl3) δ 7,59 (1H, d, J=1,8Hz), 7,45-7,20 (9H, m), 6,98 (1H, br, s), 5,58 (1H, dd, J=5,9, 10,6Hz), 4,24 (1H, d, J=13,6Hz), 3,91 (1H, d, J=13,6Hz), 3,28 (1H, dd, J =11,3, 11,7Hz), 2,60 (1H, dd, J=5,9, 12,5Hz), 2,45-2,30 (4H, m), 1,60-1,30 (4H, m).
IR(čisti, slobodni amin): 1650cm-1.
Pripravak 2
1.4-dijodo-2-(S)-(tetrahidropiraniloksi)butan
Uz miješanje otopini (S)-(-)-1,2,4-butantriola (10,61g, 0,1 mol) u piridinu (100 ml) dodan je p-toluensulfonil klorid (38,13g, 0,2 mol) u obrocima na 0°C. Nakon 2h miješanja, reakcijska smjesa je ulivena u otopinu 10% HCl u ledu i zakiseljena na pH2. Smjesa je ekstrahirana etil acetatom (150mlx3). Sjedinjeni ekstrakti su isprani slanom otopinom, osušeni (Na2SO4) i koncentrirani da se dobije 42,88g bezbojnog ulja. Smjesa sirovoga tozilata (42,88g, 0,1 mmol) i Nal (44,97g, 0,3mol) u acetonu (300ml) refluksirana je uz miješanje tijekom 5h. Izlučena krutina je uklonjena filtriranjem i filtrat je koncentriran. Rezidue su otopljene u etil acetatu i isprane vodenom otopinom Na2S2O3 i slanom otopinom. Nakon sušenja (Na2SO4) otapalo je upareno i rezidue su pročišćene kromatografijom na koloni (silika-gel 250g, heksan/etil acetat: 10/1) da se dobije 24,81g bezbojnog ulja. Smjesa ovog ulja (24,81g, 76,lmmol), 3,4-dihidro-2H-pirana (21,9ml, 0,24mol) i piridinij p-toluenesulfonata (125mg) u CH2Cl2 (100 ml) miješana je na sobnoj temperaturi tijekom 12h. Reakcijska smjesa je razrijeđena sa CH2Cl2 (100 ml), isprana vodenom otopinom NaHCO3 i osušena (Na2SO4). Isparavanje otapala dalo je 33,56g blijedožutog ulja koje je pročišćeno kromatografijom na koloni (silika-gel 250g, heksan/etil acetat: 20/1) da se dobije 28,75g (70,1% za 3 stupnja) bezbojnog ulja.
1H NMR (270MHz, CDCl3) δ 4,80-4,75 (1H, m), 4,02-3,85 (1H, m), 3,70-3,17 (6H, m), 2,27-2,01 (2H, m), 1,90-1,55 (6H, m).
Pripravak 3
2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanol
Suspenzijska smjesa l,4-dijodo-2-(S)-(tetrahidropiraniloksi)-butana (12,50g, 30mmol), R-(-)-fenilglicinola (3,43g, 25mmol) i K2CO3 (6,91g, 50mmol) u etanolu (50ml) re-fluksirana je uz miješanje tijekom 6h. Bijela krutina uklonjena je filtriranjem i filtrat je koncentriran. Rezidue su razrijeđene vodenom otopinom NaHCO3 (30ml) i ekstrahirane sa CH2Cl2 (20mlx3). Nakon sušenja (Na2SO4) otapalo je upareno da se dobije 9,54g čistog žutog ulja, koje je pročišćeno kromatografijom na koloni (silika-gel 150g, CH2Cl2/MeOH: 20/1) da se dobije 7,22g (99%) bezbojnog viskoznog ulja.
1H NMR (270MHz, CDCl3) δ 7,37-7,27 (5H, m), 4,61- 4,51 (1H, m), 4,40-4,28 (1H, m), 3,91- 3,75 (3H, m), 3,55-3,42 (2H, m), 2,92-2,72 (1H, m), 2,70-2,57 (2H, m), 2,55-2,25 (2H, m), 2,20-1,95 (1H, m), 1,93-1,60 (3H, m), 1,60-1,45 (4H, m).
IR(čisti): 3450 cm-1.
Pripravak 4
1-(S)-fenil-N-tetrahidropiraniloksi-2-(3-(S)-tetrahidropiraniloksipirolidin-1-il)etilamin
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidro-piraniloksipirolidin-l-il)etanola i O-tetrahidropiranil- hidroksilamina (R. N. Warrener i E. N. Cain, Angew. Chem. Int. Edit. 1966, 5, 511) s prinosom 42,5% kao smeđe ulje sukladno postupku slično onom koji je opisan u pripravku 1.
1H NMR (270MHz, CDCl3) δ 7,45-7,25 (5H, m), 6,51 (1H, br, s), 4,80-4,73 (1H, m), 4,65-4,55 (1H, m), 4,45-4,33 (1H, m), 4,28-4,15 (1H, m), 4,00-3,75 (2H, m), 3,70-2,55 (9H, m), 2,30-2,05 (1H, m), 1,90-1,35 (12H, m).
Primjer 10
2-(3,4-diklorofenil)-N-tetrahidropiraniloksi-N-[2-(3-(S)-tetrahidropiramloksipirolidin-1-il)-1-(S)-fenil]acetamid
Ovaj spoj je priređen iz l-(S)-fenil-N-tetrahidropiramloksi-2-(3-(S)tetrahidropiranil-oksipirolidin-l-il)etilamina i 3,4-diklorofeniloctene kiseline s prinosom 69,8% čisto smeđe viskozno ulje sukladno postupku slično onom koji je opisan u pripravku 1.
1H NMR (270MHz, CDCL3) δ 7,43-7,15 (7,4H, m), 6,98-6,91 (0,6H, m), 5,69 (0,4H, dd, J=4,0,11,OHz), 5,58 (0,6H, dd, J=4,8, 11,4Hz), 5,35-5,20 (1H, m), 4,65-4,53 (1H, m), 4,41-4,21 (1H, m), 4,15-3,80 (4H, m), 3,68-3,10 (4H, m), 3,03-2,80 (2H, m), 2,70-2,35 (3H, m), 2,20-1,10 (13H, m).
IR(čisti): 1660 cm-1.
Primjer 11
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletiljacetamid
Smjesa 2-(3,4-diklorofenil)-N-tetrahidropiraniloksi-N-[2-(3-(S)tetrahidropiraniloksipiro-lidin-l-il)-l-(S)-feniletil)acetamida (1,13g, 1,96mmol) i plinovitim HCl zasićenog MeOH (4ml) u MeOH (20ml) miješana je na sobnoj temperaturi tijekom 7h. Otapalo je ispareno. Rezidue su zalužene zasićenom vodenom otopinom NaHCO3, ekstrahirane sa CH2Cl2 i osušene (Na2SO4). Isparavanje otapala je dalo 0,80g smedeg viskoznog ulja koje je kristaliziralo dodatkom etera i tarenjem. Kristalinični talog je sakupljen filtriranjem i ispran eterom da se dobije 377mg (47,1%) bijelog praška.
tt 98,5-99,5°C.
1H NMR (270MHz, CDCl3) δ 7,45-7,20 (7H, m), 7,14 (1H, dd, J=1,8, 9,9Hz), 5,62 (1H, dd, J=5,5, 11,OHz), 5,00-3,00 (2H, gotovo ravan br, s), 4,35-4,25 (1H, m), 3,85 (1H, d, J=14,3 Hz), 3,73 (1H, d, J=13,9Hz), 3,38 (1H, dd, J=11,0, 12,5Hz), 2,95 (1H, dt, J=5,l, 8,8Hz), 2,73 (1H, d, J=10,6Hz), 2,65 (1H, dd, J=5,5, 12,5Hz), 2,51 (1H, dd, J=5,5, 10,6Hz), 2,40-2,27 (1H, m), 2,22-2,07 (1H, m), 1,65-1,50 (1H, m).
IR(Nujol): 3070, 1640cm-1.
MS m/z: 412(M++4, 10,3), 410(M++2, 85,7), 408(M+,100), 304(8,6), 149(50,2), 114(22,7), 112(24,2).
[a]o= + 102.9(c=0,516, MeOH).
HCl sol: tt 65,5-67,0 C.
Analiza izračunata za C20H22Cl2N2O3-HCl-0,5H2O: C, 52,82; H, 5,32; N, 6,16.
Nađeno: C, 53,09; H, 5,29; N, 6,17.
Pripravak 5
(R)-(-)-2-(4-fluorofenil)glicinol
Ovaj spoj je priređen iz 4-fluoro-D-a-fenilglicina s prinosom 88% sukladno postupku D.A. Evans (Organic Synthesis, 68., 77).
1H NMR (270MHz, CDCl3) δ 7,30 (2H, dd, J=5,5, 8,4Hz), 7,03 (2H, t, J=8,4Hz), 4,05 (1H, dd, J=4,4, 8,lHz), 3,71 (1H, dd, J=4,4, 10,6Hz), 3,53 (1H, dd, J=8,4, 10,6Hz), 2,19 (3H, br, s).
IR(KBr): 3350, 3280 cm-1.
Pripravak 6
2-(R)-(4-fluorofenil)-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanol
Ovaj spoj je priređen iz (R)-(-)-2-(4-fluorofenil)glicinola s prinosom 68,8% sukladno postupku slično onom koji je opisan u pripravku 3.
1H NMR (270MHz, CDCl3) δ 7,31-7,26 (2H, m), 7,03 (2H, dd, J=8,4, 8,8Hz), 4,65-4,51 (1H, m), 4,40-4,27 (1H, m), 3,90-3,75 (3H, m), 3,55-3,40 (2H, m), 2,90-2,70 (1H, m), 2,70-2,50 (2H, m), 2,50-2,35 (1H, m), 2,30-1,95 (2H, m), 1,95-1,60 (3H, m), 1,60-1,45 (4H, m).
IR(čisti): 3450cm-1.
Primjer 12
2-(3,4-diklorofenil)-N-[l-(S)-(4-fluorofenil)etil-2-(3-(S)-hidroksipirolidin-l-il]-N-hidroksiacetamid
Ovaj spoj je priređen iz 2-(R)-(4-fluorofenil)-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 3,4-diklorofeniloctene kiseline s prinosom 52,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,41-7,26 (4H, m), 7,12 (1H, dd, J=l,8, 8,1Hz), 6,99 (2H, dd, J = 8,4, 8,8Hz), 5,60 (1H, dd, J=5,1, 11,OHz), 4,35-4,25 (1H, m), 3,82 (1H, d, J=l3,9Hz), 3,72 (1H, d, J=14,3Hz), 3,71 (1H, s), 3,58 (1H, s), 3,35 (1H, dd, J=11,7. 12,lHz), 3,00-2,90 (1H, m), 2,73 (1H, br, d, J=11,OHz), 2,58 (1H, dd, J=5,1, 12,5Hz), 2,51 (1H, dd, J=5,5, 10,6Hz), 2,37-2,10 (2H, m), 1,65-1,55 (1H, m).
IR(čisti): 3200, 1640 cm-1.
MS m/z: 426(M4).
HCl sol: amorfna krutina.
Analiza izračunata za C20H21Cl2FN2O3-HCl-0,7H2O: C, 50,43; H, 4,95; N, 5,88.
Nađeno: C, 50,80; H, 4,96; N, 5,45.
Primjer 13
2-(4-bromofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletiljacetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 4-bromofeniloctcne kiseline s prinosom 44,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,50-7,14 (9H, m), 5,61 (1H, dd, J=5,1, 11,OHz), 4,28-4,22 (1H, m), 3,90 (1H, d, J=13,6Hz), 3,70 (1H, d, J=13,9Hz), 3,33 (1H, dd, J=11,0, 12,5Hz). 2,92-2,82 (1H, m), 2,72-2,64 (2H, m), 2,50 (1H, dd, J=5,5, 10,6Hz), 2,38-2,2S (1H, m), 2,20 (2H, br, s), 2,16-2,01 (1H, m), 1,60-1,50 (1H, m).
IR(čisti): 3200, 1630 cm-1.
MS m/z: 418(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H23BrN2O3-HCl-0,5H2O: C, 51,68; H, 5,42; N, 6,03.
Nađeno: C, 51.75; H, 5,51; N, 5,71.
Primjer 14
2-(3-bromofenil)-N-hidroksi-N-[2-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 3-bromofenioctene kiseline s prinosom 29,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,51-7,15 (9H, m), 5,62 (1H, dd, J=5,5, 11,OHz), 4,28-4,20 (1H, m), 3,94 (1H, d, J=13,9Hz), 3,70 (1H, d, J=13,6Hz), 3,35 (1H, dd, J=11,4, 12,5Hz), 2,92-2,83 (1H, m), 2,70-2,62 (2H, m), 2,51 (1H, dd, J=5,1, 10,6Hz), 2,42 (2H, br, s), 2,38-2,28 (1H, m), 2,18-2,03 (1H, m), 1,60-1,46 (1H, m).
IR(čisti): 3200, 1630cm-1.
MS m/z: 418(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H23BrN2O3-HCl-H2O: C, 50,70; H, 5,53; N, 5,91.
Nađeno: C, 50,57; H, 5,58; N, 5,90.
Primjer 15
2-(4-fluorofenil)-N-hidroksi-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 4-tluorofeniloctene kiseline s prinosom 23,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,40-7,22 (7H, m), 7,10-6,95 (2H,m), 5,67-5,61 (1H, m), 4,34-4,22 (1H, m), 3,92 (1H, d, J=13,6Hz), 3,73 (1H, d, J=13,9Hz), 3,36 (1H, dd, J=10,6, 12,5Hz), 2,96-2,86 (1H, m), 2,76-2,62 (2H, m), 2,58-2,48 (1H, m), 2,40-2,28 (1H, m), 2,24-1,70 (3H, m), 1,64-1,48 (1H, m).
IR(čisti): 3400, 1630 cm-1.
MS m/z: 358(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H23FN2O3-HCl-0,4H2O: C, 59,74; H, 6,22; N, 6,97.
Nađeno: C, 59,81; H, 6,43; N, 6,88.
Primjer 16
2-(3,4-dimetoksifenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 3,4-dimetoksifeniloctene kiseline s prinosom 10,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,40-7,22 (5H, m), 6,95-6,78 (3H, m), 5,70-5,60 (1H, m), 4,25-4,15 (1H, m), 3,91 (1H, d, J=13,9Hz), 3,88 (3H, s), 3,87 (3H, s), 3,68 (1H, d, J=13,9Hz), 3,33 (1H, dd, J =11,4, 11,7Hz), 2,90-2,78 (1H, m), 2,74-2,60 (2H, m), 2,47 (1H, dd, J=5,l, 10,6Hz), 2,34-2,20 (1H, m), 2,14-1,98 (1H, m), 1,90 (2H, br, s), 1,50-1,36 (1H, m).
IR(čisti): 3400, 1640cm-1.
MS m/z: 400(M+).
HC1 sol: amorfna krutina.
Analiza izračunata za C22H28N2O5 HCl 2,7 H2O: C, 54,42; H, 7,14; N, 5,77.
Nađeno: C, 54,31; H, 6,77; N, 5,92.
Primjer 17
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(3-trifluorometilfenil] acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 3-trifluorometilfeniloctene kiseline s prinosom 18,9% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,60-7,26 (9H, m), 5,75-5,65 (1H, m), 4,35-4,25 (1H, m), 3,99 (1H, d, J=14,3Hz), 3,86 (1H, d, J=14,3Hz), 3,54-3,38 (1H, m), 3,04-2,94 (1H, m), 2,84-2,40 (6H, m), 2,20-2,06 (1H, m), 1,70-1,55 (1H, m).
IR(čisti): 3350, 1630 cm-1.
MS m/z: 408(M+H)+.
HCl sol: amorfna krutina.
Analiza izračunata za C21H23F3N2O3-HCM,9H2O: C, 54,70; H, 5,64; N, 6,08.
Nađeno: C, 54,83; H, 5,97; N, 6,21.
Primjer 18
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(4-trifluorometilfenil)acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 4-tritluorometilfeniloctene kiseline s prinosom 35,4% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,56 (2H, d, J=8,lHz), 7,44 (2H, d, J=8,1Hz), 7,33-7,26 (5H, m), 5,65 (1H, dd, J=5,9, 11,OHz), 4,35-4,20 (1H, m), 3,99 (1H, d, J=14,3Hz), 3,85 (1H, d, J=13,9Hz), 3,41 (1H, dd, J =12,1, 12,5Hz), 3,00-2,90 (1H, m), 2,82-2,02 (7H, m), 1,64-1,50 (1H, m).
IR(čisti): 3100, 1650 cm-1.
MS m/z: 408(M+).
HCl sol: tt 142,5-144,2°C
Analiza izračunata za C21H23F3N2O3-HCl-0,2H2O: C, 56,24; H, 5,48; N, 6,25.
Nađeno: C, 56,27; H, 5,61; N, 6,08.
Primjer 19
2-(4-bifenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 4-bifeniloctene kiseline s prinosom 38,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,60-7,26 (14H, m), 5,66 (1H, dd, J=5,l, 11.OHz), 4,20-4,14 (1H, m), 4,04 (1H, d, J=13,6Hz), 3,76 (1H, d, J=13,2Hz), 3,35 (1H, dd, J=10,3, 13,6Hz), 2,90-2,80 (1H, m), 2,73-2,63 (2H, m), 2,55-2,45 (1H, m), 2,35-2,22 (1H, m), 2,10-1,96 (1H, m), 1,90 (2H, br, s), 1,50-1,35 (1H, m).
MS m/z: 417(M+H)+.
HCl sol: tt 163,8-165,5°C
Analiza izračunata za C26H28N2O3-HCl-0,5H2O: C, 67,60; H, 6,55; N, 6,06.
Nađeno: C, 67,77; H, 6,42; N, 5,76.
Primjer 20
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(4-nitrofenil)acetamid
Ovaj spoj je priređen iz 2-(R)-feni]-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 4-nitrofeniloctene kiseline s prinosom 11,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 8,14 (2H, d, J=8,BHz), 7,44 (2H, d, J=8,8Hz), 7,35-7,16 (5H, m), 5,74 (1H, dd, J=4,8, 10,3Hz), 4,46-4,38 (1H, m), 4,03 (1H, d, J=15,OHz), 3,96 (1H, d, J=15,OHz), 3,64-3,50 (1H, m), 3,20-3,10 (1H, m), 2,96 (1H, br, d, J=10,3Hz), 2,90-2,74 (3H, m), 2,66 (2H, br, s), 2,30-2,16 (1H, m), 1,84-1,70 (1H, m).
IR(čisti): 3400, 1630 cm-1.
MS m/z: 385(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H23N3O5-HCl,5H2O: C, 53,51; H, 6,06; N, 9,36.
Nađeno: C, 53,71; H, 6,01; N, 9,11.
Primjer 21
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(3-nitrofenil)acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 3-nitrofeniloctene kiseline s prinosom 11,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 8,17-8,08 (2H, m), 7,66-7,20 (7H, m), 5,64 (1H, dd, 3=5,9, 11,0Hz), 4,38-4,30 (1H, m), 4,03 (1H, d, J=14,7Hz), 3,90 (1H, d, J=14,3Hz), 3,50-3,38 (1H, m), 3,06-2,94 (1H, m), 2,84-2,70 (2H, m), 2,66-2,56 (1H, m), 2,50-2,32 (1H, m), 2,20-2,04 (1H, m), 1,96 (2H, br, s), 1,70-1,50 (1H, m).
MS m/z: 386(M+H)+.
HCl sol: tt 154,3-155,5°C.
Analiza izračunata za C20H23N3O5-HCl-0,3H2O: C, 56,22; H, 5,80; N, 9,83.
Nađeno: C, 56,29; H, 5,80; N, 9,55.
Primjer 22
2-(4-klorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 4-klorofeniloctene kiseline s prinosom 49,4% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,40-7,20 (9H, m), 5,65 (1H, dd, J=5,1,11,OHz), 5,00-3,30 (2H, široki br, s), 4,35-4,25 (1H, m), 3,86 (1H, d, J=13,9Hz), 3,74 (1H, d, J=13,9Hz), 3,40 (1H, dd, 3=11,7, 12,1 Hz), 3,02-2,90 (1H, m), 2,75 (1H, br, d, J=10,6Hz), 2,61 (1H, dd, J=5,l, 12,5Hz), 2,51 (1H, dd, J=5,1, 10,3Hz), 2,40-2,25 (1H, m), 2,23-2,08 (1H, m), 1,65-1,50 (1H, m).
IR(čisti): 3400, 1630cm-1.
MS m/z: 374(M+).
HCl sol: tt 146,5-147,3°C.
Analiza izračunata za C20H23ClN2O3-HCl-0,3H2O: C, 57,64; H, 5,95; N, 6,72.
Nađeno: C, 57,87; H, 5,88; N, 6,78.
Primjer 23
2-(3-klorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-lil)etanola i 3-klorofeniloctene kiseline s prinosom 29,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,34-7,20 (9H, m), 5,75-5,62 (1H, m), 4,35-4,25 (1H, m), 3,94 (1H, d, J=13,9Hz), 3,74 (1H, d, J=13,9Hz), 3,45 (1H, dd, J=9,5, 12,1Hz), 3,05-2,92 (1H, m), 2,80 (1H, br, d, J=10,6Hz), 2,77-2,30 (3H, m), 3,80-2,30 (2H, gotovo ravan peak), 2,23-2,06 (1H, m), 1,68-1,54 (1H, m).
IR(čisti): 3350, 1630 cm-1.
MS m/z: 374(M+).
HCl sol: tt 113,2-114,3°C.
Analiza izračunata za C20H23ClN2O3-HCl-0,4H2O: C, 57,40; H, 5,97; N, 6,69.
Nađeno: C, 57,79; H, 5,84; N, 6,74.
Primjer 24
2-2-(2-klorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2-klorofeniloctene kiseline s prinosom 31,2% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,16 (9H, m), 5,85-5,70 (1H, m), 4,44-4,34 (1H, m), 4,14 (1H, d, J=16,lHz), 3,91 (1H, d, J=16,1Hz), 3,68-3,48 (1H, m), 3,24-3,10 (1H, m), 2,98-2,40 (6H, m), 2,34-2,18 (1H, m), 1,86-1,70 (1H, m).
IR(čisti): 3400, 1640 cm-1.
MS m/z: 374(M+).
HCl sol: tt 146°C.
Analiza izračunata za C20H23ClN2O3-HCl-H2O: C, 55,95; H, 6,10; N, 6,52.
Nađeno: C, 56,18 ; H, 6,00 ; N, 6,55.
Primjer 25
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il]-l-(S)-feniletil]-2-(2,3,5-triklorofenil)acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2,3,5-triklorofeniloctene kiseline s prinosom 51,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,26 (6H, m), 7,14 (1H, d, J=2,2Hz), 5,70 (1H, dd, J=4,8, 11,OHz), 4,48-4,30 (1H, m), 4,20-3,00 (2H, široki br, s), 4,06 (1H, d, J=16,5Hz), 3,90 (1H, d, J=16,1Hz), 3,50 (1H, dd, J=11,4, 12,1Hz), 3,20-3,10 (1H, m), 2,86 (1H, br, d, J=10,3Hz), 2,75-2,60 (2H, m), 2,55-2,35 (1H, m), 2,35-2,20 (1H, m), 1,85-1,70 (1H, m).
IR(čisti): 3400, 1640 cm-1.
MS m/z: 444(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H21Cl3N2O3-HCl-H2O: C, 48,21; H, 4,86; N, 5,62.
Nađeno: C, 48,56; H, 5,17; N, 5,40.
Primjer 26
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il]-1-(S)-feniletil]-2-(2,4,6-triklorofenil)acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2,4,6-triklorofeniloctene kiseline s prinosom 14,0% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,50-7,26 (7H, m), 5,60 (1H, dd, J=4,8, 11,4Hz), 4,47-4,38 (1H, m), 4,19 (2H, s), 3,49 (1H, dd, J=11,7,12,1Hz), 3,25-3,10 (1H, m), 2,84 (1H, br, d, J=9,5Hz), 2,75-2,60 (2H, m), 2,50-2,35 (2H, m), 2,35-2,20 (2H, m), 1,90-1,70 (1H, m).
IR(KBr): 3450, 1640 cm-1.
MS m/z: 442(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H21Cl3N2O3-HCl-0,2H2O: C, 49,65; H, 4,67; N, 5,79.
Nađeno: C, 49,42; H, 4,39; N, 5,96.
Primjer 27
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il]-l-(S)-feniletil]-2-(2,4,6-trimetilfenil)acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2,4,6-trimetilfeniloctene kiseline s prinosom 67,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,25 (5H, m), 6,81 (2H, s), 5,80-5,65 (1H, m), 4,40-4,30 (1H, m), 3,86 (2H, s), 3,49 (1H, dd, J=11,7, 13,2Hz), 3,20-3,10 (1H, m), 2,80 (1H, br, d, J=10,3Hz), 2,65-2,50 (2H, m), 2,35-2,25 (3H, m), 2,23 (3H, s), 2,18 (6H, s), 1,90-1,65 (1H, m), 1,65-1,50 (1H, m).
IR(čisti): 3250, 1630 cm-1.
MS m/z: 382(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C23H30N2O3-HCl-0,2H2O: C, 64,01; H, 7,57; N, 6,49.
Nađeno: C, 64,08; H, 7,85; N, 6,61.
Primjer 28
2-(2,3-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2,3-diklorofeniloctene kiseline s prinosom 56% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,50-7,05 (8H, m), 5,69 (1H, dd, J=5,1, 11,4Hz), 5,00-3,00 (2H, gotovo ravan br, s), 4,45-4,35 (1H, m), 4,10 (1H, d, J=16,1Hz), 3,92 (1H, d, J=16,1Hz), 3,48 (1H, dd, J=11,7, 12,1Hz), 3,20-3,10 (1H, m), 2,82 (1H, d, J=10,3Hz), 2,70-2,55 (2H, m), 2,45-2,20 (2H, m), 1,80-1,70 (1H, m).
IR(čisti): 3200, 1640 cm-1.
MS m/z: 408(M+).
HCl sol: tt 155,3-158,1°C.
Analiza izračunata za C20H22Cl2N2O3 HCl: C, 53,89; H, 5,20; N, 6,28.
Nađeno: C, 53,72; H, 5,24; N, 6,16.
Primjer 29
2-(2,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2,4-diklorofeniloctene kiseline s prinosom 71,9% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,15 (8H, m), 5,69 (1H, dd, J=5,1, 11,4Hz), 6,50-4,50 (2H, gotovo ravan br, s), 4,35-4,25 (1H, m), 4,00 (1H, d, J=16,1Hz), 3,86 (1H, d, 3=16,1 Hz), 3,47 (1H, dd, J=11,7, 12,1Hz), 3,20-3,10 (1H, m), 2,83 (1H, d, J=10,6Hz), 2,61 (2H, dd, J=5,5, 12,1Hz), 2,45-2,20 (2H, m), 1,80-1,65 (1H, m).
IR(čisti): 3200, 1635 cm-1.
MS m/z: 408(M+).
HCl sol: tt 149-151,5°C.
Analiza izračunata za C20H22Cl2N2O3-HCl-0,2H2O: C, 53,46; H, 5,25; N, 6,23.
Nađeno: C, 53,46; H, 5,19; N, 6,19.
Primjer 30
2-(2,5-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(R)-fenil-2-(3-(S)-tetrahidropiraniloksipirolidin-l-il)etanola i 2,5-diklorofeniloctene kiseline s prinosom 56,3% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,15 (8H, m), 5,69 (1H, dd, J=5,1, 11,OHz), 5,60-4,50 (2H, gotovo ravan br, s), 4,35-4,25 (1H, m), 4,03 (1H, d, J=16,1Hz), 3,86 (1H, d, J=16,1Hz), 3,47 (1H, t, J=11,7Hz), 3,20-3,10 (1H, m), 2,82 (1H, d, J=10,6Hz), 2,63 (2H, dd, J=5,1, 12,1Hz), 2,45-2,20 (2H, m), 1,85-1,70 (1H, m).
IR(čisti): 3200, 1635 cm-1.
MS m/z: 408(M+).
HCl sol: 157,5-158,2°C.
Analiza izračunata za C20H22Cl2N2O3-HCl-0,2H2O: C, 53,46; H, 5,25; N, 6,23.
Nađeno: C, 53,35; H, 5,21; N, 6,14.
Pripravak 7
2-(3-(S)-metoksimetilpirolidin-l-il)-2-(R)-feniletanol
Uz miješanje otopini (S)-(-)-butantriola (10,61g, 0,1mol) u piridinu (50ml) dodan je p-toluenesulfonil klorid (38,13g, 0,2mol) u obrocima na 0°C (ledena kupelj). Nakon miješanja 1H, reakcijska smjesa je stavljena u vodenu otopinu c-HCl zajedno s ledom i zakiseljena na pH2. Smjesa je ekstrahirana etil acetatom (100mlx3). Sjedinjeni ekstrakti su isprani slanom otopinom, osušeni (Na2SO4), i koncentrirani da se dobije 36,22g blijedo smeđeg čistog ulja. Otopini ovoga sirovog tozilata uz miješanje (36,22g) i metilal (50 ml) u CH2Cl2 (50ml) dodan je P2O5 (20g). Nakon miješanja 1H, dodano je daljnjih 0g P2O5 u reakcijsku smjesu. Nakon miješanja 2h, sloj CH2Cl2 je odijeljen. Rezidualna tamnosmeđa krutina isprana je sa CH2Cl2- Sjedinjeni sloj CH2Cl2 ispran je s vodenom otopinom NaHCO3, osušen (Na2SO4), i koncentriran da se dobije 38,51g smeđeg viskoznog ulja. Smjesa ovog ulja (38,51g, 84mmol), (R)-(-)-2-fenilglicinola (10,97g, 80mmol) i trietilamina (23mmol, 160mmol) u etanolu (40ml) refluksirana je uz miješanje tijekom 15h. Otapalo je ispareno i rezidue su otopljene u CH2Cl2 (200ml), isprane vodenom otopinom NaHCO3 i slanom otopinom, osušene (Na2SO4) i koncentrirane da se dobije 28,43g smeđeg viskoznog ulja. Ovo ulje je pročišćeno kromatografijom na koloni (silika-gel 200g, CH2Cl2/metanol: 40/1 do 20/1) da se dobije 9,74g (48,4%) čistog smedeg viskoznog ulja.
1H NMR (270MHz, CDCl3) δ 7,40-7,25 (5H, m), 4,62 (1H, d, J=7,OHz), 4,58 (1H, d, J=6,6Hz), 4,26-4,18 (1H, m), 3,92 (1H, dd, J=6,2, 11,OHz), 3,82 (1H, dd, J=5,5, 11,OHz), 3,54 (2H, t, J=5,9Hz), 3,33 (3H, s), 2,93 (1H, br,s), 2,85-2,66 (3H, m), 2,56-2,47 (1H, m), 2,16-2,02 (1H, m), 1,88-1,77 (1H, m).
Primjer 31
2-(2,6-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksirnetiloksipirolidin-l-il)-2-(R)feniletanola i 2,6-diklorofeniloctene kiseline s prinosom 47,2% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 750-7,25 (7H, m), 7,20-7,10 (1H, m), 5,71 (1H, dd, J=5,1, 11,4Hz), 5,40-3,70 (2H, gotovo ravan br, s), 4,50-4,40 (1H, m), 4,25 (2H, s), 3,50 (1H, dd, J=11,0, 12,5Hz), 3,28-3,15 (1H, m), 2,87 (1H, d, J=10,3Hz), 2,75-2,55 (2H, m), 2,50-2,25 (2H, m), 1,90-1,70 (1H, m).
IR(KBr): 3400, 1640 cm-1.
MS m/z: 408(M+).
HCl sol: tt 95,5-96,8°C.
Analiza izračunata za C20H22Cl2N2O3-HCl-0,5H2O: C, 52,82; H, 5,32; N, 6,16.
Nađeno: C, 52,61; H, 5,13; N, 6,10.
Primjer 32
2-(3,5-diklorofenil)-N-hidroksi-N- [2-(3-(S)-hidroksipirolidin-1 -il)-1 -(S)-f eniletil] acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 3,5-diklorofeniloctene kiseline s prinosom 47,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,15 (8H, m), 5,63 (1H, dd, J=5,5 11,OHz), 4,50-3,00 (2H, gotovo ravan br, s), 4,40-4,28 (1H, m), 3,87 (1H, d, J=14,3Hz), 3,71 (1H, d, J=14,3Hz), 3,39 (1H, dd, J=11,4, 12,1Hz), 3,05-2,95 (1H, m), 2,74 (1H, d, J=11,OHz), 2,65 (1H, dd, J=5,5, 12,5Hz), 2,54 (1H, dd, J=5,5, 10,6Hz), 2,45-2,30 (1H, m), 2,25-2,10 (1H, m), 1,70-1,55 (1H, m).
IR(čisti): 3350, 1650 cm-1.
MS m/z: 408(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H22Cl2N2O3 2H2O: C, 49,86; H, 5,65; N, 5,81.
Nađeno: C, 49,49; H, 5,53; N, 5,59.
Primjer 33
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(2,3,6-triklorofenil)acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 2,3,6-triklorofeniloctene kiseline s prinosom 46,7% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,20 (7H, m), 5,69 (1H, dd, J=4,8, 11,0Hz), 5,00-3,50 (2H, gotovo ravan br, s), 4,50-4,40 (1H, m), 4,29 (2H, s), 3,49 (1H, t, J=11,7Hz), 3,25-3,15 (1H, m), 2,85 (1H, d, J=10,3Hz), 2,70-2,60 (2H, m), 2,45-2,20 (2H, m), 1,90-1,70 (1H, m).
IR(KBr): 3400, 1640 cm-1.
MS m/z: 442(M+).
HCl sol: tt 102-103°C.
Analiza izračunata za C20H21Cl3N2O3-HCl H2O: C, 48,21; H, 4,86; N, 5,62.
Nađeno: C, 48,40; H, 4,64; N, 5,52.
Primjer 34
2-(benzo[b]furan-4-il)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 4-benzo[b]furanoctene kiseline s prinosom 57,5% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,64 (1H, d, J=2,2Hz), 7,50-7,25 (7H, m), 7,14 (1H, d, J=7,3Hz), 6,84 (1H, dd, J=0,7, 2,2Hz), 5,61 (1H, dd, J=5,5, 11,4Hz), 4,24 (1H,d, J=13,6Hz), 4,05-3,95 (1H, m), 3,91 (1H, d, J=13,2Hz), 3,31 (1H, dd, J=11,7, 12,1Hz), 2,75-2,65 (1H, m), 2,63-2,50 (2H, m), 2,30 (1H, dd, J=5,1, 10,3Hz), 2,20-2,10 (1H, m), 2,00-1,85 (1H,m).
IR(čisti): 3400, 1635 cm-1.
MS m/z: 380(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C22H24N2O4-HCl, 1,1 H2O: C, 60,51; H, 6,28; N, 6,41.
Nađeno: C, 60,31; H, 5,98; N, 6,47.
Primjer 35
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]-2-(1-tetralon-6-il)acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-1-il)-2-(R)feniletanola i (I-tetralon-6-il)octene kiseline s prinosom 59,4% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,96 (1H, d, J=8,1Hz), 7,40-7,18 (7H, m), 5,66 (1H, dd, J=5,5, 11,0Hz), 4,30-4,20 (1H, m), 3,94 (1H, d, J=14,3Hz), 3,81 (1H, d, J=13,9Hz), 3,80-2,00 (2H, gotovo ravan br, s), 3,40 (1H, dd, 3=11,7, 12,1Hz), 3,00-2,85 (3H, m), 2,80-2,50 (5H, m), 2,45-2,30 (1H, m), 2,20-2,05 (3H, m), 1,65-1,50 (1H, m).
IR(čisti): 3400, 1680, 1640 cm-1.
MS m/z: 408(M+).
HCL sol: amorfna krutina.
Analiza izračunata za C24H28N2O4-HCl-1,2H2O: C, 61,78; H, 6,78; N, 6,00.
Nađeno: C, 61,60; H, 6,59; N, 6,35.
Primjer 36
2-(3,4-dimetilfenil)-N-hidroksi-N-[2-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 3,4-dimetilfeniloctene kiseline s prinosom 66,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,25 (5H, m), 7,20-7,00 (3H, m), 5,66 (1H, dd, J=5,1, 11,4Hz), 4,25-4,10 (1H, m), 3,87 (1H, d, J=13,9Hz), 3,67 (1H, d, J=13,9Hz), 3,37 (1H, dd, J=11,7, 12,1Hz), 3,00-2,85 (1H, m), 2,71 (1H, d, J=9,9Hz), 2,55 (1H, dd, J=5,5, 12,5Hz), 2,42 (1H, dd, J=5,1, 9,9Hz), 2,35-2,05 (9H, m, uklj. svaki 3H, s, na 2,22 i 2,21 ppm), 1,80-1,35 (2H, m).
IR(čisti): 3350, 1630 cm-1.
MS m/z: 368(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C22H28N2O3-HCl-1,8H2O: C, 60,42; H, 7,51; N, 6,41.
Nađeno: C, 60,51; H, 7,71; N, 6,29.
Primjer 37
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(S)feniletanola i 3,4-diklorofeniloctene kiseline s prinosom 32,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,25 (7H, m), 7,13 (1H, dd, J=l,5, 8,lHz), 5,61 (1H, dd, J=5,5, 10,6Hz), 5,00-3,90 (2H, gotovo ravan br, s), 4,45-4,35 (1H, m), 3,85 (1H, d, J=14,7Hz), 3,77 (1H, d, J=14,3Hz), 3,37 (1H, dd, J=11,0, 12,5Hz), 2,89 (1H, dd, J=4,7, 8,4Hz), 280-2,60 (3H, m), 2,45-2,35 (1H, m), 2,15-2,00 (1H, m), 1,80-1,65 (1H, m).
IR(KBr): 3450, 3250, 1650 cm-1.
MS m/z: 408(M+).
tt 125,5-126,0°C.
[a]D=-95.4° (c=0,218, metanol)
Analiza izračunata za C22H22Cl2N2O3: C, 58,69; H, 5,42; N, 6,84.
Nađeno: C, 58,51; H, 5,42; N, 6,70.
Primjer 38
2-(3,4-difluorofenil)-N-hidroksi-N-[2-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 3,4-ditfluorofeniloctene kiseline s prinosom 53,6% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,40-7,25 (5H, m), 7,18-6,95 (3H, m), 5,65 (1H, dd, J=5,5, 11,4Hz), 5,00-3,90 (2H, gotovo ravan br, s), 4,35-4,25 (1H, m), 3,82 (1H, d, J=14,3Hz), 3,74 (1H, d, J=14,3Hz), 3,40 (1H, dd, J=10,6, 13,2Hz), 2,95 (1H, dt, J=4,4, 8,8Hz), 2,75 (1H, d, J=10,6Hz), 2,61 (1H, dd, J=5,l, 12,5Hz), 2,51 (1H, dd, J=5,5, 10,6Hz), 2,40-2,10 (2H, m), 1,70-1,50 (1H, m).
IR(čisti): 3350, 3250, 1630cm-1.
MS m/z: 376(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H22F2N2O3'HCl-0,5 H2O: C 56,94; H, 5,73; N, 6,64.
Nađeno: C, 57,21; H, 6,07; N, 6,63.
Primjer 39
2-(benzo[b]tiofen-4-il)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil] acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola and (benzo[b]tiofen-4-il)octene kiseline s prinosom 48,8% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,79 (1H, d, J=7,7Hz), 7,66 (1H, d, J=5,5Hz), 7,50-7,20 (8H, m), 5,60 (1H, dd, J=5,5, 11,4Hz), 4,60-3,20 (2H, gotovo ravan br, s), 4,32 (1H, d, J=13,6Hz), 4,01 (1H, d, J=13,6Hz), 4,00-3,90 (1H, m), 3,30 (1H, dd, J=11,7, 12,1Hz), 2,70-2,45 (3H, m), 2,28 (1H, dd, J=5,1, 10,3Hz), 2,20-2,10 (1H, m), 1,95-1,80 (1H, m), 1,20-1,05 (1H, m).
IR(čisti): 3400, 3200, 1630 cm-1.
MS m/z: 396(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C22H24N2O3S-HCl-0,5H2O: C, 59,79; H, 5,93; N, 6,34.
Nađeno: C, 59,85; H, 6,09; N, 6,27.
Primjer 40
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]-2-(3,4-metilendioksifenil)acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 3,4-metilendioksifeniloctene kiseline s prinosom 59,7% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,45-7,25 (5H, m), 6,85-6,70 (3H, m), 5,92 (2H, s), 5,66 (1H, dd, J=5,5, 11,4Hz), 4,50-3,30 (2H, gotovo ravan br, s), 4,30-4,20 (1H, m), 3,86 (1H, d, J=13,6Hz), 3,64 (1H, d, J=13,9Hz), 3,39 (1H, t, J=12,1Hz), 3,05-2,95 (1H, m), 2,72 (1H, d, J=10,3Hz), 2,59 (1H, dd, J=5,5, 12,5Hz), 2,48 (1H, dd, J=5,5, 10,3Hz), 2,35-2,10 (2H, m), 1,65-1,50 (1H, m).
IR(čisti): 3400, 3250, 1630 cm-1.
MS m/z: 384(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C21H24N2O3S-HCl,1,4H2O: C, 56,54; H, 6,28; N, 6,28.
Nađeno: C, 56,74; H, 6,38; N, 5,89.
Primjer 41
2-(3,5-difluorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletiljacetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)feniletanola i 3,4-difluorofeniloctene kiseline s prinosom 40,0% sukladno postupku slično onom koji je opisan u pripravku 4, te primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,40-7,25 (5H, m), 6,82 (2H, d, J=8,lHz), 6,72-6,64 (1H, m), 5,65 (1H, dd, J=5,1, 110,Hz), 5,30-4,20 (2H, gotovo ravan br, s), 4,40-4,30 (1H, m), 3,86 (1H, d, J=14,3Hz), 3,74 (1H, d, J = 14,3Hz), 3,41 (1H, dd, 3=11,7, 12,1Hz), 3,10-2,95 (1H, m), 2,76 (1H, d, J=10,6Hz), 2,61 (1H, dd, J=5,l, 12,5Hz), 2,52 (1H, dd, J=5,5, 10,6Hz), 2,40-2,10 (2H, m), 1,70-1,55 (1H, m).
IR(čisti): 3350, 3200, 1630 cm-1.
MS m/z: 376(M+).
HCl sol: amorfna krutina.
Analiza izračunata za C20H22F2N2O3 HCl 0,5H2O C 56,94; H, 5,73; N, 6,64.
Nađeno: C, 57,01; H, 5,93; N, 6,45.
Pripravak 8
1-benzil-3- (R)-tetrahidropiraniloksipirolidin
Uz miješanje otopini (R)-(+)-l-benzil-3-pirolidinol (5,00g, 28mmol) i D-kamfor-10-sulfonske kiseline (6,97g, 30mmol) u CH2Cl2 (10 ml) dodan je 3,4-dihidro-2H-piran (20ml) na sobnoj temperaturi i reakcijska smjesa miješana je tijekom 14h (u većini slučajeva, reakcija je završena sa završetkom egzotermnog efekta). Reakcijska smjesa je razrijeđena sa CH2Cl2 (100 ml), isprana zasićenom vodenom otopinom NaHCO3, osušena (Na2SO4) i koncentrirana da se dobije smeđe ulje. Ono je pročišćeno kromatografijom na koloni (silika-gel: 200g, CH2Cl2/MeOH: 40/1 kao eluens) da se dobije 8,78g (97,6%) željenog spoja kao smeđeg ulja.
1H NMR (270MHz, CDCl3) δ 7,34-7,22 (5H, m); 4,61 (0,5H, dd, J=2,9, 4,4Hz), 4,54 (0,5H, dd, J=2,9, 4,4Hz), 4,42-4,31 (1H, m), 3,90-3,79 (1H, m), 3,67 (1H, d, J=12,8Hz), 3,59 (0,5H, d, J=12,8Hz), 3,58 (0,5H, d, J=12,8Hz), 3,50-3,40 (1H, m), 2,88 (0,5H, dd, 3=6,6, 10,3Hz), 2,74-2,45 (3,5H, m), 2,25-2,05 (1H, m), 1,95-1,45 (7H, m).
Pripravak 9
3-(R)-tetrahidropiraniloksipirolidin
Smjesi 1-benzil-3-(R)-tetrahidropiraniloksipirolidina (8,78g, 27,3mmol) i Pearlmanova katalizatora (3,50g) in MeOH (100 ml) miješana je u atmosferi vodika na sobnoj temperaturi tijekom 4h. Nakon uklanjanja katalizatora Celite filtriranjem, filtrat je koncentriran da se dobije 5,74g čistog svijetlosmeđeg ulja. Ono se koristi za sljedeću reakciju bez pročišćavanja.
1H NMR (270MHz, CDCl3) δ 4,62 (1H, br, s), 4,45-4,30 (1H, m), 3,90-3,80 (1H, m), 3,55-3,45 (1H, m), 3,20-2,80 (5H, m), 2,00-1,40 (8H, m).
Pripravak 10
l-(S)-fenil-2-(3-(R)-tetrahidropiraniloksipirolidin-l-il)etanol i
2-(R)-fenil-2-(3-(R)-tetrahidropiraniloksipirolidin-l-il)etanol
Smjesa 3-(R)-tetrahidropiraniloksipirolidina (1,43g, 8,32 mmol) i (S)-(-)-stiren oksida (l,00g, 8,32mmol) u EtOH (10 ml) refluksirana je uz miješanje 1H. Uparavanje otapala dalo je 3,098g smeđeg ulja koje je pročišćeno kromatografijom na koloni (silika-gel: 100 g, CH2Cl2/MeOH: 40/1 do 15/1 kao eluens) da se dobije 1,68g (69,3%) čistog svijetlosmeđeg ulja kao približno 2 prema 1 smjesa naslovljen1H spojeva u kojoj je prevladavajući 1-(S)-fenil-2- (3-(R)- tetrahidro-piraniloksipirolidin-1-il)etanol.
1H NMR (270MHz, CDCl3) δ 7,40-7,24 (5H, m), 4,72 i 4,68 (tot. 0,67H, pr. svaki d, J=2,6Hz, OCHO), 4,63-4,55 (1H,m, PhCHHOH i OCHO), 4,43-4,25 (1H, m, OCHCH2N), 3,89-3,81 (1,67H, m), 3,52-3,46 (1,33H, m), 2,88-2,47 (5,33H, m), 2,15-1,90 (2H, m), 1,86-1,66 (3H, m), 1,58-1,51 (4H, m).
Primjer 42
2-(3,4-diklorofenil)-N-[1-(S)-fenil-2-(3-(R)-tetrahidropiraniloksipirolidin-1-il)etil]-N-tetrahidropiraniloksiacetamid
Uz miješanje otopini l-(S)-fenil-2-(3-(R)-tetrahidropiraniloksipirolidin-l-il)etanola (1,67g, 5,73mmol) and Et3N (0,96ml, 6,88mmol) in CH2Cl2 (20ml) dodan je dokapavanjem mezil klorid (0,53ml, 6,88mmol) na 0°C. Reakcijska smjesa je miješana na sobnoj temperaturi tijekom 16h. Reakcijska smjesa je isprana zasićenom vodenom otopinom NaHCO3 i slanom otopinom, osušena (Na2SO4) i koncentrirana da se dobije 2,02g smeđeg ulja. Ovo ulje je korišteno za sljedeću reakciju bez pročišćavanja.
1H NMR (270MHz, CDCl3) δ 7,42-7,30 (5H, m), 4,94 (1H, dd, J=5,9, 8,lHz, PhCHCl), 4,60 i 4,52 (tot. 1H, svaki m, OCHO), 4,35-4,31 (1H, m, OCHCH2N), 3,88-3,82 (1H, m), 3,48-3,45 (1H, m), 3,25-3,17 (1H, m), 3,02-2,69 (3H, m), 2,66-2,50 (3H, m), 1,88-1,67 (3H, m), 1,56-1,51 (4H, m).
Smjesa sirovog kloridnog derivata (2,02g, 5,73 mmol) i O-(tetrahidropiranil) hidroksilamina (0,806g, 6,88mmol) u EtOH (lOml) refluksirana je uz miješanje tijekom 0,5h. Reakcijska smjesa je koncentrirana, razrijeđena sa CH2Cl2 (30 ml), isprana zasićenom vodenom otopinom NaHCO3 i slanom otopinom, osušena (Na2SO4) i koncentrirana da se dobije 2,59g smeđeg ulja. Ovo ulje je korišteno za sljedeću reakciju bez pročišćavanja.
Smjesa gornjeg sirovog aminskog derivata (2,59 g, 5,73mmol), 3,4-diklorofeniloctene kiseline (1,41g, 6,88mmol) i 1-etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida (skraćeno WSC; 1,32g, 6,88mmol) u CH2Cl2 (15ml) miješana je na sobnoj temperaturi tijekom 0,5h. Reakcijska smjesa je isprana zasićenom vodenom otopinom NaHCO3 i slanom otopinom, osušena (Na2SO4) i koncentrirana da se dobije 4,12g smeđeg ulja. Ovo ulje je pročišćeno kromatografijom na koloni (silika-gel: 100 g, CH2Cl2/MeOH: 50/1 do 40/1 kao eluens) da se dobije 2,22g (67,1%) blijedožutog ulja.
Primjer 43
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(R)-hidroksipirolidin-l-il)-l-(S)-feniletil] acetamid
Smjesa gornjeg aminskog derivata (2,20g, 3,81mmol) i metanola koji sadrži plinoviti HCl (10 ml) miješana je na sobnoj temperaturi tijekom 1H. Reakcijska smjesa je koncentrirana, zalužena vodenom otopinom NH3 i ekstrahirana sa CH2Cl2 (30ml). Ekstrakt je ispran slanom otopinom, osušen (Na2SO4) i koncentriran da se dobije svijetlosmeđi prašak. On je sakupljen filtriranjem i ispran heksanom da se dobije l,117g (71,6%) svijetlosmedeg praška.
1H NMR (270MHz, CDCl3) δ 7,41-7,28 (7H, m), 7,13 (1H, dd, J=l,8, 8,4Hz), 5,61 (1H, dd, J=5,5, 10,6Hz), 4,50-3,50 (2H, gotovo ravan br, s), 4,40-4,35 (1H, m), 3,84 (1H, d, J=14,7Hz), 3,77 (1H, d, J= 14,3Hz), 3,38 (1H, dd, J=11,0, 12,1Hz), 2,94-2,85 (1H, m), 2,74-2,63 (3H, m), 2,44-2,3S (1H, m), 2,15-2,01 (1H, m), 1,80-1,65 (1H, m).
IR(KBr): 3250, 1650 cm-1.
MS m/z: 408(M+)
HCl sol: amorfna krutina.
Analiza izračunata za C20H22Cl2N2O-HCl-0,8H2O: C, 52,20; H, 5,39; N, 6,09.
Nađeno: C, 52,22; H, 5,39; N, 6,12.
Primjer 44
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(R)-hidroksipirolidin-1-il)-1-(R)-feniletil] acetamid
Ovaj spoj je priređen iz 3-(R)-tetrahidropiraniloksipirolidina i (R)-(+)stiren oksida s prinosom 33,3% sukladno postupku slično onom koji je opisan u primjerima 3 do 5.
1H NMR (270MHz, CDCl3) δ 7,38 (1H, d, J=8,4Hz), 7,36-7,25 (6H, m), 7,13 (1H, dd, J=1,8, 8,1Hz), 5,64 (1H, dd, J=5,1, 11,0Hz), 5,00-3,50 (2H, gotovo ravan br, s), 4,35-4,25 (1H, m), 3,84 (1H, d, J=14,3Hz), 3,73 (1H, d, J=13,2Hz), 3,40 (1H, dd, J=11,4, 12,5Hz), 3,05-2,95 (1H, mn), 2,74 (1H, br, d, J=10,3Hz), 2,62 (1H, dd, J=5,1, 12,5Hz), 2,51 (1H, dd, J=5,5, 10,6Hz), 2,40-2,25 (1H, m), 2,25-2,10 (1H, m), 1,70-1,55 (1H, m).
IR(KBr): 3400, 3200, 1640 cm-1.
MS m/z : 408(M+)
HCl sol: amorfna krutina
Analiza izračunata za C20H22Cl2N2O3-HCl-0,5H2O: C, 52,82; H, 5,32; N, 6,16.
Nađeno: C, 52,71; H, 5,59; N, 6,15.
Pripravak 11
(S)-l-(3-metilfenil)-l,2-etandiol
Smjesa 3-metilstirena (1,69ml, 12,7mmol) i AD-smjese (17,78g, 12,7mmol) u vodi (65ml) i t-BuOH (65ml) miješana je na 0°C tijekom 3,5h. Ovoj reakcijskoj smjesi dodan je Na2SO3 (20g) i smjesa je miješana na sobnoj temperaturi tijekom llh. Reakcijska smjesa je ekstrahirana etil acetatom. Ekstrakt je ispran slanom otopinom, osušen (Na2SO4) i koncentriran da se dobije 2,07g svijetlo smeđeg ulja koje je pročišćeno kromatografijom na koloni (silika-gel: 110 g, etil acetat/heksan: 3/2) da se dobije l,89g (98%) željenog produkta kao svijetlo smeđeg ulja.
1H NMR (270MHz, CDCl3) δ 7,24 (1H, dd, J=7,3, 7,7Hz), 7,19-7,09 (3H, m), 4,77 (1H, dd, J=3,7, 8,1Hz), 3,74 (1H, dd, J=3,7, 11,4Hz), 3,65 (1H, dd, J=8,1, 11,4Hz), 2,82 (1H, br, s), 2,35 (3H, s), 1,77 (1H, br, s).
Pripravak 12
(S)-l-(3-metilfenil)-1,2-etandiol 2-tozilat
Uz miješanje otopini (S)-1-(3-metilfenil)-1,2-etandiola (1,78g, 11,7mmol) u piridinu (35ml) dodan je p-toluenesulfonil klorid (2,46g, 12,9mmol) i 4-dimetilaminopiridin (l,58g, 12,9mmol) na 0°C i rekacijska smjesa miješana je na 0°C do sobne temperature tijekom 17h. Reakcijska smjesa je zakiseljena sa vodenom otopinom 6N HCl i ekstrahirana sa CH2Cl2. Ekstrakt je ispran vodom i slanom otopinom, osušen (Na2SO4) i koncentriran da se dobije 3,02g žutog ulja koje je pročišćeno kromatografijom na koloni (silika-gel: 100 g, etil acetat/heksan: 1/9 do 1/3) da se dobije 2,63g (73%) željenog produkta kao svijetložutog ulja. Njegova optička čistoća je bila 97% ee određeno pomoću HPLC koristeći kiralnu nepokretnu fazu (chiral pak AS, Daicel Chemical Industries, eluirano sa n-heksan/EtOH: 98/2; vrijeme detekcije: 55min za (R)-izomer, 59min za (S)-izomer).
1H NMR (270MHz, CDCl3) δ 7,77 (2H, d, J=8,4Hz), 7,33 (2H, d, J=8,1Hz), 7,22 (1H, dd, J=7,7, 8,1Hz), 7,15-7,05 (3H, m), 4,94 (1H, ddd, J=2,9, 2,9, 8,4Hz), 4,15 (1H, dd, J=2,9, 10,3Hz), 4,04 (1H, dd, J=8,4, 10,3Hz), 2,54 (1H, br, d, J=2,9Hz), 2,45 (3H, s), 2,33 (3H, s), 1,58 (3H, s).
Pripravak 13
2-(3-(S)-metoksimetiloksipirolidin-l-il)-l-(S)-(3-metilfenil)-etanol i
2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)-(3-metilfenil)-etanol
Smjesa (S)-l-(3-metilfenil)-1,2-etandiol 2-tozilata (2,63g, 8,59mmol), (S)-3-metoksi-metiloksipirolidina (l,24g, 9,45mmol) i K2CO3 (1,31g, 9,45mmol) u etanolu (25ml) je refluksirana uz miješanje tijekom 2h. Nakon uklanjanja otapala isparavanjem rezidue su razrijeđene vodom i ekstrahirane sa CH2Cl2- Ekstrakt je ispran sa slanom otopinom, osušen (Na2SO4) i koncentriran da se dobije 2,llg smeđeg ulja koje je pročišćeno kromatografijom na koloni (silika-gel: HOg, CH2Cl2/MeOH: 15/1 do 10/1) da se dobije 1,72g (76%) od 3 do 2 smjese željenih spojeva kao svijetlo smeđe ulje.
1H NMR (270MHz, CDCl3) δ 7,26-7,05 (4H, m), 4,68 (0,6H, dd, J=2,9, 10,6Hz, PhCHOH), 4,67 (0,6H, d, J=7,OHz, OCH2O), 4,63 (0,6H, d, J=6,6Hz, OCH2O), 4,62 (0,4H, d, J=7,OHz, OCH2O), 4,59 (0,4H, d, J=7,OHz, OCH2O), 4,34-4,24 (0,6H, m, OCHCH2N), 4,24-4,16 (0,4H, m, OCHCH2N), 3,88 (0,4H, dd, J=6,2, 10,6Hz, CHCH2OH), 3,79 (0,4H, dd, J=5,8, 11,OHz, CHCH2OH), 3,47 (0,4H, dd, J=5,8, 6,2Hz, NCHPh), 3,38 (1,8H, s), 3,33 (1,2H, s), 3,05-2,92 (1,2H, m), 2,82-2,40 (4H, m), 2,35 (3H, s), 2,25-1,50 (3H, m).
Primjer 45
2-(3,4-diklorfenil)-N-[2-(3-(S)-metoksimetiloksipirolidin-l-il)-l-(S)-(3-metilfenil)etil]-N-tetrahidropiraniloksiacetamid
Ovaj spoj je priređen iz smjese 2-(3-(S)-metoksimetiloksipirolidin-l-il)-l-(S)-(3-metilfenil)etanola i 2-(3-(S)- metoksi metiloksipirolidin-l-il)-2 -(R)(3-metilfenil)etanola s prinosom 60% sukladno postupku slično onom koji je opisan u primjeru 4.
1H NMR (270MHz, CDCl3) δ 7,39 (0,5H, d, J=l,8Hz), 7,35 (0,5H, d, J=8,4Hz), 7,27-7,02 (5,5H, m), 6,96 (0,5H, dd, J=1,8, 8,4Hz), 5,65 (0,5H, dd, J=5,1, 11,4Hz, PhCHN), 5,52 (0,5H, dd, J=4,8, 11,OHz, PhCHN), 5,30-5,20 (1H, m, NOCHO), 4,64 (O,5H, d, J=6,6Hz, OCH2O), 4,63 (O,5H, d, J=7,OHz, OCH2O), 4,61 (0,5H, d, J=6,6Hz, OCH2O), 4,60 (0,5H, d, J=6,6Hz, OCH2O), 4,30-4,20 (0,5H, m, OCHCH2N), 4,20-4,10 (0,5H, m, OCHCH2N), 4,06-3,85 (3H, m), 3,56- 3,36 (1,5H, m), 3,35 (1,5H, s, OMs), 3,34 (1,5H, s, OMe). 3,24-3,10 (0,5H, m), 3,01-2,80 (2H, m), 2,66-2,40 (3H, m), 2,34 (1,5H, s), 2,28 (1,5H, s), 2,15-1,15 (8H, m).
Primjer 46
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-(3-metilfenil)etil]acetamid
Ovaj spoj je priređen iz 2-(3,4-diklorofenil)-N-[2-(3-(S)- metoksi metiloksipirolidin-l-il) -l-(S) -(3- metilfenil) etil)-N-tetrahidropiraniloksiacetamida s prinosom 77% sukladno postupku slično onom koji je opisan u primjeru 5.
1H NMR (270MHz, CDCl3) δ 7,42-7,05 (7H, m), 5,59 (1H, dd, J=5,1, 11,0Hz, PhCHN), 4,35-4,25 (1H, m, CHOH), 3,85 (1H, d, J=14,3Hz, COCH2Ph), 3,74 (1H, d, J=15,8Hz, COCH2Ph), 3,50-2,50 (2H, gotovo ravan br, s, OHx2), 3,38 (1H, dd, J=11,7, 12,1Hz), 3,00-2,90 (1H, m), 2,73 (1H, br, d, J=10,6Hz), 2,62 (1H, dd, J=5,l, 12,5Hz), 2,53 (1H, dd, J=5,5, 10,6Hz), 2,40-2,25 (4H, m, uklj. 3H, s na 2,30ppm), 2,23-2,07 (1H, m), 1,65-1,55 (1H, m).
IR(čisti): 3350, 1650 cm-1.
MS m/z : 422(M+)
HCl sol: amorfna krutina
Analiza izračunata za C21H24Cl2N2O3-HCl-1,5H2O: C, 51,81; H, 5,80; N, 5,75.
Nađeno: C, 51,85; H, 5,72; N, 5,47.
Primjer 47
N-[l-(S)-(4-klorofenil)-2-(3-(S)-hidroksipirolidin-l-il)etil]-2-(3,4-diklorofenil)-N-hidroksiacetamid
Ovaj spoj je priređen iz 4-klorostirena i 3-(S)-metoksimetiloksipirolidina s ukupnim prinosom 12% sukladno postupku slično onom koji je opisan u primjerima 7 do 11.
1H NMR (270MHz, CDCl3) δ 7,40 (1H, d, J=2,2Hz), 7,36 (1H, d, J=8,4Hz), 7,30-7,20 (4H, m), 7,14 (1H, dd, 3=2,2, 8,1Hz), 5,58 (1H, dd, J=5,1, 11,OHz, PhCHN), 5,00-3,00 (2H, gotovo ravan br, s, OHx2), 4,35-4,25 (1H, m, CHOH), 3,85 (1H, d, J=14,3Hz, COCH2Ph), 3,72 (1H, d, J=13,9Hz, COCH2Ph), 3,33 (1H, t, J=11,7Hz), 3,00-2,85 (1H, m), 2,74 (1H, br, d, J=10,3Hz), 2,65 (1H, dd, J=5,1, 12,5Hz), 2,60-2,45 (1H, m), 2,45-2,25 (1H, m), 2,25-2,05 (1H, m), 1,70-1,50 (1H, m).
HCl sol: amorfna krutina
IR(KBr): 3400, 3100, 1650 cm-1.
MS m/z : 443(M+H)+.
Analiza izračunata za C20H21Cl3N2O3-HCl-0,7H2O: C, 48,74; H, 4,79; N, 5,68.
Nađeno: C, 49,15; H, 5,21; N, 5,58.
Primjer 48
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-(4-metoksifenil)etil]acetamid i
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksi-pirolidin-1-il)-1-(R)-(4-metoksifenil)etil] acetamid
Ovi spojevi su priređeni iz 4-metoksistirena i 3-(S)metoksirnetiloksipirolidina s ukupnim prinosom 5,2% sukladno postupku slično onom koji je opisan u primjerima 7 do 11.
U ovom slučaju do racemizacije dolazi na 1-položaju da se dobije naslovljeni spoj tijekom sljedećih reakcija (meziliranje, adicija THPONH2 i aciliranje).
1H NMR (270MHz, CDCl3) δ 7,40-7,26 (4H, m), 7,12 (0,5H, dd, J=2,2, 8,4Hz), 7,11 (0,5H, dd, J=2,6, 8,4Hz), 6,84 (2H, d, J=8,4Hz), 5,70-5,60 (1H, m, PhCHN), 4,50-4,40 (0,5H, m, CHOH), 4,50-3,00 (2H, gotovo ravan br, s, OHx2), 4,40-4,30 (0,5H, m, CHOH), 3,84 (1H, d, J=14,3Hz, COCH2Ph), 3,79 (3H, s), 3,73 (1H, d, J=14,7Hz, COCH2Ph), 3,65-3,40 (1H, m), 3,15-3,00 (1H, m), 2,90-2,40 (4H, m), 2,30-2,10 (1H, m), 1,90-1,78 (0,5H, m), 1,78-1,60 (0,5H, m).
HCl sol: amorfna krutina
IR(KBr): 3400, 3150, 1650 cm-1.
MS m/z: 438(M+)
Analiza izračunata za C21H24Cl2N2O4-HCl-2,5H2O: C, 48,43; H, 5,81; N, 5,38.
Nađeno: C, 48,21; H, 5,75; N, 5,35.
Primjer 49
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-(4-trifluorometilfenil)etil]acetamid
Ovaj spoj je priređen iz 4-tritluorometilstirena i 3-(S)-metoksirnetiloksipirolidina s ukupnim prinosom 25,3% sukladno postupku slično onom koji je opisan u primjerima 7 do 11.
1H NMR (270MHz, CDCl3) δ 7,60-7,35 (6H, m), 7,20-7,10 (1H, m), 5,65 (1H, dd, J=5,5, 11,0Hz, PhCHN), 4,40-4,30 (1H, m, CHOH), 3,90 (1H, d, J=13,9Hz, COCH2Ph), 3,73 (1H, d, J=12,5Hz, COCH2Ph), 3,34 (1H, dd, J=11,0, 12,5Hz), 3,00-2,90 (1H, m), 2,75-2,65 (2H, m), 2,54 (1H, dd, J=5,l, 10,6Hz), 2,50-2,00 (4H, m), 1,70-1,55 (1H, m).
IR(čisti): 3400, 3250, 1635 cm-1.
MS m/z: 476(M+)
HCl sol: amorftia krutina
Analiza izračunata za C21H21Cl2F3N2O3-HCl-2H2O: C, 45,88; H, 4,77; N, 5,10.
Nađeno: C, 45,90; H, 4,83; N, 4,71,
Pripravak 14
(S)-l-(4-metilfenil)-l,2-etandiol 2-tozilat
Ovaj spoj je priređen iz 4-metilstirena s ukupnim prinosom 75% sukladno postupku slično onom koji je opisan u primjerima 7 i 8. Optička čistoća bila je 98,3% ee određeno HPLC analizom.
1H NMR (270MHz, CDCl3) δ 7,77 (2H, d, J=8,1Hz), 7,33 (2H, d, J=8,4Hz), 7,20 (2H, d, J=8,1Hz), 7,14 (2H, d, J=8,1Hz), 5,00-4,90 (1H, m), 4,13 (1H, dd, J=3,3, 10,3Hz), 4,03 (1H, d, J=8,4, 10,3Hz), 2,49 (1H, d, J=2,9Hz), 2,45 (3H, s), 1,57 (3H, s).
Pripravak 15
(S)-4-metilstiren oksid
Smjesa (S)-1-(4-metilfenil)-1,2-etandiol-2-tozilata (4,13g, 13,5mmol) i 50% vodene otopine NaOH (5ml) in THF (25ml) miješana je na sobnoj temperaturi tijekom 1H i na 50°C tijekom 2h. Nakon hlađenja na sobnu temperaturu, reakcijska smjesa je razrijeđena vodom i ekstrahirana etil acetatom. Ekstrakt je ispran vodom i slanom otopinom, osušen (Na2SO4) i koncentriran da se dobije 1,59g (88%) željenog spoja kao blijedosmeđe ulje. Ulje je korišteno za sljedeću reakciju bez pročišćavanja.
1H NMR (270MHz, CDCl3) δ 7,20-7,10 (4H, m), 3,83 (1H, dd, J=2,6, 4,OHz), 3,13 (1H, dd, J=4,0, 5,5Hz), 2,80 (1H, dd, J=2,6, 5,5Hz), 2,34 (3H, s).
Pripravak 16
2-(3-(S)-metoksimetiloksipirolidin-l-il)-l-(S)-(4-metilfenil)-etanol i
2-(3-(S)-metoksimetiloksipirolidin-l-il)-2-(R)-(4-metilfenil)-etanol
Smjesa (S)-4-metilstiren oksida (1,59g, 11,9mmol) i 3-(S)metoksimetiloksipirolidina (1,55g, 11,9mmol) u izopropanolu (25ml) refluksirana je tijekom 7h. Otapalo je ispareno i rezidue su pročišćene kromatografijom na kolon (silika-gel: 150g, CH2Cl2/MeOH: 50/1 do 15/1) da se dobije 2,39g (76%) željenih produkata kao blijedosmeđe ulje. To je 3 prema 2 smjesa naslovljenih spojeva.
1H NMR (270MHz, CDCl3) δ 7,26 (1,2H, d, J=8,1Hz), 7,21-7,10 (2,8H, m), 4,75-4,55 (2,6H, m, uklj. 0,6H, d, 1=6,6Hz na 4,66ppm, 0,6H, d, J=7,0Hz na 4,63ppm, 0,4H, d, J=7,0Hz na 4,62ppm, 0,4H, d, J=7,0Hz na 4,58ppm), 4,35-4,23 (0,6H, m, OCHCH2N), 4,23-4,15 (0,4H, m, OCHCH2N ), 3,87 (0,4H, dd, J=6,2, 10,6Hz, CHCH2OH), 3,77 (0,4H, dd, J=5,9, 10,6Hz, CHCH2OH), 3,49 (0,4H, dd, J=5,9, 6,2Hz, NCHPh), 3,38 (1,8H, s), 3,33 (1,2H, s), 3,05-2,90 (1,2H, m), 2,80- 2,40 (5H, m), 2,34 (3H, s), 2,25-2,00 (1H, m), 1,95-1,75 (1H, m).
Primjer 50
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-(4-metilfenil)etil]acetamid
Ovaj spoj je priređen iz 2-(3-(S)-metoksimetiloksipirolidin-1-il)-1-(S)-(4-metilfenil) etanola i 2-(3-(S) -metoksi metiloksipirolidin-1-il)-2-(R)-(4-metilfenil)etanola s ukupnim prinosom 29,5% sukladno postupku slično onom koji je opisan u primjerima 10 i 11.
1H NMR (270MHz, CDCl3) δ 7,40-7,30 (2H, m), 7,23 (2H, pr. d, J=8,1Hz), 7,11 (3H, pr. d, J=7,7Hz), 5,64 (1H, dd, J=5,1, 11,4Hz, PhCHN), 5,00-3,00 (2H, gotovo ravan br, s, OHx2), 4,40-4,30 (1H, m, CHOH), 3,84 (1H, d, J=14,7Hz, COCH2Ph), 3,73 (1H, d, J=14,3Hz, COCH2Ph), 3,46 (1H, dd, J=11,4, 12,1Hz), 3,10-2,95 (1H, m), 2,83 (1H, br, d, J=11,0Hz), 2,75-2,40 (3H, m), 2,32 (3H, s), 2,25- 2,10 (1H, m), 1,75-1,60 (1H, m).
HC1 sol: amorfna krutina
MS m/z: 422(M+)
IR(KBr): 3420, 3180, 1650 cm-1.
Analiza izračunata za C21H24Cl2N2O3-HCl-0,5H2O: C, 53,80; H, 5,59; N, 5,98.
Nađeno: C, 53,51; H, 5,67; N, 6,04.
Pripravak 17
(S)-1-(3-metoksimetiloksifenil)-1,2-etandiol
Ovaj spoj je priređen iz 3-metoksimetiloksistirena (priređen metoksimetiliranjem 3-hidroksistirena standardnim postupkom) s kvantitativnim prinosom sukladno postupku slično onom koji je opisan u primjeru 7.
1H NMR (270MHz, CDCl3) δ 7,2,5 (1H, dd, J=7,7, 8,1Hz), 7,03 (1H, d, J=1,8Hz), 6,98-6,92 (2H, m), 5,15 (2H, s, OCH2OMe), 4,74 (1H, dd, J=3,3, 8,1Hz, ArCHOH), 3,71 (1H, br, d, J=9,9Hz, CHCH2OH), 3,65-3,55 (2H, m, uklj. 1H, dd, J=8,1, 11,0Hz na 3,61ppm, CHCH2OH), 3,44 (3H, s, OCH2OMe), 3,14 (1H, br, s, OH).
Pripravak 18
(S)-l-(3-metoksimetiloksifenil)-1,2-etandiol 2-tozilat
Ovaj spoj je priređen iz (S)-1-(3-metoksimetiloksifenil)-1,2-etandiola s prinosom 64% sukladno postupku slično onom koji je opisan u primjeru 8. Njegova optička čistoća bila je 96% ee određeno HPLC.
1H NMR (270MHz, CDCl3) δ 7,77 (2H, d, J=8,4Hz), 7,34 (2H, d, J=8,1Hz), 7,25 (1H, dd, J=7,7, 8,4Hz), 7,00-6,92 (3H, m), 5,15 (2H, s), 4,95 (1H, ddd, J=3,3, 3,3, 8,4Hz, ArCHOH), 4,15 (1H, dd, J=3,3, 10,3Hz, CHCH2OTs), 4,03 (1H, dd, J=8,4, 10,3Hz, CHCH2OTs), 3,46 (3H, s, OCH2OMe), 2,65 (1H, d, J=3,3Hz, ArCHOH), 2,45 (3H, s, PhMe).
Primjer 51
2-(3,4-diklofenil)-N-[l-(S)-(3-metoksimetiloksifenil)-2-(3-(S)-tetrahidropiranil-oksipirolidin-l-il)etil]-N-tetrahidropiraniIoksi-acetamid
Ovaj spoj je priređen iz (S)-l-(3-metoksimetiloksifenil)-1,2-etandiola 2-tozilata s ukupnim prinosom 52% sukladno postupku slično onom koji je opisan u primjerima 9 i 10.
1H NMR (270MHz, CDCl3) δ 7,42-6,91 (7H, m), 5,65 (0,5H, dd, J=3,3, 9,9Hz, PhCHN), 5,54 (0,5H, dd, J=4,4, 11,0Hz, PhCHN), 5,35-5,25 (1H, m, NOCHO), 5,19 (0,5H, d, J=6,6Hz, OCH2O), 5,15 (0,5H, d, J=6,6Hz, OCH2O), 5,14 (0,5H, d, J=7,OHz, OCH2O), 5,10 (0,5H, d, J=7,OHz, OCH2O), 4,65-4,55 (1H, m, CHOCHO), 4,40-4,30 (0,5H, m, OCHCH2N), 4,30-4,20 (0,5H, m, OCHCH2N), 4,10-3,85 (4H, m, uklj. 0,5H, d, J=16,5Hz na 4,06ppm, 0,5H, d, J=16,5Hz na 3,92ppm, i 1H, s na 3,92ppm, COCH2Ph), 3,68-3,15 (6H, m, uklj. svaki 1,5H, s, na 3,47 i 3,46ppm, OMe). 3,02-2,80 (2H, m), 2,66-2,35 (3H, m), 2,20-1,15 (14H, m).
Primjer 52
2-(3,4-diklorofenil)-N-hidroksi-N-[l-(S)-(3-hidroksifenil)-2-(3-(S)-hidroksipirolidin-l-il)etil]acetamid
Ovaj spoj je priređen iz 2-(3,4-diklorofenil)-N-[l-(S)- (3-metoksimetiloksifenil)N -2-(3-(S)- tetrahidropiraniloksipirolidin-l-il)etil)-N-tetrahidropiraniloksiacetamida s ukupnim prinosom 46% sukladno postupku slično onom koji je opisan u primjeru 11.
1H NMR (270MHz, CDCl3 i DMSOd6) δ 7,56 (1H, s, PhOH), 7,40 (1H, d, J=1,8Hz), 7,37 (1H, d, J=8,4Hz), 7,17 (1H, dd, J=1,8, 8,1Hz), 7,11 (1H, dd, J=7,7, 8,1Hz), 6,90-6,70 (3H, m), 5,56 (1H, dd, J=5,1, 10,6Hz, PhCHN), 4,30-4,20 (1H, m, CHOH), 3,90 (1H, d, J=15,0Hz, COCH2Ph), 3,74 (1H, d, J=14,5Hz COCH2Ph), 4,50-2,50 (2H, gotovo ravan br, s, OHx2), 3,32 (1H, dd, J =11,4, 11,7Hz), 3,00-2,85 (1H, m), 2,75-2,55 (3H, m, uklj. 1H, dd, J=5,1, 11,0Hz), 2,40-2,30 (1H, m), 2,15-2,00 (1H, m), 1,80-1,60 (1H, m).
IR(KBr) : 3350, 3200, 1630 cm-1.
MS m/z : 424(M+)
Freeamine : tt 151,6-153,1°C
Analiza izračunata za C20H22Cl2N2O4-7H2O: C, 54,85; H, 5,39; N, 6,40.
Nađeno: C, 54,70; H, 4,99; N, 6,42.
Kemijske strukture spojeva priređenih u primjerima l do 52 prikazane su u sljedećim tablicama.
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Claims (13)
1. Spoj sljedeće formule, naznačen time:
[image]
i njegove soli, gdje
A je vodik, hidroksi ili OY, gdje Y je hidroksi zaštitna grupa;
Ar je fenil proizvoljno supstituiran s jednim ili više (poželjno do tri) supstituenta odabranih između halo, hidroksi, C1-C4 alkil, C1-C4 alkoksi, CF3, C1-C4 alkoksi- C1-C4 alkiloksi, te karboksi- C1-C4 alkiloksi;
X je fenil, naftil, bifenil, indanil, benzofuranil, benzotiofenil, l-tetralon-6-il, C1-C4 alkilendioksi, piridil, furil i tienil, ove grupe mogu proizvoljno biti supstituirane sa do tri supstituenta odabranih između halo, C1-C4 alkil, C1-C4 alkoksi, hidroksi, NO2, CF3 i SO2CH3; i
R je vodik, C1-C4 alkil ili hidroksi zaštitna grupa.
2. Spoj prema zahtjevu 1, naznačen time, gdje A je vodik ili hidroksi, te R je vodik ili C1-C4 alkil.
3. Spoj prema zahtjevu 2, naznačen time, gdje je Ar fenil.
4. Spoj prema zahtjevu 3, naznačen time, gdje je X fenil supstituiran sa do tri supstituenta odabranih između kloro, metil i CF3, i R je vodik.
5. Spoj prema zahtjevu 4, naznačen time, gdje je X 3,4-diklorofenil.
6. Spoj prema zahtjevu 4, naznačen time jer je odabran između
2-(3,4-diklorofenil)-N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil)acetamid;
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinIl)etil]-2-(2,3,6-triklorofenil)acetamid;
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(4-trifluorometilfenil)acetamid;
N-hidroksi-N-[1-(S)-fenil-2-(1-pirolidinil)etil]-2-(2,4,6-trimetilfenil)acetamid;
2-(3,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(4-bromofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]-2-(4-trifluorometilfenil)acetamid;
2-(4-klorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(2,3-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil)acetamid;
2-(2,4-diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(2,5-diklorofenil)-N-hidroksi-N-(2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
2-(2,6-Diklorofenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil]acetamid;
N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-l-il)-l-(S)-feniletil]-2-(2,3,6-triklorofenil)acetamid;
2-(3,4-diklorofenil)-N-[2-(3-(S)-hidroksipirolidinl-il)-1-(S)-feniletil)acetamid; i
2-(3,4-dimetilfenil)-N-hidroksi-N-[2-(3-(S)-hidroksipirolidin-1-il)-1-(S)-feniletil)acetamid.
7. Spoj prema zahtjevu 1, naznačen time, gdje je A OY, i R je hidroksi zaštitna grupa, i gdje je hidroksi zaštitna grupa odabrana između benzil, trifenilmetil, tetrahidropiranil, metoksimetil i R1R2R3Si, gdje su R1, R2, R3 svaki C1-C6 alkil ili fenil.
8. Farmaceutski pripravak koristan kao analgetički, antiupalni, diuretički, ane-stetički ili neuroprotektivni agens, ili agens za liječenje inzulta ili funkcionalnih crijevnih bolesti kao što je abdominalna bol, naznačen time, koji sadrži spoj prema zahtjevu 1 i farmaceutski inertan nosač.
9. Metoda za tretiranje medicinskih stanja za koje je nužna agonistička aktivnost opijatskih kapa receptora, za sisavce, naznačena time što obuhvaća primjenu terapeutski efektivne količine spoja sukladno zahtjevu 1.
10. Spoj sljedeće formule:
[image]
i njegove soli, naznačen time, gdje
A je vodik, hidroksi ili OY, gdje Y je hidroksi zaštitna grupa;
Ar je fenil proizvoljno supstituiran s jednim ili više (poželjno do tri) supstituenta odabranih između halo, hidroksi, C1-C4 alkil, C1-C4 alkoksi, CF3, C1-C4 alkoksi- C1-C4 alkiloksi, te karboksi- C1-C4 alkiloksi; i
R je vodik, C1-C4 alkil ili hidroksi zaštitna grupa.
11. Postupak za dobivanje spoja formule (II), naznačen time, koji uključuje reakciju etanol aminskog spoja formule (III) sa hidroksilaminom formule (IV):
[image]
da se dobije spoj formule (V):
[image]
a zatim reakciju spoja formule (V) sa metansulfonil kloridom u prisutnosti baze nakon čega slijedi dodatak zaštićenog hidroksilamina i, ako je potrebno, uklanjanje zaštitine grupe.
12. Postupak za dobivanje spoja formule (II), naznačen time, koji uključuje reakciju pirolidinil spoja formule (VII) sa supstituiranim ili nesupstituiranim fenil-oksidom formule (VIII):
[image]
da se dobije smjesa spoja formule (IX) i spoja formule (X);
[image]
te zatim reakciju dobivene smjese sa metansulfonil kloridom u prisutnosti baze nakon čega slijedi dodatak zaštićenog hidroksilamina i, ako je potrebno, uklanjanje zaštitne grupe.
13. Postupak za dobivanje spoja formule (I), naznačen time, koji obuhvaća reakciju spoja formule (II) gdje je R hidroksi zaštitna grupa sa karboksilnom kiselinom formule XCH2COOH, uklanjanje zaštitine grupe sa dobivenog spoja, nakon čega slijedi, ako je potrebno, alkiliranje dobivenog spoja.
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MX9701042A (es) * | 1996-02-07 | 1998-05-31 | Pfizer | Compuestos del acido hidroxamico. |
TNSN97092A1 (ar) | 1996-09-18 | 1999-12-31 | Agouron Pharma | مثبطات انزيم بروتيني فلزي وتركيبات صيدلانية تحتوي على تلك المثبتطات واستخدامها الصيدلاني وطرق ومركبات وسيطة مفيدة لتحضير التركيبات المذكورة. |
DE69720518T2 (de) * | 1996-12-02 | 2004-02-26 | Kyorin Pharmaceutical Co., Ltd. | Neue derivate von n-substituierten pyrrolidin derivaten und deren herstellungsverfahren |
WO1998030540A1 (en) * | 1997-01-10 | 1998-07-16 | Merck & Co., Inc. | Efficient synthesis of a chiral mediator |
EP0982297A3 (en) * | 1998-08-24 | 2001-08-01 | Pfizer Products Inc. | Process for the preparation of hydroxy-pyrrolidinyl hydroxamic acid derivatives being opioid kappa receptor agonists |
KR100295740B1 (ko) * | 1998-09-17 | 2001-11-05 | 박영구 | N-치환된-하이드록시고리화알킬아민유도체의제조방법 |
US6444829B1 (en) * | 2000-07-19 | 2002-09-03 | Hoffmann-La Roche Inc. | Pyrrolidine compounds |
WO2002088082A2 (en) | 2001-04-30 | 2002-11-07 | Pfizer Products Inc. | Process for preparing hydroxypyrrolidinyl ethylamine compounds useful as kappa agonists |
US7091357B2 (en) * | 2001-12-26 | 2006-08-15 | University Of Kentucky Research Foundation | Chain-modified pyridino-N substituted nicotine compounds for use in the treatment of CNS pathologies |
AU2003269399A1 (en) * | 2002-11-01 | 2004-05-25 | Pfizer Products Inc. | Process for the preparation of pyrrolidinyl ethylamine compounds via a copper-mediated aryl amination |
GB0821010D0 (en) * | 2008-11-17 | 2008-12-24 | Univ Warwick | Plant development control composition |
US9493451B2 (en) | 2011-05-16 | 2016-11-15 | Bionomics Limited | Amine derivatives as potassium channel blockers |
KR101773331B1 (ko) * | 2012-03-05 | 2017-08-31 | 닥터 레디스 레보러터리즈 리미티드 | 카파 오피오이드 수용체(κor) 작용제인 치환된 헤테로시클릭 아세트아미드 |
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