RO133248A2 - Bicyclo[2.2.1.]heptane amines protected at hydroxyl group - Google Patents
Bicyclo[2.2.1.]heptane amines protected at hydroxyl group Download PDFInfo
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- RO133248A2 RO133248A2 ROA201700850A RO201700850A RO133248A2 RO 133248 A2 RO133248 A2 RO 133248A2 RO A201700850 A ROA201700850 A RO A201700850A RO 201700850 A RO201700850 A RO 201700850A RO 133248 A2 RO133248 A2 RO 133248A2
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- Romania
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- exo
- endo
- silyl
- trityl
- Prior art date
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- -1 heptane amines Chemical class 0.000 title claims abstract description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000468 ketone group Chemical group 0.000 claims abstract description 6
- 239000000543 intermediate Substances 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 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 15
- 125000004185 ester group Chemical group 0.000 claims description 8
- 125000000075 primary alcohol group Chemical group 0.000 claims description 8
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 3
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 3
- 150000003138 primary alcohols Chemical class 0.000 claims description 3
- TUFKXBSYCAKZAV-UHFFFAOYSA-N C.C.F Chemical compound C.C.F TUFKXBSYCAKZAV-UHFFFAOYSA-N 0.000 claims description 2
- 101000804877 Schizosaccharomyces pombe (strain 972 / ATCC 24843) 5'-3' exoribonuclease 1 Proteins 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 108010036895 endo-alpha-sialidase Proteins 0.000 claims description 2
- 108010079846 endometriosis protein II Proteins 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003198 secondary alcohol group Chemical group 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 3
- 230000001131 transforming effect Effects 0.000 claims 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- 150000003333 secondary alcohols Chemical class 0.000 claims 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 20
- 230000015572 biosynthetic process Effects 0.000 abstract description 19
- 125000004170 methylsulfonyl group Chemical class [H]C([H])([H])S(*)(=O)=O 0.000 abstract description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003328 mesylation reaction Methods 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 235000019441 ethanol Nutrition 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000001540 azides Chemical class 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000011736 potassium bicarbonate Substances 0.000 description 9
- 235000015497 potassium bicarbonate Nutrition 0.000 description 9
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 9
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 9
- 102100037091 Exonuclease V Human genes 0.000 description 8
- 108050006542 Exonuclease V Proteins 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 150000007530 organic bases Chemical group 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002689 soil Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- 238000006266 etherification reaction Methods 0.000 description 4
- CETWDUZRCINIHU-UHFFFAOYSA-N methyl-n-amyl-carbinol Natural products CCCCCC(C)O CETWDUZRCINIHU-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UOIFTOBIGNZZSO-UHFFFAOYSA-N acetic acid;ethyl acetate;hexane Chemical compound CC(O)=O.CCCCCC.CCOC(C)=O UOIFTOBIGNZZSO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000006884 silylation reaction Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- JEPPYVOSGKWVSJ-UHFFFAOYSA-N bicyclo[2.2.1]heptan-3-amine Chemical compound C1CC2C(N)CC1C2 JEPPYVOSGKWVSJ-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MNKYQPOFRKPUAE-UHFFFAOYSA-N chloro(triphenyl)silane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 MNKYQPOFRKPUAE-UHFFFAOYSA-N 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000010956 selective crystallization Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- UTXPCJHKADAFBB-UHFFFAOYSA-N tribenzyl(chloro)silane Chemical compound C=1C=CC=CC=1C[Si](CC=1C=CC=CC=1)(Cl)CC1=CC=CC=C1 UTXPCJHKADAFBB-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- LIEGWYWVCCBSKN-UHFFFAOYSA-N 3-bicyclo[2.2.1]heptanyl methanesulfonate Chemical compound C1CC2C(OS(=O)(=O)C)CC1C2 LIEGWYWVCCBSKN-UHFFFAOYSA-N 0.000 description 1
- FSMHNRHLQAABPS-UHFFFAOYSA-N 4-methoxy-3,6-dihydro-2h-pyran Chemical compound COC1=CCOCC1 FSMHNRHLQAABPS-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- VVBXKASDRZXWON-UHFFFAOYSA-N N=[PH3] Chemical compound N=[PH3] VVBXKASDRZXWON-UHFFFAOYSA-N 0.000 description 1
- 241001230134 Phasis Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000003428 Staudinger Azide reduction reaction Methods 0.000 description 1
- 241001104043 Syringa Species 0.000 description 1
- 235000004338 Syringa vulgaris Nutrition 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical group CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000005670 ethenylalkyl group Chemical group 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Invenția se referă la amine biciclo[2.2.1]heptanice și la un procedeu de obținere a acestoraThe invention relates to heptane bicyclo [2.2.1] amines and to a process for obtaining them
Se cunoaște că în strategiile de sinteză ale nucleozidelor carbociclice, prin construirea inelului pirimidinic sau puririic, aminele funcționalizate corespunzător la grupele chimice atașate la fragmentul structural, pot fi utilizate neprotejate, sau mai convenabil pentru reacțiile ulterioare sau pentru izolarea compușilor, sau protejate mai ales la grupele hidroxilice cu grupe esterice sau (silii )eterice.It is known that in the synthesis strategies of carbocyclic nucleosides, by constructing the pyrimidine or puririic ring, the functionalized amines corresponding to the chemical groups attached to the structural fragment, may be used unprotected, or more convenient for subsequent reactions or for isolation of the compounds, or especially protected at hydroxyl groups with ester or (sily) ether groups.
Anterior amina biciclo[2.2.1]heptanică, (1), sau protejată cu o grupă benzoat, (2), au fost utilizate la obținerea de nucleozide carbociclice de tip pirimidinic (3) sau purinic (4) ce conțin fragmentul structural al aminei, cu activitate antivirală [C. Tănase et al., Bioorg. Med. Chem. 2014, 22, 513522]:Previously heptane bicyclo [2.2.1] amine, (1), or protected with a benzoate group, (2), have been used to obtain pyrimidine (3) or purine (4) carbocyclic nucleosides containing the structural fragment of the amine. , with antiviral activity [C. Tanase et al., Bioorg. Med. Chem. 2014, 22, 513522]:
Dar modificările la nivelul radicalilor R1-R4 necesită protejarea selectivă a grupei hidroxil, de preferat cu grupe eterice, silil-eterice, tritil, sau cu grupe esterice aromatice, ca de ex. pfenilbenzoat, p-nitrobenzoat, sau fenil substituit, sau cu grupe esterice alifatice.But modifications at R 1 -R 4 radicals require selective protection of the hydroxyl group, preferably with etheric, silyl-etheric, trityl, or aromatic ester groups, e.g. pphenylbenzoate, p-nitrobenzoate, or substituted phenyl, or with aliphatic ester groups.
Invenția prezintă o variantă eficientă de transformare a cetoalcoolului 1 în aminele 8, ce conțin o grupă protectoare eterică, silil-eterică, tritil, stabile în condiții bazice, sau o grupă ester, stabile în ondiții acide, precum și transformarea acestora în amina 9, intermediari utili pentru sinteza de analogi de nucleozide carbociclice, în sinteza organică fină, ca intermediari în sinteza de compuși de interes terapeutic (Schema 1).The invention discloses an effective variant for the conversion of ketoalcohol 1 into amines 8, containing an ethereal, silyl-ethereal, trityl group, stable under basic conditions, or an ester group, stable in acidic amino acids, and their conversion to amine 9, Useful intermediates for the synthesis of carbocyclic nucleoside analogues, in fine organic synthesis, as intermediates in the synthesis of compounds of therapeutic interest (Scheme 1).
a 2017 00850to 2017 00850
20/10/201710/20/2017
llaIIa
exo-IVa, R = Tr endo-IVa, R = Tr endo-IVb, R = TBDMS exo-IVb, R = TBDMSexo-IVa, R = Tr endo-IVa, R = Tr endo-IVb, R = TBDMS exo-IVb, R = TBDMS
endo-llla, R = Tr exo-llla, R = Tr endo-lllb, R = TBDMS exo-lllb, R = TBDMSendo-llla, R = Tr exo-llla, R = Tr endo-lllb, R = TBDMS exo-lllb, R = TBDMS
endo-IX exo-ΙΧ endo-X endo-llla, R1 = Tr 'OH .CI exo-VII exo-VIa, R = Tr exo-Va, R = Tr exo-Vlb, R = TBDMS exo-Vb, R = TBDMSendo-IX exo-ΙΧ endo-X endo-llla, R 1 = Tr 'OH .CI exo-VII exo-VIa, R = Tr exo-Va, R = Tr exo-Vlb, R = TBDMS exo-Vb, R = TBDMS
VIIIVIII
Schema 1. Transformarea cetoalcoolului I în aminele substituite la grupele hidroxilice exo-V, amina VIII și azida exo-V llc; pentru simplificare este prezentat numai halogenul CI, dar transformările sunt valabile și pentru compușii cu atom de F, Br, I în loc de CI.Scheme 1. Transformation of ketoalcohol I into substituted amines in exo-V hydroxyl groups, amine VIII and exo-V azc; for simplification, only the halogen CI is shown, but the transformations are also valid for compounds with F, Br, I instead of CI.
Invenția se referă la un procedeu (Procedeul 1) de transformare a cetoalcoolului / în aminele exoVI ce conțin o grupă protectoare eterică, silil-eterică, tritil, stabile în condiții bazice, sau o grupă ester, procedeu în care separarea alcoolului endo se realizează la etapa compușilor mesilați prin cristalizare selectivă, în care:The invention relates to a process (Process 1) for the transformation of ketoalcohol / into exoVI amines containing an etheric, silyl-etheric, trityl, stable conditions under basic conditions, or an ester group, wherein the endo alcohol separation is performed at the phase of the mesylate compounds by selective crystallization, in which:
R este o grupă eterică: THP, benzii, etoxietil, etoxi-7-butil, etc., tritil nesubstituit sau ubstituit cu una sau mai multe grupe fenil cu un atom de halogen, OH, nitro, CN, CF3, silileterică: trietilsilil, TBDMS, PhDMS, diPhMeS, PhaSi, etc sau esterică: p-fenilbenzoil, p-nitrobenzoil,R is an ether group: THP, benzyl, ethoxyethyl, ethoxy-7-butyl, etc., trityl unsubstituted or substituted by one or more phenyl groups with a halogen atom, OH, nitro, CN, CF3, silyl ether: triethylsilyl, TBDMS, PhDMS, diPhMeS, PhaSi, etc. or steric: p-phenylbenzoyl, p-nitrobenzoyl,
R este o grupă esterică aromatică sau alifaticăR is an aromatic or aliphatic ester group
Atomul de halogen din Schema 1 poate fi un atom de CI, F, Br sau IThe halogen atom of Scheme 1 can be a CI, F, Br or I atom
Acesta constă în protejarea grupei alcoolice a intermediarului I cu o grupă eterică sau esterică, reducerea selectivă a grupei cetonice a compusului II la alcoolul endo-lll în prezență de 6-10% alcool exo-lll, mesilarea amestecului de alcooli la compușii endo- și exo-lll, separarea selectivă a mesilatului endo-IV prin cristalizare, transformarea grupei mesil în grupă azidă exo-V, cu inversia configurației și reducerea grupei azidă la grupa amină a compușilor VI; azida exo-V deprotejată la azida exo-VII (care poate fi redusă la amina VIII), iar amina VI la amina VIIIt consists in protecting the alcohol group of intermediate I with an ether or ester group, the selective reduction of the ketone group of compound II to the endo-III alcohol in the presence of 6-10% exo-III alcohol, the mesylation of the mixture of alcohols to the endo- and III compounds. exo-II, selective separation of endo-IV mesylate by crystallization, transformation of the mesyl group into exo-V azide group, with the inversion of the configuration and reduction of the azide group to the amine group of compounds VI; deprotected exo-V azide to exo-VII azide (which can be reduced to amine VIII), and amine VI to amine VII
I.C.C.F.I.C.C.F.
F.UCUPESF.UCUPES
II
X L a2017 00850 20/10/2017X L a2017 00850 10/20/2017
Invenția se teferă deasemenea la un procedeu alternativ (Procedeul 2), pentru transformarea cetoalcoolului I în aminele exo-VI, prin reducerea inițială selectivă a grupei cetonice la diolul endoIII și separatea alcoolului 5-endo prin cristalizare selectivă și purificare cromatografică la această etapă, urmată de protejarea selectivă a grupei de alcool primar, etapele ulterioare encfo-lll e endo-N H exo-V e exo-VI, respectiv exo-V la exo-VII și exo-VI la VIII, fiind identice, R și X au semnificația de mai sus.The invention also refers to an alternative process (Process 2), for the conversion of ketoalcohol I into exo-VI amines, by the initial selective reduction of the ketone group to the endoIII diol and the separation of the 5-endo alcohol by selective crystallization and chromatographic purification at this stage, followed the selective protection group of the primary alcohol subsequent steps encfo-III is endo-N H exo-V is exo-VI, respectively exo-V exo-VII and exo-VI to VIII, are identical, R and X have the meaning above.
Etapele de sinteză cuprinse în cele două procedee, constau din:The synthesis stages included in the two processes consist of:
1. Eterificarea grupării de alcool primar a cetoalcoolului I la compusul protejat II, se realizează într-un solvent inert, ca de ex.: toluen, xilen, diclormetan, dicloretan, cloroform, metilcloroform, tetrahidrofuran, dioxan, eter etilic, eter propilic, eter izopropilic, metil-terț-butileter, ,:metoxietan, etc, de preferat diclormetan, cloroform, tetrahidrofuran, cu 3,4-dihidro-2H-piran, 5,6dihidro-4-metoxi-2H-piran, 2,3-dihidrofuran, vinil-alchil-eter, în care grupa alchil este un radical liniar cu 1 la 10 atomi de carbon, de preferință 2 la 4 atomi de carbon, sau ramificat cu 3 la 10 atomi de carbon, de preferință 3 la 5 atomi de carbon, în prezența unui acid organic sulfonic ca de ex. acid benzensulfonic, acid pioluensulfonic, rășină schimbătoare de ioni puternic acidă în forma1. The etherification of the primary alcohol group of the ketoalcohol I to the protected compound II is carried out in an inert solvent, such as toluene, xylene, dichloromethane, dichloromethane, chloroform, methylchloroform, tetrahydrofuran, dioxane, ethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether,,: methoxyethane, etc., preferably dichloromethane, chloroform, tetrahydrofuran, 3,4-dihydro-2H-pyran, 5,6-dihydro-4-methoxy-2H-pyran, 2,3- dihydrofuran, vinyl alkyl ether, wherein the alkyl group is a linear radical with 1 to 10 carbon atoms, preferably 2 to 4 carbon atoms, or branched with 3 to 10 carbon atoms, preferably 3 to 5 atoms. carbon, in the presence of a sulfonic organic acid such as e.g. benzenesulfonic acid, pioluensulfonic acid, strongly acid ion exchange resin in the form
H, sau carboxilic ca de ex. acid oxalic, trifluoracetic, tricloracetic, sau a unei sări a acestora cu o bază organică terțiară ca piridină, trietilamină, ca de ex. tosilatul de piridiniu, la temperaturi cuprinse între OnC și 50iiC, de preferință între 15 și 40iiC, cu un raport de agent de eterificare/cet oalcool cuprins între 1:1 și 2.5:1, de preferat cuprins între 1.1:1 și 1.5:1, sub agitare la un timp determinat prin CSS.H, or carboxylic as e.g. oxalic, trifluoroacetic, trichloroacetic acid, or a salt thereof with a tertiary organic base such as pyridine, triethylamine, e.g. pyridinium tosylate, at temperatures between OnC and 50iiC, preferably between 15 and 40iiC, with an etherification / alcohol ratio of alcohol between 1: 1 and 2.5: 1, preferably between 1.1: 1 and 1.5: 1 , under agitation at a time determined by CSS.
Sililarea grupării de alcool primar a cetoalcoolului I la compusul protejat II, se realizează într-un Jvent inert, ca cei menționați mai sus, de preferat diclormetan sau tetrahidrofuran, în prezența unei baze organice terțiare, ca de ex. piridină, trietilamină, imidazol, cu un trialchil-, triaril- sau arilalchil-halogeno-silan (halogen: clor, brom), de preferat clorsilan, ca de ex.: tert-butildimetilclorsilan, terț-butil -difenilclorsilan, dimetil-texilThe silylation of the primary alcohol group of the ketoalcohol I to the protected compound II is carried out in an inert vent, as mentioned above, preferably dichloromethane or tetrahydrofuran, in the presence of a tertiary organic base, e.g. pyridine, triethylamine, imidazole, with a trialkyl-, triaryl- or arylalkyl-halogen-silane (halogen: chlorine, bromine), preferably chlorsilane, such as: tert-butyldimethylchlorosilane, tert-butyl-diphenylchlorosilane, dimethyl-texil
-clorsilan, trietilclorsilan, trifenilclorsilan, tribenzilclorsilan, trietilclorsilan, cu sau fără DMAP catalizator, la temperaturi cuprinse între -20nC și 60nC, de preferință între OiiC și 30iiC, cu un raport de agent de sililare/cetoalcool cuprins între 1:1 și 2.5:1, de preferat cuprins între 1.1:1 și-chlorosilane, triethylchlorosilane, triphenylchlorosilane, tribenzylchlorosilane, triethylchlorosilane, with or without catalyst DMAP, at temperatures between -20nC and 60nC, preferably between OiiC and 30iiC, with a ratio of silylation / ketoalcohol to 2.5: 1 1, preferably between 1.1: 1 and
I. 5:1, sub agitare energică la un timp determinat prin CSS.I. 5: 1, under energetic agitation at a time determined by CSS.
Eterificarea grupării de alcool primar a cetoalcoolului I la compusul protejat II, cu o grupare benzii, tritil, sau tritil substituit la unul sau mai multe inele fenil, se realizează în prezența unei baze organice terțiare, ca de ex. piridină, trietilamină, cu sau fără un co-solvent inețu cu clorura dibenzil sau de tritil corespunzătoare, fără sau de preferat cu DMAP catalizatorJ^ țș'Țri^rațuri a 2017 00850Etherification of the primary alcohol group of the ketoalcohol I to the protected compound II, with a benzyl, trityl, or trityl group substituted on one or more phenyl rings, is performed in the presence of a tertiary organic base, e.g. pyridine, triethylamine, with or without an appropriate co-solvent with the corresponding dibenzyl chloride or trityl, without or preferably with DMAP catalyst ducks of 2017 00850
20/10/2017 J cuprinse între OuC și 60uC, de preferință între OnC și 30iiC, cu un raport de agent de eterilîcare (halogenură de alchil)/cetoalcool cuprins între 1:1 și 2.5:1, de preferat cuprins între 1.1:1 și 1.5:1, sub agitare la un timp determinat prin CSS.10/20/2017 J ranging from OuC to 60uC, preferably between OnC and 30iiC, with a ratio of etherylating agent (alkyl halide) / ketoalcohol between 1: 1 and 2.5: 1, preferably between 1.1: 1 and 1.5: 1, under shaking at a time determined by CSS.
Sililarea sau eterificarea selectivă a grupei de alcool primar a diolului endo-IX la compusul protejat endo-lll, se realizează cu reactivi cu grupe voluminoase, ca de ex. tert-butildimetilclorsilan, terf-butil-difenilclorsilan, dimetil-texil-cbrsilan, trietilclorsilan, trifenilclorsilan, tribenzilclorsilan sau tritil (ne)substituit, în condițiile menționate mai sus.Selective silylation or etherification of the primary alcohol group of the endo-IX diol to the endo-III protected compound is performed with reagents with large groups, such as. tert-butyldimethylchlorosilane, tert-butyl-diphenylchlorosilane, dimethyl-texil-cbrsilane, triethylchlorosilane, triphenylchlorosilane, tribenzylchlorosilane or substituted trityl (not) under the conditions mentioned above.
Esterificarea grupei de alcool a cetoalcoolului I la compusul II se realizează prin reacții cunoscute de acilare cu o clorură sau anhidridă de arii sau alchil în prezența unei baze organice terțiare, ca de ex. piridină, trietilamină, etc, care poate fi utilizată și ca solvent, cu un co-solvent inert, ca deThe esterification of the alcohol group of the ketoalcohol I to compound II is performed by known acylation reactions with an aryl or alkyl chloride or anhydride in the presence of a tertiary organic base, e.g. pyridine, triethylamine, etc., which can also be used as a solvent, with an inert co-solvent, such as
x.: toluen, xilen, diclormetan, dicloretan, cloroform, metilcloroform, tetrahidrofuran, dioxan, eter etilic, eter propilic, eter izopropilic, metil-tert-butileter, dimetoxietan, etc, la temperaturi cuprinse între OnC și 6O-8O11C, de preferat cuprinse între O11C și temperatura camerei, cu un raport de agent de acilare/cetoalcool cuprins între 1:1 și 2.5:1, de preferat cuprins între 1.1:1 și 1.5:1, sub agitare la un timp determinat prin CSS.x .: toluene, xylene, dichloromethane, dichloromethane, chloroform, methylchloroform, tetrahydrofuran, dioxane, ethyl ether, propyl ether, isopropyl ether, methyl-tert-butyl ether, dimethoxyethane, etc., at temperatures between OnC and 6O-8O11C, preferably between O11C and room temperature, with an acylation / ketoalcohol ratio of between 1: 1 and 2.5: 1, preferably between 1.1: 1 and 1.5: 1, with stirring at a time determined by CSS.
2. Reducerea selectivă a grupei cetonice a compusului protejat II la alcoolul endo-lll, în prezența unor cantități <10% de alcool exo-lll, se realizează cu un reactiv de reducere, ca de ex. borohidrură de sodiu, litiu, potasiu sau a unei baze terțiare organice, hidrură de litiu și aluminiu, boran, alchilboran, într-un solvent adecvat reactivului de reducere, de preferință cu borohidrură de sodiu în metanol sau metanol-tetrahidrofuran, la temperaturi cuprinse între -60°C și temperatura amerei, sub agitare la un timp determinat prin CSS.2. The selective reduction of the ketone group of the protected compound II to the alcohol endo-II, in the presence of quantities <10% of exo-III alcohol, is carried out with a reduction reagent, as for example. sodium, lithium, potassium or an organic tertiary base, lithium and aluminum hydride, borane, alkylborane, in a solvent suitable for the reducing reagent, preferably with sodium borohydride in methanol or methanol-tetrahydrofuran, at temperatures between -60 ° C and bitter temperature, with stirring at a time determined by CSS.
3. Acilarea grupei de alcool secundar a amestecului de alcooli endo-lll +exo-lll, sau al alcoolului pur endo-X la amestecul de compuși endo-IV + exo-IV, sau la compusul endo-XI, se realizează cu un reactiv ce conduce la o grupă ușor de substituit în etapa următoare, ca de ex. mesil, trifluorometansulfonil, tosil, etc. cu clorură de mesil, trifluorometansulfonil, tosil sau anhidridă trifluorometansulfonică, de preferat cu clorură de mesil, în prezența unei baze organice terțiare, ca de ex. piridină, trietilamină, etc, care poate fi utilizată și ca solvent, în prezen La unui solvent inert, men *-ionat mai sus, la temperaturi cuprinse între O11C și 60°C, de preferat cuprinse între OnC și temperatura camerei, cu un raport de agent de acilare/alcool cuprins între 1:1 și3. Acylation of the secondary alcohol group of the mixture of endo-III + exo-III alcohol, or of pure endo-X alcohol to the mixture of endo-IV + exo-IV compounds, or to the endo-XI compound, is performed with a reagent. which leads to an easily substitutable group in the next step, e.g. mesyl, trifluoromethanesulfonyl, tosyl, etc. with mesyl chloride, trifluoromethanesulfonyl, tosyl or trifluoromethanesulfonic anhydride, preferably with mesyl chloride, in the presence of a tertiary organic base, e.g. pyridine, triethylamine, etc., can be used as a solvent in the presence of an inert solvent L, the above-mentioned * ion, O11C at temperatures between 60 ° C, preferably between room temperature and ONC with a ratio of acylating agent / alcohol between 1: 1 and
5:1, de preferat cuprins între 1.1:1 și 1.5:1, sub agitare la un timp determinat prin CSS.5: 1, preferably between 1.1: 1 and 1.5: 1, with stirring at a time determined by CSS.
Acilarea selectivă a grupei de alcool primar al compusului endo-IX sau I, se realizează^ clorură < /Bi' I.C.C.F. ':·Τ\ de pfenilbenzoil, p-nitro-benzoil, sau benzoil substituit, în condițiile menționate mai sus.- bucurești 77The selective acylation of the primary alcohol group of the endo-IX or I compound is carried out ^ chloride </ Bi 'ICCF' : · Τ \ of pphenylbenzoyl, p-nitro-benzoyl, or substituted benzoyl, under the conditions mentioned above.- Bucharest 77
T -A J.10!’>1997 '· y a 2017 00850 20/10/2017T -A J.10! '> 1997' · y to 2017 00850 10/20/2017
4. Substituția grupei mesil, tr’rfluorometansulfonil, tosil, etc. cu o grupă azidă, reacție ce are loc cu inversia configurației, se realizează cu o azidă anorganică sau organică, de preferință cu azidă de sodiu, într-un solvent polar, ca de ex. dimetilformamidă (DMF), hexametilfosfortriamidă (HMPA), dimetilsulfoxid (DMSO), de preferat DMF, la temperaturi cuprinse între 80°Cși 130°C, de preferat cuprinse între 110°C și 130°C cu un raport de azidă/compus mesil cuprins între 2:1 și 6:1, de preferat cuprins între 4:1 și 5:1, sub agitare la un timp determinat prin CSS.4. Substitution of the mesyl group, trfluoromethanesulfonyl, tosyl, etc. with an azide group, a reaction that occurs with the inversion of the configuration, is carried out with an inorganic or organic azide, preferably with sodium azide, in a polar solvent, such as. dimethylformamide (DMF), hexamethyl phosphoriamide (HMPA), dimethylsulfoxide (DMSO), preferably DMF, at temperatures between 80 ° C and 130 ° C, preferably between 110 ° C and 130 ° C with an azide / mesyl compound ratio between 2: 1 and 6: 1, preferably between 4: 1 and 5: 1, with stirring at a time determined by CSS.
5. Reducerea grupei azidă la grupă amină se realizează prin hidrogenare catalitică pe un catalizator de 10-20%Pd(OH)2/C, 5 —Tl0%Pd/C, într-un solvent convenabil, ca de ex. metanol, etanol, acetat de etil, tetrahidrofuran, dioxan, diclormetan, cloroform, la presiune atmosferica sau la 1-30 atm, sau prin reducere Staudinger cu trifenilfosfină sau un fosfit la un iminofosforan, într-un solvent ca de ex. piridină, urmată de descompunerea acestuia cu amoniac apos, 25-30%.5. The reduction of the azide group to the amine group is accomplished by catalytic hydrogenation on a catalyst of 10-20% Pd (OH) 2 / C, 5 -Tl0% Pd / C, in a suitable solvent, e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, chloroform, at atmospheric pressure or 1-30 atm, or by Staudinger reduction with triphenylphosphine or phosphite to an iminophosphorane, in a solvent such as. pyridine, followed by its decomposition with aqueous ammonia, 25-30%.
6. Deprotejarea grupei protectoare eterice, silil-eterice sau tritil a alcoolului primar în compușii exo-V și exo-VI, la compușii exo-VII și VIII, se poate realiza într-o soluție apoasă a unui acid organic carboxilic, ca de ex.: acid acetic, oxalic, citric sau sulfonic, ca de ex. acid ptoluensulfonic, rășină schimbătoare de ioni puternic acidă în forma H, sau într-o soluție apoasă a unui acid anorganic, ca de ex.: acid clorhidric, acid fluorhidric, acid percloric. Pentru îmbunătățirea solubilității se poate adăuga un solvent inert, miscibil cu apa, de tip alcool, ales între metanol, etanol, izopropanol, sau un eter, ales între tetrahidrofuran, dioxan, dimetoxietan, de preferință metanol sau tetrahidrofuran; în unele cazuri, deprotejarea se poate realiza numai în alcool, ca de ex. metanol. Grupările silil-eterice pot fi îndepărtate și în condiții mai blânde cu fluorură de tetra butii amoniu sau amestec de clorură de tetrabutilamoniu și fluorură de potasiu, fluorură de6. Deprotection of the etheric, silyl-etheric or trityl protecting group of the primary alcohol in exo-V and exo-VI compounds, in exo-VII and VIII, can be carried out in an aqueous solution of an organic carboxylic acid, e.g. .: acetic, oxalic, citric or sulfonic acid, such as Ptoluensulphonic acid, a strongly acidic H-ion exchange resin, or in an aqueous solution of an inorganic acid, such as hydrochloric acid, hydrofluoric acid, perchloric acid. In order to improve the solubility, an inert, water-miscible, alcohol-like solvent selected from methanol, ethanol, isopropanol, or an ether, selected from tetrahydrofuran, dioxane, dimethoxyethane, preferably methanol or tetrahydrofuran, may be added; In some cases, deprotection can only be done in alcohol, such as. methanol. Silyl ether groups may also be removed under milder conditions with tetra-butyl ammonium fluoride or a mixture of tetrabutylammonium chloride and potassium fluoride,
3siu, complex HF * piridină. Unele grupări eterice sau silileterice pot fi deprotejate selectiv cu catalizatori neutri, ca de ex. sulfat de cupru, în mediu de acetonă-apă [Z.P. Tan et al., Chin, Chem. Lett, 11(9), 2000, 753-6], ZrCUîn acetonitril [G.V.M. Sharma etal., Let. in Org. Chem, 2005, 2, 5760], etc. Grupa benzii se îndepărtează prin hidrogenare catalitică pe un catalizator de 5—*-10%Pd/C.3siu, HF * pyridine complex. Some ether or silyl ether groups may be selectively deprotected with neutral catalysts, e.g. copper sulphate, in acetone-water medium [Z.P. Tan et al., Chin, Chem. Lett, 11 (9), 2000, 753-6], ZrCUin acetonitrile [G.V.M. Sharma et al., Let. in Org. Chem, 2005, 2, 5760], et al. The benzyl group is removed by catalytic hydrogenation on a 5 - * - 10% Pd / C catalyst.
Deprotejarea grupei protectoare estetice la aceiași compuși se realizează într-un solvent hidroxilic de tip alcool, de preferat alcool metilic, etilic, sau eter miscibil cu apa, ca de ex.: tetrahidrofuran, dioxan, în prezența sau absența unui co-solvent inert ca cei menționați mai sus, cu un hidroxid alcalin, de concentrație cuprinsă între 1M și 5M, de preferat între 1 prin transesterificare cu metoxid de sodiu în metanol, la temperatura camerei, sub a un timp determinat prin CSS.Deprotection of the esthetic protecting group on the same compounds is carried out in a hydroxyl solvent of alcohol type, preferably methyl, ethyl alcohol, or ether miscible with water, such as: tetrahydrofuran, dioxane, in the presence or absence of an inert co-solvent such as those mentioned above, with an alkaline hydroxide, of a concentration between 1M and 5M, preferably between 1 by transesterification with sodium methoxide in methanol, at room temperature, under a time determined by CSS.
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Compușii intermediari și produșii finali pot fi purificați prin cromatografie rapidă pe coloană de silicagel sau prin cristalizare, pentru compușii solizi.Intermediate compounds and final products can be purified by silica gel column chromatography or crystallization for solid compounds.
Se dau în continuare exemple care să ilustreze invenția în exemplele de mai jos au fost utilizați compușii enantiomerici ai celor cu configurația naturală sau compuși racemici, dar este de la sine înțeles că invenția se referă atât la compușii racemici, cât și la ambii enantiomeri. Numerotarea atomilor în moleculă se schimbă în funcție de ordinea de prioritate al substituenților, dar pentru o ușoară comparație, în spectrele RMN se păstrează numerotarea din Schema 1. Spectrele FT-IR au fost efectuate prin ATR, frecvențele sunt exprimate în număr de undă [cm·1], iar intensitatea benzilor prin w-slab, m-mediu, s-intens, vs-foarte intens.Following are examples that illustrate the invention in the examples below, the enantiomeric compounds of those with the natural configuration or racemic compounds were used, but it is understood that the invention relates to both racemic compounds and to both enantiomers. The numbering of the atoms in the molecule changes according to the priority order of the substituents, but for easy comparison, the numbering in the NMR spectra is kept in Scheme 1. The FT-IR spectra were performed by ATR, the frequencies are expressed in wave number [cm · 1 ], and the intensity of the bands through w-weak, m-medium, s-intense, vs-very intense.
Exemplul 1. Sinteza compusului lla, (1S,4S,5S,7R)-5-cloro-7-((tritiloxi)metil)biciclo[2.2.1]heptan-2onă g (0.475 moli) (1S,4S,5S,7R)-5-cloro-7-(hidroximetil)biciclo[2.2.1]heptan-2-onă I, cu [o]d = -40.5 * (1% în MeOH), s-au dizolvat în 220 ml_ Py distilată, apoi s-au adăugat 158.9 g(0.57 moli, 1.2 echiv.) clorură de tritil în porții, la temperature camerei, în decurs de 3h. S-a agitat peste noapte urmărind evoluția reacției prin CSS (Silicagel, acetatde etil-hexan-acid acetic, 5:4:0.1,1, Rfi = 0.37, Rfiia = 0.75, hexan-acetat de etil-acid acetic, 5:2:0.1, II, Rn = 0.15, Rfiia = 0.58). S-a distilat piridina la presiune redusă, rezidiul s-a reluat în 700 mL toluene-hexan (2:1), s-a adăugat 150g gheață pisată, s-a agitat până s-a topit gheața, s-au separat fazele, faza organică s-a spălat cu 400mL sol. 20% KHCO3, 200 mL saramură, s-a uscat (NaaSCU anh.) s-a filtrat și s-a concentrat la sec (Apele j fost extrase cu 300 mL solvent recuperat de la evaporatorul rotativ), produsul brut (236.2 g) s-a dizolvat în 500 mL metanol și peste noapte, la temperatura camerei, au cristalizat 83.4 g produs pur, p.t. = (se înmoaie la 96.9°C și se topește la) 112.8-114.9°C, [o]d = - 38.6°(1% în CHCI3), IR: 3083w, 3058w, 3023w, 2938w, 2883w, 1750vs, 1489m, 1445m, 1399w, 1316w, 1277w, 1179w,Example 1. Synthesis of Compound IIa, (1S, 4S, 5S, 7R) -5-chloro-7 - ((trityloxy) methyl) bicyclo [2.2.1] heptane-2on g (0.475 mol) (1S, 4S, 5S, 7R) -5-chloro-7- (hydroxymethyl) bicyclo [2.2.1] heptane-2-one I, with [o] d = -40.5 * (1% in MeOH), dissolved in 220 ml of distilled Py , then 158.9 g (0.57 moles, 1.2 equiv.) of trityl chloride were added in portions, at room temperature, within 3h. It was stirred overnight following the evolution of the reaction by CSS (Silicagel, ethyl acetate-hexane-acetic acid, 5: 4: 0.1,1, Rfi = 0.37, Rfiia = 0.75, hexane-ethyl acetate-acetic acid, 5: 2: 0.1 , II, Rn = 0.15, Rfiia = 0.58). Pyridine was distilled under reduced pressure, the residue was taken up in 700 mL toluene-hexane (2: 1), 150g of weighed ice was added, the ice was stirred, the phases were separated, the organic phase was washed with 400mL of soil. 20% KHCO3, 200 mL brine, dried (NaaSCU anh.) Was filtered and concentrated to dry (Waters were extracted with 300 mL solvent recovered from the rotary evaporator), the crude product (236.2 g) was dissolved in 500 mL methanol and overnight, at room temperature, crystallized 83.4 g pure product, for = (soften at 96.9 ° C and melt at) 112.8-114.9 ° C, [o] d = - 38.6 ° (1% in CHCI3), IR: 3083w, 3058w, 3023w, 2938w, 2883w, 1750vs, 1489m, 1445m, 1399w, 1316w, 1277w, 1179w,
1147w, 1122w, 1089w, 1063m, 1029w, 971w, 899w, 755s, 701s, 633m, 1H-RMN (CDCI3, Λ ppm,1147w, 1122w, 1089w, 1063m, 1029w, 971w, 899w, 755s, 701s, 633m, 1H-NMR (CDCl3, ppm Λ,
J Hz): 7.28 (d, 6H, H-o, 7.2), 7.33-7.20 (m, 9H, 6H-m, 3H-p), 3.88 (dd, 1H, H-2, 4.1, 7.6), 3.53 (t, 1H, H-8, 9.7), 3.41 (dd, 1H, H-8, 5.0, 9.7), 2.77 (d, 1H, H-1, 3.9), 2.70 (d, 1H, H-4, 4.2), 2.43 (dd, 1H, H-7, 5.0, 8.9), 2.21 (dd, 1H, H-6, 4.7, 18.1), 2.10 (dd, 1H, H-3, 8.0, 15.0), 1.84 (d, 1H, H-6, 18.1), 1.79 (dt, 1H, H-3, 4.2, 15.0), 13C-RMN-300MHz (CDCI3, δ ppm): 213.62 (C-5), 144.04 (Cq), 128.73 (C-m), 127.90 (C-o), 127.13 (C-p), 86.69 (Cq-Tr), 60.61 (C-8), 57.71 (C-2), Ό-1),J Hz): 7.28 (d, 6H, Ho, 7.2), 7.33-7.20 (m, 9H, 6H-m, 3H-p), 3.88 (dd, 1H, H-2, 4.1, 7.6), 3.53 (t , 1H, H-8, 9.7), 3.41 (dd, 1H, H-8, 5.0, 9.7), 2.77 (d, 1H, H-1, 3.9), 2.70 (d, 1H, H-4, 4.2) , 2.43 (dd, 1H, H-7, 5.0, 8.9), 2.21 (dd, 1H, H-6, 4.7, 18.1), 2.10 (dd, 1H, H-3, 8.0, 15.0), 1.84 (d, 1H, H-6, 18.1), 1.79 (dt, 1H, H-3, 4.2, 15.0), 13 C-NMR-300MHz (CDCl3, δ ppm): 213.62 (C-5), 144.04 (C q ), 128.73 (Cm), 127.90 (Co), 127.13 (Cp), 86.69 (Cq-Tr), 60.61 (C-8), 57.71 (C-2), Ό-1),
49.29 (C-7), 46.93 (C-4), 45.91 (C-6), 34.16 (C-3). Prin concentrarea soluție mu j s^49.29 (C-7), 46.93 (C-4), 45.91 (C-6), 34.16 (C-3). By concentrating the solution mu j s ^
BUCURFSTI :'2!j obținut 80.0 g produs pur, randament total 83.2%. 'BUCURFSTI : '2! J obtained 80.0 g pure product, total yield 83.2%. '
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Exemplul 2. Sinteza compusului llb, (1R,4R,5R,7R)-7-(((tert-butildimetilsilil)oxi)metil)-5clorobiciclo[2.2.1 ]heptan-2-on.Example 2. Synthesis of Compound IIb, (1R, 4R, 5R, 7R) -7 - ((((tert-butyldimethylsilyl) oxy) methyl) -5-chlorobicyclo [2.2.1] heptane-2-one.
116.5 g (0.667 moli) (1 R,4R,5R,7R)-5-cloro-7-(hidroximetil)biciclo[2.2.1]heptan-2-onă I, s-au dizolvat în 0.8 L THF anh. (în locul THF-ului a fost utilizat ulterior CH2CI2), s-au adăugat 90.8 g (1.334 moli) imidazol, apoi s-au adăugat, în porții (45 min), 110.6 g (0.7337 moli) clorură de terțbutildimetilsilil (TBDMSCI) la temperatura camerei. S-a agitat apoi încă 1.5 h, controlând sfârșitul reacției prin CSS ( I, Rf 1 = 0.35, Rf «t> = 0.72). S-a filtrat clorhidratul de imidazoliu sub vid, s-a spălat pe filtru cu tetrahidrofuran (300 ml_), filtratul s-a concentrat la sec, s-a dizolvat în 800 mL toluen, soluția obținută a fost spălată cu soluție de acid oxalic (10 g în 500 mL apă), soluție de KHCO3 (100 ml 20% + 400 mL apă), saramură (400 mL), uscată (Na2SO4 anh.), concentrată la sec și co-evaporată cu toluen, rezultând 208 g produs brut sub forma de ulei, ce a cristalizat în asă la rece (în frigider). Prin cristalizare din 0.6 L hexan si 50 mL acetat de etil s-au obtinut 153.06 g (în trei fracții) ( soluțiile mume au fost purificate prin cromatografie pe coloană de silicagel, rezultând 30.95 g; randament total 95.5%) llb, (1R,4R,5R,7R)-7-(((tertbutildimetilsilil)oxi)metil)-5-clorobiciclo[2.2.1]heptan-2-onă, p.t. = 40.5-41.6 °C, [o]d = - 35.3°C (1% in CHCh), IR: 1741s, 1471 m, 1255m, 1070vs, 833vs, 771 vs, 721m, 1H-RMN (CDCI3, -* ppm, J116.5 g (0.667 moles) (1 R, 4R, 5R, 7R) -5-chloro-7- (hydroxymethyl) bicyclo [2.2.1] heptan-2-one I, dissolved in 0.8 L THF anh. (instead of THF CH2Cl2 was subsequently used), 90.8 g (1,334 moles) of imidazole were added, then 110.6 g (0.7337 moles) of tert -butyldimethylsilyl chloride (TBDMSCI) were added in portions (45 min). at room temperature. It was then stirred for a further 1.5 h, controlling the end of the reaction by CSS (I, Rf 1 = 0.35, Rf «t> = 0.72). The imidazole hydrochloride was filtered under vacuum, washed on the filter with tetrahydrofuran (300 ml), the filtrate was concentrated to dryness, dissolved in 800 mL toluene, the solution obtained was washed with oxalic acid solution (10 g in 500 mL water). , KHCO3 solution (100 ml 20% + 400 mL water), brine (400 mL), dried (Na2SO4 anh.), concentrated to dryness and co-evaporated with toluene, yielding 208 g of crude oil as a result. cold crystallized (in the refrigerator). By crystallization from 0.6 L hexane and 50 mL ethyl acetate 153.06 g (in three fractions) were obtained (the solutions were purified by silica gel column chromatography, yielding 30.95 g; total yield 95.5%) llb, (1R, 4R, 5R, 7R) -7 - ((((tert-butyldimethylsilyl) oxy) methyl) -5-chlorobicyclo [2.2.1] heptan-2-one, mp = 40.5-41.6 ° C, [o] d = - 35.3 ° C (1% in CHCl) IR: 1741s, 1471 m, 1255m, 1070vs, 833vs, 771 vs, 721m, 1 H-NMR (CDCl 3, - * ppm, J
Hz): 4.01, (d, 1H, H-2, 3.9, 7.5), 4.01 (dd, 1H, H-8, 6.8, 10.8), 3.88 (dd, 1H, H-8, 5.8, 10.8), 2.79 (d, 1H, H-1,5.0), 2.73 (m, 1H, H-4), 2.30-2.26 (m, 4H, 2H-3, H-6, H-7), 1.85 (d, 1H, H-6, 18.3), 0.88 (s, 9H, CH3C); -0.05 (s, 6H, CH3Si), 13C-RMN-300MHz (CDCI3, δ ppm): 213.92 (C-5), 60.28 (C-8), 57.29 (C-2), 52.60 (C-1), 51.91 (C-7), 46.52 (C-4), 45.97 (C-6), 34.37 (C-3), 25.94 (CH3C), 18.34 (CH3C), -5.20, -5.26 (CHsSi).Hz): 4.01, (d, 1H, H-2, 3.9, 7.5), 4.01 (dd, 1H, H-8, 6.8, 10.8), 3.88 (dd, 1H, H-8, 5.8, 10.8), 2.79 (d, 1H, H-1,5.0), 2.73 (m, 1H, H-4), 2.30-2.26 (m, 4H, 2H-3, H-6, H-7), 1.85 (d, 1H, H-6, 18.3), 0.88 (s, 9H, CH3C); -0.05 (s, 6H, CH 3 Si), 13 C-NMR-300MHz (CDCl3, δ ppm): 213.92 (C-5), 60.28 (C-8), 57.29 (C-2), 52.60 (C-) 1), 51.91 (C-7), 46.52 (C-4), 45.97 (C-6), 34.37 (C-3), 25.94 (CH 3 C), 18.34 (CH 3 C), -5.20, -5.26 (CHsSi).
Exemplul 3. Sinteza compusului (1S,2R,4S,5S,7R)-5-cloro-7-((tritiloxi)metil)biciclo[2.2.1]heptan-2ol, endo-llla.Example 3. Synthesis of (1S, 2R, 4S, 5S, 7R) -5-chloro-7 - ((trityloxy) methyl) bicyclo [2.2.1] heptane-2ol, endo-IIIa.
Compusul Ila (148 g, 0.357 moli) s-a dizolvat în 1.5L THF si 1L metanol, soluția s-a răcit la -50’C, apoi s-a picurat o soluție rece de 20.28 g (0.536 moli) NaBH4 în 250 mL apă în decurs de 90 min., monitorizând sfârșitul reacției prin CSS (I, Rf na = 0.42, Rf ma = 0.20). S-au adăugat apoi în picături 45 mL AcOH, s-a agitat 30 min, s-au adăugat în porții 30g (0.283 M) Na2CO3 solid, metanolul s-a distilat la presiune redusă, apoi s-a concentrat la sec. Produsul a fost extras la cald cu acetat de etil (1L + 2Ά 0.5L), s-a filtrat, filtratul concentrat la evaporator până începe să cristalizeze, s-a redizolvat la cald si s-a lăsat să cristalizeze în prisme. Au cristalizat 78.69 g endo-llla. Soluțiile mume au fost purificate prin cromatografie pe o coloană de silicagel preparată în CH2CL2și eluată cu sistemul CH2Cl2-MeOH, 9:1. Au rezultat 14.64g endo-llla pur, si 17.59 g amestec ,d§ alcooli \ endo-llla (Rf = 0.43 în sistemul 9:1) și exo-llla (Rf = 0.35). i.c.c.f. ; \Compound Ila (148 g, 0.357 moles) was dissolved in 1.5L THF and 1L methanol, the solution cooled to -50'C, then a cold solution of 20.28 g (0.536 moles) NaBH 4 was dropped into 250 mL water over 90 min., monitoring the end of the reaction through CSS (I, Rf n a = 0.42, Rf m a = 0.20). 45 mL of AcOH was then added dropwise, stirred for 30 min, solid portions of 30 g (0.283 M) were added, the methanol was distilled under reduced pressure, then concentrated to dryness. The product was warm extracted with ethyl acetate (1L + 2 Ά 0.5L), filtered, the filtrate concentrated in the evaporator until it started to crystallize, redissolved in hot and allowed to crystallize in prisms. They crystallized 78.69 g of endo-IIa. The mother solutions were purified by chromatography on a silica gel column prepared in CH 2 Cl 2 and eluted with the CH 2 Cl 2 -MeOH system, 9: 1. The result was 14.64g pure endo-IIIa, and 17.59 g mixture, two endo-IIIa alcohols (Rf = 0.43 in the 9: 1 system) and exo-IIIa (Rf = 0.35). iccf; \
Si. BUCUREȘTI Ț ; \\ J40/9U3' 1997 ? /' , ?· -......And. BUCHAREST Ț; \\ J40 / 9U3 '1997? / ',? · -......
a 2017 00850 20/10/2017 /// endo-llla: p.t. = 177.5-181.5‘C, [a]o= -15.8’(1% in CDCIs), IR: 3356brw, 2965m, 2159s, 2029m, 1977m, 1489m, 1448m, 1058s, 1031m, 1001 m, 899m, 760m, 745s, 703.7vs, 695vs, 632s, 1HRMN-300MHz (CDCI3, δ ppm, J Hz): 7.45 (d, 6H, H-o, 7.3), 7.31-7.18 (m, 9H, 6H-m, 3H-p), 4.20 (m, 1H, H-5a, 9.8), 3.84 (dd, 1H, H-2, 4.1, 8.0), 3.47 (t, 1H, H-8, 9.6), 3.28 (dd, 1H, H-8, 4.9, 9.6), 2.58 (dd, 1H, H-3, 8.0, 14.5), 2.49 (t, 1H, H-4, 4.1), 2.26 (d, 1H, H-1, 5.2), 2.05 (dd, 1H, H-7, 4.9, 9.9), 2.08 (ddd, 1H, H-6, 5.2, 9.9, 13.7), 1.52 (dt, 1H, H-3, 3.7, 14.5), 0.81 (dd, 1H, H-6, 2.9, 13.7), 13C-RMN-75 MHz (CDCI3, δ ppm): 144.40 (Cq), 128.44 (C-m), 127.83 (C-o), 127.02 (C-p), 86.43 (Cq-Tr), 70.45 (C-5), 61.40 (C-8), 60.51 (C-2), 49.46 (C-7), 48.36 (C-1), 45.58 (C-4), 39.87 (C-6), 32.43 (C-3).a 2017 00850 10/20/2017 /// endo-llla: pt = 177.5-181.5'C, [a] o = -15.8 '(1% in CDCIs), IR: 3356brw, 2965m, 2159s, 2029m, 1977m, 1489m, 1448m, 1058s, 1031m, 1001 m, 899m, 760m, 745s, 703.7vs, 695vs, 632s, 1 HRMN-300MHz (CDCI3, δ ppm, J Hz): 7.45 (d, 6H, Ho, 7.3), 7.31 -7.18 (m, 9H, 6H-m, 3H-p), 4.20 (m, 1H, H-5a, 9.8), 3.84 (dd, 1H, H-2, 4.1, 8.0), 3.47 (t, 1H, H-8, 9.6), 3.28 (dd, 1H, H-8, 4.9, 9.6), 2.58 (dd, 1H, H-3, 8.0, 14.5), 2.49 (t, 1H, H-4, 4.1), 2.26 (d, 1H, H-1, 5.2), 2.05 (dd, 1H, H-7, 4.9, 9.9), 2.08 (ddd, 1H, H-6, 5.2, 9.9, 13.7), 1.52 (dt, 1H , H-3, 3.7, 14.5), 0.81 (dd, 1H, H-6, 2.9, 13.7), 13 C-NMR-75 MHz (CDCI3, δ ppm): 144.40 (Cq), 128.44 (Cm), 127.83 (Co), 127.02 (Cp), 86.43 (Cq-Tr), 70.45 (C-5), 61.40 (C-8), 60.51 (C-2), 49.46 (C-7), 48.36 (C-1) , 45.58 (C-4), 39.87 (C-6), 32.43 (C-3).
Exemplul 4. Sinteza compușilor (1S,2R,4S,5S,7R)-7-(((terț-butildimetilsilil)oxi)metil)-5dorobiciclo[2.2.1 ]heptan-2-ol, endo-lllb și (1S, 2S, 4S, 5S, 7R)-7-(((terț-butildimetilsilil)oxi)metil)-5clorobiciclo[2.2.1 ]heptan-2-ol, exo-lllb.Example 4. Synthesis of the compounds (1S, 2R, 4S, 5S, 7R) -7 - ((((tert-butyldimethylsilyl) oxy) methyl) -5dorobicyclo [2.2.1] heptane-2-ol, endo-IIIb and (1S, 2S, 4S, 5S, 7R) -7 - ((((tert-butyldimethylsilyl) oxy) methyl) -5-chlorobicyclo [2.2.1] heptane-2-ol, exo-IIIb.
181.6 g Compus brut llb (~ 0.594 moli) s-au dizolvat în 1.5L metanol și 1.5 L tetrahidrofuran întrun KPG de 6 L, prevăzut cu agitare mecanică, pâlnie de picurare, termometru, și soluția obținută s-a răcit la criostat la -60°C. S-a picurat apoi o soluție de 22.7 g (0.7 moli) NaBH4, în 250 mL apă (Soluția a fost preparată în porții de 10g în 100 mL apă, ultima de 8 g în 100 mL apă) în decurs de 2.5 h, controlând evoluția reacției prin CSS (acetat de etil-hexan-acid acetic, 5:4:0.1, I, Rf nb = 0.72, Rt 111 = 0.65). S-au picurat apoi cu atenție 60 mL acid acetic glacial, pentru distrugerea excesului de hidrură, vasul de reacție a fost scos din baia de răcire și agitat încă 1 h. S-a concentrat la evaporator aproape la sec, s-a diluat cu 700 mL diclormetan, soluția obținută s-a spălat cu apă (1.5L), soluție KHCO3 20% (500 mL), saramură (250 mL), s-a uscat, s-a concentrat la sec (Apele j fost extrase cu 500 mL diclormetan), s-a co-evaporat cu 500 mL toluen. S-au obținut 174 g produs brut, sub formă de ulei, cu [a]o= ’(1% in CHCI3), IR: 3333br w, 2954m, 2929m, 2857m, 1472m, 1255s, 1080s, 1004m, 836vs, 776s, 1H-RMN-300 MHz (CDCI3, δ ppm, J Hz): 4.12 (dddd, 1H, Η-5-exo, 1.4, 3.0, 4.4, 9.6), 3.90 (dd, 1H, H-8, 9.1, 10.4), 3.72 (dd, 1H, H-8, 5.5, 10.4), 2.66 (dd, 1H, H-6, 8.0, 14.3), 2.36 (t, 1H, H-4, 4.4), 2.25 (d, 1H, H-1, 4.9), 2.28 (+ TFA, br s, 1H, H-7), 2.03 (ddd, 1H, H-3, 5.1, 9.9, 13.5), 1.84 (m, 1H, H-3), 1.83 (dt, 1H, H-6, 4.4, 14.3), 0.82(s, 9H, CHsC), -0.02 (s, 6H, CH3Si), 13C-RMN-300MHz (CDCI3, δ ppm): 70.27 (C-5), 61.02 (C-8), 60.79 (C-2), 52.17 (C-7), 47.91 (C-1), 45.00 (C-4), 39.86 (C-6), 32.56 (C-3), 26.02 (CHsC), 18.38 (CHsC), -5.14,-5.19 (CHsSi).181.6 g Crude compound llb (~ 0.594 mol) was dissolved in 1.5L methanol and 1.5 L tetrahydrofuran in 6 L KPG, provided with mechanical stirring, drip funnel, thermometer, and the solution obtained was cooled to cryostat at -60 ° C. A solution of 22.7 g (0.7 moles) of NaBH4 was then dropped, in 250 mL of water (the solution was prepared in 10g portions in 100 mL of water, the last of 8 g in 100 mL of water) within 2.5 h, controlling the evolution of the reaction. by CSS (ethyl acetate-hexane-acetic acid, 5: 4: 0.1, I, Rf nb = 0.72, Rt 111 = 0.65). Then 60 mL of glacial acetic acid was carefully dropped to destroy excess hydride, the reaction vessel was removed from the cooling bath and stirred for another 1 h. It was concentrated to evaporator almost to dryness, diluted with 700 mL of dichloromethane, the solution obtained was washed with water (1.5L), 20% KHCO3 solution (500 mL), brine (250 mL), dried, concentrated to dryness (Water was extracted with 500 mL dichloromethane), co-evaporated with 500 mL of toluene. 174 g of crude oil were obtained, with [a] o = '(1% in CHCI3), IR: 3333br w, 2954m, 2929m, 2857m, 1472m, 1255s, 1080s, 1004m, 836vs, 776s 1 H-NMR 300 MHz (CDCl 3, δ ppm, J Hz): 4.12 (dddd, 1H, Η-5-exo, 1.4, 3.0, 4.4, 9.6), 3.90 (dd, 1 H, H-8, 9.1 , 10.4), 3.72 (dd, 1H, H-8, 5.5, 10.4), 2.66 (dd, 1H, H-6, 8.0, 14.3), 2.36 (t, 1H, H-4, 4.4), 2.25 (d , 1H, H-1, 4.9), 2.28 (+ TFA, br s, 1H, H-7), 2.03 (ddd, 1H, H-3, 5.1, 9.9, 13.5), 1.84 (m, 1H, H- 3), 1.83 (dt, 1H, H-6, 4.4, 14.3), 0.82 (s, 9H, CHsC), -0.02 (s, 6H, CH 3 Si), 13 C-NMR-300MHz (CDCI3, δ ppm ): 70.27 (C-5), 61.02 (C-8), 60.79 (C-2), 52.17 (C-7), 47.91 (C-1), 45.00 (C-4), 39.86 (C-6) , 32.56 (C-3), 26.02 (CHsC), 18.38 (CHsC), -5.14, -5.19 (CHsSi).
Exemplul 5. Sinteza diolului (1S,2R,4S,5S,7R)-5-cloro-7-(hidroximetil)biciclo[2.2.1]heptan-2-ol, endo-IX, din compusul /Example 5. Synthesis of (1S, 2R, 4S, 5S, 7R) -5-chloro-7- (hydroxymethyl) bicyclo [2.2.1] heptane-2-ol, endo-IX, from compound /
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•Compusul I (100 g, 0.5726 moli) s-a dizolvat în 1L metanol, soluția s-a răcit la -50°C, apoi s-a picurat o soluție rece de 23.8 g (~0.63 moli) NaBFL în 300 ml_ apă în decurs de 90 min., monitorizând sfârșitul reacției prin CSS (I, Rf i = 0.42, Rtendo-ιχ + exo-ιχ = 0.20). S-au adăugat apoi în picături 55 ml_ AcOH s-a agitat 30 min, s-au adăugat în porții 30g (0.283 moli) Na2CO3 solid (soluția are pH 7-7.5), s-a distilat metanolul la presiune redusă, apoi s-a concentrat la sec. Concentratul a fost extras la cald (60°C) cu acetat de etil (1 L + 2* 0.5 L), s-a filtrat, filtratul s-a concentrat la evaporator până începe să cristalizeze, nedizolvat la cald si lăsat să cristalizeze în prisme, rezultând 78.69 g alcool endo-IX pur, cu Rf3= 0.43 (diclormetan-metanol, 9:1), p.t. = 115.2-117.3 °C, [a]D= 11.4’(1% în MeOH), IR: 3650w, 3240w, 2518m, 1348m, 1305m, 1080s, 1001s, 874s, 679s, 1H-NMR-300MHz (DMSO-d6, δ ppm, J Hz): 4.69 (d, 1H, OH, 3.8), 4.43 (t, 1H, OH, 8-OH, 5.2), 4.00 (dd, 1H, H-5, 3.8, 8.0), 3.94 (dd, 1H, H-2, 4.1, 8.0), 3.71 (ddd, 1H, H-8, 5.2, * 1, 11.0), 3.56 (dt, 1H, H-8, 5.2, 11.0), 2.63 (dd, 1H, H-3, 8.0, 14.0), 2.26 (t, 1H, H-4, 4.1), 2.20 (d, 1H, H-1,5.2), 1.97 (ddd, 1H, H-6, 5.2, 8.0, 13.2), 1.76 (dd, 1H, H-7, 5.2, 9.1), 1.75 (dt, 1H, H-3, 4.1, 14.0), 0.75 (dd, 1H, H-6, 3.2, 13.2), 13C-NMR-75 MHz (DMSO-d6, δ ppm): 68.66 (C-5), 61.68 (C2), 59.15 (C-8), 51.76 (C-7), 47.69 (C-1), 44.81 (C-4), 39.45 (C-6), 32.65 (C-3).• Compound I (100 g, 0.5726 moles) was dissolved in 1L methanol, the solution cooled to -50 ° C, then a cold solution of 23.8 g (~ 0.63 moles) NaBFL in 300 ml_ water was dropped over 90 min. , monitoring the end of the reaction through CSS (I, Rf i = 0.42, Rtendo-ιχ + exo-ιχ = 0.20). 55 ml were then added dropwise. AcOH was stirred for 30 min, solid Na2CO3 (0.283 mol) was added in portions (the solution was pH 7-7.5), the methanol was distilled under reduced pressure, then concentrated to dryness. The concentrate was extracted hot (60 ° C) with ethyl acetate (1 L + 2 * 0.5 L), filtered, the filtrate was concentrated in the evaporator until it started to crystallize, not dissolved in hot and allowed to crystallize in prisms, yielding 78.69 g pure endo-IX alcohol, with Rf3 = 0.43 (dichloromethane-methanol, 9: 1), mp = 115.2-117.3 ° C, [a] D = 11.4 '(1% in MeOH), IR: 3650w, 3240w, 2518m , 1348m, 1305m, 1080s, 1001s, 874s, 679s, 1H-NMR, 300MHz (DMSO-d6, δ ppm, J Hz): 4.69 (d, 1H, OH, 3.8), 4.43 (t, 1H, OH, 8-OH, 5.2), 4.00 (dd, 1H, H-5, 3.8, 8.0), 3.94 (dd, 1H, H-2, 4.1, 8.0), 3.71 (ddd, 1H, H-8, 5.2, * 1, 11.0), 3.56 (dt, 1H, H-8, 5.2, 11.0), 2.63 (dd, 1H, H-3, 8.0, 14.0), 2.26 (t, 1H, H-4, 4.1), 2.20 ( d, 1H, H-1,5.2), 1.97 (ddd, 1H, H-6, 5.2, 8.0, 13.2), 1.76 (dd, 1H, H-7, 5.2, 9.1), 1.75 (dt, 1H, H -3, 4.1, 14.0), 0.75 (dd, 1H, H-6, 3.2, 13.2), 13 C-NMR-75 MHz (DMSO-d6, δ ppm): 68.66 (C-5), 61.68 (C2) , 59.15 (C-8), 51.76 (C-7), 47.69 (C-1), 44.81 (C-4), 39.45 (C-6), 32.65 (C-3).
Soluțiile mume s-au purificat pe o coloană de silicagel preparată în CH2CI2 și eluată cu sistemul CH2CL2-MeOH (9:1), rezultând 13.64 g endo-IX pur (randament total, 91.3%) și un amestec de alcool endo-IX cu alcool exo-IX (Rf4= 0.35) de 9.1 g.The solutions were purified on a silica gel column prepared in CH2Cl2 and eluted with the CH2CL2-MeOH system (9: 1), giving 13.64 g pure endo-IX (total yield, 91.3%) and a mixture of endo-IX alcohol with 9.1 g exo-IX alcohol (Rf4 = 0.35).
Exemplul 6. Sinteza compusului (1S,2R,4S,5S,7R)-5-cloro-7-((tritiloxi)metil)biciclo[2.2.1]heptan-2d, lila din diolul endo-IX.Example 6. Synthesis of compound (1S, 2R, 4S, 5S, 7R) -5-chloro-7 - ((trityloxy) methyl) bicyclo [2.2.1] heptane-2d, lilac from endo-IX diol.
Diolul endo-IX (12.22 g, 70 mmoli) a fost tritilat selectiv, în 100 ml_ piridină, cu clorură de tritil (29.27 g, 105 mmoli, 1.5 echiv) ca în exemplul 1 (agitare peste noapte, monitorizare prin CSS în sistemul I, Rfendo-ιχ = 0.12, Rfendo-iiia = 0.54 și sistemul II, Rtendo-ιχ = 0.10, Rtendoiiia = 0.43). S-a distilat piridină la presiune redusă, concentratul s-a reluat în 200 ml_ toluen și 200 ml_ hexan, s-a adăugat sub agitare peste 150 g gheață pisată, s-a agitat până s-a topit gheața, s-au separat fazele, faza organică s-a spălat cu 200mL sol. 20% KHCO3, 200 ml_ saramură, s-a uscat (Na2SC>4 anh.) s-a filtrat și s-a concentrat la sec (Apele au fost extrase cu amestec: 100 rnL toluen -100 ml_ hexan). Produsul brut a fost purificat prin cromatografie rapidă pe coloană de silicagel (eluent: hexan-acetat de etil, 5:2), rezultând 28.94 g produs pur sub formă de ulei, care în timp devine un produs sticlos, cu aceleași caracteristici fizico-chimice ca cel obținut în exemplul 3: 1H-RMNEndo-IX diol (12.22 g, 70 mmol) was selectively tritylated, in 100 ml pyridine, with trityl chloride (29.27 g, 105 mmol, 1.5 equiv) as in example 1 (stirring overnight, monitoring by CSS in system I , Rfendo-ιχ = 0.12, Rf en do-iiia = 0.54 and system II, Rtendo-ιχ = 0.10, Rtendoiiia = 0.43). Pyridine was distilled under reduced pressure, the concentrate was taken up in 200 ml toluene and 200 ml hexane, over 150 g of weighed ice was stirred, the ice was stirred, the phases were separated, the organic phase was washed with 200 mL of soil. 20% KHCO3, 200 mL brine, dried (Na 2 SO 4), filtered and concentrated to dryness (Waters were extracted with mixture: 100 rnL toluene -100 mL hexane). The crude product was purified by flash column chromatography on silica gel (eluent: hexane-ethyl acetate, 5: 2), giving 28.94 g of pure product as an oil, which in time becomes a glass product, with the same physico-chemical characteristics. as that obtained in Example 3: 1 H-NMR
300MHz (CDCI3, δ ppm, JHz): 7.44 (d, 6H, H-o, 7.4), 7.31-7.20 (m, 9H, 6H-m, 3H-p), 4.22^rtH,300MHz (CDCI3, δ ppm, JHz): 7.44 (d, 6H, H-o, 7.4), 7.31-7.20 (m, 9H, 6H-m, 3H-p), 4.22 ^ rtH,
H-5a, 9.8), 3.84 (dd, 1H, H-2, 3.7, 7.8), 3.48 (t, 1H, H-8, 9.6), 3.29 (dd, 1H, H-8, 5.1, 9W>.58 (dd,: 1H, H-3, 8.0, 14.5), 2.49 (t, 1H, H-4, 3.9), 2.26 (d, 1H, H-1,4.7), 2.12-2.03 (m, 2H, Η-6-fcH-5a, 9.8), 3.84 (dd, 1H, H-2, 3.7, 7.8), 3.48 (t, 1H, H-8, 9.6), 3.29 (dd, 1H, H-8, 5.1, 9W>. 58 (dd,: 1 H, H-3, 8.0, 14.5), 2.49 (t, 1 H, H-4, 3.9), 2.26 (d, 1 H, H-1,4.7), 2.12-2.03 (m, 2H, Η-6-fc
a 2017 00850to 2017 00850
20/10/2017 3(/ ' 1H, H-3, 3.7, 14.5), 0.82 (dd, 1H, H-6, 2.9, 13.7), 13C-RMN-100 MHz (CDCI3, δ ppm): 144.31 (Cq),10/20/2017 3 (/ '1H, H-3, 3.7, 14.5), 0.82 (dd, 1H, H-6, 2.9, 13.7), 13 C-NMR-100 MHz (CDCI 3 , δ ppm): 144.31 (C q ),
128.44 (C-m), 127.70 (C-o), 126.90 (C-p), 86.35 (Cq-Tr), 70.36 (C-5), 61.31 (C-8), 60.39 (C-2), 49.39 (CH, C-7), 48.27 (C-1), 45.50 (C-4), 39.81 (C-6), 32.52 (C-3).128.44 (Cm), 127.70 (Co), 126.90 (Cp), 86.35 (Cq-Tr), 70.36 (C-5), 61.31 (C-8), 60.39 (C-2), 49.39 (CH, C-7 ), 48.27 (C-1), 45.50 (C-4), 39.81 (C-6), 32.52 (C-3).
Exemplul 7. Sinteza compusului endo-IVa din amestecul de alcooli endo-llla și exo-llla.Example 7. Synthesis of the endo-IVa compound from the mixture of endo-IIa and exo-IIIa alcohols.
43.36 g (0.104 moli) Produs brut de alcooli izomeri endo-llla și exo-llla s-au dizolvat în 55 mL piridină și 300 mL toluen, soluția s-a răcit pe baie de gheață, apoi s-au picurat 12.1 mL (17.9 g, 0.156 moli) clorură de metansulfonil (mesil) și s-a agitat peste noapte, monitorizând sfârșitul reacției prin CSS (Benzen, Rt ni^iva = 0.26, Rf va*va = 0.46). S-a turnat peste 250 mL sol. 20% KHCO3 și 400 g gheață, sub agitare mecanică, după topirea gheții s-au separate fazele, faza organică s-a spălat cu 250 mL sol. 20% KHCO3, 250 mL saramură, uscat și concentrat la -200 mL vapele au fost extrase cu 3* 200 mL toluen). Au cristalizat 41.44 g (80.5%) produs pur endo-IVa, (1S,2R,4S,5S,7R)-5-cloro-7-(((terț-butildimetilsilil)oxi)metil)-biciclo[2.2.1]heptan-2-il metansulfonat, p.t. = 96.9-97.9 °C, [a]D= °( 1% in CHCI3), IR: 17.10.2017: 2953m, 2929m, 2881w, 2856w, 1471w, 1357s, 1341 s, 1251 m, 1173s, 1078vs, 967vs, 832vs, 780vs, 677s, 663s, 523vs 1H-RMN-300 MHz (CDCI3, δ, ppm, JHz): 7.46 (d, 6H, H-o, 7.4), 7.34-7.17 (m, 9H, 6H-m, 3H-p), 4.99 (dddd, 1H, H-5a, 1.4, 3.0, 4.9, 9.9), 3.84 (dd, 1H, H-2, 4.4, 8.0), 3.50 (t, 1H, H-8, 9.6), 3.35 (dd, 1H, H-8, 4.9, 9.6), 2.98 (s, 3H, CHa), 2.80 (t, 1H, H-4, 4.4), 2.52 (dd, 1H, H-3, 8.0, 15.1), 2.37 (d, 1H, H-1,4.9), 2.24 (ddd, 1H, H-6, 4.9, 9.9, 14.3), 2.09 (dd, 1H, H-7, 5.2, 9.6), 1.62 (dt, 1H, H-3, 4.4, 15.1), 1.23 (dd, 1H, H-6, 3.0, 14.3), 13C-RMN-75MHz (CDCI3, δ ppm): 144.18 (Cq), 128.79 (C-m), 127.91 (C-o), 127.13 (C-p), 84.64 (Cq-Tr), 79.28 (C-5), 60.75 (C-8), 59.19 (C-2), 48.97 (C-7), 47.34 (C-1), 44.46 3-4), 38.39 (S-CH3), 37.56 (C-6), 32.96 (C-3).43.36 g (0.104 moles) The crude product of endo-III and exo-III isomers was dissolved in 55 mL pyridine and 300 mL toluene, the solution cooled on ice bath, then 12.1 mL (17.9 g, 0.156 moles) of methanesulfonyl chloride (mesyl) and stirred overnight, monitoring the end of the reaction by CSS (Benzen, Rt ni ^ iva = 0.26, Rf va * va = 0.46). Over 250 mL of soil was poured. 20% KHCO3 and 400 g ice, under mechanical stirring, after the ice melt the phases were separated, the organic phase was washed with 250 mL soil. 20% KHCO3, 250 mL brine, dried and concentrated to -200 mL v water were extracted with 3 * 200 mL of toluene). They crystallized 41.44 g (80.5%) pure endo-IVa product, (1S, 2R, 4S, 5S, 7R) -5-chloro-7 - ((((tert-butyldimethylsilyl) oxy) methyl) -bicyclo [2.2.1] heptan-2-yl methanesulfonate, mp = 96.9-97.9 ° C, [a] D = ° (1% in CHCI3), IR: 17.10.2017: 2953m, 2929m, 2881w, 2856w, 1471w, 1357s, 1341 s, 1251 m, 1173s, 1078vs, 967vs, 832vs, 780vs, 677s, 663s, 523vs 1 H-NMR-300 MHz (CDCI3, δ, ppm, JHz): 7.46 (d, 6H, Ho, 7.4), 7.34-7.17 (m , 9H, 6H-m, 3H-p), 4.99 (dddd, 1H, H-5a, 1.4, 3.0, 4.9, 9.9), 3.84 (dd, 1H, H-2, 4.4, 8.0), 3.50 (t, 1H, H-8, 9.6), 3.35 (dd, 1H, H-8, 4.9, 9.6), 2.98 (s, 3H, CHa), 2.80 (t, 1H, H-4, 4.4), 2.52 (dd, 1H, H-3, 8.0, 15.1), 2.37 (d, 1H, H-1.4.9), 2.24 (ddd, 1H, H-6, 4.9, 9.9, 14.3), 2.09 (dd, 1H, H-7 , 5.2, 9.6), 1.62 (dt, 1H, H-3, 4.4, 15.1), 1.23 (dd, 1H, H-6, 3.0, 14.3), 13 C-NMR-75MHz (CDCI 3 , δ ppm): 144.18 (C q ), 128.79 (Cm), 127.91 (Co), 127.13 (Cp), 84.64 (Cq-Tr), 79.28 (C-5), 60.75 (C-8), 59.19 (C-2), 48.97 (C-7), 47.34 (C-1), 44.46 3-4), 38.39 (S-CH3), 37.56 (C-6), 32.96 (C-3).
Exemplul 8. Sinteza compușilor mesilați endo-IVb și exo-IVb din amestecul de alcooli endo-lllb și exo-lllb.Example 8. Synthesis of endo-IVb and exo-IVb mesylate compounds from the mixture of endo-IIIb and exo-IIIb alcohols.
80.92 g (-0.278 moli) Produs brut de alcooli endo-lllb și exo-lllb, obținut în reacția de reducere, sau dizolvat în 150 mL piridină și 300 mL toluen anh., soluția s-a răcit pe baie de gheată, apoi s-au picurat 32.6 mL (0.417 moli) clorură de metansulfonil în decurs de 1.5 h, controlând evoluția reacției prin CSS. ( Silicagel, I, 1Rf endo-mb+exo-iiib = 0.65, Rf endo-rvb+exo-ivb = 0.71). S-au mai picurat 9.5 ml clorură de metansulfonil, apoi amestecul de reacție a fost lăsat peste noapte, sub agitare, pe baia de gheață. A doua zi, amestecul de reacție a fost turnat în porții, sub agitare mecanică, peste 300 mL soluție 20% KHCO3 și s-a agitat încă 1h. S-au separat fazele, faza organicăâfost80.92 g (-0.278 moles) Crude product of endo-IIl and exo-IIIl alcohols, obtained in the reduction reaction, or dissolved in 150 mL pyridine and 300 mL toluene anh., The solution was cooled on an ice bath, then 32.6 mL (0.417 moles) of methanesulfonyl chloride was dropped within 1.5 h, controlling the evolution of the reaction by CSS. (Silicagel, I, 1Rf endo-mb + exo-iiib = 0.65, Rf endo-rvb + exo-ivb = 0.71). 9.5 ml of methanesulfonyl chloride were further dropped, then the reaction mixture was left overnight under stirring on the ice bath. The next day, the reaction mixture was poured into portions, under mechanical stirring, over 300 mL of 20% KHCO3 solution and stirred for another 1h. The phases were separated, the organic phase was
X LC < f spălată cu 250 mL soluție 20% KHCO3, uscată și concentrată la sec (Apele au fost extras 'X LC <f washed with 250 mL 20% KHCO3 solution, dried and concentrated to dryness (Waters were extracted
mL toluen), apoi produsul uleios s-a co-evaporat cu toluen. S-au obținut 97.9 g (95.6% a 2017 00850(toluene), then the oily product was co-evaporated with toluene. 97.9 g (95.6% of 2017 00850) were obtained
20/10/2017 JJ2 brut, care cristalizează in bloc în frigider. Produsul a fost cristalizat din hexan, rezultând 80.5 g (în trei fracții) endo-IVb, (1S,2R,4S,5S,7R)-5-cloro-7-((tritiloxi)metil)biciclo[2.2.1]heptan-2-il metansulfonat, p.t.= 51.5-52.6°C, [ci]d = ’(1% in CHCh), 1H-RMN-300 MHz (CDCh, δ ppm, J Hz): 4.93 (dddd, 1H, H-5a, 1.6, 2.7, 4.4, 9.9), 3.97 (ddd, 1H, H-2, 1.1,4.1, 8.0), 3.97 (dd, 1H, H-8, 9.1,20/10/2017 JJ 2 crude, which crystallizes in block in the fridge. The product was crystallized from hexane, yielding 80.5 g (in three fractions) endo-IVb, (1S, 2R, 4S, 5S, 7R) -5-chloro-7 - ((trityloxy) methyl) bicyclo [2.2.1] heptane 2-yl methanesulfonate, mp = 51.5-52.6 ° C, [CI] = d '(1% in CHCl), 1 H-NMR 300 MHz (CDCl, δ ppm, J Hz): 4.93 (dddd, 1H, H-5a, 1.6, 2.7, 4.4, 9.9), 3.97 (ddd, 1H, H-2, 1.1,4.1, 8.0), 3.97 (dd, 1H, H-8, 9.1,
10.7) , 3.80 (dd, 1H, H-8, 5.5, 10.7), 2.99 (s, 3H, CH3), 2.74 (dt, 1H, H-4, 1.1 4.4), 2.67 (dd, 1H, H3, 8.0, 14.8), 2.41 (d, 1H, H-1, 4.9), 2.25 (ddd, 1H, H-6, 4.9, 9.9, 14.3), 2.02 (dt, 1H, H-3, 4.4,10.7), 3.80 (dd, 1H, H-8, 5.5, 10.7), 2.99 (s, 3H, CH 3 ), 2.74 (dt, 1H, H-4, 1.1 4.4), 2.67 (dd, 1H, H3, 8.0, 14.8), 2.41 (d, 1H, H-1, 4.9), 2.25 (ddd, 1H, H-6, 4.9, 9.9, 14.3), 2.02 (dt, 1H, H-3, 4.4,
14.8) , 1.97 (dd, 1H, H-7, 5.5, 9.1), 1.26 (dd, 1H, H-6, 3.0, 14.3), 0.89 (s, 9H, CHsC), -0.04, 0.01 (2 singlets, 6H, CH3Si), 13C-RMN-300MHz (CDCI3, δ ppm): 79.32 (C-5), 60.50 (C-8), 59.58 (C-2), 51.75 (C-7), 46.98 (C-1), 44.02 (C-4), 38.40 (S-CH3), 37.69 (C-6), 32.21 (C-3), 26.09 (CH3C), 18.44 (CH3C), -5.14, -5.19 (CH3Si).14.8), 1.97 (dd, 1H, H-7, 5.5, 9.1), 1.26 (dd, 1H, H-6, 3.0, 14.3), 0.89 (s, 9H, CHsC), -0.04, 0.01 (2 singles, 6H, CH 3 Si), 13 C-NMR-300MHz (CDCl3, δ ppm): 79.32 (C-5), 60.50 (C-8), 59.58 (C-2), 51.75 (C-7), 46.98 ( C-1), 44.02 (C-4), 38.40 (S-CH3), 37.69 (C-6), 32.21 (C-3), 26.09 (CH3C), 18.44 (CH 3 C), -5.14, -5.19 (CH 3 Yes).
Soluțiile mume (17.1 g) ce conțin endo-IVb și exo-IVb au fost purificate prin cromatografie pe o îloană de silicagel, rezultând 10.1 g endo-IVb pur și 7.2 g amestec de alcooli isomeri mesilați.The end solutions (17.1 g) containing endo-IVb and exo-IVb were purified by chromatography on a silica gel, resulting in 10.1 g of pure endo-IVb and 7.2 g of mesylated isomeric alcohols.
Exemplul 9. Sinteza compusului (1S,2S,4S,5S,7R)-2-azido-5-cloro-7((trrtiloxi)metil)biciclo[2.2.1]heptan, exo-Va din compusul endo-IVa.Example 9. Synthesis of compound (1S, 2S, 4S, 5S, 7R) -2-azido-5-chloro-7 ((triltyloxy) methyl) bicyclo [2.2.1] heptane, exo-Va from endo-IVa.
24.85 g (50 mmoli) Compus endo-IVa s-au dizolvat în170 mL DMF, s-au adăugat 4 echivalenți NaN3 (13g, 200 mmoli) și s-a încălzit la 120°C sub agitare electromagnetică timp de 36 h, monitorizând sfârșitul reației prin CSS (II, Rfendo-iva = 0.37, Rf exo-va = 0.76). S-a distilat DMF la presiune redusă, concentratul s-a reluat în 150 mL toluen și 150 mL apă, s-au separat fazele, faza organică s-a spălat cu 150 mL sol. 20% KHCO3, 150 mL apă, 150 mL saramură, uscată (Na2SO4) și concentrată la sec (Apele extrase cu 100 mL toluen), rezultând 20.5 g produs brut, cristalizat în masă. S-a dizolvat la cald în toluen și puțin izopropanol, s-a decolorat cu cărbune activ, s-a lăsat 'ă cristalizeze peste noapte, rezultând 9.28 g produs pur exo-Va. Soluțiile mume au fost concentrate la sec și au fost purificate prin cromatografie sub presiune pe coloană de silicagel (eluent, benzină de extracție-acetat de etil, 5:1), rezultând o fracție pură de 9.5 g exo-Va, care, prin cristalizare s-au obținut 8.35 g (randament total, 83.9%), p.t. = 118.3-119.8°C, [o]d = -21.8 ‘(1% in CHCh), IR: 2974m, 2948m, 2895m, 2081 vs (N3), 1492m, 1446m, 1335m, 1268m, 1061 s, 1034m, 972m, 755s, 696s, 633s, 1H-RMN-300 MHz (CDCh, δ ppm, J Hz): 7.48 (d, 6H, H-o, 8.0), 7.32-7.22 (m, 9H, 6H-m, 3H-p), 3.64 (dd, 1H, H-2 , 4.1,8.0), 3.44-3.36 (m, 3H, 2H-8, H-5), 2.46 (d, 1H, H-4, 4.7), 2.37-2.32 (m, 2H, H-1, H-7), 1.80 (dd, 1H, H-3, 8.0, 14.8), 1.62 (dd, 1H, H-3, 4.4,24.85 g (50 mmol) Endo-IVa compound was dissolved in 170 mL DMF, 4 equivalents NaN3 (13g, 200 mmol) was added and heated to 120 ° C under electromagnetic stirring for 36 h, monitoring the end of the reaction by CSS (II, Rfendo-yes = 0.37, Rf exo-va = 0.76). DMF was distilled under reduced pressure, the concentrate was taken up in 150 mL toluene and 150 mL water, the phases were separated, the organic phase was washed with 150 mL soil. 20% KHCO3, 150 mL water, 150 mL brine, dried (Na2SO4) and concentrated to dry (Waters extracted with 100 mL toluene), yielding 20.5 g crude product, crystallized by mass. It was dissolved hot in toluene and a little isopropanol, discolored with activated carbon, allowed to crystallize overnight, resulting in 9.28 g of pure exo-Va product. The mother solutions were concentrated to dryness and purified by silica gel column chromatography (eluent, extraction gasoline-ethyl acetate, 5: 1), resulting in a pure fraction of 9.5 g exo-Va, which, by crystallization 8.35 g (total yield, 83.9%), mp = 118.3-119.8 ° C, [o] d = -21.8 '(1% in CHCh), IR: 2974m, 2948m, 2895m, 2081 vs (N 3 ), 1492m, 1446m, 1335m, 1268m, 1061 s, 1034m, 972m, 755s, 696s, 633s, 1 H-NMR 300 MHz (CDCl, δ ppm, J Hz): 7.48 (d, 6H, Ho, 8.0) , 7.32-7.22 (m, 9H, 6H-m, 3H-p), 3.64 (dd, 1H, H-2, 4.1,8.0), 3.44-3.36 (m, 3H, 2H-8, H-5), 2.46 (d, 1H, H-4, 4.7), 2.37-2.32 (m, 2H, H-1, H-7), 1.80 (dd, 1H, H-3, 8.0, 14.8), 1.62 (dd, 1H , H-3, 4.4,
14.8), 1.60-1.56 (m, 2H, H-6), 13C-RMN-75MHz (CDCh, δ ppm): 144.34 (Ci-Ar), 128.84 (C-m), 127.86 (C-o), 127.02 (C-p), 86.48 (Cq-Tr), 62.58 (C-5), 60.88 (C-8), 59.24 (C14.8), 1.60-1.56 (m, 2H, H-6), 13 C-NMR-75MHz (CDCh, δ ppm): 144.34 (Ci-Ar), 128.84 (Cm), 127.86 (Co), 127.02 (Cp) , 86.48 (Cq-Tr), 62.58 (C-5), 60.88 (C-8), 59.24 (C
46.71 (C-1), 44.54 (C-4), 37.64, 37.54 (C-3, C-6).46.71 (C-1), 44.54 (C-4), 37.64, 37.54 (C-3, C-6).
Exemplul 10. Sinteza azidei, exo-Vb, din compusul mesilat endo-IVb.Example 10. Synthesis of azide, exo-Vb, from the endo-IVb mesylate compound.
a 2017 00850to 2017 00850
20/10/201710/20/2017
22.14 g (60 mmoli) Produs pur endo-IVb, dizolvat în 180 mL DMF anhidră, s-a agitat la 120 ± 10°C pe o baie de ulei timp de 24 h, cu 23.4 g (0.36 moli) NaN3, monitorizând sfârșitul reacției prin CSS (II, Rf endo-ivb = 0.35, Rf exo-vb = 0.77). DMF a fost distilată la presiune nedusă, reziduul a fost reluat în 200 mL acetat de etil și soluția rezultată a fost spălată cu 200 mL apă, 200 mL saramură, uscată (Na2SO4), filtrată, concentrată la sec și reziduul purificat prin cnomatografie pe coloană de silicagel (eluent, hexan-acetat de etil, 5:1), rezultând 13.9 g compus pur exo-Vb, (1 S,2S,4S,5S,7R)-2-azido-5-cloro-7-(((terf-butildimetilsilil)oxi)metil)-biciclo[2.2.1]heptan, (73.3%), sub formă de ulei, [o]d= °(1% in CHCh), IR: 2954m, 2929m, 2856m, 2101s, 1472m, 1338w, 1252s, 1105s, 1079s, 838s, 777s, RMN-300 MHz (CDCI3, δ ppm, J Hz): 3.88 (dd, 1H, 10.8, 8.7, H-8), 3.80 (dd, 1H, 10.8, 6.3, H-8), 3.74 (ddd, 1H, 4.2, 1.3, H-2), 3.41 (dd, 1H, 7.3, 3.7, H-5), 2.38-2.37 (m, 2H, H-1, H-4), 2.13 (brt, 1H, 7.5, H-7), 2.01 (dt, 1H, 15.2, 4.4, H-3), 1.92 (dd, 1H, 15.2, 8.4, HΛ 1.57 (dd, 1H, 13.6, 7.6, H-6), 1.50 (dd, 1H, 13.6, 4.6, H-6), 13C-RMN-75MHz (CDCh, δ ppm): 62.67 (C-2), 60.64 (C-8), 59.66 (C-5), 50.38 (C-7), 46.38 (C-1), 44.08 (C-4), 37.86 (C-3), 37.71 (C6), 26.10 (CH3C), 18.44 (C-CH3), -5.04 (CH3Si).22.14 g (60 mmol) Pure endo-IVb product, dissolved in 180 mL anhydrous DMF, was stirred at 120 ± 10 ° C in an oil bath for 24 h with 23.4 g (0.36 moles) NaN3, monitoring the end of the reaction by CSS (II, Rf endo-ivb = 0.35, Rf exo-vb = 0.77). The DMF was distilled off under reduced pressure, the residue was taken up in 200 mL of ethyl acetate and the resulting solution was washed with 200 mL of water, 200 mL of brine, dried (Na2SO4), filtered, concentrated to dryness and the residue purified by column chromatography. of silica gel (eluent, hexane-ethyl acetate, 5: 1), yielding 13.9 g of pure exo-Vb compound, (1S, 2S, 4S, 5S, 7R) -2-azido-5-chloro-7 - (( (tert-butyldimethylsilyl) oxy) methyl) -bicyclo [2.2.1] heptane, (73.3%), as an oil, [o] d = ° (1% in CHCl3), IR: 2954m, 2929m, 2856m, 2101s , 1472m, 1338w, 1252s, 1105s, 1079s, 838s, 777s, 300 MHz NMR (CDCI3, δ ppm, J Hz): 3.88 (dd, 1H, 10.8, 8.7, H-8), 3.80 (dd, 1H, 10.8, 6.3, H-8), 3.74 (ddd, 1H, 4.2, 1.3, H-2), 3.41 (dd, 1H, 7.3, 3.7, H-5), 2.38-2.37 (m, 2H, H-1 , H-4), 2.13 (brt, 1H, 7.5, H-7), 2.01 (dt, 1H, 15.2, 4.4, H-3), 1.92 (dd, 1H, 15.2, 8.4, HΛ 1.57 (dd, 1H , 13.6, 7.6, H-6), 1.50 (dd, 1H, 13.6, 4.6, H-6), 13 C-NMR-75MHz (CDCh, δ ppm): 62.67 (C-2), 60.64 (C-8 ), 59.66 (C-5), 50.38 (C-7), 46.38 (C-1), 44.08 (C-4), 37.86 (C-3), 37.71 (C6), 26.10 (CH 3 C), 18.44 (C-CH3), -5.04 (CH 3 Si).
și 2.3 g (19.0%) azidă deprotejată exo-VII, cu aceleași caracteristici prezentate anterior [C. Tănase et al., Bioorg. Med. Chem. 2014, 22, 513-522 x].and 2.3 g (19.0%) exo-VII deprotected azide, with the same characteristics presented previously [C. Tanase et al., Bioorg. Med. Chem. 2014, 22, 513-522 x ].
Exemplul 11. Sinteza azidei exo-VII din tritii-azidă exo-\fa.Example 11. Synthesis of exo-VII azide from tritium-exo-azide.
1.22 g (2.75 mmoli) Tritii-azidă exo-Va, s-au dizolvat în 30 mL metanol și 10 mL CH2CI2, s-au adăugat 0.55 g rășină Dowex 50WA 2 (spălată cu metanol) și s-a nefluxat monitorizând sfârșitul reacției prin CSS (II, Rf exo-va = 0.76, Rf exo-νιι = 0.35). Soluția s-a răcit la temperature camerei, s-a filtrat rășina, s-a spălat pe filtru cu metanol, filtratul s-a concentrat la sec și a fost purificat ca în exemplul 10, rezultând o fracție pură de 502 mg (90.5%) azidă exo-VII,x 1.22 g (2.75 mmol) Exo-Va tritium azide, dissolved in 30 mL methanol and 10 mL CH2Cl2, 0.55 g Dowex 50W A 2 resin (methanol washed) was added and non-flushed monitoring the end of the reaction by CSS (II, Rf exo-va = 0.76, Rf exo-νιι = 0.35). The solution was cooled to room temperature, the resin was filtered, washed on the methanol filter, the filtrate was concentrated to dryness and purified as in Example 10, resulting in a pure fraction of 502 mg (90.5%) exo-VII azide, x
Exemplul 12. Sinteza azidei exo-VII din azida exo-Vb.Example 12. Synthesis of exo-VII azide from exo-Vb azide.
La o soluție de 13.58 g (43 mmoli) de azidă exo-Vbîn 80 mL metanol s-au adăugat 10 mL 48% HF și s-a agitat peste noapte la temperatura camerei, monitorizând sfârșitul reacției prin CSS (II, Rf exo-vb = 0.77, Rf exo-νιι = 0.35). Amestecul de reacție a fost neutralizat cu NaHCCh solid, concentrat la presiune redusă și produsul brut a fost purificat prin cnomatografie rapidă sub presiune (eluent, hexani-acetat de eti, 5:1), rezultând 8.06 g (93.0%) azidă pura exo-Vll.x Exemplul 13. Sinteza aminei exo-V/a din azida exo-Va.To a solution of 13.58 g (43 mmol) of exo-Vb azide in 80 mL methanol 10 mL 48% HF was added and stirred overnight at room temperature, monitoring the end of the reaction by CSS (II, Rf exo-vb = 0.77 , Rf exo-νιι = 0.35). The reaction mixture was neutralized with solid NaHCCh, concentrated under reduced pressure and the crude product was purified by flash pressure chromatography (eluent, hexanes-ethyl acetate, 5: 1), yielding 8.06 g (93.0%) pure exo- azide. VII. x Example 13. Synthesis of exo-V / a amine from exo-Va azide.
2.22g (5 mmoli) Tritii-azidă exo-Va s-au dizolvat în 20 mL piridină, s-au adăugat 2 echiy (10 mM, 2.62g) Ph3P și s-a agitat la t.c., monitorizând sfârșitul reacției prin CSS (II, Rf7a ^șa start). După 7h, s-au adăugat în picături 7 mL amoniac 25% și soluția s-a agitatlpeâte noapte. [CSS (diclormetan-metanol, 4:1, Rfe»-via = 0.39, comparativ Rf e»-via, r = oh = 0.08)]. Amestecul de a 2017 008502.22g (5 mmol) Exo-Va tritium azide was dissolved in 20 mL pyridine, 2 echiy (10 mM, 2.62g) Ph 3 P was added and stirred at rt, monitoring the end of the reaction by CSS (II). , Rf7a ^ sa start). After 7h, 7 mL 25% ammonia was added dropwise and the solution was stirred overnight. [CSS (dichloromethane-methanol, 4: 1, Rfe »-via = 0.39, compared to Rf and » -via, r = oh = 0.08)]. The mixture of 2017 00850
20/10/2017 reacție a fost concentrat la sec și produsul brut a fost purificat prin cnomatografie rapidă pe o coloană de silicagel (eluent, diclormetan-metanol, 4:1), rezultând 1.92 g (92%) amină exo-Vla, (1S,2S,4S,5S,7R)-5-cloro-7-((tritiloxi)metil)biciclo[2.2.1]heptan-2-amină sub formă de ulei, [sub forma de clorhidrat, p.t. = 233.2-234.5°C(desc.)], [a]o = *(1% in CHCh), 3060w, 3024w, 2973w, 2948w, 2896w, 1445m, 1336m, 1267m, 1062s, 973m, 756s, 697vs, 1H-RMN-300 MHz (DMSO-de, δ ppm, J Hz): 8.28 (NH3+, pentru clorhidrat), 7.43-7.26 (m, 15H, 6H-o, 6H-m, 3H-p), 3.90 (dd, 1H, H-2, 4.7, 8.0), 3.27 (t, 1H, H-8, 9.6), 3.18 (dd, 1H, H-8, 5.5, 9.6), 3.04 (m, 1H, H-5), 2.71 (brt, m 1H, H-7), 2.53 (m, 1H, H-4, in DMSO), 2.33 (d, 1H, H-1, 4.1), 1.99 (dd, 1H, H-3, 8.0, 14.6), 1.74 (dd, 1H, H-6, 8.0, 13.5), 1.53 (dt, 1H, H-6, 4.1, 13.5), 1.46 (dt, 1H, H-3, 4.7, 14.6), 13C-RMN75MHz (CDCIs, δ ppm): 143.87 (CrAr), 128.23 (C-m), 127.84 (C-o), 126.99 (C-p), 85.61 (Cq-Tr), 60.38 (C-8), 58.90 (C-2), 51.13 (C-5), 46.52 (C-4), 46.02 (C-7), 42.78 (C-1), 37.44 (C-3), 35.24 (CExemplul 14. Sinteza aminei exo~Vlb din azida exo-Vb.10/20/2017 reaction was concentrated to dryness and the crude product was purified by flash chromatography on a silica gel column (eluent, dichloromethane-methanol, 4: 1), yielding 1.92 g (92%) exo-Vla amine, ( 1S, 2S, 4S, 5S, 7R) -5-chloro-7 - ((trityloxy) methyl) bicyclo [2.2.1] heptane-2-amine as oil, [as hydrochloride, pt = 233.2-234.5 ° C (desc.)], [A] o = * (1% in CHCh), 3060w, 3024w, 2973w, 2948w, 2896w, 1445m, 1336m, 1267m, 1062s, 973m, 756s, 697vs, 1 H-NMR. 300 MHz (DMSO-d, δ ppm, J Hz): 8.28 (NH3 + , for hydrochloride), 7.43-7.26 (m, 15H, 6H-o, 6H-m, 3H-p), 3.90 (dd, 1H, H-2, 4.7, 8.0), 3.27 (t, 1H, H-8, 9.6), 3.18 (dd, 1H, H-8, 5.5, 9.6), 3.04 (m, 1H, H-5), 2.71 ( brt, m 1H, H-7), 2.53 (m, 1H, H-4, in DMSO), 2.33 (d, 1H, H-1, 4.1), 1.99 (dd, 1H, H-3, 8.0, 14.6 ), 1.74 (dd, 1H, H-6, 8.0, 13.5), 1.53 (dt, 1H, H-6, 4.1, 13.5), 1.46 (dt, 1H, H-3, 4.7, 14.6), 13 C- 75 MHz NMR (CDCIs, δ ppm): 143.87 (CrAr), 128.23 (Cm), 127.84 (Co), 126.99 (Cp), 85.61 (Cq-Tr), 60.38 (C-8), 58.90 (C -2), 51.13 (C-5), 46.52 (C-4), 46.02 (C-7), 42.78 (C-1), 37.44 (C-3), 35.24 (EC Example 14. Exo-Vlb amine synthesis from azido exo-Vb.
5.61 g (17.7 mmoli) TBDMS-azidă exo-Vb s-au dizolvat în 100 ml_ metanol, s-au adăugat 212 mg 10-20% Pd(OH)2/C și s-a hidrogenat la presiune atmosferică barbotând hidrogen sub agitare magnetică la t.c., monitorizând sfârșitul reacției prin CSS (diclormetan-metanol, 95:5, Rf exo-vb = 0.76, Rfexo-vib = 0.06). Catalizatorul a fost filtrat, spalat pe filtru cu methanol, filtratul concentrat la sec, rezultând 5.02 g produs brut ce a fost purificat prin cnomatografie rapidă pe o coloană de silicagel (eluent, heptan-acetat de etil, 5:2, apoi diclormetan-metanol, 9:1). Au rezultat 3.5 g (68.2%) amină exo- Vlb, (1S,2S,4S,5S,7R)-5-cloro-7-(((te/>5.61 g (17.7 mmol) TBDMS-exo-Vb azide was dissolved in 100 ml methanol, 212 mg 10-20% Pd (OH) 2 / C was added and hydrogenated at atmospheric pressure by bubbling hydrogen under magnetic stirring at tc, monitoring the end of the reaction by CSS (dichloromethane-methanol, 95: 5, Rf exo-vb = 0.76, Rfexo-vib = 0.06). The catalyst was filtered, washed with methanol filter, the filtrate concentrated to dryness, yielding 5.02 g of crude product which was purified by flash chromatography on a silica gel column (eluent, heptane-ethyl acetate, 5: 2, then dichloromethane-methanol. , 9: 1). 3.5 g (68.2%) of amine exo-Vlb, (1S, 2S, 4S, 5S, 7R) -5-chloro-7 - (((te />
butildimetilsilil)oxi)metil)biciclo[2.2.1]heptan-2-amină, [sub forma de clorhidrat, p.t. = 202.0205.3°C(desc.)], IR: 3229w, 2953w, 2929w, 2956w, 1466w, 1279w, 1253w, 1110w, 1065m, 834s, 38s, [a]D= ’(1% in CHCI3), 1H-RMN-300 MHz (CDCI3, δ ppm, JHz): 8.20 (NH3+, pentru clorhidrat), 3.95 (brt, 1H, 10.5, H-8), 3.89 (dd, 1H, 10.5, 7.1 H-8), 3.80 (dd, 1H, 7.1, 4.4 H-2), 3.14 (t, 1H, 5.8, H-5), 2.60 (brs, m 1H, H-1), 2.51 (br s, 1H, H-4), 2.45 (t, 1H, H-7, 7.3), 2.09 (m, 2H, H-3), 1.80 (m, 2H, H-6), 13C-RMN-75MHz (CDCI3, δ ppm): 60.41 (C-8), 58.50 (C-2), 52.65 (C-5), 49.72 (C-7), 46.76 (C-1), 43.01 (C-4), 38.45 (C-3), 36.55 (C-6), 26.25 (CH3C), 18.56 (_CCH3), -4.96 (CH3S1), și 1.08 g (20.8%) amină neprotejată exo-VIII.butyldimethylsilyl) oxy) methyl) bicyclo [2.2.1] heptane-2-amine, [as hydrochloride, mp = 202.0205.3 ° C (desc.)], IR: 3229w, 2953w, 2929w, 2956w, 1466w, 1279w , 1253w, 1110w, 1065m, 834s, 38s, [a] D = '(1% in CHCl3), 1 H-NMR 300 MHz (CDCl 3, δ ppm, JHz): 8.20 (NH3 +, the hydrochloride), 3.95 (brt, 1H, 10.5, H-8), 3.89 (dd, 1H, 10.5, 7.1 H-8), 3.80 (dd, 1H, 7.1, 4.4 H-2), 3.14 (t, 1H, 5.8, H -5), 2.60 (brs, m 1H, H-1), 2.51 (br s, 1H, H-4), 2.45 (t, 1H, H-7, 7.3), 2.09 (m, 2H, H-3 ), 1.80 (m, 2H, H-6), 13 C-NMR-75MHz (CDCl3, δ ppm): 60.41 (C-8), 58.50 (C-2), 52.65 (C-5), 49.72 (C -7), 46.76 (C-1), 43.01 (C-4), 38.45 (C-3), 36.55 (C-6), 26.25 (CH3C), 18.56 (_CCH 3 ), -4.96 (CH3S1), and 1.08 g (20.8%) unprotected amine exo-VIII.
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