CA2085716A1 - Heterocyclically substituted carbamates and process for their preparation - Google Patents
Heterocyclically substituted carbamates and process for their preparationInfo
- Publication number
- CA2085716A1 CA2085716A1 CA002085716A CA2085716A CA2085716A1 CA 2085716 A1 CA2085716 A1 CA 2085716A1 CA 002085716 A CA002085716 A CA 002085716A CA 2085716 A CA2085716 A CA 2085716A CA 2085716 A1 CA2085716 A1 CA 2085716A1
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- chain
- formula
- straight
- branched alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 150000004657 carbamic acid derivatives Chemical class 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 30
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- -1 phentl Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000012039 electrophile Substances 0.000 claims description 5
- 150000004985 diamines Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229960001945 sparteine Drugs 0.000 claims description 2
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- 229910052726 zirconium Inorganic materials 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000005595 deprotonation Effects 0.000 description 7
- 238000010537 deprotonation reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 6
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NPDYECIIWQIFIY-UHFFFAOYSA-N 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylic acid Chemical compound CC1(C)COC(C)(C)N1C(O)=O NPDYECIIWQIFIY-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- ZAIQBJPTOXDDKA-LBPRGKRZSA-N [(2s)-1-benzylpyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1CC1=CC=CC=C1 ZAIQBJPTOXDDKA-LBPRGKRZSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-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
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 229920001577 copolymer Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- WOCMGZWJJQPFGY-UHFFFAOYSA-N ethyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate Chemical compound CCOC(=O)N1C(C)(C)COC1(C)C WOCMGZWJJQPFGY-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Heterocyclically substituted carbamates and process for their preparation Abstract The invention relates to a new process for the preparation of new heterocyclically substituted carbamates, which are important imtermediates for the synthesis of pharmaceutical active substances, in particular for the synthesis of biologically active peptides and peptide mimetics.
Le A 28 841
Le A 28 841
Description
The invention relates to a new process for the preparation of new heterocyclically substituted carbamates, which are important intermediates for the synthesis of pharmaceutical active substances, in particular for the synthesis of biologically active peptide~ and peptide mimetics.
The invention also relates to new heterocyclically substituted carbamates of the general formula (I) oR3 Rl A (1).
in which 0 R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 heteroatoms from the series comprising S and 0 or having a group of the formula -NR', -SiR5RsR7 or -SnR5R6R7, in which R' denote~ hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or Le A 28 841 - 1 -, , .
.,..... . ,~
, ' , ,.
, . - . .
`` ~ 7~;
benzyl, Rs, R6 and R' are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, S where these substitutents can optionally be sub-stituted up to 3 times b~ identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsat-urated heterocycle having up to 3 heteroatoms from the series comprising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiRsR6R7, in which Rs, R6 and R7 have the abovementioned meaning, R3 represents a group of the formula -CO-NRl0R1l, in which Le A 28 841 - 2 -.
Rl and R1l, together with the nitrogen atom, form a heterocyclic radical of the formula R~<RI3 N O
Rl, ¦ I Rl4 Rl6 Rls in which Rl2 Rl3 R14, Rl5, Rl0 and Rl7 are identical or dif-S ferent and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and Rl3, Rl4 and Rls and/or Rl6 and Rl7 together form a 3- to 6-membered, saturated carbocycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally sub6tituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NRl0Rl9 -HN-CO-OR20, -SiR2lR22R23 or -SnR2lR22R23 in which Rl8 and Rl9 have the abovementioned meaning of R4 and are identical to or different from this Le A 28 841 - 3 -..-` ~ : -:
~c~
and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 have the abovementioned meaning of Rs, R6 and R7 and are identical to or different from this, or represents straight-chain or branched acyl Xaving up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiRZ1R22R23, -SnR21R22R23 or R24-co in which R21, R22 and R23 have the abovementioned meaning and R2~ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which i8 optionally substituted up to 3 times by phenyl or by the group of the Le A 28 841 - 4 -' .
The invention also relates to new heterocyclically substituted carbamates of the general formula (I) oR3 Rl A (1).
in which 0 R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 heteroatoms from the series comprising S and 0 or having a group of the formula -NR', -SiR5RsR7 or -SnR5R6R7, in which R' denote~ hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or Le A 28 841 - 1 -, , .
.,..... . ,~
, ' , ,.
, . - . .
`` ~ 7~;
benzyl, Rs, R6 and R' are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, S where these substitutents can optionally be sub-stituted up to 3 times b~ identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsat-urated heterocycle having up to 3 heteroatoms from the series comprising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiRsR6R7, in which Rs, R6 and R7 have the abovementioned meaning, R3 represents a group of the formula -CO-NRl0R1l, in which Le A 28 841 - 2 -.
Rl and R1l, together with the nitrogen atom, form a heterocyclic radical of the formula R~<RI3 N O
Rl, ¦ I Rl4 Rl6 Rls in which Rl2 Rl3 R14, Rl5, Rl0 and Rl7 are identical or dif-S ferent and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and Rl3, Rl4 and Rls and/or Rl6 and Rl7 together form a 3- to 6-membered, saturated carbocycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally sub6tituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NRl0Rl9 -HN-CO-OR20, -SiR2lR22R23 or -SnR2lR22R23 in which Rl8 and Rl9 have the abovementioned meaning of R4 and are identical to or different from this Le A 28 841 - 3 -..-` ~ : -:
~c~
and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 have the abovementioned meaning of Rs, R6 and R7 and are identical to or different from this, or represents straight-chain or branched acyl Xaving up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiRZ1R22R23, -SnR21R22R23 or R24-co in which R21, R22 and R23 have the abovementioned meaning and R2~ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which i8 optionally substituted up to 3 times by phenyl or by the group of the Le A 28 841 - 4 -' .
2~
formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
In the sub-substitution, heterocycle in general S represents a 5- to 7-membered, preferably 5- to 6-membered, saturated or unsaturated ring which as heteroatoms can contain up to 2 oxygen, sulphur and/or nitrogen stoms. Preferred S- and 6-membered rings are those having an oxygen, sulphur and/or up to 2 nitrogen atoms. The following are mentioned as being particularly preferred: pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrazolyl or morpholinyl.
A 3- to 8-membered, saturated heterocycle is in general represented by pyrrolidine, piperidine, pyrazolidine, imidazolidine or oxazolan. Pyrrolidine and oxazolan are preferred.
Preferred compounds of the general formula (I) are those in which R2 represents a heterocyclic radical of the formula Le A 28 841 - 5 -........ ...... ..
,: - ~ . . . . . . . :
. , . . . - ::
;.
.: . - : .
. - .. ~ . ..
\
R~ H3C
or O y N-R~
in which R~ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, Rl represents hydrogen, R3 represents a group of the formula -CO-NRlRll, in which R10 and Rll, together with the nitrogen atom, form a heterocyclic radical of the formula Rl2 R~3 O
¦ ¦ Rl4 Rl6 Rl5 in which Rl2 Rl3 R1~, Rls, R16 and R17 are identical or dif-ferent and denote hydrogen, straight-Le A 28 841 - 6 -chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case Rl2 and Rl3, Rl~
and Rls or Rl6 and Rl7 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different substituents from the group comprising hydroxyl, phenyl, cyclobutyl, cyclopentyl and cyclohexyl or by a group of the formula -NR1~R19, _NH_co-OR20, -SiR2lR22R23 or -SnR2lR22R23 in which R19 and Rl9 have the abovementioned meaning of R~
and are identical to or different from this, R20 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally sub-stituted by phenyl, R21, R22 and R23 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, or Le A 28 841 - 7 -' . .
., ~ .
', ...
~s~l6 represents straight-chain or branched acyl having up to 6 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiRZlR22R23, -SnR2lR22R23 or R24-co in which R21, R22 and R23 have the abovementioned meaning and RZ4 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -N~-CO-ORZ, in which RZ has the abovementioned meaning.
Particularly preferred compounds of the general formula (I) are those in which Le A 28 841 - 8 -~, .. ' :
~ ¢~ 5 ~ 6 R2 represents a heterocyclic radical of the formula N-R4 H3C ~
or N-R4 in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, Rl represents hydrogen, R3 represents a group of the formula -CO-NRl0R1l, in which Rl and Rll, together with the nitrogen atom, form a heterocyclic ring of the formula \NXO
R" ~ R~4 R~6 R15 in which R12 R'3 Rl~, Rls, Rls and Rl7 are identical or dif-ferent and denote hydrogen, straight-chain or branched alkyl having up to 4 Le A 28 841 - 9 -. ~
.. - - ~ ~ - - . ~ ............... :
. ; - .
carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case Rl2 and R1~, Rl4 and Rls or Rl6 and Rl7 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by hydroxyl, phenyl, cyclobutyl or cyclohexyl or by a group of the formula -NR~8R~9 -NH-CO-OR20, -SiR2~R22~23 or -SnR2lR22R23 in which Rl3 and R19 are identical or different and have the abovementioned meaning of R4 and are identical to or different from this, R20 denotes methyl or ethyl, each of which is optionally substituted by phenyl, R2l, R22 and R23 denote straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydxoxyl, Le A 28 841 - 10 -~?.G~57~fi) represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiR21R22R23, -SnR2~R22R23 or R24-co_, in which R2l, R22 and R23 have the abovementioned meaning and R2~ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
Additionally, a new process for the preparation of the compounds of the general formula (I) according to the invention has been found, characterised in that carbamates of the general formula (II) Le A 28 841 - 11 -~, , .
~¢~5~
Rl Rl in which Rl, R2, Rl and Rll have the abovemen~ioned meaning, are first enantio electively deprotonated in inert solvents, in the presence of a selective base, preferably S sec-butyllithium, and of a chelate-forming di~mine (in the following designated by D) to give the carbanion complex compounds of the general formula (III) Rlo ~ N`
~ B ~0 in which Rl, R2, R10 and Rll have the abovementioned meaning, 0 B represents a lithium, magnesium, titanium, zirconium or potassium atom, preferably lithium, and Le ~ 28 841 - 12 -D represents a chelate-forming diamine such as, for example, tetramethylethylenediamine (TMEDA) or (-)-sparteine, preferably TNEDA, and then reacted with electrophiles of the general formulae (IV) and (V) o A-M (rV) T ~ T' in which A has the abovementioned meaning, M represents halogen, C,-C,-alkoxy or another typical leaving group, preferably chlorine, and T and T' are identical or different and represent hydrogen or a chemi- cally useful radical shown under the substituent A, or with CO2.
The process according to the invention can be illustrated by way of example by the following reaction scheme:
Le A 28 841 - 13 -. ~ ' ''' :
-U ~ ~EDA
CH2 u~ auU / TMEDA ~ o CH
s ~ 2 O-C~ C~ H,C,~ ~CH, CHJ HaC
S u r -- HCC~'H~C Cl 1, 0 C- H, prisin gly, the proce~s according to the invention gives the desired compounds of the general formula ~I) in high yields.
The process is distinguished by ~everal advantages: in contrast to the prior art, stoichiometric amounts of bases, preferably sec-butyllithium, are adequate for deprotonation. Additionally, the process according to the invention enables both control of the diastereo-selectivity by the choice of the electrophilic sub-stituents and the influencing of asymmetric induction in the case of prochiral carbamates in the presence of chiral complex-forming diamines.
By the use of enantiomerically pure diamine compounds such a~, for example, TMEDA, deprotonation of the compounds of the formula (II) takes place enantioselectlvely and in very good yields to give the Le A 28 841 - 14 --35~
corresponding chiral compounds, preferably to give the (S)-lithium compounds of the formula (III), which can preferably be converted into the R-configuration by further reaction with electrophiles.
It is additionally surprising with knowledge of the prior art that the metallated compounds of the general formula (III) undergo no decomposition and a deprotonation in the benzyl radical. In particular, a high diastereo-selectivity and stereochemical control in the attack of the electrophile due to the induction of the stereocentre already present is of great advantage.
In addition to chlorine, bromine and iodine, the radicals tosylate, meaylate or -OS02-CF3 are also covered under the definition leaving group. Chlorine is preferred.
Suitable solvents for the deprotonation are preferably inert organic solvents such a6 hydrocarbons such as hexane, pentane, ligroin or toluene, and ethers, for example tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, diglyme, triglyme or tert-butyl methyl ether. Tetrahydrofuran and diethyl ether are particularly preferred.
Deprotonation is carried out in a temperature range from -lOO-C to room temperature, preferably at about -78-C to O-C .
Deprotonation can be carried out either at normal Le A 28 841 - 15 --' .- ~ ~ . .
.
;7~6 pressure or at elevated or reduced pressure (for example 0.5 to 2 bar)l preferably at normal pressure.
Suitable selective bases are alkyllithium compounds having up to 6 C atoms in the alkyl group, preferably n-butyllithium or sec-butyllithium.
The base is employed in an amount from 0.5 to 5 mol, preferably in stoichiometric amounts, relative to 1 mol of the compounds of the general formula (II).
Electrophilic substitution likewise takes place in the abovementioned solvents, preferably in tetrahydrofuran at normal pressure.
Electrophilic substitution is carried out in a tempera-ture range from about -100-C to +40-C, preferably in the range from -78-C to room temperature.
The compounds of the general formula (II) are also new and can be prepared by a process in which compounds of the general formula (VI) Rl ~C-OH (Vl), I
in which Le A 28 841 - 16 -: . . .: . .
: . ~
-. ...
,: ' , :-: '.:. ~
. .: ; . . .:
.. . . ::, - ~:
7~Lfi R' and R2 have the abovementioned meaning are reacted with compounds of the general formula (VII) O
Il Z - C NRlR~l (VII), in which R10 and R11 have the abovementioned meaning and Z represents halogen, preferably chlorine, in one of the abovementioned solvents, preferably ether, in the presence of a base, preferably sodium hydride.
The compounds of the general formulae (VI) and (VII) are known or can be prepared by a customary method [cf., for example, J. Chem. Soc., Perkin Trans l, 1074, 1101].
The compound of the general formula (III) are new and can be prepared by the process indicated above.
The compounds of the general formulae (IV) and (V) are known or can be prepared by customary methods.
The compounds according to the invention are also Le A 28 841 - 17 -' : ' ,. ~ .
5~ 3L6 distinguished by the fact that, after the enantio-selective introduction of the electrophile, the pro-tective group -CO-NR10Rl1 can be very easily removed with the formation of the free hydroxyl group.
Removal of the protective groups (carbamic acid esters) i8 carried out by a customary method, for example by sequential treatment with acids and bases, preferably in methanol.
Suitable acids are strong inorganic acids and organic sulphonic or carboxylic acids such as, for example, methanesulphonic acid, ethanesulphonic acid, benzene-sulphonic acid, toluenesulphonic acid, acetic acid or propionic acid.
Suitable bases are alkali metal and alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide. Barium hydroxide is preferred.
The acids and bases are employed in an amount from 0.01 to 10 mol, preferably l mol, relative to 1 mol of the compounds of the general formula (I).
Removal of the protective groups is carried out at normal pressure in a temperature range from 0C to +130-C, preferably from +20-C to +lOO-C.
Le A 28 841 - 18 -, ,~ -.
...
35~3~fi Removal can al80 be carried out with lithium aluminium hydride in one of the abovementioned solvents, preferably tetrahydrofuran.
The compounds according to the invention are thus useful S intermediates for the preparation of hydroxy-substituted heterocycles, some of which are known and some of which are new, in particular proline derivatives, which are of great importance for the synthesis of biologically active peptidec or peptide mimetics.
The abbreviations a and b used in the following have the following meaning:
0~
-C-N ~ 0 0~
Il /
b= -C-N~x~O
/\
Le A 28 841 - 19 -;, ., . ' ; -. ' ~ . ~ ` ' .
:
~,2~q~6 ,startinq Compounds Example I
(S)-2-(Hydroxymethyl)-l-benzyl-pyrrolidine ~CH2C~s C~H
formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
In the sub-substitution, heterocycle in general S represents a 5- to 7-membered, preferably 5- to 6-membered, saturated or unsaturated ring which as heteroatoms can contain up to 2 oxygen, sulphur and/or nitrogen stoms. Preferred S- and 6-membered rings are those having an oxygen, sulphur and/or up to 2 nitrogen atoms. The following are mentioned as being particularly preferred: pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrazolyl or morpholinyl.
A 3- to 8-membered, saturated heterocycle is in general represented by pyrrolidine, piperidine, pyrazolidine, imidazolidine or oxazolan. Pyrrolidine and oxazolan are preferred.
Preferred compounds of the general formula (I) are those in which R2 represents a heterocyclic radical of the formula Le A 28 841 - 5 -........ ...... ..
,: - ~ . . . . . . . :
. , . . . - ::
;.
.: . - : .
. - .. ~ . ..
\
R~ H3C
or O y N-R~
in which R~ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, Rl represents hydrogen, R3 represents a group of the formula -CO-NRlRll, in which R10 and Rll, together with the nitrogen atom, form a heterocyclic radical of the formula Rl2 R~3 O
¦ ¦ Rl4 Rl6 Rl5 in which Rl2 Rl3 R1~, Rls, R16 and R17 are identical or dif-ferent and denote hydrogen, straight-Le A 28 841 - 6 -chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case Rl2 and Rl3, Rl~
and Rls or Rl6 and Rl7 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different substituents from the group comprising hydroxyl, phenyl, cyclobutyl, cyclopentyl and cyclohexyl or by a group of the formula -NR1~R19, _NH_co-OR20, -SiR2lR22R23 or -SnR2lR22R23 in which R19 and Rl9 have the abovementioned meaning of R~
and are identical to or different from this, R20 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally sub-stituted by phenyl, R21, R22 and R23 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, or Le A 28 841 - 7 -' . .
., ~ .
', ...
~s~l6 represents straight-chain or branched acyl having up to 6 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiRZlR22R23, -SnR2lR22R23 or R24-co in which R21, R22 and R23 have the abovementioned meaning and RZ4 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -N~-CO-ORZ, in which RZ has the abovementioned meaning.
Particularly preferred compounds of the general formula (I) are those in which Le A 28 841 - 8 -~, .. ' :
~ ¢~ 5 ~ 6 R2 represents a heterocyclic radical of the formula N-R4 H3C ~
or N-R4 in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, Rl represents hydrogen, R3 represents a group of the formula -CO-NRl0R1l, in which Rl and Rll, together with the nitrogen atom, form a heterocyclic ring of the formula \NXO
R" ~ R~4 R~6 R15 in which R12 R'3 Rl~, Rls, Rls and Rl7 are identical or dif-ferent and denote hydrogen, straight-chain or branched alkyl having up to 4 Le A 28 841 - 9 -. ~
.. - - ~ ~ - - . ~ ............... :
. ; - .
carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case Rl2 and R1~, Rl4 and Rls or Rl6 and Rl7 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by hydroxyl, phenyl, cyclobutyl or cyclohexyl or by a group of the formula -NR~8R~9 -NH-CO-OR20, -SiR2~R22~23 or -SnR2lR22R23 in which Rl3 and R19 are identical or different and have the abovementioned meaning of R4 and are identical to or different from this, R20 denotes methyl or ethyl, each of which is optionally substituted by phenyl, R2l, R22 and R23 denote straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydxoxyl, Le A 28 841 - 10 -~?.G~57~fi) represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiR21R22R23, -SnR2~R22R23 or R24-co_, in which R2l, R22 and R23 have the abovementioned meaning and R2~ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
Additionally, a new process for the preparation of the compounds of the general formula (I) according to the invention has been found, characterised in that carbamates of the general formula (II) Le A 28 841 - 11 -~, , .
~¢~5~
Rl Rl in which Rl, R2, Rl and Rll have the abovemen~ioned meaning, are first enantio electively deprotonated in inert solvents, in the presence of a selective base, preferably S sec-butyllithium, and of a chelate-forming di~mine (in the following designated by D) to give the carbanion complex compounds of the general formula (III) Rlo ~ N`
~ B ~0 in which Rl, R2, R10 and Rll have the abovementioned meaning, 0 B represents a lithium, magnesium, titanium, zirconium or potassium atom, preferably lithium, and Le ~ 28 841 - 12 -D represents a chelate-forming diamine such as, for example, tetramethylethylenediamine (TMEDA) or (-)-sparteine, preferably TNEDA, and then reacted with electrophiles of the general formulae (IV) and (V) o A-M (rV) T ~ T' in which A has the abovementioned meaning, M represents halogen, C,-C,-alkoxy or another typical leaving group, preferably chlorine, and T and T' are identical or different and represent hydrogen or a chemi- cally useful radical shown under the substituent A, or with CO2.
The process according to the invention can be illustrated by way of example by the following reaction scheme:
Le A 28 841 - 13 -. ~ ' ''' :
-U ~ ~EDA
CH2 u~ auU / TMEDA ~ o CH
s ~ 2 O-C~ C~ H,C,~ ~CH, CHJ HaC
S u r -- HCC~'H~C Cl 1, 0 C- H, prisin gly, the proce~s according to the invention gives the desired compounds of the general formula ~I) in high yields.
The process is distinguished by ~everal advantages: in contrast to the prior art, stoichiometric amounts of bases, preferably sec-butyllithium, are adequate for deprotonation. Additionally, the process according to the invention enables both control of the diastereo-selectivity by the choice of the electrophilic sub-stituents and the influencing of asymmetric induction in the case of prochiral carbamates in the presence of chiral complex-forming diamines.
By the use of enantiomerically pure diamine compounds such a~, for example, TMEDA, deprotonation of the compounds of the formula (II) takes place enantioselectlvely and in very good yields to give the Le A 28 841 - 14 --35~
corresponding chiral compounds, preferably to give the (S)-lithium compounds of the formula (III), which can preferably be converted into the R-configuration by further reaction with electrophiles.
It is additionally surprising with knowledge of the prior art that the metallated compounds of the general formula (III) undergo no decomposition and a deprotonation in the benzyl radical. In particular, a high diastereo-selectivity and stereochemical control in the attack of the electrophile due to the induction of the stereocentre already present is of great advantage.
In addition to chlorine, bromine and iodine, the radicals tosylate, meaylate or -OS02-CF3 are also covered under the definition leaving group. Chlorine is preferred.
Suitable solvents for the deprotonation are preferably inert organic solvents such a6 hydrocarbons such as hexane, pentane, ligroin or toluene, and ethers, for example tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, diglyme, triglyme or tert-butyl methyl ether. Tetrahydrofuran and diethyl ether are particularly preferred.
Deprotonation is carried out in a temperature range from -lOO-C to room temperature, preferably at about -78-C to O-C .
Deprotonation can be carried out either at normal Le A 28 841 - 15 --' .- ~ ~ . .
.
;7~6 pressure or at elevated or reduced pressure (for example 0.5 to 2 bar)l preferably at normal pressure.
Suitable selective bases are alkyllithium compounds having up to 6 C atoms in the alkyl group, preferably n-butyllithium or sec-butyllithium.
The base is employed in an amount from 0.5 to 5 mol, preferably in stoichiometric amounts, relative to 1 mol of the compounds of the general formula (II).
Electrophilic substitution likewise takes place in the abovementioned solvents, preferably in tetrahydrofuran at normal pressure.
Electrophilic substitution is carried out in a tempera-ture range from about -100-C to +40-C, preferably in the range from -78-C to room temperature.
The compounds of the general formula (II) are also new and can be prepared by a process in which compounds of the general formula (VI) Rl ~C-OH (Vl), I
in which Le A 28 841 - 16 -: . . .: . .
: . ~
-. ...
,: ' , :-: '.:. ~
. .: ; . . .:
.. . . ::, - ~:
7~Lfi R' and R2 have the abovementioned meaning are reacted with compounds of the general formula (VII) O
Il Z - C NRlR~l (VII), in which R10 and R11 have the abovementioned meaning and Z represents halogen, preferably chlorine, in one of the abovementioned solvents, preferably ether, in the presence of a base, preferably sodium hydride.
The compounds of the general formulae (VI) and (VII) are known or can be prepared by a customary method [cf., for example, J. Chem. Soc., Perkin Trans l, 1074, 1101].
The compound of the general formula (III) are new and can be prepared by the process indicated above.
The compounds of the general formulae (IV) and (V) are known or can be prepared by customary methods.
The compounds according to the invention are also Le A 28 841 - 17 -' : ' ,. ~ .
5~ 3L6 distinguished by the fact that, after the enantio-selective introduction of the electrophile, the pro-tective group -CO-NR10Rl1 can be very easily removed with the formation of the free hydroxyl group.
Removal of the protective groups (carbamic acid esters) i8 carried out by a customary method, for example by sequential treatment with acids and bases, preferably in methanol.
Suitable acids are strong inorganic acids and organic sulphonic or carboxylic acids such as, for example, methanesulphonic acid, ethanesulphonic acid, benzene-sulphonic acid, toluenesulphonic acid, acetic acid or propionic acid.
Suitable bases are alkali metal and alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide. Barium hydroxide is preferred.
The acids and bases are employed in an amount from 0.01 to 10 mol, preferably l mol, relative to 1 mol of the compounds of the general formula (I).
Removal of the protective groups is carried out at normal pressure in a temperature range from 0C to +130-C, preferably from +20-C to +lOO-C.
Le A 28 841 - 18 -, ,~ -.
...
35~3~fi Removal can al80 be carried out with lithium aluminium hydride in one of the abovementioned solvents, preferably tetrahydrofuran.
The compounds according to the invention are thus useful S intermediates for the preparation of hydroxy-substituted heterocycles, some of which are known and some of which are new, in particular proline derivatives, which are of great importance for the synthesis of biologically active peptidec or peptide mimetics.
The abbreviations a and b used in the following have the following meaning:
0~
-C-N ~ 0 0~
Il /
b= -C-N~x~O
/\
Le A 28 841 - 19 -;, ., . ' ; -. ' ~ . ~ ` ' .
:
~,2~q~6 ,startinq Compounds Example I
(S)-2-(Hydroxymethyl)-l-benzyl-pyrrolidine ~CH2C~s C~H
3.79 g (37.5 mmol) of (S)-prolinol and 5.5 ml (47.4 mmol) of benzyl chloride are heated under reflux for~48 h with 3.7 g of potassium carbonate in 100 ml of ~toluene.
Contrary to the literature procedure;, the mixture is fractionated in vacuo. 5.52 g (77%, Lit.s66%) of the title compound are obtained a~ a colourless oil. The ~pectro~copic~data correspond to those given in the literature.
~U
(S)-(-)-(l-Benzylpyrrolidinyl)-methyl 2,2,4,4_ eetramethy~ 3-oxazolidine-3-carboxylate CH2-C,H, ~ ~O-b 402 mg (14 mmol) of sodium hydride (80% strength in mineral oi}) are initially introduced into 10 ml of ether at room temperature. 1.91 g (10 mmol) of the compound from ~xample I are added dropwi~e to thi~ mixture. It 1 Le A 28 841 - 20 -= ...... . . . .
- : - ~, . . - : .
.. ...
5~:~L6 stirred for 1 h for complete deprotonation and then treated with 2.30 g (12 mmol) of the carbamoyl chloride, dissolved in 5 ml of ether. The reaction mixture is stirred for 5 days at room tempersture. Hydrolysi~ i8 then carried out with 5 ml of water. The aqueous pha~e is extracted three times with 5 ml of ether each time, and the combined organic phases are dried over magnesium sulphate and concentrated in vacuo. After separation by column chromatography on silica gel (ether~pentane = 1:2, silica gel 0.2-0.06), 2.84 g (82%) of the title compound are obtained as a colourless oil.
R~ = 0.37 (silica gel, ether/pentane = 1:1) la]20 = -60.2 (c = 2.1, CHC13).
Preparation Examples Example 1 (lR,2'S)-(-)-(l-Benzylpyrrolidinyl)ethyl 2,2,4,4-tetra-methyl-1,3-oxazolidine-3-carboxylate a) Precursor CH2-C~
N
C~b U x T~ED~
Le A 28 841 - 21 -Zj,~
CH2-C,H~
b) N/
r ~ O~b CH~
346 mg (1.0 mmol) of the compound from Example II and 446 ~1 of tetramethylethylenediamine (TMEDA, 3.0 mmol) are dissolved in 8 ml of ether. This solution is treated at -78C with 2.17 ml (3.0 mmol) of sec-butyllithium (1.4M in cyclohexane/isopentane); in this process the solution changes colour to orange-yellow (a). The mixture is stirred at this temperature for 3 h and 187 ~1 (3.0 mmol) of iodomethane are then in~ected. The mixture is additionally stirred at this temperature for a further 1 h and the cooling bath is then removed. After thawing at room temperature, the solution is hydrolysed with 2 ml of water. After separation of the phases, the aqueous phase is extracted a further three times with 5 ml of ether cach time. The combined organic phases are dried over magnesium sulphate and concentrated in vacuo. After separation by column chromatography on alumina (activity stage II), 259 mg (72~) of the title compound are isolated as colourless crystals.
M.p.: 52-C ~from the melt) R~ = 0.67 (a~umina, ether/pentane = 1:1) [a]20 = -51.0 (c = 0.5, CHCl3).
Le A 28 841 - 22 -- -- - , ': . . -,..-.
-~5~
Example 2 (IR,2'S)~ (l-Benzylpyrrolidinyl)-trimethylsilyl-methyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate ~ H2-C,Hs N
r ~. Ob By the method described above, in the case of the reaction of 346 mg (1.0 mmol) of the compound from Example II with 2.17 ml (3.0 mmol) of sec-butyllithium, 446 ~1 (3.0 mmol) of TMEDA and 378 ~1 of trimethylsilyl chloride, 140 mg (33%) of the title compound are obtained as a waxy ~olid. M.p.: 45C (from the melt) Rf = 0.55 (alumina, ether/pentane = 1:1) t]20 = -54.8 (c = 1.5, CHCl3).
Example 3 (IR,2'S)-(-)-(l-Benzylpyrrolidinyl)tributylstannyl-methyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate Le A 28 841 - 23 -:
' '~
. . .
:
' ~ :
7~Ç~
CH2 C6Hs r s Ob Sn(C~H~
Analogously, from 346 mg (1.O mmol) of the compound from Example II and 865 ~1 (3.0 mmol) of tributylstannyl chloride, 451 mg (71~) of the title compound are obtained as a colourless oil.
R~ = O.66 (alumina, ether/pentane = 1:1) t~]20 = -69.6 (c = 1.0, CHCl3).
Example 4 Methyl (2S,2'S)-(-)-2-[1-benzylpyrrolidinyl-(2,2,4,4-tetramethyl-1,3-oxazolidin-3-yl-carbonyl)oxy]ethanoate CH2 C,~s r S. 0~
COOCH, 346 mg ll.0 mmol) of the compound from Example II are metallated for 3 h by the method described above. Carbon dioxide is then introduced at -78C for 1 h and the mixture is warmed to room temperature under a carbon dioxide atmosphere. The reaction solution is hydrolysed with 10 ml of 2N hydrochloric acid. The aqueous pha~e is Le A 28 841 - 24 -.
' , , .
.. . ... ..
~C~357~6 extracted a further three times with 10 ml of ether each time. The combined ethereal phases are dried over magnesium sulphate and concentrated in vacuo. The residue is dissolved in 10 ml of ether and treated with diazomethane (0.6M in ether) until a yellow coloration remains; excess diazomethane is destroyed using ~ilica gel. The solution is freed of solvent in vacuo and purified by column chromatography on silica gel (ether/pentane = 1:4). 162 mg (40%) of the title compound are obtained as a colourless oil.
Rf = 0.46 (silica gel, ether/pentane = 1:1) ta]20 = -19.2 (c = 1.0, CHC13).
Example 5 (lS;2'S)-(-)-l-(l-Benzylpyrrolidinyl)-2-hydroxymethyl-propyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate CH2-C,H5 ~O b ~--OH
In the metallation 346 mg (1.0 mmol) of the compound from Example II with 446 ~1 (3.0 mmol) of TNEDA and 2.1~ ml (3.0 mmol) of sec-butyllithium and subsequent reaction with 220 ~1 (3.0 mmol) of acetone, 135 mg (35%) of the title compound result as colourless crystals.
N.p.: 102-C (ether/pentane) Le A 28 841 - 25 -~C~71fi Rf = 0.20 (silica gel, ether/pentane = 1:1) [a]236S = -17.4 (c = 1.0, CHC13).
Example 6 (lS,2RS, 2'S)-(-)-1-(1-Benzylpyrrolidinyl)-2-hydroxy-3-methylbutyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate CH2-C,Hs ~' H3C ~ OH
Two dia~tereomers are obtained from the reaction of 346 mg (1.O mmol) of the compound from Example II with 273 ~l (3.0 mmol) of isobutyraldehyde. One diastereomer is isolated as colourless crystals in 23% (95 mg) yield.
M.p.: 64C
Rr = O.52 (alumina, ether/pentane = 1:1) ta]D = -8.1; [a]2355 = -13.7 (c = 1.2; CHC13).
The second diastereomer is obtained as 8 colourless oil in 62% (260 mg) yield.
Rf = O . 43 (alumina, ether/pentane = 1:1) [a]20 = -1.3; [a]235S = -15.8 (c = 1.2; CHCl3).
By Examples A and B, it is intended to illustrate by way of example how the compounds of the general formula (I) according to the invention can be converted into the Le A 28 841 - 26 -corresponding hydroxy compound~.
Example A
(IR, 2'Sj-(-)-(1-Benzylpyrrolidinyl)-ethanol ~ 1'12 C~Hs r s 0 ~ ',~
CH, 1.41 g (3.9 mmol) of the compound from Example 1 are heated under reflux for 16 h with 74Q ~1 (11.4 mmol) of mathanesulphonic acid in 15 ml of methanol. After addi-tion of 5 g of barium hydroxide, the mixt ~-e is then heated under reflux for a further 4 h. After cooling to room temperature, the inorganic residue is filtered off on a short silica gel column. The filtrate i8 concen-trated in vacuo, the residue is taken up with ether and the solution is dried over magnesium sulphate. After removal of the solvent in vacuo, the residual oil is purified on alumina (activity stage III, ether/pentane = 1:2). 532 mg (66~) of the title compound are obtained as a colourless, slightly unstable oil.
Rr = 0.56 (alumina, ether/pentane = 1:1) t]20 = -85.0 (c = 0.7, CHCl3).
Example B
(2S, 3S)-(-)-2-(Hydroxyethyl)-pyrrolidine Le A 28 841 - 27 -.- -, , 2~35716 ~OH
CH, For the removal of the benzyl group, 481 mg (2.3 mmol) of the compound from Example A are hydrogenated for 8 h under a slight hydrogen overpressure using 488 mg (0.46 mmol) of palladium (10% strength on carbon) in lS ml of methanol and 0.5 ml of formic acid. After completion of the reaction, the palladium is filtered off through a thin silica gel layer. The filtrate is concen-trated in vacuo and taken up with 5 ml of SN hydrochloric acid. The hydrochloric acid solution is extracted three times with 5 ml of ether each time and the extracts are discarded. After careful neutralisation with 30% strength sodium hydroxide solution, the aqueous phase is extracted three times with 10 ml of ethyl acetate each time. The combined organic ethyl acetate phases are dried over magnesium sulphate and freed of solvents in vacuo. The residue is recrystallised from ethyl acetate/pentane.
112 mg (42%) of the title compound are thus obtained as slightly unstable, colourless crystals.
M.p.: 86C
[a]20 = -36.4 (c = 1.0, CH30H).
Le A 28 841 - 28 -- ' ' . ' ''' ~ ~ ',' .
: ~ . .
Contrary to the literature procedure;, the mixture is fractionated in vacuo. 5.52 g (77%, Lit.s66%) of the title compound are obtained a~ a colourless oil. The ~pectro~copic~data correspond to those given in the literature.
~U
(S)-(-)-(l-Benzylpyrrolidinyl)-methyl 2,2,4,4_ eetramethy~ 3-oxazolidine-3-carboxylate CH2-C,H, ~ ~O-b 402 mg (14 mmol) of sodium hydride (80% strength in mineral oi}) are initially introduced into 10 ml of ether at room temperature. 1.91 g (10 mmol) of the compound from ~xample I are added dropwi~e to thi~ mixture. It 1 Le A 28 841 - 20 -= ...... . . . .
- : - ~, . . - : .
.. ...
5~:~L6 stirred for 1 h for complete deprotonation and then treated with 2.30 g (12 mmol) of the carbamoyl chloride, dissolved in 5 ml of ether. The reaction mixture is stirred for 5 days at room tempersture. Hydrolysi~ i8 then carried out with 5 ml of water. The aqueous pha~e is extracted three times with 5 ml of ether each time, and the combined organic phases are dried over magnesium sulphate and concentrated in vacuo. After separation by column chromatography on silica gel (ether~pentane = 1:2, silica gel 0.2-0.06), 2.84 g (82%) of the title compound are obtained as a colourless oil.
R~ = 0.37 (silica gel, ether/pentane = 1:1) la]20 = -60.2 (c = 2.1, CHC13).
Preparation Examples Example 1 (lR,2'S)-(-)-(l-Benzylpyrrolidinyl)ethyl 2,2,4,4-tetra-methyl-1,3-oxazolidine-3-carboxylate a) Precursor CH2-C~
N
C~b U x T~ED~
Le A 28 841 - 21 -Zj,~
CH2-C,H~
b) N/
r ~ O~b CH~
346 mg (1.0 mmol) of the compound from Example II and 446 ~1 of tetramethylethylenediamine (TMEDA, 3.0 mmol) are dissolved in 8 ml of ether. This solution is treated at -78C with 2.17 ml (3.0 mmol) of sec-butyllithium (1.4M in cyclohexane/isopentane); in this process the solution changes colour to orange-yellow (a). The mixture is stirred at this temperature for 3 h and 187 ~1 (3.0 mmol) of iodomethane are then in~ected. The mixture is additionally stirred at this temperature for a further 1 h and the cooling bath is then removed. After thawing at room temperature, the solution is hydrolysed with 2 ml of water. After separation of the phases, the aqueous phase is extracted a further three times with 5 ml of ether cach time. The combined organic phases are dried over magnesium sulphate and concentrated in vacuo. After separation by column chromatography on alumina (activity stage II), 259 mg (72~) of the title compound are isolated as colourless crystals.
M.p.: 52-C ~from the melt) R~ = 0.67 (a~umina, ether/pentane = 1:1) [a]20 = -51.0 (c = 0.5, CHCl3).
Le A 28 841 - 22 -- -- - , ': . . -,..-.
-~5~
Example 2 (IR,2'S)~ (l-Benzylpyrrolidinyl)-trimethylsilyl-methyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate ~ H2-C,Hs N
r ~. Ob By the method described above, in the case of the reaction of 346 mg (1.0 mmol) of the compound from Example II with 2.17 ml (3.0 mmol) of sec-butyllithium, 446 ~1 (3.0 mmol) of TMEDA and 378 ~1 of trimethylsilyl chloride, 140 mg (33%) of the title compound are obtained as a waxy ~olid. M.p.: 45C (from the melt) Rf = 0.55 (alumina, ether/pentane = 1:1) t]20 = -54.8 (c = 1.5, CHCl3).
Example 3 (IR,2'S)-(-)-(l-Benzylpyrrolidinyl)tributylstannyl-methyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate Le A 28 841 - 23 -:
' '~
. . .
:
' ~ :
7~Ç~
CH2 C6Hs r s Ob Sn(C~H~
Analogously, from 346 mg (1.O mmol) of the compound from Example II and 865 ~1 (3.0 mmol) of tributylstannyl chloride, 451 mg (71~) of the title compound are obtained as a colourless oil.
R~ = O.66 (alumina, ether/pentane = 1:1) t~]20 = -69.6 (c = 1.0, CHCl3).
Example 4 Methyl (2S,2'S)-(-)-2-[1-benzylpyrrolidinyl-(2,2,4,4-tetramethyl-1,3-oxazolidin-3-yl-carbonyl)oxy]ethanoate CH2 C,~s r S. 0~
COOCH, 346 mg ll.0 mmol) of the compound from Example II are metallated for 3 h by the method described above. Carbon dioxide is then introduced at -78C for 1 h and the mixture is warmed to room temperature under a carbon dioxide atmosphere. The reaction solution is hydrolysed with 10 ml of 2N hydrochloric acid. The aqueous pha~e is Le A 28 841 - 24 -.
' , , .
.. . ... ..
~C~357~6 extracted a further three times with 10 ml of ether each time. The combined ethereal phases are dried over magnesium sulphate and concentrated in vacuo. The residue is dissolved in 10 ml of ether and treated with diazomethane (0.6M in ether) until a yellow coloration remains; excess diazomethane is destroyed using ~ilica gel. The solution is freed of solvent in vacuo and purified by column chromatography on silica gel (ether/pentane = 1:4). 162 mg (40%) of the title compound are obtained as a colourless oil.
Rf = 0.46 (silica gel, ether/pentane = 1:1) ta]20 = -19.2 (c = 1.0, CHC13).
Example 5 (lS;2'S)-(-)-l-(l-Benzylpyrrolidinyl)-2-hydroxymethyl-propyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate CH2-C,H5 ~O b ~--OH
In the metallation 346 mg (1.0 mmol) of the compound from Example II with 446 ~1 (3.0 mmol) of TNEDA and 2.1~ ml (3.0 mmol) of sec-butyllithium and subsequent reaction with 220 ~1 (3.0 mmol) of acetone, 135 mg (35%) of the title compound result as colourless crystals.
N.p.: 102-C (ether/pentane) Le A 28 841 - 25 -~C~71fi Rf = 0.20 (silica gel, ether/pentane = 1:1) [a]236S = -17.4 (c = 1.0, CHC13).
Example 6 (lS,2RS, 2'S)-(-)-1-(1-Benzylpyrrolidinyl)-2-hydroxy-3-methylbutyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate CH2-C,Hs ~' H3C ~ OH
Two dia~tereomers are obtained from the reaction of 346 mg (1.O mmol) of the compound from Example II with 273 ~l (3.0 mmol) of isobutyraldehyde. One diastereomer is isolated as colourless crystals in 23% (95 mg) yield.
M.p.: 64C
Rr = O.52 (alumina, ether/pentane = 1:1) ta]D = -8.1; [a]2355 = -13.7 (c = 1.2; CHC13).
The second diastereomer is obtained as 8 colourless oil in 62% (260 mg) yield.
Rf = O . 43 (alumina, ether/pentane = 1:1) [a]20 = -1.3; [a]235S = -15.8 (c = 1.2; CHCl3).
By Examples A and B, it is intended to illustrate by way of example how the compounds of the general formula (I) according to the invention can be converted into the Le A 28 841 - 26 -corresponding hydroxy compound~.
Example A
(IR, 2'Sj-(-)-(1-Benzylpyrrolidinyl)-ethanol ~ 1'12 C~Hs r s 0 ~ ',~
CH, 1.41 g (3.9 mmol) of the compound from Example 1 are heated under reflux for 16 h with 74Q ~1 (11.4 mmol) of mathanesulphonic acid in 15 ml of methanol. After addi-tion of 5 g of barium hydroxide, the mixt ~-e is then heated under reflux for a further 4 h. After cooling to room temperature, the inorganic residue is filtered off on a short silica gel column. The filtrate i8 concen-trated in vacuo, the residue is taken up with ether and the solution is dried over magnesium sulphate. After removal of the solvent in vacuo, the residual oil is purified on alumina (activity stage III, ether/pentane = 1:2). 532 mg (66~) of the title compound are obtained as a colourless, slightly unstable oil.
Rr = 0.56 (alumina, ether/pentane = 1:1) t]20 = -85.0 (c = 0.7, CHCl3).
Example B
(2S, 3S)-(-)-2-(Hydroxyethyl)-pyrrolidine Le A 28 841 - 27 -.- -, , 2~35716 ~OH
CH, For the removal of the benzyl group, 481 mg (2.3 mmol) of the compound from Example A are hydrogenated for 8 h under a slight hydrogen overpressure using 488 mg (0.46 mmol) of palladium (10% strength on carbon) in lS ml of methanol and 0.5 ml of formic acid. After completion of the reaction, the palladium is filtered off through a thin silica gel layer. The filtrate is concen-trated in vacuo and taken up with 5 ml of SN hydrochloric acid. The hydrochloric acid solution is extracted three times with 5 ml of ether each time and the extracts are discarded. After careful neutralisation with 30% strength sodium hydroxide solution, the aqueous phase is extracted three times with 10 ml of ethyl acetate each time. The combined organic ethyl acetate phases are dried over magnesium sulphate and freed of solvents in vacuo. The residue is recrystallised from ethyl acetate/pentane.
112 mg (42%) of the title compound are thus obtained as slightly unstable, colourless crystals.
M.p.: 86C
[a]20 = -36.4 (c = 1.0, CH30H).
Le A 28 841 - 28 -- ' ' . ' ''' ~ ~ ',' .
: ~ . .
Claims (7)
1. Heterocyclically substituted carbamates of the general formula (I) (I), in which R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 hetero-atoms from the series comprising S and O or having a group of the formula -NR4, -SiR5R6R7 or -SnR5R6R7, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or benzyl, R5, R6 and R7 are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, where these substitutents can optionally be Le A 28 841 - 29 -substitued up to 3 times by identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsaturated heterocylce having up to 3 heteratoms from the series comprising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiR5R6R7, in which R5, R6 and R7 have the abovementioned meaning, R3 represents a group of the formula -CO-NR10R11, in which R10 and R11, together with the nitrogen atom, form a heterocyclic radical of the formula Le A 28 841 - 30 - in which R12 Rl3 R14 R15, R16 and R17 are identical or different and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and R13, R14 and R15 and/or R16 and R17 together form a 3- to 6-membered, saturated carbo-cycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NR18R19, -HN-CO-OR20, -SiR21R22R23 or -SnR21R22R23 in which R18 and R19 have the abovementioned meaning of R4 and are identical to or different from this Le A 28 841 - 31 -and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally sub-stituted by phenyl, R21, R22 and R23 have the abovementioned meaning of R5, R6 and R7 and are identical to or different from this, or represents straight-chain or branched acyl having up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-, in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by Le A 28 841 - 32 -phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
2. Compounds of the general formula (I) according to Claim 1, in which R2 represents a heterocyclic radical of the formula or in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, R1 represents hydrogen, R3 represents a group of the formula -CO-NR10R11, in which R10 and R11, together with the nitrogen atom, form Le A 28 841 - 33 -a heterocyclic radical of the formula in which R12, R13, R14, R15, R16 and R17 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case R12 and R13, R14 and R15 or R16 and R17 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different substituents from the group comprising hydroxyl, phentl, cyclobutyl, cyclopentyl and cyclohexyl or by a group of the formula -NR18R19, -NH-CO-OR20, -SiR21R22R23 or -SnR21R22R23, in which R18 and R19 have the abovementioned meaning of R4 Le A 28 841 - 34 -and are identical to or different from this, R20 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, or represents straight-chain or branched acyl having up to 6 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to
3 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-, in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each havinq up to 6 Le A 28 841 - 35 -carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
3. Compounds of the general formula (I) according to Claim 1, in which R2 represents a heterocyclic radical of the formula or in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, R1 represents hydrogen, R3 represents a group of the formula -CO-NR10R11, in which Le A 28 841 - 36 -R10 and R11, together with the nitrogen atom, form a heterocyclic ring of the formula in which R12 R13 R14 R15, R16 and R17 are identical or dif-ferent and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case R12 and R13, R14 and R15 or R16 and R17 toqether form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by hydroxyl, phenyl, cyclobutyl or cyclohexyl or by a group of the formula -NR18R19, -NH-CO-OR20, -SiR21R22R23 or -SnR21R22R23 in which Le A 28 841 - 37 -R18 and R19 are identical or different and have the abovementioned meaning of R4 and are identical to or different from this, R20 denotes methyl or ethyl, each of which is optionally substituted by phenyl, R21, R22 and R23 denote straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by phenyl or by the qroup of the Le A 28 841 - 38 -formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
3. Compounds of the general formula (I) according to Claim 1, in which R2 represents a heterocyclic radical of the formula or in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, R1 represents hydrogen, R3 represents a group of the formula -CO-NR10R11, in which Le A 28 841 - 36 -R10 and R11, together with the nitrogen atom, form a heterocyclic ring of the formula in which R12 R13 R14 R15, R16 and R17 are identical or dif-ferent and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case R12 and R13, R14 and R15 or R16 and R17 toqether form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by hydroxyl, phenyl, cyclobutyl or cyclohexyl or by a group of the formula -NR18R19, -NH-CO-OR20, -SiR21R22R23 or -SnR21R22R23 in which Le A 28 841 - 37 -R18 and R19 are identical or different and have the abovementioned meaning of R4 and are identical to or different from this, R20 denotes methyl or ethyl, each of which is optionally substituted by phenyl, R21, R22 and R23 denote straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by phenyl or by the qroup of the Le A 28 841 - 38 -formula -NH-CO-OR20, in which R20 has the abovementioned meaning.
4. Process for the preparation of compounds of the general formula (I) (I), in which R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 hetero-atoms from the series comprising S and O or having a group of the formula -NR4, -SiRsR6R7 or -SnR5R6R7, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or benzyl, Le A 28 841 - 39 -R5, R6 and R7 are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, where these substitutents can optionally be substituted up to 3 times by identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series com-prising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiR5R6R7, in which R5, R6, R7 have the abovementioned meaning, R3 represents a group of the formula -CON-R10R11, in which Le A 28 841 - 40 -R10 and R11, together with the nitrogen atom, form a heterocyclic radical of the formula in which R12, R13, R14, R15, R16 and R17 are identical or different and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and R13, R14 and R15 and/or R16 and R17 together form a 3-to 6-membered, saturated carbocycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NR18R19 -HN-CO-OR20, -SiR21R22R23 or Le A 28 841 - 41 --SnR21R22R23 in which R18 and R19 have the abovementioned meaning of R4 and are identical to or different from this and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 have the abovementioned meaning of R5, R6 and R7 and are identical to or dif-ferent from this, or represents straight-chain or branched acyl having up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-, in which R21, R22 and R23 have the abovementioned meaning Le A 28 841 - 42 -and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning, characterised in that carbamates of the general formula (II) (II), in which R1, R2, R10 and R11 have the abovementioned meaning, are first enantioselectively deprotonated in inert solvents, in the presence of a selective base and of a chelate-forming diamine (in the following designated by D) to give the carbanion complex compounds of the general formula (III) Le A 28 841 - 43 - (III), in which R1, R2, R10 and R11 have the abovementioned meaning, B represents a lithium, magnesium, titanium, zirconium or potassium atom, and D represents a chelate-forming diamine such as, for example, tetramethylethylenediamine (TMEDA) or (-)-sparteine, and then reacted with electrophiles of the general formulae (IV) and (V) A-M (IV) (V), in which A has the abovementioned meaning, Le A 28 841 - 44 -M represents halogen, C1-C4-alkoxy or another typical leaving group, and T and T' are identical or different and represent a chemically useful radical shown under the substituent A, or with CO2.
5. Carbamates of the general formula (II) (II), in which R1, R2, R10 and R11 have the meaning indicated in Claim 4.
6. Process for the preparation of carbamates of the general formula (II) according to Claim 4, characterised in that compounds of the general formula (VI) Le A 28 841 - 45 - (VI), in which R1 and R2 have the meaning indicated in Claim 4, are reacted with compounds of the general formula (VII) (VII), in which R10 and R11 have the meaning indicated in Claim 4 and Z represents halogen, in an inert solvent, in the presence of a base, at temperatures between 0°C and +130°C.
7. Use of the compounds of the general formula (I) Le A 28 841 - 46 -according to Claim 1 in the preparation of 1-hydroxy-substituted cycloalkyl compounds which can be employed for the synthesis of biologically active peptides and peptide mimetics.
Le A 28 841 - 47 -
Le A 28 841 - 47 -
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4142188.4 | 1991-12-20 | ||
DE4142188A DE4142188A1 (en) | 1991-12-20 | 1991-12-20 | HETEROCYCLICALLY SUBSTITUTED CARBAMATES AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
Publication Number | Publication Date |
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CA2085716A1 true CA2085716A1 (en) | 1993-06-21 |
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ID=6447623
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002085716A Abandoned CA2085716A1 (en) | 1991-12-20 | 1992-12-17 | Heterocyclically substituted carbamates and process for their preparation |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0549927A3 (en) |
JP (1) | JPH05286928A (en) |
CA (1) | CA2085716A1 (en) |
DE (1) | DE4142188A1 (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4020942A1 (en) * | 1990-06-30 | 1992-01-02 | Bayer Ag | METHOD FOR PRODUCING SEC. OR TERT. ALCOHOLS |
-
1991
- 1991-12-20 DE DE4142188A patent/DE4142188A1/en not_active Withdrawn
-
1992
- 1992-12-09 EP EP19920120946 patent/EP0549927A3/en not_active Withdrawn
- 1992-12-15 JP JP4354049A patent/JPH05286928A/en active Pending
- 1992-12-17 CA CA002085716A patent/CA2085716A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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DE4142188A1 (en) | 1993-06-24 |
JPH05286928A (en) | 1993-11-02 |
EP0549927A3 (en) | 1993-08-04 |
EP0549927A2 (en) | 1993-07-07 |
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