DE19645361A1 - Production of epothilone compounds with taxol-like activity - Google Patents
Production of epothilone compounds with taxol-like activityInfo
- Publication number
- DE19645361A1 DE19645361A1 DE19645361A DE19645361A DE19645361A1 DE 19645361 A1 DE19645361 A1 DE 19645361A1 DE 19645361 A DE19645361 A DE 19645361A DE 19645361 A DE19645361 A DE 19645361A DE 19645361 A1 DE19645361 A1 DE 19645361A1
- Authority
- DE
- Germany
- Prior art keywords
- mmol
- solution
- benzyl
- epothilone
- tetrahydropyranyl
- 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.)
- Withdrawn
Links
- -1 epothilone compounds Chemical class 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 229930013356 epothilone Natural products 0.000 title description 3
- 230000000694 effects Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims abstract description 11
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract description 11
- OORUMIIDKDTTNO-UHFFFAOYSA-N 2-methylhept-6-enal Chemical compound O=CC(C)CCCC=C OORUMIIDKDTTNO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 abstract description 6
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 abstract description 6
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- NABMPOXTCLBNMV-JUVOFCAFSA-N (4s,6s)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-5-hydroxy-2,4,6-trimethylundecan-3-one Chemical compound CCCCC[C@H](C)C(O)[C@H](C)C(=O)C(C)(C)C1CCOC(C)(C)O1 NABMPOXTCLBNMV-JUVOFCAFSA-N 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- LTXBCDHAKVAGQV-UHFFFAOYSA-N 3,7-dihydroxy-5-oxotridec-2-enoic acid Chemical compound OC(=CC(=O)O)CC(CC(CCCCCC)O)=O LTXBCDHAKVAGQV-UHFFFAOYSA-N 0.000 abstract 4
- SRLDRAQKTUVOIC-UHFFFAOYSA-N 2,6-dimethylhept-6-enal Chemical compound O=CC(C)CCCC(C)=C SRLDRAQKTUVOIC-UHFFFAOYSA-N 0.000 abstract 2
- 238000010511 deprotection reaction Methods 0.000 abstract 2
- QGPKAFNRXHKSMT-UHFFFAOYSA-N 2-(2,2-dimethyl-1,3-dioxan-4-yl)-2-methylpentan-3-one Chemical compound CCC(=O)C(C)(C)C1CCOC(C)(C)O1 QGPKAFNRXHKSMT-UHFFFAOYSA-N 0.000 abstract 1
- 238000005865 alkene metathesis reaction Methods 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 229930184531 desoxyepothilone Natural products 0.000 abstract 1
- 238000006735 epoxidation reaction Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 229910000510 noble metal Inorganic materials 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000011097 chromatography purification Methods 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- KRCIFTBSQKDYMH-UHFFFAOYSA-N (2-methyl-1,3-thiazol-4-yl)methanol Chemical compound CC1=NC(CO)=CS1 KRCIFTBSQKDYMH-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- WGWCJTNWUFFGFH-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxypropanal Chemical compound CC(C)(C)[Si](C)(C)OCCC=O WGWCJTNWUFFGFH-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical compound CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-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
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- DPQBHNZNJADHJG-NSHDSACASA-N (3s)-5-[tert-butyl(dimethyl)silyl]oxy-2-methylpent-1-en-3-ol Chemical compound CC(=C)[C@@H](O)CCO[Si](C)(C)C(C)(C)C DPQBHNZNJADHJG-NSHDSACASA-N 0.000 description 1
- FCMBGMCKXDKQSN-KRWDZBQOSA-N (3s)-5-[tert-butyl(dimethyl)silyl]oxy-3-phenylmethoxypentan-2-one Chemical compound CC(C)(C)[Si](C)(C)OCC[C@@H](C(=O)C)OCC1=CC=CC=C1 FCMBGMCKXDKQSN-KRWDZBQOSA-N 0.000 description 1
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 1
- YBUPWRYTXGAWJX-RXMQYKEDSA-N (4s)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1 YBUPWRYTXGAWJX-RXMQYKEDSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- JEMOXRNBPABXIC-UHFFFAOYSA-N 1-(2,2-dimethyl-1,3-dioxan-4-yl)-2-methylpentan-3-one Chemical compound CC1(OCCC(O1)CC(C(CC)=O)C)C JEMOXRNBPABXIC-UHFFFAOYSA-N 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical compound CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- PHMRPWPDDRGGGF-UHFFFAOYSA-N 2-bromoprop-1-ene Chemical compound CC(Br)=C PHMRPWPDDRGGGF-UHFFFAOYSA-N 0.000 description 1
- DQLJSQJTRLFHRI-UHFFFAOYSA-L 2-hydroxypropane-1,2,3-tricarboxylic acid;iron(2+);sulfate Chemical compound [Fe+2].[O-]S([O-])(=O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O DQLJSQJTRLFHRI-UHFFFAOYSA-L 0.000 description 1
- DHEKCFIOOSCJRW-UHFFFAOYSA-N 2-methylheptanal Chemical compound CCCCCC(C)C=O DHEKCFIOOSCJRW-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- PXQAYUYKRCWQFY-UHFFFAOYSA-N 3-[6-[tert-butyl(dimethyl)silyl]oxy-2-methylhexanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)C1COC(=O)N1C(=O)C(C)CCCCO[Si](C)(C)C(C)(C)C PXQAYUYKRCWQFY-UHFFFAOYSA-N 0.000 description 1
- UAAOYKNPKKCHAT-UHFFFAOYSA-N 3-[6-[tert-butyl(dimethyl)silyl]oxyhexanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound [Si](C)(C)(C(C)(C)C)OCCCCCC(=O)N1C(OCC1C(C)C)=O UAAOYKNPKKCHAT-UHFFFAOYSA-N 0.000 description 1
- NETUFVYVNJNFMU-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxypropan-1-ol Chemical compound CC(C)(C)[Si](C)(C)OCCCO NETUFVYVNJNFMU-UHFFFAOYSA-N 0.000 description 1
- HCPDMNGEYVWAAY-UHFFFAOYSA-N 4-(bromomethyl)-2-methyl-1,3-thiazole Chemical compound CC1=NC(CBr)=CS1 HCPDMNGEYVWAAY-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- DPQBHNZNJADHJG-UHFFFAOYSA-N 5-[tert-butyl(dimethyl)silyl]oxy-2-methylpent-1-en-3-ol Chemical compound CC(=C)C(O)CCO[Si](C)(C)C(C)(C)C DPQBHNZNJADHJG-UHFFFAOYSA-N 0.000 description 1
- KHSHOIVSAPWKAC-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxy-2-methylhexan-1-ol Chemical compound OCC(C)CCCCO[Si](C)(C)C(C)(C)C KHSHOIVSAPWKAC-UHFFFAOYSA-N 0.000 description 1
- NSXHDWGJNADSKS-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxy-2-methylhexanal Chemical compound O=CC(C)CCCCO[Si](C)(C)C(C)(C)C NSXHDWGJNADSKS-UHFFFAOYSA-N 0.000 description 1
- IYFMRXJBXNNNDL-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxyhexanoic acid Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC(O)=O IYFMRXJBXNNNDL-UHFFFAOYSA-N 0.000 description 1
- DIMLZGVFOXGJIW-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxyhexanoyl chloride Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC(Cl)=O DIMLZGVFOXGJIW-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- MCYHPZGUONZRGO-VKHMYHEASA-N L-cysteine methyl ester hydrochloride Natural products COC(=O)[C@@H](N)CS MCYHPZGUONZRGO-VKHMYHEASA-N 0.000 description 1
- WHOHXJZQBJXAKL-DFWYDOINSA-N Mecysteine hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CS WHOHXJZQBJXAKL-DFWYDOINSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- LCKIEQZJEYYRIY-UHFFFAOYSA-N Titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 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
- 244000309464 bull Species 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- XEBCWEDRGPSHQH-UHFFFAOYSA-N diisopropyl tartrate Chemical compound CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C XEBCWEDRGPSHQH-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- SCHJIKPVOOCORF-UHFFFAOYSA-M sodium;6-hydroxyhexanoate Chemical compound [Na+].OCCCCCC([O-])=O SCHJIKPVOOCORF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- UTWKBDHAEQSXMH-SFHVURJKSA-N tert-butyl-dimethyl-[(3S)-4-methyl-3-phenylmethoxypent-4-enoxy]silane Chemical compound C(C1=CC=CC=C1)O[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=C)C UTWKBDHAEQSXMH-SFHVURJKSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- 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
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
Description
Die Erfindung betrifft Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B.The invention relates to intermediates within the total synthesis of epothilone A and B.
Epothilon A und B sind Naturstoffe, die durch Mikroorganismen hergestellt werden können und die Taxol ähnliche Eigenschaften besitzen und somit besonderes Interesse in der Arzneimittelchemie besitzen. Diese Epothilone A und B werden innerhalb des Standes der Technik in DE 41 38 042 C2 und in European Chemistry Chronicle, Vol. 1/No. 1 S. 7-10 beschrieben.Epothilon A and B are natural products that are produced by microorganisms can and the Taxol have similar properties and therefore special Interest in drug chemistry. These are epothilones A and B. within the state of the art in DE 41 38 042 C2 and in European Chemistry Chronicle, Vol. 1 / No. 1 pp. 7-10.
Aufgabe der vorliegenden Erfindung ist es, Zwischenprodukte für die Totalsynthese von Epothilon A und B bereitzustellen, die es erlauben, die Naturstoffe einfach herzustellen und ebenso die Strukturen in der üblichen Art und Weise zu variieren, um Verbindungen mit stärkeren bzw. nebenwirkungsärmeren Eigenschaften herstellen zu können.The object of the present invention is to provide intermediates for total synthesis of epothilones A and B, which allow the natural products to be easily to manufacture and also to vary the structures in the usual way, to compounds with stronger or less side effects to be able to manufacture.
Die Erfindung beinhaltet Verbindungen der allgemeinen Formel 2a
The invention includes compounds of the general formula 2a
worin A = Wasserstoff oder eine niedrige Alkylgruppe (Methyl, Ethyl, Propyl, Iso- Propyl, Butyl-, iso- und ter. Butyl)) und B = Wasserstoff, Benzyl-, Tetrahydro pyranyl- oder eine Silylschutzgruppe (beispielsweise Trimethyl-, tert.-Buty dimethyl-, Diphenyl-tert.-butyl-silyl) bedeutet. where A = hydrogen or a lower alkyl group (methyl, ethyl, propyl, iso- Propyl, butyl, iso and ter. Butyl)) and B = hydrogen, benzyl, tetrahydro pyranyl or a silyl protective group (for example trimethyl, tert-buty dimethyl-, diphenyl-tert-butyl-silyl) means.
Weiter beinhaltet die Erfindungen Verbindungen der allgemeinen Formel 2b
The inventions furthermore comprise compounds of the general formula 2b
worin A = Wasserstoff oder eine niedrige Alkylgruppe (C1-C4) und B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe bedeutet. Die Bedeutung von B im Molekül kann unterschiedlich sein kann.wherein A = hydrogen or a lower alkyl group (C 1 -C 4 ) and B = hydrogen, benzyl, tetrahydropyranyl or a silyl protective group. The meaning of B in the molecule can be different.
Weiter beinhaltet die Erfindung 2-Methyl-6-heptenal 4a
The invention further includes 2-methyl-6-heptenal 4a
und Verbindungen der allgemeinen Formel 8a
and compounds of general formula 8a
worin B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe
bedeutet und die Bedeutung von B im Molekül ebenfalls unterschiedlich sein
können und Verbindungen der allgemeinen Formel 8b
where B = hydrogen, benzyl, tetrahydropyranyl or a silyl protective group and the meaning of B in the molecule can also be different and compounds of the general formula 8b
worin B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe bedeutet und die Bedeutung von B im Molekül unterschiedlich sein kann weiter werden die Stereoisomere der Verbindungen umfaßt. where B = hydrogen, benzyl, tetrahydropyranyl or a silyl protecting group means and the meaning of B in the molecule can be different the stereoisomers of the compounds are further included.
Synthese von Segment 4Synthesis of segment 4
Das Natrium-6-hydroxyhexanoat 20 wird nach einer Vorschrift von Wulff, Krüger und Röhle Chem. Ber. 1971, 104, 1387-1399 [6] aus w-Caprolacton 19 hergestellt.The sodium 6-hydroxyhexanoate 20 is produced according to a regulation by Wulff, Krüger and Röhle Chem. Ber. 1971, 104, 1387-1399 [6] made from w-caprolactone 19.
Eine Mischung aus 2.00 g (12.97 mmol) des Salzes 20, 25 ml DMF, 5.87 g
(38.93 mmol, 3 equiv) TBDMSCl und 5.3 g (77.85 mmol, 6 equiv) Imidazol wird
48 Stunden bei RT gerührt. Das Reaktionsgemisch wird flashfiltriert und
anschließend mit Pentan:DE = 4 : 1 säulen-chromatographisch gereinigt. Man erhält
3.99 g (11.1 mmol) der bissilylierten Verbindung 21, entsprechend einer Ausbeute
von 85%.
Allgemeine Daten: C18H40O3Si2, FG = 360.69 g/mol
13C-NMR (100 MHz, CDCl3): 174.17 (s), 63.00 (t), 36.02 (t), 32.53 (t), 25.95 (q),
25.55 (q), 25.40 (t), 24.91(t), 18.33 (s), 17.57 (s), -4.83(q), -5.32(q)A mixture of 2.00 g (12.97 mmol) of the salt 20, 25 ml of DMF, 5.87 g (38.93 mmol, 3 equiv) TBDMSCl and 5.3 g (77.85 mmol, 6 equiv) imidazole is stirred for 48 hours at RT. The reaction mixture is flash filtered and then purified by column chromatography with pentane: DE = 4: 1. 3.99 g (11.1 mmol) of the bissilylated compound 21 are obtained, corresponding to a yield of 85%.
General data: C 18 H 40 O 3 Si 2 , FG = 360.69 g / mol
13 C-NMR (100 MHz, CDCl 3 ): 174.17 (s), 63.00 (t), 36.02 (t), 32.53 (t), 25.95 (q), 25.55 (q), 25.40 (t), 24.91 (t ), 18.33 (s), 17.57 (s), -4.83 (q), -5.32 (q)
Eine Lösung von 3.25 g (9.02 mmol) der bissilylierten Verbindung 21 in
130 ml Methanol und 44 ml THF wird mit einer Lösung von 4.4 g (31.8 mmol,
3.5 equiv) K2CO3 in 44 ml H2O versetzt und 1 h bei RT gerührt. Danach wird das
Volumen der Reaktionslösung im Vakuum auf ein Viertel reduziert. Man verdünnt mit
130 ml ges. NaCl-Lösung und stellt mit 1 M KHSO4-Lösung auf pH 4-5 ein. Es wird
mit Diethylether extrahiert. Die vereinigten organischen Phasen werden über
MgSO4 getrocknet und das Lösungsmittel am Rotationsverdampfer abdestilliert.
Man erhält 2.01 g (8.17 mmol) der Carbonsäure 22, entsprechend einer Ausbeute
von 90%.
Allgemeine Daten: C12H26O3Si, FG = 246.42 g/mol
13C-NMR (100 MHz, CDCl3): 180.09 (s), 62.90 (t), 34.05 (t), 32.37 (t), 25.93 (q),
25.31(t), 24.46 (t), 18.32 (s), -5.33(q)
A solution of 3.25 g (9.02 mmol) of the bissilylated compound 21 in 130 ml of methanol and 44 ml of THF is mixed with a solution of 4.4 g (31.8 mmol, 3.5 equiv) of K 2 CO 3 in 44 ml of H 2 O and added for 1 h RT stirred. The volume of the reaction solution is then reduced to a quarter in vacuo. It is diluted with 130 ml of sat. NaCl solution and adjust to pH 4-5 with 1 M KHSO 4 solution. It is extracted with diethyl ether. The combined organic phases are dried over MgSO 4 and the solvent is distilled off on a rotary evaporator. 2.01 g (8.17 mmol) of carboxylic acid 22 are obtained, corresponding to a yield of 90%.
General data: C 12 H 26 O 3 Si, FG = 246.42 g / mol
13 C-NMR (100 MHz, CDCl 3 ): 180.09 (s), 62.90 (t), 34.05 (t), 32.37 (t), 25.93 (q), 25.31 (t), 24.46 (t), 18.32 (s ), -5.33 (q)
Eine Lösung von 0.5 g (2.03 mmol) Carbonsäure in 4 ml Benzol wird mit 362 mg (3.04 mmol, 1.5 equiv) SOCl2 versetzt und 2 h unter Rückfluß erhitzt. Man läßt abkühlen und destilliert das Lösungsmittel am Rotationsverdampfer ab. Um das überschüssige SOCl2 aus der Reaktionsmischung zu entfernen, wird der Rückstand wieder mit Benzol versetzt und erneut abdestilliert. Man erhält 494 mg (1.865 mmol, 92%) des Säurechlorids 23. Dieses Rohprodukt wird ohne Aufreinigung und Charakterisierung weiter umgesetzt.A solution of 0.5 g (2.03 mmol) carboxylic acid in 4 ml benzene is mixed with 362 mg (3.04 mmol, 1.5 equiv) SOCl 2 and heated under reflux for 2 h. The mixture is allowed to cool and the solvent is distilled off on a rotary evaporator. In order to remove the excess SOCl 2 from the reaction mixture, the residue is mixed again with benzene and distilled off again. 494 mg (1,865 mmol, 92%) of the acid chloride 23 are obtained. This crude product is reacted further without purification and characterization.
Eine Lösung von 755 mg (5.845 mmol) (4S)-4-(1-Methylethyl)-2-oxazolidinon 24
in 8 ml THF wird auf -78°C gekühlt und tropfenweise mit 4.0 ml (6.43 mmol,
1.1 equiv) einer n-BuLi-Lösung (1.6 M in Hexan) versetzt. Anschließend wird bei
-78°C innerhalb von 2 Minuten eine Lösung von 1.703 g (6.43 mmol, 1.1 equiv)
Säurechlorid 23 in 7 ml THF zugegeben. Man läßt auf RT erwärmen und versetzt mit
11 ml einer 1 M wäßrigen K2CO3-Lösung und läßt 15 Minuten rühren. Es wird mit
CH2Cl2 extrahiert, über MgSO4 getrocknet und das Lösungsmittel am
Rotationsverdampfer abdestilliert. Der Rückstand wird säulen-chromatographisch
mit Pentan:DE = 1 : 1 gereinigt. Man erhält 1.352 g (3.78 mmol) der Verbindung 7,
entsprechend einer Ausbeute von 65%.
Allgemeine Daten: C18H35NO4Si, FG = 357.56 g/mol
13C-NMR (100 MHz, CDCl3): 173.22 (s), 154.02 (s), 63.26 (t), 62.94 (t), 58.32 (d),
35.47 (t), 32.52 (t), 28.32 (d), 25.92 (q), 25.36 (t), 24.18 (t), 18.29 (s), 17.92 (q),
14.61(q), -5.34(q)
A solution of 755 mg (5,845 mmol) of (4S) -4- (1-methylethyl) -2-oxazolidinone 24 in 8 ml of THF is cooled to -78 ° C and added dropwise with 4.0 ml (6.43 mmol, 1.1 equiv) of a n -BuLi solution (1.6 M in hexane) added. A solution of 1,703 g (6.43 mmol, 1.1 equiv) of acid chloride 23 in 7 ml of THF is then added at -78 ° C. in the course of 2 minutes. The mixture is allowed to warm to RT and 11 ml of a 1 M aqueous K 2 CO 3 solution are added and the mixture is stirred for 15 minutes. It is extracted with CH 2 Cl 2 , dried over MgSO 4 and the solvent is distilled off on a rotary evaporator. The residue is purified by column chromatography with pentane: DE = 1: 1. 1,352 g (3.78 mmol) of compound 7 are obtained, corresponding to a yield of 65%.
General data: C 18 H 35 NO 4 Si, FG = 357.56 g / mol
13 C-NMR (100 MHz, CDCl 3 ): 173.22 (s), 154.02 (s), 63.26 (t), 62.94 (t), 58.32 (d), 35.47 (t), 32.52 (t), 28.32 (d ), 25.92 (q), 25.36 (t), 24.18 (t), 18.29 (s), 17.92 (q), 14.61 (q), -5.34 (q)
Es werden 1.231 ml (1.231 mmol, 1.1 equiv) einer 1 M Lösung von NaHMDS in THF
auf -78°C gekühlt und tropfenweise mit einer auf 0°C gekühlten Lösung von 400 mg
(1.119 mmol) Oxazolidinon 7 in 3.5 ml THF versetzt. Man läßt 30 Minuten bei
-78°C rühren, addiert 793 mg (5.593 mmol, 5 equiv) Mel gelöst in 2 ml THF und läßt
für 4 h bei -78°C rühren. Anschließend wird mit ges. NH4Cl-Lösung gequencht, mit
Diethylether extrahiert, über MgSO4 getrocknet und eingeengt. Der Rückstand wird
säulenchromatographisch mit Pentan:DE = 2 : 1 gereinigt, wobei das in geringem
Maße entstandene unerwünschte Diastereomer leicht abgetrennt werden kann. Man
erhält 328 mg (0.917 mmol) des methylierten Produkts 25, entsprechend einer
Ausbeute von 82%.
Allgemeine Daten: C19H37NO4Si, FG = 371.59 g/mol
13C-NMR (100 MHz, CDCl3): 177.13 (s), 153.60 (s), 63.13 (t), 62.95 (t), 58.38 (d),
37.63 (d), 32.83 (t), 32.78 (t), 28.37 (d), 25.92 (q), 23.50 (t), 18.29 (s), 17.89 (q),
17.76 (q), 14.63 (q), -5.33(q)1,231 ml (1,231 mmol, 1.1 equiv) of a 1 M solution of NaHMDS in THF are cooled to -78 ° C and a solution of 400 mg (1,119 mmol) oxazolidinone 7 in 3.5 ml THF, cooled to 0 ° C, is added dropwise. The mixture is stirred at -78 ° C. for 30 minutes, 793 mg (5,593 mmol, 5 equiv) of Mel dissolved in 2 ml of THF are added and the mixture is stirred at -78 ° C. for 4 h. Then with sat. Quenched NH 4 Cl solution, extracted with diethyl ether, dried over MgSO 4 and concentrated. The residue is purified by column chromatography with pentane: DE = 2: 1, the undesirable diastereomer which has formed to a small extent being able to be separated off easily. 328 mg (0.917 mmol) of the methylated product 25 are obtained, corresponding to a yield of 82%.
General data: C 19 H 37 NO 4 Si, FG = 371.59 g / mol
13 C-NMR (100 MHz, CDCl 3 ): 177.13 (s), 153.60 (s), 63.13 (t), 62.95 (t), 58.38 (d), 37.63 (d), 32.83 (t), 32.78 (t ), 28.37 (d), 25.92 (q), 23.50 (t), 18.29 (s), 17.89 (q), 17.76 (q), 14.63 (q), -5.33 (q)
Zu einer auf 0°C gekühlten Lösung von 168 mg (0.452 mmol) der Verbindung 25
in 3 ml Diethylether wird über einen Zeitraum von 40 Minuten mit Hilfe einer
Dosierpumpe 452 µl (0.452 mmol, 1 equiv) einer 1 M Lösung von LAH in
Diethylether zugegeben. Falls sich DC-chromatographisch noch Edukt nachweisen
läßt, wird weitere LAH-Lösung zugetropft bis die Umsetzung vollständig ist. Es wird
gequencht durch die Zugabe von 17 µl Wasser, 17 µl 15%iger wäßriger NaOH-
Lösung und 52 µl Wasser. Anschließend wird über grobes Kieselgel mit Diethylether
flashfiltriert und säulenchromatographisch mit Pentan:DE = 1 : 1 gereinigt. Man erhält
94 mg (0.381 mmol) des Alkohols 26, entsprechend einer Ausbeute von 84%.
Allgemeine Daten: C13H30O2Si, FG = 246.46 g/mol
13C-NMR (100 MHz, CDCl3): 68.25 (t), 63.12 (t), 35.72 (d), 33.03 (t), 32.84 (t),
25.94 (q), 23.13 (t), 18.34 (s), 16.51(q), -5.29(q)
452 μl (0.452 mmol, 1 equiv) of a 1 M solution of LAH in diethyl ether is added to a solution of 168 mg (0.452 mmol) of compound 25 in 3 ml of diethyl ether cooled to 0 ° C. over a period of 40 minutes admitted. If starting material can still be detected by TLC, further LAH solution is added dropwise until the reaction is complete. It is quenched by adding 17 µl water, 17 µl 15% aqueous NaOH solution and 52 µl water. It is then flash-filtered over coarse silica gel with diethyl ether and purified by column chromatography with pentane: DE = 1: 1. 94 mg (0.381 mmol) of alcohol 26 are obtained, corresponding to a yield of 84%.
General data: C 13 H 30 O 2 Si, FG = 246.46 g / mol
13 C-NMR (100 MHz, CDCl 3 ): 68.25 (t), 63.12 (t), 35.72 (d), 33.03 (t), 32.84 (t), 25.94 (q), 23.13 (t), 18.34 (see ), 16.51 (q), -5.29 (q)
Eine Lösung aus 64 mg (0.505 mmol, 1.4 equiv) Oxalylchlorid in 2 ml CH2Cl2 wird
auf -78°C gekühlt und 79 mg (1.011 mmol, 12.8 equiv) DMSO addiert.
Nach 5 Minuten wird eine Lösung aus 89 mg (0.361 mmol) des Alkohols 26 in
1 ml CH2Cl2 zugetropft. Man läßt 30 Minuten bei -78°C rühren und addiert dann
161 mg (1.589 mmol, 4.4 equiv) NEt3. Man ersetzt das -78°C-Kältebad durch ein
-30°C-Bad und läßt eine weitere Stunde rühren. Anschließend wird mit 5.2 ml
Pentan verdünnt, mit 3.4 ml einer 1 M wäßrigen NaHSO4-Lösung und 3 mal mit je
3.4 ml Wasser gewaschen, über MgSO4 getrocknet und eingeengt. Der Rückstand
wird mit Pentan:DE = 2 : 1 säulenchromatographisch gereinigt. Man erhält
77 mg (0.315 mmol) des Aldehyds 4, entsprechend einer Ausbeute von 87%.
Allgemeine Daten: C13H28O2Si, FG = 244.45 g/mol
13C-NMR (100 MHz, CDCl3): 205.24 (d), 62.81(t), 46.30 (d), 32.73 (t), 30.25 (t),
25.93 (q), 23.25 (t), 18.33 (s), 13.25 (q), -5.32(q)A solution of 64 mg (0.505 mmol, 1.4 equiv) oxalyl chloride in 2 ml CH 2 Cl 2 is cooled to -78 ° C and 79 mg (1.011 mmol, 12.8 equiv) DMSO are added. After 5 minutes, a solution of 89 mg (0.361 mmol) of the alcohol 26 in 1 ml of CH 2 Cl 2 is added dropwise. The mixture is stirred at -78 ° C. for 30 minutes and then 161 mg (1,589 mmol, 4.4 equiv) NEt 3 are added . The -78 ° C cold bath is replaced by a -30 ° C bath and the mixture is stirred for another hour. The mixture is then diluted with 5.2 ml of pentane, washed with 3.4 ml of a 1 M aqueous NaHSO 4 solution and 3 times with 3.4 ml of water each time, dried over MgSO 4 and concentrated. The residue is purified by column chromatography with pentane: DE = 2: 1. 77 mg (0.315 mmol) of aldehyde 4 are obtained, corresponding to a yield of 87%.
General data: C 13 H 28 O 2 Si, FG = 244.45 g / mol
13 C-NMR (100 MHz, CDCl 3 ): 205.24 (d), 62.81 (t), 46.30 (d), 32.73 (t), 30.25 (t), 25.93 (q), 23.25 (t), 18.33 (see ), 13.25 (q), -5.32 (q)
Die Herstellung von 2-Methyl-6-heptenal 4a erfolgt aus der käuflichen 6-Hepten säure; es wird analog der Herstellung von 23 das entsprechende Säurechlorid synthetisiert und dann über die beschriebenen Stufen 7 (Oxazolidinon), 25 (Methylierung), 26 (Reduktion mit LAH) und 4 (Oxalylchlorid-Oxidation zum Aldehyd) das 2-Methyl-6-heptenal 4a erhalten. The production of 2-methyl-6-heptenal 4a takes place from the commercially available 6-heptene acid; analogously to the preparation of 23, the corresponding acid chloride synthesized and then via the described steps 7 (oxazolidinone), 25 (Methylation), 26 (reduction with LAH) and 4 (oxalyl chloride oxidation to Aldehyde) receive the 2-methyl-6-heptenal 4a.
Synthese von Segment 8Synthesis of segment 8
Synthese durch Monosilylierung von 1,3-Propandiol und anschließende Swern-
Oxidation des entstandenen 3-[(t-Butyldimethylsilyl)oxy]-1-propanols.
Allgemeine Daten: C9H20O2Si; FG=188.36; CAS-Nr. [89922-82-7]
13C-NMR (100 MHz, CDCl3): d=202.05 (d), 57.42 (t), 46.58 (t), 25.82 (q), 18.23 (s),
-5.43(q)
Synthesis by monosilylation of 1,3-propanediol and subsequent Swern oxidation of the resulting 3 - [(t-butyldimethylsilyl) oxy] -1-propanol.
General data: C 9 H 20 O 2 Si; FG = 188.36; CAS number [89922-82-7]
13 C-NMR (100 MHz, CDCl 3 ): d = 202.05 (d), 57.42 (t), 46.58 (t), 25.82 (q), 18.23 (s), -5.43 (q)
Zu 443 mg Mg-Drehspänen (18.2 mmol) und 1.5 ml abs. THF unter N2 werden 0.2
ml 2-Brompropen gegeben, so daß die Reaktion anspringt. Es wird unter
gelegentlicher Kühlung eine Lösung von 1.7 ml 2-Brompropen (insgesamt 22 mmol)
in 6 ml abs. THF langsam zugetropft, bis alle Mg-Späne gelöst sind. Zu der noch
warmen Mischung wird eine Lösung von 2.862 g 1(15.2 mmol) in 6 ml abs. THF
getropft. Es wird 6 h bei RT gerührt. Danach gibt man 25 ml ges. NH4Cl-Lsg. zu der
Reaktionslösung und läßt 10 Min. rühren. Die Mischung wird in 30 ml ges. NH4Cl-
Lsg. gegossen und zweimal mit Ether extrahiert. Die vereinigten org. Phasen
werden je einmal mit ges. NH4Cl-Lsg. und ges. NaCl-Lsg. gewaschen. Man trocknet
über MgSO4, engt im Vakuum ein und reinigt flashchromatographisch
(Ether:Pentan = 1 : 6).
Man erhält 2.749 g 2 (11.9 mmol; 79% d. Th.) als farbloses Öl.
Allgemeine Daten: C12H26O2Si; FG=230.43
13C-NMR (100 MHz1 CDCl3): d=147.10(s), 110.39(t), 75.21(d), 62.17 (t), 36.79 (t),
25.89 (q), 18.41(s), -5.49(q), -5.53(q)To 443 mg Mg turnings (18.2 mmol) and 1.5 ml abs. THF under N 2 are given 0.2 ml of 2-bromine propene so that the reaction starts. With occasional cooling, a solution of 1.7 ml of 2-bromopropene (22 mmol in total) in 6 ml of abs. THF slowly added dropwise until all Mg chips are dissolved. A solution of 2,862 g 1 (15.2 mmol) in 6 ml abs. THF dropped. The mixture is stirred at RT for 6 h. Then 25 ml of sat. NH 4 Cl solution. to the reaction solution and allowed to stir for 10 minutes. The mixture is sat in 30 ml. Poured NH 4 Cl solution and extracted twice with ether. The united org. Phases are recorded once with sat. NH 4 Cl solution. and sat. NaCl solution. washed. It is dried over MgSO 4 , concentrated in vacuo and purified by flash chromatography (ether: pentane = 1: 6).
2,749 g 2 (11.9 mmol; 79% of theory) are obtained as a colorless oil.
General data: C 12 H 26 O 2 Si; FG = 230.43
13 C-NMR (100 MHz 1 CDCl 3 ): d = 147.10 (s), 110.39 (t), 75.21 (d), 62.17 (t), 36.79 (t), 25.89 (q), 18.41 (s), - 5.49 (q), -5.53 (q)
Man löst 600 mg 2 (2.60 mmol) und 91.5 mg (-)-Diisopropyltartrat (0.391 mmol) unter N2 in 10.4 ml abs. CH2Cl2 und versetzt mit 180 mg gepulvertem, frisch aktiviertem Molsieb 4 A. Als interner Standard für die GC werden 100 ml n-Decan dazugegeben. Man kühlt auf -20°C ab und gibt unter Rühren 74 mg Titan(IV)- isopropylat (0.260 mmol) dazu. Nach 30 Min. wird ein aliquoter Teil von etwa 4 Tropfen entnommen und bei 0°C mit einer Mischung von je etwa 0.15 ml Ether und Eisen(II)-sulfat-Zitronensäure-Lösung (s. unten) aufgearbeitet. Die org. Phase dient als t0 -Probe für die GC. Man gibt 610 ml einer ca. 3 M-Lösung von t-Butylhydroperoxid in Isooctan (1.82 mmol) dazu. Die Reaktionsmischung wird im Kühlschrank bei -22°C aufbewahrt. Ein- bis zweimal täglich werden Proben entnommen und wie oben aufgearbeitet. Die jeweilige Konzentration von 11 wird gaschromatographisch bestimmt.600 mg 2 (2.60 mmol) and 91.5 mg (-) - diisopropyl tartrate (0.391 mmol) are dissolved in 10.4 ml abs under N 2 . CH 2 Cl 2 and mixed with 180 mg of powdered, freshly activated molecular sieve 4 A. 100 ml of n-decane are added as an internal standard for the GC. It is cooled to -20 ° C. and 74 mg of titanium (IV) isopropylate (0.260 mmol) are added with stirring. After 30 minutes, an aliquot of about 4 drops is removed and worked up at 0 ° C. with a mixture of about 0.15 ml of ether and iron (II) sulfate-citric acid solution (see below). The org. Phase serves as a t 0 sample for the GC. 610 ml of an approximately 3 M solution of t-butyl hydroperoxide in isooctane (1.82 mmol) are added. The reaction mixture is stored in the refrigerator at -22 ° C. Samples are taken once or twice a day and processed as above. The respective concentration of 11 is determined by gas chromatography.
Nach 118 h wird die Reaktion bei etwa 50%-iger Umsetzung von 27 abgebrochen.After 118 h, the reaction is terminated with a 50% conversion of 27.
Bei -20°C wird eine frisch angesetzte, auf 0°C gekühlte Lösung von
3.3 g Eisen(II)-sulfat-heptahydrat und 1.1 g Zitronensäuremonohydrat in 10 ml dest.
Wasser dazugegeben. Nach 20 Min. kräftigem Rühren ohne weitere Kühlung wird
die Mischung dreimal mit CH2Cl2 extrahiert. Die ges. org. Phasen werden auf ca. 10
ml eingeengt und bei 0°C 30 Min. lang mit 3 ml NaOH-Lsg. (30% in ges. NaCl-Lsg)
gerührt. Es wird wiederum dreimal mit CH2Cl2 extrahiert, und die vereinigten org.
Phasen werden mit ges. NaCl-Lsg. gewaschen, über MgSO4 getrocknet und
eingeengt. Flashchromatographische Reinigung (Ether:Pentan = 1 : 6) liefert 274 mg
11 (1.19 mmol; 46% des Eduktes) als farbloses Öl.
Allgemeine Daten: C12H26O2Si; FG=230.43
(c=1, CHCl3), [a]D = -4.6°; ee = 90% (berechnet durch Integration der olefinischen
1H-NMR-Signale sowie des 1H-NMR-Signals der C-4-Methylprotonen der
diastereomeren Reaktionsprodukte von 11 mit S(+)-a-Methoxy-a-trifluor- methyl
phenylessigsäurechlorid, S(+)-MTPA-Cl).A freshly prepared, cooled to 0 ° C solution of 3.3 g iron (II) sulfate heptahydrate and 1.1 g citric acid monohydrate in 10 ml dist. Water added. After vigorous stirring for 20 minutes without further cooling, the mixture is extracted three times with CH 2 Cl 2 . The total org. Phases are concentrated to approx. 10 ml and at 0 ° C. for 30 minutes with 3 ml NaOH solution. (30% in saturated NaCl solution). It is extracted again three times with CH 2 Cl 2 , and the combined org. Phases are with sat. NaCl solution. washed, dried over MgSO 4 and concentrated. Flash chromatographic purification (ether: pentane = 1: 6) yields 274 mg 11 (1.19 mmol; 46% of the educt) as a colorless oil.
General data: C 12 H 26 O 2 Si; FG = 230.43
(c = 1, CHCl 3 ), [a] D = -4.6 °; ee = 90% (calculated by integrating the olefinic 1 H-NMR signals and the 1 H-NMR signal of the C-4-methyl protons of the diastereomeric reaction products of 11 with S (+) - a-methoxy-a-trifluoromethyl phenylacetic acid chloride, S (+) - MTPA-Cl).
Die absolute Konfiguration des überwiegenden Enantiomers wurde nach der Methode von MOSHER durch Vergleich der 1H-NMR-Spektren der Reaktionsprodukte von 11 mit S(+)-MTPA-Cl bzw. R(-)-MTPA-Cl bestimmt.The absolute configuration of the predominant enantiomer was determined by the MOSHER method by comparing the 1 H-NMR spectra of the reaction products of 11 with S (+) - MTPA-Cl and R (-) - MTPA-Cl.
70 mg einer Suspension von 35% Kaliumhydrid in Mineralöl (0.609 mmol) werden
unter N2 mit 0.5 ml abs. THF versetzt und auf 0°C gekühlt. Man gibt 1.5 ml
Benzylbromid (12.6 mmol) dazu. Unter Rühren wird eine Lösung von
117 mg 11(0.508 mmol) und 3 mg Tetra-n-butylammoniumiodid (8 mmol) in 1 ml
abs. THF dazugetropft. Nach 15 Min. läßt man auf RT erwärmen. Es wird 19 h
gerührt, danach werden 8 ml ges. NH4Cl-Lsg. eingespritzt. Die Mischung wird
zweimal mit Ether extrahiert, die vereinigten org. Phasen werden zweimal mit ges.
NaCl-Lsg. und einmal mit Wasser gewaschen und über MgSO4 getrocknet. Nach
dem Einengen am Rotationsverdampfer wird der Hauptteil des noch vorhandenen
Benzylbromides bei RT im Hochvakuum abgezogen. Flashchromatographische
Reinigung (Ether:Petrolether = 1 : 100) liefert 96 mg 28 (0.299 mmol; 59% d.Th.) als
farbloses Öl.
Allgemeine Daten: C19H32O2Si, FG=320.54
13C-NMR (100 MHz, CDCl3): d=144.70 (s), 138.87 (s), 128.33 (d), 127.78 (d),
127.40(d), 113.54(t), 80.03(d), 70.07(t), 59.71(t), 37.18(t), 25.97(q), 18.30(s),
16.75 (q), -5.28(q), -5.31(q)
70 mg of a suspension of 35% potassium hydride in mineral oil (0.609 mmol) of abs ml under N 2 with 0.5. THF added and cooled to 0 ° C. 1.5 ml of benzyl bromide (12.6 mmol) are added. A solution of 117 mg of 11 (0.508 mmol) and 3 mg of tetra-n-butylammonium iodide (8 mmol) in 1 ml of abs. THF added dropwise. After 15 minutes, the mixture is allowed to warm to RT. The mixture is stirred for 19 h, then 8 ml are sat. NH 4 Cl solution. injected. The mixture is extracted twice with ether, the combined org. Phases are recorded twice with sat. NaCl solution. and washed once with water and dried over MgSO 4 . After concentrating on a rotary evaporator, the main part of the benzyl bromide still present is removed at RT in a high vacuum. Flash chromatographic purification (ether: petroleum ether = 1: 100) yields 96 mg 28 (0.299 mmol; 59% of theory) as a colorless oil.
General data: C 19 H 32 O 2 Si, FG = 320.54
13 C-NMR (100 MHz, CDCl 3 ): d = 144.70 (s), 138.87 (s), 128.33 (d), 127.78 (d), 127.40 (d), 113.54 (t), 80.03 (d), 70.07 (t), 59.71 (t), 37.18 (t), 25.97 (q), 18.30 (s), 16.75 (q), -5.28 (q), -5.31 (q)
Zu einer Mischung aus 1.5 ml THF und 1.5 ml Wasser werden 38 mg 28 (118 mmol)
gegeben. 48 mg einer Lsg. von 2.5% OsO4 in t-Butanol (4.7 mmol) werden mit
0.5 ml THF gemischt und dazugetropft. Es wird 5 Min. gerührt; dann werden
127 mg NalO4 (590 mmol) dazugegeben. Nach 12 h kräftigem Rühren bei RT wird
die Reaktionsmischung in 20 ml Ether gegossen und mit 5 ml Wasser verdünnt. Man
extrahiert zweimal mit Ether, trocknet die vereinigten org. Phasen über MgSO4 und
engt ein. Flashchromatographische Reinigung (Ether:Pentan = 1 : 4) liefert 14 mg 5
(43.4 mmol; 37% d.Th.) als graubraunes Öl.
Allgemeine Daten: C18H30O3Si; FG=322.53
13C-NMR (100 MHz, CDCl3): d=211.00(s), 137.67 (s), 128.51(d), 127.94(d),
127.90 (d), 82.00 (d), 72.59 (t), 58.68 (t), 35.23 (t), 25.94 (q), 25.68 (q), 18.30 (s),
-5.38 (q), -5.43(q)38 mg 28 (118 mmol) are added to a mixture of 1.5 ml THF and 1.5 ml water. 48 mg of a solution of 2.5% OsO 4 in t-butanol (4.7 mmol) are mixed with 0.5 ml THF and added dropwise. The mixture is stirred for 5 minutes; then 127 mg of NalO 4 (590 mmol) are added. After vigorous stirring at RT for 12 h, the reaction mixture is poured into 20 ml of ether and diluted with 5 ml of water. It is extracted twice with ether, the combined org. Phases over MgSO 4 and concentrated. Flash chromatographic purification (ether: pentane = 1: 4) yields 14 mg 5 (43.4 mmol; 37% of theory) as a gray-brown oil.
General data: C 18 H 30 O 3 Si; FG = 322.53
13 C-NMR (100 MHz, CDCl 3 ): d = 211.00 (s), 137.67 (s), 128.51 (d), 127.94 (d), 127.90 (d), 82.00 (d), 72.59 (t), 58.68 (t), 35.23 (t), 25.94 (q), 25.68 (q), 18.30 (s), -5.38 (q), -5.43 (q)
Die Verbindung 29 wird durch Ringschluß von L-Cystein-methylester-hydrochlorid
mit Acetaldehyd, anschließender Dehydrierung über MnO2 und Reduktion der
Methylestergruppe durch LAH hergestellt.
Allgemeine Daten: C5H7NOS; FG=129.19; CAS-Nr. [76632-23-0]
13C-NMR (50 MHz, CDCl3): d=167(s), 156.0(s), 114.4 (d), 60.5(t), 19.0 (q)Compound 29 is prepared by ring closure of L-cysteine methyl ester hydrochloride with acetaldehyde, subsequent dehydrogenation over MnO 2 and reduction of the methyl ester group by LAH.
General data: C 5 H 7 NOS; FG = 129.19; CAS number [76632-23-0]
13 C-NMR (50 MHz, CDCl 3 ): d = 167 (s), 156.0 (s), 114.4 (d), 60.5 (t), 19.0 (q)
Man löst 60 mg 29 (0.464 mmol) in 1 ml abs. Ether und gibt unter Rühren
47 mg Triphenylphosphin (0.511 mmol) und 169 mg Tetrabrommethan (0.511 mmol)
dazu. Nach 16 h Rühren (RT) wird der Niederschlag abfiltriert und mit Ether
gewaschen. Das Filtrat wird eingeengt und flashchromato-graphisch gereinigt
(Ether:Pentan = 1 : 5). Man erhält 33 mg 30 (0.172 mmol; 37% d.Th.) als helles
bräunliches Öl.
Allgemeine Daten: C5H6BrNS; FG=192.08
13C-NMR (100 MHz, CDCl3): d=166.91(s), 151.63(s), 117.25(d), 27.11(t), 19.25
(q)
60 mg of 29 (0.464 mmol) are dissolved in 1 ml of abs. Ether and with stirring 47 mg triphenylphosphine (0.511 mmol) and 169 mg tetrabromomethane (0.511 mmol). After stirring for 16 h (RT), the precipitate is filtered off and washed with ether. The filtrate is concentrated and purified by flash chromatography (ether: pentane = 1: 5). 33 mg of 30 (0.172 mmol; 37% of theory) are obtained as a light brownish oil.
General data: C 5 H 6 BrNS; FG = 192.08
13 C-NMR (100 MHz, CDCl 3 ): d = 166.91 (s), 151.63 (s), 117.25 (d), 27.11 (t), 19.25 (q)
150 mg 1(0.78 mmol) und 300 ml Triethylphosphit (1.75 mmol) werden 1.5 h lang
auf 160°C erhitzt. Nach dem Abkühlen wird das überschüssige Triethylphosphit im
Vakuum abdestilliert. Flashchromatographische Reinigung (Ether/Methanol = 19 : 1)
liefert 173 mg 2 (89% d. Th.) als schwach gelbliches Öl.
13C-NMR (100 MHz, CDCl3): d = 165.44(s), 145.96 (ds, 2J(C,P)=8.2 Hz), 115.67
(dd, 3J(C,P)=7.4 Hz), 62.19 (dt, 2 C, 2J(C,P)=6.4 Hz), 29.35 (dt, 1J(C,P)=141 Hz),
19.05 (q), 16.35 (dq, 2 C, 3J(C,P)=6.0 Hz)
(Anmerkung: Bei den zweifachen Angaben zur Signalmultiplizität bezieht sich das
führende Zeichen auf die im Spektrum sichtbare durch C,P-Kopplung verursachte
Multiplizität und das folgende Zeichen auf die durch C,H-Kopplung verursachte, im
Standardspektrum unsichtbare Multiplizität.)150 mg 1 (0.78 mmol) and 300 ml triethyl phosphite (1.75 mmol) are heated to 160 ° C for 1.5 h. After cooling, the excess triethyl phosphite is distilled off in vacuo. Flash chromatographic purification (ether / methanol = 19: 1) yields 173 mg 2 (89% of theory) as a slightly yellowish oil.
13 C-NMR (100 MHz, CDCl 3 ): d = 165.44 (s), 145.96 (ds, 2 J (C, P) = 8.2 Hz), 115.67 (dd, 3 J (C, P) = 7.4 Hz) , 62.19 (dt, 2 C, 2 J (C, P) = 6.4 Hz), 29.35 (dt, 1 J (C, P) = 141 Hz), 19.05 (q), 16.35 (dq, 2 C, 3 J (C, P) = 6.0 Hz)
(Note: In the case of the double information on signal multiplicity, the leading symbol refers to the multiplicity visible in the spectrum caused by C, P coupling and the following symbol to the multiplicity invisible in the standard spectrum caused by C, H coupling.)
Unter N2 werden 33 mg 2 (132 mmol) in 2 ml abs. THF gelöst und auf -78°C
gekühlt. Man tropft 78 ml n-BuLi-Lsg. (15% in Hexan; 125 mmol) dazu und läßt
45 Min. rühren. Anschließend wird bei -78°C eine Lösung von 35 mg Methylketon 9
(109 mmol) in 1 ml abs. THF dazugegeben. Nach langsamer Erwärmung auf RT
läßt man noch 40 h rühren und gibt dann 10 ml ges. NH4Cl-Lsg. zu der
Reaktionsmischung. Es wird dreimal mit je 15 ml Ether extrahiert. Die vereinigten
org. Phasen werden zweimal mit wenig Wasser und einmal mit ges. NaCl-Lsg.
gewaschen. Nach dem Trocknen über MgSO4 wird das Lösungsmittel am
Rotationsverdampfer abdestilliert. Flashchromatographische Reinigung
(Pentan/Dichlormethan = 1 : 1, dann 1 : 2) liefert 17 mg 4 (38% d. Th.) als farbloses
Öl.
13C-NMR (100 MHz, CDCl3): d = 164.4 (s), 152.90 (s), 139.74 (s), 138.84 (s),
128.33 (d, 2 C), 127.77 (d, 2 C), 127.41(d), 121.33(d), 115.67 (d), 82.00(d), 70.30
(t), 59.69 (t), 37.58 (t), 25.98 (q, 3 C), 19.26 (q), 18.30 (s), 13.44 (q), -5.25(q), -5.31
(q)Under N 2, 33 mg of 2 (132 mmol) in 2 ml of abs. THF dissolved and cooled to -78 ° C. 78 ml of n-BuLi solution are added dropwise. (15% in hexane; 125 mmol) and let stir for 45 min. A solution of 35 mg of methyl ketone 9 (109 mmol) in 1 ml of abs. THF added. After slowly warming to RT, stirring is continued for 40 h and then 10 ml of sat. NH 4 Cl solution. to the reaction mixture. It is extracted three times with 15 ml ether each. The united org. Phases are carried out twice with a little water and once with sat. NaCl solution. washed. After drying over MgSO 4 , the solvent is distilled off on a rotary evaporator. Flash chromatographic purification (pentane / dichloromethane = 1: 1, then 1: 2) yields 17 mg 4 (38% of theory) as a colorless oil.
13 C-NMR (100 MHz, CDCl 3 ): d = 164.4 (s), 152.90 (s), 139.74 (s), 138.84 (s), 128.33 (d, 2 C), 127.77 (d, 2 C), 127.41 (d), 121.33 (d), 115.67 (d), 82.00 (d), 70.30 (t), 59.69 (t), 37.58 (t), 25.98 (q, 3 C), 19.26 (q), 18.30 ( s), 13.44 (q), -5.25 (q), -5.31 (q)
Die Darstellung von 8b
The representation of 8b
erfolgt aus
takes place from
wobei der TBDMS-Ether mit Fluorid gespalten wird, der primäre Alkohol mittels Dess.-Martin-Oxidatin (Perjodat) in den Aldehyd und dieser mit dem Methylen- Wittig-Reagenz (Ph3=CH2) in die Verbindung 8b überführt wird. Die Schutzgruppe Benzyl ist beliebig gegen andere gängige Hydroxyl-Schutzgruppen austauschbar. whereby the TBDMS ether is cleaved with fluoride, the primary alcohol is converted into the aldehyde by means of Dess.-Martin oxidatin (periodate) and this is converted into the compound 8b with the methylene-Wittig reagent (Ph 3 = CH 2 ). The protective group benzyl is interchangeable with other common hydroxyl protective groups.
Zu einer Lösung von 23 mg Diisopropylamin (0.227 mmol, leq.) in ml THF werden
bei 0°C 142 γl (0.227 mmol, 1 eq.) einer 1.6 M Lösung von n-BuLi in Hexan
zugetropft und 30 Minuten bei 0°C gerührt, bevor dann auf -78°C heruntergekühlt
wird. Nun werden 49 mg (0.227 mmol, 1 eq.) (S)-2-(2,2-dimethyl-
[1,3]dioxan-4-yl-2-methyl-pentan-3-on 3 (siehe Stammanmeldung), gelöst in 1 ml
THF langsam zugetropft. Die Lösung wird 35 Minuten bei -78°C gerührt.
Anschließend werden 55 mg (0.224 mmol, 099 eq.) 2-Methyl-heptanal 4a zugetropft
und 1 h bei -78°C gerührt. Die Reaktionslösung wird durch Zugabe von gesättigter
NH4Cl-Lösung gequenscht und auf RT erwärmt. Die wäßrige Phase wird mit Ether
extrahiert, die vereinigten organischen Phasen über MgSO4 getrocknet und das
Lösungsmittel am Rotationsverdampfer abdestestilliert. Der Rückstand wird
säulenchromatographisch mit Pentan:Diethylether = 2 : 1 gereinigt. Man erhält
55 mg (0.107 mmol, 52%) des Aldolprodukts als farbloses Öl.
142 γl (0.227 mmol, 1 eq.) Of a 1.6 M solution of n-BuLi in hexane are added dropwise to a solution of 23 mg of diisopropylamine (0.227 mmol, leq.) In ml of THF at 0 ° C. and at 30 ° C. for 30 minutes stirred before cooling down to -78 ° C. Now 49 mg (0.227 mmol, 1 eq.) (S) -2- (2,2-dimethyl- [1,3] dioxan-4-yl-2-methyl-pentan-3-one 3 (see parent application) , dissolved in 1 ml of THF is slowly added dropwise. The solution is stirred for 35 minutes at -78 ° C. Then 55 mg (0.224 mmol, 099 eq.) 2-methyl-heptanal 4a are added dropwise and the mixture is stirred at -78 ° C. for 1 h. The reaction solution is quenched by adding saturated NH 4 Cl solution and warmed to RT, the aqueous phase is extracted with ether, the combined organic phases are dried over MgSO 4 and the solvent is distilled off on a rotary evaporator 2: 1. 55 mg (0.107 mmol, 52%) of the aldol product are obtained as a colorless oil.
Gemäß konventioneller Methoden wird der Benzyl- oder TBDMS-Ether 91
hergestellt, es können hier auch andere Hydroxylschutzgruppen, wie bereits für B
offenbart, verwendet werden.
The benzyl or TBDMS ether 91 is prepared in accordance with conventional methods; other hydroxyl protecting groups, as already disclosed for B, can also be used here.
Die Stufenfolge bis 94 ist analog dem Stand der Technik, dem Fachmann also
bekannt, konventionelle Schutzgruppenchemie.
The step sequence up to 94 is analogous to the prior art, that is to say to the person skilled in the art, conventional protective group chemistry.
Durch Oxidation, z. B. Pyridiniumdichromat wird die Carbonsäure 95 erhalten
By oxidation, e.g. B. pyridinium dichromate, the carboxylic acid 95 is obtained
Die Veresterung zu Verbindungen der allgemeinen Formel 2b erfolgt hier
beispielsweise mit DMAP/DCCl, (Angew. Chem. 90, (1978), S. 556).
The esterification to give compounds of the general formula 2b takes place here, for example, with DMAP / DCCl, (Angew. Chem. 90, (1978), p. 556).
Für die Synthese ist besonders der Methylester 96 geeignet,
Methyl ester 96 is particularly suitable for the synthesis,
In analoger Weise lassen sich aus 80
In an analogous way, 80
wie bereits in der Stammanmeldung offenbart, die Verbindungen der allgemeinen
Formel 2a
as already disclosed in the parent application, the compounds of general formula 2a
herstellen. produce.
Die Erfindung betrifft auch Stereoisomere der Verbindungen gemäß Ansprüche 1-6, wie diese üblicherweise innerhalb der Synthese anfallen. Die Erfindung beinhaltet auch Verfahren zur Herstellung der Verbindungen gemäß Ansprüche 1-6.The invention also relates to stereoisomers of the compounds according to Claims 1-6, as they usually arise within the synthesis. The invention also includes processes for the preparation of the compounds according to Claims 1-6.
Claims (7)
worin
A = Wasserstoff oder eine niedrige Alkylgruppe (C1-C4) und
B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe bedeuten.1. Compounds of the general formula 2a
wherein
A = hydrogen or a lower alkyl group (C 1 -C 4 ) and
B = hydrogen, benzyl, tetrahydropyranyl or a silyl protective group.
worin
A = Wasserstoff oder eine niedrige Alkylgruppe (C1-C4) und
B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe bedeuten.2. Compounds of the general formula 2b
wherein
A = hydrogen or a lower alkyl group (C 1 -C 4 ) and
B = hydrogen, benzyl, tetrahydropyranyl or a silyl protective group.
4. 2-methyl-6-heptenal 4a
worin
B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe bedeutet und die Bedeutung von B im Molekül unterschiedlich sein kann.5. Compounds of the general formula 8a
wherein
B = hydrogen, benzyl, tetrahydropyranyl or a silyl protecting group and the meaning of B in the molecule can be different.
worin
B = Wasserstoff, Benzyl-, Tetrahydropyranyl- oder eine Silylschutzgruppe bedeutet und die Bedeutung von B im Molekül unterschiedlich sein kann.6. Compounds of the general formula 8b
wherein
B = hydrogen, benzyl, tetrahydropyranyl or a silyl protecting group and the meaning of B in the molecule can be different.
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19645361A DE19645361A1 (en) | 1996-08-30 | 1996-10-28 | Production of epothilone compounds with taxol-like activity |
EP97914077A EP0923583A1 (en) | 1996-08-30 | 1997-01-15 | Method for producing epothilones, and intermediate products obtained during the production process |
JP10511141A JP2001500851A (en) | 1996-08-30 | 1997-01-15 | Process for producing epothilone and intermediate products obtained during the process |
PCT/DE1997/000111 WO1998008849A1 (en) | 1996-08-30 | 1997-01-15 | Method for producing epothilones, and intermediate products obtained during the production process |
AU21493/97A AU716610B2 (en) | 1996-08-30 | 1997-01-15 | Method for producing epothilones, and intermediate products obtained during the production process |
NZ334821A NZ334821A (en) | 1996-08-30 | 1997-01-15 | Method for producing epothilones |
US08/921,512 US5969145A (en) | 1996-08-30 | 1997-09-02 | Process for the production of epothilones and intermediate products within the process |
US09/344,713 US6043372A (en) | 1996-08-30 | 1999-06-25 | Intermediates in the process for preparing epothilones |
US09/478,466 US6156905A (en) | 1996-08-30 | 2000-01-06 | Deoxy epothilones and intermediates utilized in the process for preparing epothilones |
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DE19636343A DE19636343C1 (en) | 1996-08-30 | 1996-08-30 | New (di:methyl)-dioxanyl-methyl-pentanone and related compounds |
DE19645361A DE19645361A1 (en) | 1996-08-30 | 1996-10-28 | Production of epothilone compounds with taxol-like activity |
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