WO2003018604A1 - Synthesis of solanum glycosides - Google Patents
Synthesis of solanum glycosides Download PDFInfo
- Publication number
- WO2003018604A1 WO2003018604A1 PCT/EP2002/009349 EP0209349W WO03018604A1 WO 2003018604 A1 WO2003018604 A1 WO 2003018604A1 EP 0209349 W EP0209349 W EP 0209349W WO 03018604 A1 WO03018604 A1 WO 03018604A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzoyl
- pivaloyl
- solamargine
- bromide
- solasodine
- Prior art date
Links
- 229930182470 glycoside Natural products 0.000 title claims abstract description 13
- 150000002338 glycosides Chemical class 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 235000002634 Solanum Nutrition 0.000 title abstract description 4
- 241000207763 Solanum Species 0.000 title abstract description 4
- MBWUSSKCCUMJHO-ZGXDEBHDSA-N Solamargine Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(NC[C@H](C)CC1)O5)C)[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O MBWUSSKCCUMJHO-ZGXDEBHDSA-N 0.000 claims abstract description 26
- MBWUSSKCCUMJHO-DVDUUUGDSA-N Solamargine Natural products O([C@@H]1[C@@H](O)[C@@H](O[C@H]2[C@H](O)[C@H](O)[C@@H](O)[C@H](C)O2)[C@H](CO)O[C@@H]1O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]5[C@@H](C)[C@@]6(O[C@H]5C4)NC[C@H](C)CC6)CC3)CC=2)CC1)[C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](C)O1 MBWUSSKCCUMJHO-DVDUUUGDSA-N 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 31
- KWVISVAMQJWJSZ-VKROHFNGSA-N solasodine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CN1 KWVISVAMQJWJSZ-VKROHFNGSA-N 0.000 claims description 16
- JXWLYDNHVXFBJA-UHFFFAOYSA-N solasodine Natural products CC1CCC2(NC1)NC3CC4C5CC=C6CC(O)CCC6(C)C5CCC4(C)C3C2C JXWLYDNHVXFBJA-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 7
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 7
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 claims description 7
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000006206 glycosylation reaction Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000013595 glycosylation Effects 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000003456 ion exchange resin Substances 0.000 claims description 4
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000005640 glucopyranosyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- SPAKMVQVTSVXES-UHFFFAOYSA-N methanol;oxolane;hydrate Chemical compound O.OC.C1CCOC1 SPAKMVQVTSVXES-UHFFFAOYSA-N 0.000 claims description 2
- INNLPFUZCMFZJM-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate hydrobromide Chemical compound Br.C[Si](C)(C)OS(=O)(=O)C(F)(F)F INNLPFUZCMFZJM-UHFFFAOYSA-N 0.000 claims description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims 1
- BSDBCYHGMPHOAL-UHFFFAOYSA-N [6-bromo-3,4,5-tris(2,2-dimethylpropanoyloxy)oxan-2-yl]methyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCC1OC(Br)C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)C1OC(=O)C(C)(C)C BSDBCYHGMPHOAL-UHFFFAOYSA-N 0.000 claims 1
- 125000000837 carbohydrate group Chemical group 0.000 claims 1
- 150000002009 diols Chemical class 0.000 claims 1
- MOSGOJUZSWKEMV-UHFFFAOYSA-N silver;trifluoromethyl trifluoromethanesulfonate Chemical compound [Ag].FC(F)(F)OS(=O)(=O)C(F)(F)F MOSGOJUZSWKEMV-UHFFFAOYSA-N 0.000 claims 1
- LXAWHMFHGHNIHC-UHFFFAOYSA-N sulfanyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OS LXAWHMFHGHNIHC-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 229960001031 glucose Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 150000003431 steroids Chemical group 0.000 description 4
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 4
- 0 *CC1(C2)C2CCC1 Chemical compound *CC1(C2)C2CCC1 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KNLOWJPFLKGYGQ-UHFFFAOYSA-N Solasodine 3-O-??-L-rhamnopyranosyl (1‘Â∆2)-O-[??-D-glucopyranosyl (1‘Â∆4)]-??-D-glucopyranoside Natural products O1C2(NCC(C)CC2)C(C)C(C2(CCC3C4(C)CC5)C)C1CC2C3CC=C4CC5OC(C(C1O)OC2C(C(O)C(O)C(C)O2)O)OC(CO)C1OC1OC(CO)C(O)C(O)C1O KNLOWJPFLKGYGQ-UHFFFAOYSA-N 0.000 description 3
- QCTMYNGDIBTNSK-UHFFFAOYSA-N Solasonin Natural products O1C2(NCC(C)CC2)C(C)C(C2(CCC3C4(C)CC5)C)C1CC2C3CC=C4CC5OC(C1OC2C(C(O)C(O)C(C)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O QCTMYNGDIBTNSK-UHFFFAOYSA-N 0.000 description 3
- QCTMYNGDIBTNSK-QCNFCIKQSA-N Solasonine Natural products O([C@@H]1[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O2)[C@@H](O[C@@H]2CC=3[C@@](C)([C@@H]4[C@H]([C@H]5[C@@](C)([C@H]6[C@@H](C)[C@@]7(O[C@H]6C5)NC[C@H](C)CC7)CC4)CC=3)CC2)O[C@@H](CO)[C@@H]1O)[C@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 QCTMYNGDIBTNSK-QCNFCIKQSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- RCTKRNCKOYYRIO-UHFFFAOYSA-N alpha-Solamarine Natural products O1C2(NCC(C)CC2)C(C)C(C2(CCC3C4(C)CC5)C)C1CC2C3CC=C4CC5OC(C1O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1OC1OC(C)C(O)C(O)C1O RCTKRNCKOYYRIO-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- -1 solasodine glycosides Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
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- QCTMYNGDIBTNSK-XEAAVONHSA-N α-Solamarine Chemical compound O([C@H]1[C@@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(NC[C@H](C)CC1)O5)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QCTMYNGDIBTNSK-XEAAVONHSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 125000003535 D-glucopyranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]([H])(O[H])[C@]1([H])O[H] 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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- 239000005457 ice water Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000008136 β-glycosides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0057—Nitrogen and oxygen
- C07J71/0068—Nitrogen and oxygen at position 16(17)
Definitions
- the present invention relates to the chemical synthesis of solanum glycosides, in particular to the synthesis of solamargine as well as to novel ⁇ -monosaccharide intermediate compounds.
- Solasodine and its glycosides are of considerable interest clinically. They are widely used as starting products for the -synthesis of various steroidal drugs. Thus the aglycon solasodine is a source for synthetic cortisone and progesterone.
- solasodine glycosides have potent antineoplastic properties.
- solasonine 22R, 25R
- solasonine 22R, 25R
- solamargine 22R, 25R
- solamargine 22R, 25R
- solamargine 22R, 25R
- the above triglycosides are conventionally obtained by extraction from a plant source.
- a commercially available extract of S. sodomaeum commonly referred to as BEC (Drug Future, 1988, vol. 13.8, pages 714-716) is a crude mixture of solamargine. solasonine and their isomeric diglycosides.
- the extraction process for making BEC involves homogenizing the fruits of S. sodomaeum in a large volume of acetic acid, filtering off the liquid through muslin followed by precipitation of the glycosides with ammonia (Drugs of today (1990), Vol. 26 No. 1 , p. 55-58, cancer letters (1991 ), Vol. 59, p. 183-192).
- the yield of the solasodine glycoside mixture is very low (approx. 1 %).
- the individual process steps are not defined to GMP in terms of scale up, definition of yield composition and product quality.
- the steroid skeleton of solasodine contains a very labile nitrogen containing ring.
- This aglycon can thus not readily be chemically modified while keeping the steroid skeleton intact.
- the prior art does not disclose the synthesis of the solamargine using the aglycon material as starting, material.
- the synthesis of solamargine requires the stereoselective glycosylation of solasodine at the relatively unreactive hydroxyl group.
- solasodine is not compatible with the conventional steroid glycosylation technique. Thus no glycosylation was observed following the treatment of solasodine with tetrabenzoyl -D-glucopyranosyl trichloroacetimidate and trimethyl-silyl triflate or trifluoride etherate (unpublished results).
- the problem underlying the present invention is t provide a cost effective method for the preparation of solamargine.
- the present invention resides in the finding that the stereoselective ⁇ -glycosylation of solasodine may be achieved in high yields using specific glucopyranosyl donors.
- the reaction is carried out in the presence of a promoter.
- each R3 independently represents a benzoyl, acetyl or pivaloyl group
- R4 is halogen selected from Cl, Br or I and R5 is hydrogen or
- R4 is hydrogen and R5 is SEt or SPh,
- D-glucopyranosyl donor tetra-O-benzoyl- ⁇ -D-glucopyranosyl bromide is preferred.
- reaction is carried out in the presence of a promoter.
- Any conventional promoter as used in saccharide chemistry may be used.
- Silver triflate (silver trifluoromethane sulfonate), silver trifluoromethantriflate, boron trifluoride (-10°C), diethyl etherate, trimethylsilyl triflate bromide, N- iodosuccinimide or dimethyl, thiomethyl sulfonium triflate, whereby silver triflate is most preferred.
- the reaction is preferably carried out using dichloromethane as the solvent.
- the reaction time is 30 min.-1 hr at -20°C.
- the present invention also provides the following novel ⁇ -glycosides of formula I which may be used as intermediates for the synthesis of solamargine:
- each of R1 and R2 which may be the same or different, represent a conventional protecting group, preferably benzoyl, pivaloyl or acetyl.
- the desired end product solamargine may be prepared by deprotecting the ⁇ - glycoside
- the partially protected ⁇ -glycoside diol is then glycosylated at OH-2 and OH-4 with a suitable ⁇ -L-rhamnopyranosyl donor.
- Suitable rhamnose donors include tri-O-benzoyl- ⁇ -rhamnopyranosyl bromide, tri- O-pivaloyl- ⁇ -L-rhamnopyranosyl trichloroacetoimidate or a glycoside of formula IV
- R 6 is Br, Cl, I, SEt or SPh and
- R7 is any conventional protecting group, preferably benzoyl, acetyl or pivaloyl.
- Tri-O- benzoyl- ⁇ - L-rhamnopyranosyl bromide is preferred as the rhamnose donor.
- ion -exchange resins may also be used in any other deprotection step in the synthesis according to the invention.
- D-Glucose (30g) (1) was placed in a 1 liter three necked round bottomed flask equipped with stirrer and thermometer. Pyridine (300ml) was added and the mixture gently heated to aid dissolution. The mixture was cooled to 10-12°C using ice/water and benzoyl cloride (116ml) added dropwise over a period of 40 min (temperature reached 20°C). After about 90ml of the benzoyl chloride had been added the mixture became more viscous and a light yellow precipitate formed. After the benzoyl chloride addition was complete, the mixture was left stirring overnight at room temperature when a light brown slurry formed.
- the fully benzoylated glucose (2) was then dissolved in dichloromethane (200ml) and cooled to 0°C in a ice/water bath. Hydrogen bromide (32% in acetic acid, (142ml)) was then added dropwise over 30 min to the reaction mixture. When addition was complete, the mixture was allowed to reach room temperature and stirred overnight. Dichloromethane (400ml) (DCM) was added and the mixture washed with ice-water (4 x 500ml), saturated NaHC0 3 (3x 500ml), dried with MgS0 4 and filtered through activated charcoal. The solvent was removed under reduced pressure to leave a light yellow oil which solidified on standing. The title compound (3) was recrystallised from diethylether (800ml) and petroleum ether (700ml) to give 85 g as an off white solid.
- L-Rhamnose (20g) (4) was placed in a 250ml round bottomed flask equipped with stirrer, thermometer and pressure equalising dropping funnel. Pyridine (25ml) was added and the mixture cooled to 0°C using a ice/water bath. Benzoyl chloride (90ml) was then added dropwise over 20min, and after the addition was complete the mixture was heated at 60°C for 2h. After the mixture had cooled to room temperature, water (30ml) was added, stirred for 20min and then diluted with dichloromethane (DCM) (500ml).
- DCM dichloromethane
- Solasodine (7) (15g, 302mmol), bromo-benzoyl-glucose (tetra-O-benzoyl- ⁇ -D- glucopyranosyl bromide) (27g, 544mmol) and 4A molecular sieve (crushed to a powder and preheated in a vacuum oven at 60°C), were placed in a 500ml round bottom flask equipped with nitrogen inlet-bubbler, pressure equalizing dropping funnel and low temperature thermometer. Anhydrous dichloromethane (250ml) was then added and the mixture was stirred at room temperature under argon for 40 min. The mixture was then cooled to -20°C.
- Step F Addition of two moles of rhamnose to the 3,6-protected glucose-solasodine adduct
- rhamnose bromide from step B (6) (19g, 355mmol), dipivaloyl-glucose- solasodine (12g, 161mmol), 4A molecular sieves (30g, preheated in an oven at 50°C) were placed in a three necked flask equipped with a stirrer, a low temperature thermometer, an argon inlet-bubbler and a pressure dropping equalizing funnel. Anhydrous DCM was added and the mixture was stirred at room temperature for 40 min under argon.
- the semi solid paste was taken up in 3% acetic acid (450ml) and stirred for 20 min until nearly all dissolved.
- the solution was decanted from any undissolved material and adjusted with concentrated ammonia to pH 8 at which point a fine precipitate formed.
- the precipitate was subjected to high speed centrifugation and the supernatant decanted from the pellet that had formed.
- the pellet was then washed three times with water and then dispersed in water (100ml) and freeze dried to give a light white solid (1.52g).
- the 78% pure solamargine (12) was then further purified with conventional reversed phase HPLC chromatography.
- Solasodine (7) (3.6g from Research Plus Inc, USA) and tetra-O-benzoyl- ⁇ -D- glucopyranosyl bromide (3) (8.60g) in dichloromethane (120ml) was stirred with powdered molecular sieve (4A) for 50 min. with cooling to -12°C.
- a solution of silver triflate (3.35g) in toluene (30ml) was added dropwise over 20 min at -12 to -10°C. The mixture was stirred for a further 30 min with slow warming to -5°C. The mixture was then filtered through Celite and washed with dichloromethane.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Saccharide Compounds (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60227536T DE60227536D1 (en) | 2001-08-21 | 2002-08-21 | CHEMICAL SYNTHESIS OF SOLAMARGIN |
JP2003523263A JP4267448B2 (en) | 2001-08-21 | 2002-08-21 | Method for synthesizing solanam glycoside |
BR0212397-5A BR0212397A (en) | 2001-08-21 | 2002-08-21 | Synthesis of solano glycosides |
AU2002336998A AU2002336998B2 (en) | 2001-08-21 | 2002-08-21 | Synthesis of solanum glycosides |
CA002458183A CA2458183A1 (en) | 2001-08-21 | 2002-08-21 | Synthesis of solanum glycosides |
EP02772183A EP1421100B1 (en) | 2001-08-21 | 2002-08-21 | Chemical synthesis of solamargine |
US10/783,821 US20040259814A1 (en) | 2001-08-21 | 2004-02-20 | Synthesis of solanum glycosides |
Applications Claiming Priority (2)
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EP01120144 | 2001-08-21 | ||
EP01120144.9 | 2001-08-21 |
Related Child Applications (1)
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US10/783,821 Continuation US20040259814A1 (en) | 2001-08-21 | 2004-02-20 | Synthesis of solanum glycosides |
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WO2003018604A1 true WO2003018604A1 (en) | 2003-03-06 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP2002/009349 WO2003018604A1 (en) | 2001-08-21 | 2002-08-21 | Synthesis of solanum glycosides |
Country Status (9)
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US (1) | US20040259814A1 (en) |
EP (1) | EP1421100B1 (en) |
JP (1) | JP4267448B2 (en) |
AT (1) | ATE400580T1 (en) |
AU (1) | AU2002336998B2 (en) |
BR (1) | BR0212397A (en) |
CA (1) | CA2458183A1 (en) |
DE (1) | DE60227536D1 (en) |
WO (1) | WO2003018604A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004096830A1 (en) * | 2003-04-30 | 2004-11-11 | Glycomed Sciences (Uk) Limited | Synthesis of solanum glycosides |
WO2005005449A2 (en) * | 2003-07-08 | 2005-01-20 | Glycomed Sciences Limited | Steroid modified solatrioses |
WO2005005454A1 (en) * | 2003-07-08 | 2005-01-20 | Glycomed Sciences Limited | Steroid modified chacotrioses and solatrioses |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE60207878T2 (en) * | 2001-09-28 | 2006-08-17 | Glycomed Sciences Ltd., Turramurra | SOLVENT EXTRACTION PROCESS |
Citations (1)
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US6214803B1 (en) * | 1999-08-25 | 2001-04-10 | Committee On Chinese Medicine And Pharmacy Department Of Health Executive Yuan | Pharmacological composition for treating cancer cells |
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DE69131861T2 (en) * | 1990-01-18 | 2000-05-18 | Cura Nominees Pty Ltd | GLYCOAL CALALID |
US5612317A (en) * | 1994-08-04 | 1997-03-18 | Holick; Michael F. | Method for delivering estrogen |
DE19621177A1 (en) * | 1996-05-24 | 1997-11-27 | Basf Ag | Carbohydrate derivatives and their synthesis on solid phase |
EP0930315A4 (en) * | 1996-09-13 | 2002-07-31 | Daikin Ind Ltd | Lewis x derivatives |
-
2002
- 2002-08-21 AT AT02772183T patent/ATE400580T1/en not_active IP Right Cessation
- 2002-08-21 BR BR0212397-5A patent/BR0212397A/en not_active IP Right Cessation
- 2002-08-21 DE DE60227536T patent/DE60227536D1/en not_active Expired - Fee Related
- 2002-08-21 WO PCT/EP2002/009349 patent/WO2003018604A1/en active IP Right Grant
- 2002-08-21 EP EP02772183A patent/EP1421100B1/en not_active Expired - Lifetime
- 2002-08-21 JP JP2003523263A patent/JP4267448B2/en not_active Expired - Fee Related
- 2002-08-21 AU AU2002336998A patent/AU2002336998B2/en not_active Expired - Fee Related
- 2002-08-21 CA CA002458183A patent/CA2458183A1/en not_active Abandoned
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US6214803B1 (en) * | 1999-08-25 | 2001-04-10 | Committee On Chinese Medicine And Pharmacy Department Of Health Executive Yuan | Pharmacological composition for treating cancer cells |
Non-Patent Citations (5)
Title |
---|
BITE, PAL ET AL: "Preparation of steroid glycosides", ACTA CHIM. ACAD. SCI. HUNG. (1967), 52(1), 79-82, XP001127494 * |
C. PACZKOWSKI ET AL: "Glucoyslation and galactosylation of diosgenin and solasodine by soluble glycosyltransferase(s) from Solanum melongena leaves", PHYTOCHEMISTRY, vol. 35, no. 6, 19 April 1994 (1994-04-19), pages 1429 - 1434, XP001132072 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BITE, PAL ET AL: "Synthesis of steroid glycosides", XP002224550, retrieved from STN Database accession no. 66:38204 * |
LI B ET AL: "An improved synthesis of the saponin, polyphyllin D", CARBOHYDRATE RESEARCH, ELSEVIER SCIENTIFIC PUBLISHING COMPANY. AMSTERDAM, NL, vol. 331, no. 1, 9 March 2001 (2001-03-09), pages 1 - 7, XP004317141, ISSN: 0008-6215 * |
MAGY. KEM. FOLY. (1966), 72(11), 512-14 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004096830A1 (en) * | 2003-04-30 | 2004-11-11 | Glycomed Sciences (Uk) Limited | Synthesis of solanum glycosides |
JP2006524664A (en) * | 2003-04-30 | 2006-11-02 | グリコメド・サイエンシーズ(ユーケイ)リミテッド | Synthesis of solanam glycoside. |
US7435816B2 (en) | 2003-04-30 | 2008-10-14 | Mohammed Shahid | Synthesis of solanum glycosides |
WO2005005449A2 (en) * | 2003-07-08 | 2005-01-20 | Glycomed Sciences Limited | Steroid modified solatrioses |
WO2005005454A1 (en) * | 2003-07-08 | 2005-01-20 | Glycomed Sciences Limited | Steroid modified chacotrioses and solatrioses |
WO2005005449A3 (en) * | 2003-07-08 | 2005-04-21 | Glycomed Sciences Ltd | Steroid modified solatrioses |
JP2009513526A (en) * | 2003-07-08 | 2009-04-02 | グライコメッド・サイエンシーズ・リミテッド | Steroid-modified chacotriose and soratriose |
Also Published As
Publication number | Publication date |
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AU2002336998B2 (en) | 2009-01-29 |
EP1421100B1 (en) | 2008-07-09 |
EP1421100A1 (en) | 2004-05-26 |
ATE400580T1 (en) | 2008-07-15 |
US20040259814A1 (en) | 2004-12-23 |
JP2005502671A (en) | 2005-01-27 |
JP4267448B2 (en) | 2009-05-27 |
BR0212397A (en) | 2004-10-19 |
CA2458183A1 (en) | 2003-03-06 |
DE60227536D1 (en) | 2008-08-21 |
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