CN1010944B - Glyoxylylspermidine and the prepn. method - Google Patents
Glyoxylylspermidine and the prepn. methodInfo
- Publication number
- CN1010944B CN1010944B CN85103298A CN85103298A CN1010944B CN 1010944 B CN1010944 B CN 1010944B CN 85103298 A CN85103298 A CN 85103298A CN 85103298 A CN85103298 A CN 85103298A CN 1010944 B CN1010944 B CN 1010944B
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- formula
- gram
- milliliters
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
- NZQZZKUBOTVFFS-UHFFFAOYSA-N n-[4-(3-aminopropylamino)butyl]-2-oxoacetamide Chemical compound NCCCNCCCCNC(=O)C=O NZQZZKUBOTVFFS-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 35
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 5
- 230000005494 condensation Effects 0.000 claims description 5
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 238000005336 cracking Methods 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- -1 glyoxyloyl spermidine Chemical compound 0.000 abstract description 24
- GDVNLLJNADMLLR-BBRMVZONSA-N Spergualin Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)C[C@@H](O)CCCCN=C(N)N GDVNLLJNADMLLR-BBRMVZONSA-N 0.000 abstract description 7
- JBVZQDJNGFOSNX-UHFFFAOYSA-N Spergualin Natural products NCCCNCCCCNC(=O)C(O)NC(=O)CC(O)CCCCNC(=CN)N JBVZQDJNGFOSNX-UHFFFAOYSA-N 0.000 abstract description 7
- ATHGHQPFGPMSJY-UHFFFAOYSA-N Spermidine Natural products NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 6
- 229940063673 spermidine Drugs 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 33
- 239000000243 solution Substances 0.000 description 27
- HAXKLTHULHEENJ-UHFFFAOYSA-N n-[4-(3-aminopropylamino)butyl]-2,2-dihydroxyacetamide;dihydrochloride Chemical compound Cl.Cl.NCCCNCCCCNC(=O)C(O)O HAXKLTHULHEENJ-UHFFFAOYSA-N 0.000 description 21
- KIDHWZJUCRJVML-UHFFFAOYSA-N Putrescine Natural products NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000003643 water by type Substances 0.000 description 17
- 229920005654 Sephadex Polymers 0.000 description 16
- 239000012507 Sephadex™ Substances 0.000 description 16
- 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
- 238000003756 stirring Methods 0.000 description 14
- 239000002994 raw material Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- TXKOYOKMBJGVLM-UHFFFAOYSA-N 6-amino-4-(aminomethyl)hexanenitrile Chemical compound NCCC(CN)CCC#N TXKOYOKMBJGVLM-UHFFFAOYSA-N 0.000 description 11
- 239000005700 Putrescine Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940095064 tartrate Drugs 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 9
- 229960002668 sodium chloride Drugs 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 235000008504 concentrate Nutrition 0.000 description 7
- 230000008030 elimination Effects 0.000 description 7
- 238000003379 elimination reaction Methods 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000003808 methanol extraction Methods 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 239000000401 methanolic extract Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- YSAVZVORKRDODB-PHDIDXHHSA-N diethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC YSAVZVORKRDODB-PHDIDXHHSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- KKKDJWWIMJIJLA-VIFPVBQESA-N (2s)-2-amino-n-[4-(3-aminopropylamino)butyl]-3-hydroxypropanamide Chemical compound NCCCNCCCCNC(=O)[C@@H](N)CO KKKDJWWIMJIJLA-VIFPVBQESA-N 0.000 description 3
- IDINUJSAMVOPCM-UHFFFAOYSA-N 15-Deoxyspergualin Natural products NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- DSFVQIUBODXRLL-UHFFFAOYSA-N acetamide;dihydrochloride Chemical compound Cl.Cl.CC(N)=O DSFVQIUBODXRLL-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001299 aldehydes Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 235000012054 meals Nutrition 0.000 description 3
- BLUYEPLOXLPVCJ-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxyethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC[C@H](O)NC(=O)CCCCCCNC(N)=N BLUYEPLOXLPVCJ-INIZCTEOSA-N 0.000 description 3
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000193417 Brevibacillus laterosporus Species 0.000 description 2
- DVILKGVZKWDBFU-UHFFFAOYSA-N CCCCCCCCCC.N1C=CC=CC=C1 Chemical compound CCCCCCCCCC.N1C=CC=CC=C1 DVILKGVZKWDBFU-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KLBIUKJOZFWCLW-UHFFFAOYSA-N thallium(iii) nitrate Chemical compound [Tl+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O KLBIUKJOZFWCLW-UHFFFAOYSA-N 0.000 description 2
- RBNPOMFGQQGHHO-UHFFFAOYSA-N -2,3-Dihydroxypropanoic acid Natural products OCC(O)C(O)=O RBNPOMFGQQGHHO-UHFFFAOYSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WLCNZYVOUPOLHO-UHFFFAOYSA-N 3-(4-aminobutylamino)propanenitrile Chemical compound NCCCCNCCC#N WLCNZYVOUPOLHO-UHFFFAOYSA-N 0.000 description 1
- ZYPJGOCQEPYWIE-UHFFFAOYSA-N 4-amino-2,3-dihydroxy-4-oxobutanoic acid Chemical compound NC(=O)C(O)C(O)C(O)=O ZYPJGOCQEPYWIE-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
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- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
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- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
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- 238000005984 hydrogenation reaction Methods 0.000 description 1
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- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
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- TWLXDPFBEPBAQB-UHFFFAOYSA-N orthoperiodic acid Chemical compound OI(O)(O)(O)(O)=O TWLXDPFBEPBAQB-UHFFFAOYSA-N 0.000 description 1
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- FJVZDOGVDJCCCR-UHFFFAOYSA-M potassium periodate Chemical compound [K+].[O-]I(=O)(=O)=O FJVZDOGVDJCCCR-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ZLUSCZLCHQSJRU-UHFFFAOYSA-N thallium(1+) Chemical compound [Tl+] ZLUSCZLCHQSJRU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention prepares glyoxyloyl spermidine showed in a preparation formula (II) through the schizolysis of a compound in a formula (I) with a selective oxidation method, and relevant compounds of spergualin as an anticancer substance showed in a preparation formula (XV) are prepared by using the glyoxyloyl spermidine. R1 in the formula (I) represents a hydroxy group or an amino group, but two R1s can not simultaneously be amino groups, and R2 represents a hydrogen atom, an alkyl group, a carboxyl group, an alkoxycarbonyl group or an aminocarbonyl group, and the alkyl group, the carboxyl group, the alkoxycarbonyl group and the aminocarbonyl group can be replaced. N in a formula (XV) is a whole number from 6 to 8.
Description
The invention relates to preparation N-[4-(3-aminopropyl) the ammonia butyl]-2, the method for 2-dihydroxyl-ethanamide (II) [hereinafter referred to as glyoxylspermidine (glyoxylylspermidine)], the structural formula of described compound is as follows:
Glyoxylspermidine (II) is synthetic cancer-resisting substance Si Baige Eyring (Sperualin) allied compound useful as intermediates, and itself also has immunoregulation effect.The invention still further relates to and utilize glyoxylspermidine to prepare anticancer (antitumor) material-N-[4-(3-aminopropyl) the ammonia butyl]-2-(ω-guanidine radicals fatty amide)-2-hydroxyl acetamide (X V) [hereinafter referred to as 15-deoxidation Si Baige Eyring (15-deoxy Spergualin) allied compound], the general formula of this compound is as follows:
N is 6～8 integer in the formula.
The inventor once proposed to prepare by hydrolysis cancer-resisting substance Si Baige Eyring (Spergualin) method of glyoxylspermidine in the past.Si Baige Eyring (Spergualin) is bacillus laterosporus (the Bacillus Late rosporus) BMG162-aF from bacillus
2Obtain in [keeping in fermentation research institute, numbering 5230(Fermentation Research Institute Under No.5230)] nutritive medium [Japanese Patent Application Publication No.52263/1984(Japanese Patent Application Kokai(Laid-open) No.52263/1984); The antibiotic magazine, No.34,1622(1981) (The Journal of Antibiotics, No.34,1622(1981)].In addition, the inventor also proposed with 3-amino-1-propyl alcohol as one of raw material, and the complete synthetic method of preparation glyoxylspermidine [Japanese Patent Application Kokai(Laid-open) No.192347/1982; The Journal, No.34,1625(1981)].
These methods that prepare glyoxylspermidine all are well, but consider that from mass production and industrial low cost all also there are some problems in these methods.
With crude substance Si Baige Eyring (Spergualin) is in first method of raw material, the Si Baige Eyring (Spergualin) that obtains from microbial nutrient solution, its purifying bothers with separating ten minutes, so that is difficult to obtain a large amount of Si Baige Eyrings (Spergualin).
With 3-amino-1-propyl alcohol is in second method of raw material, and another raw material Glyoxylic acid hydrate (III) is difficult to obtain.
And this method also needs to introduce and slough the aldehyde protecting group, and therefore operation very bothers.Can protect the derivative of aldehyde radical to have: acetal, sulfo-acetal, hydrazone, oxime and diacyl derivative.
The method of aldehyde radical is pretty troublesome in the general protection Glyoxylic acid hydrate, so there are many problems in mass production.
One of order of the present invention ground provides the method for easy synthetic glyoxylspermidine.Another purpose is to utilize the glyoxylspermidine that obtains to prepare 15-deoxidation Si Baige Eyring (15-deoy Spergualin) allied compound.
Briefly, the objective of the invention is to study the preparation method of the glyoxylspermidine shown in the formula II.
The characteristics of this method are to make in the compound shown in the logical formula I, and suitable C-C carries out the selective oxidation cracking.
R in the formula
1Representation hydroxy or amino, but two R
1Must not be amino simultaneously, R
2Represent hydrogen molecule, can substituted alkyl, carboxyl, carbalkoxy or can substituted formamyl.
In order to overcome the problem that general method exists, the inventor's broad research novel method of preparation glyoxylspermidine, it is simple finally to have set up a synthesis technique, and has not both protected aldehyde radical, does not slough the novel method of aldehyde protecting group again.Therefore, the inventor has finished the present invention.
According to the reflection course of the inventive method, the starting compound by shown in the logical formula I can obtain compound (II) by oxicracking, and oxicracking does not influence substituent R
2This oxidizing reaction itself is the famous reaction of preparation aldehydes or ketones, and reaction is that the C-C oxicracking by adjacent glycol or corresponding functional group carries out.Reagent or method commonly used all can be applicable to the present invention.Periodic acid is the reaction reagent that is widely used in the logical formula I compound of preparation.Two R in logical formula I
1When being hydroxyl, can from following reagent, select suitable reagent to use: lead tetra-acetate, iodoso compound, oxygen (catalyzer organic acid cobalt (II) salt exists down), peroxidation sulfuric acid-Yin (I) salt, thallium trinitrate (TTN) (III), oxyethyl group thallium (I), bisulphate cerium (IV), bismuth acid salt, nickel peroxide etc. with Periodic acid.
Reagent is different to be changed needed reaction conditions with using.For example water, acetic acid, Tricholroacetic Acid, methyl alcohol, ethanol, ether, diox, benzene, benzonitrile, acetonitrile, pyridine, 4-cyanopyridine, N, dinethylformamide, methyl-phenoxide, chlorobenzene, tetramethylene sulfone etc., can also can be used in combination separately as reaction reagent.The variation range of temperature of reaction is bigger, for example can be from 0 ℃ of boiling point until agents useful for same.Reaction times also changes according to each reaction conditions, usually from the several minutes to a couple of days.
When logical formula I is water-soluble cpds, in mentioned reagent, particularly satisfied as oxicracking reagent with Periodic acid.For example positive Periodic acid (H
5IO
6), sodium metaperiodate (NaIO
4) or potassium metaperiodate (KIO
4) be ideal reagent.When using these Periodic acid class reagent, reaction can be carried out in the aqueous solution usually, but also can contain organic solvent [as alcohols (methyl alcohol, ethanol), diox, ether etc.] the aqueous solution in carry out.
The compound of logical formula I representative is the starting raw material of reaction; it can be synthetic by the reaction of knowing, and promptly carries out condensation with the corresponding acid and the amine that have protected group (protection if desired), to form amido linkage; then if required, slough protecting group in the functional group again.With α-or β-position on have hydroxyl or amino acid raw material as preparation compound (I), such acid is easily from obtaining natural compounds or the synthetic compound widely, and low price.For example beta-hydroxy-a-amino acid (as Serine, Threonine), poly-hydroxy-carboxylic acid (as R-Glyceric acid, various glyconic acid) and dihydroxyl dihydroxy acid (as tartrate, α, beta-dihydroxyl pentanedioic acid) can raw materials.
About amine, spermidine or the shielded spermidine precursor of functional group in case of necessity, all can be used as the raw material of preparation compound (I).For example, N
1And N
5All shielded 1,5,10-three azepine decane (IV)
(X in the formula
1And X
2Respectively be amino protecting group)
The N-(2-cyanoethyl)-1,4-diaminobutane (V) (hereinafter referred to as the cyanoethyl putrescine)
H
2N（CH
2）
4NH（CH
2）
2CN （Ⅴ）
With 1,4-diaminobutane (VI) (hereinafter referred to as putrescine) etc. all can be used as raw material.
H
2N（CH
2）
4NH
2（Ⅵ）
To narrate below with the examples for compounds that acid and the synthetic logical formula I of amine are represented.
For example, two R in the logical formula I
1Be amino and hydroxyl, R
2Represented compound during for hydrogen atom or alkyl (as methyl), available Serine or other suitable amino acid (as Threonine) are synthesized into cyanoethyl putrescine (V).R in the logical formula I
2Represented compound can be pressed method and makes during for hydrogen atom: at first the amino on the Serine is protected with known amino protecting group [as carbobenzoxy-(Cbz) (Z yl)]; carry out condensation with cyanoethyl putrescine (V) again; obtain compound (VII), this is the reaction of well-known formation amido linkage.
After the deaminize protecting group, cyano reduction is become aminomethyl, perhaps after reduction cyano group was aminomethyl, the deaminize protecting group obtained the compound N-seryl spermidine that needs.
Represented compound can be a raw material with Threonine when R was alkyl (as methyl) in the logical formula I, and is synthetic with similar method.
Two R in the logical formula I
1Be hydroxyl, R
2Represented compound can be pressed method and makes during for carboxyl: make diacetyl winestone acid anhydrides (VIII)
And putrescine (VI) reaction, then under alkaline condition with the ethanoyl hydrolysis, obtain N-(4-ammonia butyl)-tartrate-acid amides (IX),
With vinyl cyanide (X) with compound (IX) N-cyanoethylation, CH
2-CHCN (X)
Obtain the N-[4-(2-cyanoethyl) the ammonia butyl] tartaric acid monoamide (XI),
And then the cyano reduction of compound (XI) become aminomethyl, obtain the compound that needs.
In addition, two R in the logical formula I
1Be hydroxyl, R
2Represented compound during for carbalkoxy can be got by the carboxyl esterification on the compound (I), and the carboxyl on the compound (I) obtains by aforementioned logical method, perhaps with the carboxyl on the compound (XI) by logical method esterification, and then reduction cyano group and making.Two R in the logical formula I
1Be hydroxyl, R
2Represented compound during for formamyl can be by R
2Separate through ammonia for the compound (making as stated above) of carbalkoxy and to make.
Especially, two R in logical formula I
1Be hydroxyl, R
2For-CONH(CH
2)
4-NH(CH
2)
3NH
2The time, the compound of representative can make by following method, productive rate is higher: with tartrate be raw material by known esterification, be easy to obtain diethyl tartrate (XII),
With (XII) and cyano group putrescine (V) reaction, obtain N, N
1-two-[the 4-(2-cyanoethyl) the ammonia butyl] wine name acid acid amides (VIII),
Cyano reduction with compound (VIII) becomes aminomethyl then, thereby obtains the compound of needs.
As mentioned above, the used synthetic method of the present invention is different from general method, and its aldehyde radical that neither needs protection again need be in order not form the aldehyde radical of glyoxylspermidine, and in the end a step is sloughed protecting group.Method of the present invention has shortened production sequence greatly, and the compound productive rate that makes is higher.The used raw material of the present invention is cheap, can be from obtaining natural compounds and the synthetic compound widely.
So, the invention provides a cheap method for preparing glyoxylspermidine.
With the glyoxylspermidine with the inventive method preparation is raw material, can prepare 15-deoxidation Si Baige Eyring (15-deoxy Spergualin) allied compound, and this method is more more economical, more superior than former method.
According to the present invention, with glyoxylspermidine (II) and ω-guanidine radicals fatty amide (X VI) condensation.
N is the integer of 6-8 in the formula, and the result obtains 15-deoxidation Si Baige Eyring (15-deoxy Spergualin) allied compound (X V):
The definition of n is the same in the formula.
The condensation reaction of glyoxylspermidine (II) and ω-guanidine radicals fatty amide (X VI) is undertaken by the method that document Japanese Patent Kokai No.62152/83 is described in detail.
Because this reaction is a dehydrating condensation, therefore reaction is preferably in the anhydrous solvent and carries out.But structure formula II and (X VI) represented compound are generally acid salt, therefore consider solubleness, and reaction can be carried out in the presence of less water.As long as compound (II) and compound (X VI) can dissolve equably, the quantity of water should reduce as far as possible, and every mole compound (II) water consumption is 4～40 moles.Because compound (II) and compound (X VI) are generally acid salt, so do not need to add acid.But consider productive rate, can be better with acid as catalyst.The acid that can make catalyzer comprises mineral acid, and example hydrochloric acid, sulfuric acid, boric acid etc., and organic acid are as acetic acid, citric acid, tartrate, succsinic acid, pentanedioic acid, hexanodioic acid etc.In above-mentioned various acid, better with organic acid such as citric acid and pentanedioic acid.Every mole compound (II) is 0～10 mole with the acid amount, is preferably 0.5～4 mole.Temperature of reaction is a room temperature to 80 ℃, and 40～60 ℃ better.Reaction times changes with each temperature of reaction, and in order to improve productive rate, the reaction times is preferably from a few hours to a couple of days.
The present invention is described in detail with following example, but is not limited to these examples.Example 1
1, N
1-(N '-carbobenzoxy-(Cbz)-L-seryl)-N
2-(2-cyanoethyl)-1,4-diaminobutane (VII) synthetic
47.8 gram (0.2 mole) N-carbobenzoxy-(Cbz)-L-Serines are dissolved in 200 milliliters of dioxs, after adding 25.3 gram (0.22 mole) N-hydroxy-butanedioic acid imines, under ice-cooled and stirring, (DCC) De dioxane solution is added dropwise in the above-mentioned solution to contain 45.4 gram (0.22 mole) dicyclohexyl carbonyl diurethane imines with 50 milliliters.
At room temperature stir and spend the night, elimination dicyclohexyl urea precipitation, filtrate decompression concentrates.The solid residue that obtains is dissolved in 150 milliliters of ethyl acetate, under agitation, this solution is splashed into 300 milliliters of ethyl acetate solutions that contain 42.36 gram (0.3 mole) cyanoethyl putrescine (V).Then 300 milliliters of ethyl acetate are added above-mentioned reaction solution, stirring is spent the night.Add 100 milliliters of ethyl acetate, 100 milliliters of saturated sodium bicarbonate aqueous solutions and 50 ml waters again, continue to stir 1 hour.
Reaction solution is divided into organic layer, and organic layer washs with 200 milliliters of saturated sodium-chloride water solutions, with anhydrous sodium sulfate drying, and concentrating under reduced pressure then.Solid residue is dissolved in 50 milliliters of ethanol, uses concentrated hydrochloric acidization down ice-cooled, in 5 ℃ of standing over night.Leach precipitation, get the N of 26.7 gram white crystals
1-(N '-carbobenzoxy-(Cbz)-L-seryl)-N
2-(2-cyanoethyl)-1,4-diaminobutane (VII) hydrochloride.Water layer ethyl acetate extraction seven times, each 200 milliliters.Ethyl acetate layer washs with 200 milliliters of saturated sodium-chloride water solutions, with anhydrous sodium sulfate drying, reduces then.The solid residue that obtains is dissolved in 65 milliliters of ethanol, and solution is used the concentrated hydrochloric acid acidifying down ice-cooled, in 5 ℃ of standing over night, gets 34.5 gram (VII) hydrochlorides.The total amount of (VII) hydrochloride is 61.2 grams (productive rate, 76.7%), 147～149 ℃ of fusing points (m.p.).
NMR（CD
3OD）：
δ1.4～1.75（CH
2×2），2.4～3.0（CH
2N×2，CH
2CN），
3.1～3.4（CONHCH
2），3.7（CH
2OH，d），
4.1～4.3（CHNH），5.07（
-CH
2），
7.29（
-）。
IR（KBr）：
γ（cm
-1）3290，3060，2940，2870
2240，1700，1640，1540，
1475，1365，1300，1240，
1140，1100，1020，700。
2, N
1-L-seryl-N
2-(2-cyanoethyl)-1,4-diaminobutane (VII) synthetic
20 gram (0.05 mole) N
1-(N '-carbobenzoxy-(Cbz)-L-seryl)-N
2-(2-cyanoethyl)-1,4-diaminobutane (VII) hydrochloride is dissolved in the methyl alcohol of 400 milliliters of heat, adds 1 gram, 10% palladium carbon, carries out hydrogenolysis in 3 hours in 40 ℃ of logical hydrogen.The logical nitrogen in reaction back 30 minutes, the elimination catalyzer.Filtrate decompression concentrates, and solid residue is dissolved in 100 ml waters, and by 250 milliliters of DoWex 50W * 8(H are housed
+Type, DOW chemical company produces) pillar, after the washing of 1 premium on currency, usefulness 2N ammoniacal liquor wash-out.Collection contains the liquid that takes off of purpose compound, and concentrating under reduced pressure, gets 9.18 gram syrupy shape N
1-L-seryl-N
2-(2-cyanoethyl)-1,4-two Frucoters (X IV) (productive rate, 80.4%).
NMR（CD
3OD）：
δ1.4～1.8（CH
2×2），2.5～3.05（CH
2N×2，CH
2CN），3.2～ 3.5（CONHCH
2，CHNH
2），3.65（CH
2OH，d）。
IR（KBr）：
ν（cm
-1）3280，3060，2930，2850，2230，1650，
1540，1460，1360，1265，1120，1050。
3, N-seryl-spermidine (I) is synthetic
With 8.82 gram (38.6 moles) N
1-L-seryl-N
2-(2-cyanoethyl)-1,4-diaminobutane (X IV) is dissolved in 200 ml methanol, adds 11.04 gram (46.4 mmole) cobalt chloride hexahydrate (CoCl
26H
2O) after, at ice-cooled 8.77 gram (231.8 mmole) sodium borohydride (NaBH that add gradually down
4), reaction solution at room temperature stirred 2 hours then.After adding 200 ml waters, regulate pH to 6.0 with 2N hydrochloric acid.The elimination black precipitate, filtrate decompression concentrates.Be dissolved in the solid residue that obtains in 200 ml waters and by 2 liters of CM-Sephadex are housed
The pillar of (production of pharmacie company) after the washing of two premium on currency, carries out gradient elution with 3 premium on currency and 3 liters of 1M sodium chloride aqueous solutions.Collect useful elutriant, and be evaporated to dried.Use the methanol extraction solid residue, methanol extract liquid is by being equipped with 500 milliliters of Sephadex
The pillar of LH-20, and use methanol-eluted fractions.Collection contains the elutriant of purpose compound, and concentrating under reduced pressure gets 5.759 gram syrupy shape N-seryl-spermidine (I) tri hydrochlorides (productive rate, 43.63%).
NMR（CD
3OD）：
δ1.5～2.5（CH
2×3），2.9～3.5（CH
2N×4），
3.95（CH
2OH），4.1（CHNH
2）。
IR（KBr）：
ν（cm
-1）3410，3030，1670，1620，1560，
1460，1270，1160，1060。
4, glyoxylspermidine (II) is synthetic
5.55 gram (16.26 mmole) N-seryl-spermidine (I) tri hydrochloride is dissolved in 40 ml waters, in room temperature with under stirring, splashes into 10 milliliters of aqueous solution that contain 3.55 gram (16.58 mmole) sodium metaperiodates.Stir after 45 minutes, regulate pH to 1, continue to stir 20 minutes, regulate pH to 4 with 2N sodium hydroxide again with 2N hydrochloric acid, and by 500 milliliters of CM-Sephadex are housed
Pillar.Carry out gradient elution with 2.5 premium on currency and 2.5 liters of 1M sodium chloride aqueous solutions then, collect useful elutriant, merge, be evaporated to dried.Obtain the solid residue methanol extraction, methanol extract liquid is by being equipped with 500 milliliters of Sephadex
The pillar of LH-20, and use methanol-eluted fractions.Collection contains the elutriant of purpose compound, and concentrating under reduced pressure gets 1.583 gram syrupy shape glyoxylspermidine (II) dihydrochlorides (productive rate, 33.3%).
Example 2
1.N-(4-the ammonia butyl) tartrate-acid amides (IX) is synthetic.
13.225 gram (150 mmole) putrescine (VI) is dissolved in 75 milliliters of tetrahydrofuran (THF)s (THF).In addition 10.8 gram (50 mmole) diacetyl-L-winestone acid anhydrides (VIII) are dissolved in 50 milliliters of tetrahydrofuran (THF)s, under ice-cooled and stirring, splash into above-mentioned solution gradually.Then, at room temperature continue to stir 2 hours, after question response finishes, under reduced pressure boil off solvent.Adding 50 ml waters, reaction solution is regulated pH to 13 with 2N sodium hydroxide, at room temperature stirs and makes the ethanoyl hydrolysis in 2 hours.
Reaction solution is by being equipped with 450 milliliters of Dowex
1 * 4 (OH
-) pillar, with after the 1.8 premium on currency washings, with 0.5N aqueous acetic acid wash-out.Collection contains the elutriant of purpose compound, be evaporated to dried, 4.03 gram white crystals N-(4-ammonia butyl) tartrate-acid amides (IX) (productive rate, 36.6%).
NMR（D
2O）：
1.4～1.9（CH
2×2），2.98（CH
2NHCO，t，J＝8Hz），
3.36（CH
2NH，t，J＝7.5Hz），4.35（CHOH，d，J＝2Hz），
4.49（CHOH，d，J＝2HZ）。
IR（KBr）：
ν（cm
-1）3320，2910，2850，1655，1630，
1550，1430，1370，1310，1280，
1225，1130，1070，980。
2.N-[4-(2-ammonia butyl cyanoethyl)] the Synthetic 2 .01 gram (9.127 mmole) of tartrate-acid amides (XI) is dissolved in 40 ml waters by the 1. N-(4-ammonia butyl tartrate-acyl ammonia (IX) that make, add 1.273 milliliters of triethylamines and 0.726 milliliter of vinyl cyanide, the mixture that obtains at room temperature stirred 27 hours.Reaction solution is evaporated to dried then.Add 20 ml waters in solid residue, solution is by being equipped with 300 milliliters of Dowex
1 * 4(OH
-) pillar, with after the 1.2 premium on currency washings, with 0.5N aqueous acetic acid wash-out.Collection contains the elutriant of purpose compound, and concentrating under reduced pressure gets 2.235 gram syrupy shape N-[4-(2-cyanoethyls) the ammonia butyl] tartrate-acid amides (XI) (productive rate, 89.6%).
NMR（DMSo-d
6）：
δ1.3～1.8（CH
2×2），2.4～3.3（NCH
2×3，CH
2CN），
4.20（HHOH×2），7.7（CONH）。
IR（KBr）：
ν（cm
-1）3390，2930，2230，1650，1630，
1540，1400，1120，1070，600。
3.N-[4-(3-ammonia butyl aminopropyl)] tartrate-acid amides (I) synthetic
2.101 gram (7.688 mmole) is by the 2. N-[4-(2-cyanoethyls that make) the ammonia butyl] tartrate-acid amides (XI) is dissolved in 50 ml methanol, adds 2.195 gram (9.226 mmole) cobalt chloride hexahydrate (CoCl
26H
2O), under ice-cooled and stirring, add 1.746 gram (46.13 mmole) sodium borohydride (NaBH gradually
4), at room temperature continue then to stir 3 hours.After question response finishes, add 100 ml waters, reaction solution is regulated pH to 5.8 with 2N hydrochloric acid.
The black crystallization that elimination is separated out, filtrate decompression concentrates to remove methyl alcohol.The dilution of concentrated solution 150 ml waters, and by 500 milliliters of CM-Sephadex are housed
C-25(Na
+) pillar, with after the 1.5 premium on currency washings, carry out gradient elution with 2 premium on currency and 2 liters of 1M sodium chloride aqueous solutions.
Collection contains the elutriant of purpose compound, and by 500 milliliters of Dowex are housed
1 * 4(OH
-) pillar, with after the 2 premium on currency washings, with 0.5N aqueous acetic acid wash-out.Collection contains the elutriant of purpose compound, and concentrating under reduced pressure gets the red syrupy shape N-[4-(3-aminopropyl of 1.225 grams) the ammonia butyl] tartrate-acid amides (I) acetate (productive rate, 39.8%).
NMR（D
2O）：
δ1.4～2.3（CH
2×3），2.8～3.4（NCH
2×4），
4.25（CHOH，d，J＝2Hz），4.4（CHOH，d，J＝2Hz）。
IR（KBr）：
ν（cm
-1）3400，3040，2950，1640，1400，
1120，1070。
4. glyoxylspermidine (II) is synthetic
1.007 gram (2.985 mmole) is by the 3. N-[4-(3-aminopropyls that make) the ammonia butyl] tartrate-acyl ammonia (I) acetate is dissolved in 80 ml waters.In addition 650 milligrams of (3.04 mmole) sodium metaperiodates are dissolved in 20 ml waters, under stirring at room, splash into above-mentioned solution, continue to stir 30 minutes.Reaction solution is by being equipped with 300 milliliters of CM-Sephadex
C-25(Na
+) pillar, with after the 1 premium on currency washing, carry out gradient elution with 1.5 premium on currency and 1.5 liters of 1M sodium chloride aqueous solutions.
Collection contains the elutriant of purpose compound, is evaporated to driedly, and with methanol extraction, methanol extract liquid is by being equipped with 300 milliliters of Sephadex
The pillar of LH-20, and use methanol-eluted fractions.Collection contains purpose compound elutriant, and concentrating under reduced pressure gets 681 milligrams of syrupy shape glyoxylspermidines (II) dihydrochloride (productive rate, 78.1%).
Example 3
1.N, N '-two [4-(2-cyanoethyl) ammonia butyl] tartrate acid amides (X III) synthetic
15.45 gram (0.075 mole) L-diethyl tartrate (XII) splashes in 23.31 gram (0.165 mole) the cyanoethyl putrescine (V), the mixture that obtains after dripping off was in 80 ℃ of heating 2 hours.Use ice-cooled reaction solution, the product washing with acetone after the curing gets the faint yellow coarse crystallization N of 29.64 grams, and N '-two [the 4-(2-cyanoethyl) the ammonia butyl] tartrate acid amides (X III) (productive rate, 99.8%).
The above-mentioned crystallization of 5 grams is dissolved in 20 milliliters of 0.5M sodium chloride aqueous solutions, makes this solution by 1.5 liters of DIAION are housed
The production of HP-20(Mi-tsubishi chemical industry company limited) pillar (DIAION
HP-20 uses 0.5M sodium chloride aqueous solution balance in advance), use 10 premium on currency, 5 liter of 5% methanol aqueous solution and 5 liter of 20% methanol aqueous solution wash-out more successively.Collection contains the elutriant of purpose compound, and concentrating under reduced pressure gets 3.1 gram white crystals N, and N '-two [the 4-(2-cyanoethyl) the ammonia butyl] tartrate acid amides (X III) (productive rate, 61.9%).
NMR（DMSO-d
6）：
δ1.3～1.7（CH
2×4），2.4～2.9（CH
2N×6，CH
2CN×2），
3.3～3.7（NH×2，OH×2），4.20（CH×2），
7.60（CONH×2）。
IR（KBr）：
ν（cm
-1）3370，2905，2220（CN），1640，
1520，1455，1125。
2.N, N '-two [4-(3-aminopropyl) ammonia butyl] tartrate acid amides (I) synthetic
19.8 gram (50 mmole) is by the 1. coarse crystallization N that make, N '-two [the 4-(2-cyanoethyl) the ammonia butyl) tartrate acid amides (X III) is dissolved in the mixed solvent of 450 ml methanol and 33 ml waters, adds 28.55 gram (120 mmole) cobalt chloride hexahydrate (CoCl
26H
2O) after, under ice-cooled, again 22.71 gram (600 mmole) sodium borohydrides are added at leisure.Reaction solution at room temperature stirred 1.5 hours, added 200 ml waters again, regulated pH to 6.5 with 6N hydrochloric acid.The black solid that elimination is separated out, filtrate decompression concentrate to remove methyl alcohol.Concentrated solution is diluted to 400 milliliters, gets wherein 40 milliliters by 500 milliliters of CM-Sephadex are housed
C-25(Na
+) pillar, carry out gradient elution with 3 premium on currency and 3 liters of 1.5M sodium chloride aqueous solutions.Collection contains the elutriant of purpose compound, is evaporated to driedly, uses methanol extraction, and methanol extract liquid is by being equipped with 500 milliliters of Sephadex
The pillar of LH-20, and use methanol-eluted fractions.Collection contains the elutriant of purpose compound, be evaporated to dried, 1.65 gram syrupy shape N, N '-two [4-(3-aminopropyl) ammonia butyl] tartrate acid amides (I) four hydrochlorides (productive rate 60.0%).
NMR（CD
3OD）：
δ1.5～2.4（CH
2×6），2.9～3.4（NCH
2×8），4.45（CH×2）。
IR（KBr）：
ν（cm
-1）3380，2950，2800，1640，1540，
1460，1125，1070，750。
3. glyoxylspermidine (II) is synthetic
The aqueous solution that will contain 16.04 gram (75 mmole) sodium metaperiodates splash into 360 milliliters and contain 45 mmoles and make by 2., not purified N, in the aqueous solution of N '-two [4-(3-aminopropyl) ammonia butyl] tartrate acid amides (I) four hydrochlorides, the mixture that obtains at room temperature stirred 2 hours, reaction finishes, add 4.5 gram (30 mmole) L-tartrate, stirred 15 minutes, elimination pistac precipitation, filtrate is regulated pH to 5.0 with 2N sodium hydroxide, by 1000 milliliters of CM-Sephadex are housed
C-25(Na) pillar after the washing of 3 premium on currency, carries out gradient elution with 3 premium on currency and 3 liters of 0.6M sodium chloride aqueous solutions.Collection contains the elutriant of purpose compound, is evaporated to driedly, uses methanol extraction, and methanol extract liquid is by being equipped with 1000 milliliters of Sephadex
The pillar of LH-20, and use methanol-eluted fractions.Collection contains the elutriant of purpose compound, and concentrating under reduced pressure gets 8.23 gram syrupy shape glyoxylspermidine (II) dihydrochlorides (productive rate, 31.3%).
NMR（CD
3OD）：
δ1.4～2.4（CH
2×3），2.8～3.4（NCH
2×4），
4.89CH。
IR（KBr）：
ν（cm
-1）3370，2950，1660，1540，
1460，1100，1070。
Example 4
300 gram (1.45 moles) L-diethyl tartrates (X II) are added in 450 gram (3.19 moles) the cyanoethyl putrescine (V), and the mixture that obtains was in 80 ℃ of heating 3 hours.Reaction mixture is dissolved in 4 liters of methyl alcohol, and under cooling, the feeding ammonia is saturated up to solution.Add 180 gram Raney nickels then, charge into 12Kg/cm in 40 ℃
2Hydrogen hydrogenation 24 hours.Reaction back elimination catalyzer, filtrate decompression concentrates, and the syrup that obtains is dissolved in 3 premium on currency, and regulates pH to 5.0 with 6N hydrochloric acid.397 gram (1.66 moles) sodium metaperiodates are dissolved in 5 premium on currency, and it is 5.0 solution that gradation adds above-mentioned pH, and mixed solution at room temperature stirred 3 hours.After question response finishes, add 10 milliliters of ethylene glycol, regulate pH to 5.0 to remove residual reagent solution with 6N sodium hydroxide, dilute with water is four times again, then by 12 liters of CM-Sephadex are housed
C-25(Na
+) pillar, use 40 liters of 0.1M sodium-chlor and 50 liters of 0.25M sodium-chlor wash-outs gradually, collect the elutriant contain the purpose compound.Four times of elutriant dilute with waters are again by being equipped with 7.5 liters of CM-Sephadex
C-25(Na
+) pillar, with 0.8M sodium-chlor wash-out.Collection contains the elutriant of purpose compound, lyophilize.Product after the lyophilize is with 4 liters of methanol extraction, and methanol extract liquid is evaporated to dried, 400.4 gram syrupy shape glyoxylspermidine (II) dihydrochlorides [overall yield that obtains from diethyl tartrate (XII), 43.5%].
Example 5
The N-[4-(-3-aminopropyl) ammonia butyl]-2-(7-guanidine radicals heptanamido)-2-hydroxyl acetamide synthetic
360 milligrams of (1.62 mmole) 7-guanidine radicals heptamide hydrochlorides, 568 milligrams of (1.94 mmole) N-[4-(3-aminopropyls) ammonia butyl-2, the mixture of 2-dihydroxyl ethanamide dihydrochloride (being made by example 4), 214 milligrams of (1.62 mmole) pentanedioic acids and 0.36 ml water was in 60 ℃ of heating 24 hours, question response finishes, in compound of reaction, add 5 ml waters, and by 150 milliliters of CM-Sephadex are housed
The C-25(Na type) pillar (internal diameter is 20 millimeters) carries out gradient elution with 1.5 premium on currency and 1.5 liters of 0.8M sodium chloride aqueous solutions.Merge required elutriant, concentrate then, use methanol extraction three times, each 10 milliliters.Methanol layer is by being equipped with 150 milliliters of Sephadex
The pillar of LH-20 is used methanol-eluted fractions.Merge the elutriant contain the purpose compound, be evaporated to dried, 317 milligrams of white meal N-[4-(3-aminopropyls) the ammonia butyl]-2-(7-guanidine radicals heptanamido)-2-hydroxyl acetamide tri hydrochloride (productive rate, 39%).
Example 6
The N-[4-(3-aminopropyl) ammonia butyl]-2-(7-guanidine radicals heptanamido)-2-hydroxyl acetamide synthetic
18 gram (80.9 mmole) 7-guanidine radicals heptamide hydrochlorides, 23.6 gram (80.9 mmole) N-[4-(3-aminopropyls) the ammonia butyl]-2,2-dihydroxyl ethanamide dihydrochloride (being made by example) and 5.7 gram (27 mmole) citric acids are dissolved in 200 ml waters, and mixed solution is evaporated to dried the syrup that contains 1.6 gram water.Syrup by the method purifying of example 5, gets the white meal N-[4-(3-aminopropyl of 19.0 grams in 60 ℃ of heating 8 hours) the ammonia butyl]-2-(7-guanidine radicals heptanamido)-2-hydroxyl acetamide tri hydrochloride (productive rate, 47.3%).
Example 7
The N-[4-(3-aminopropyl) ammonia butyl]-2-(9-guanidine radicals nonanoyl amino)-2-hydroxyl acetamide synthetic
316 milligrams of (1.26 mmole) 9-guanidine radicals pelargonamide hydrochlorides, 442 milligrams of (1.51 mmole) N-[4-(3-aminopropyls) the ammonia butyl]-2, the mixture of 2-dihydroxyl ethanamide dihydrochloride (being made by example 4), 166 milligrams of (1.26 mmole) pentanedioic acids and 0.01 ml water was in 60 ℃ of heating 24 hours.Question response finishes, and by the method for example 5, uses CM-Sephadex
The c-25(Na type) and Sephadex
LH-20 carries out purifying, gets 324 milligrams of white meal N-[4-(3-aminopropyls) the ammonia butyl]-2-(9-guanidine radicals nonanoyl amino)-2-hydroxyl acetamide tri hydrochloride (productive rate, 49%).
Claims (1)
1, a kind of method for preparing general formula (X V),
(wherein n is 6～8 integer), this method comprise the suitable C-C oxicracking that makes compound shown in the logical formula I, N-[4-(3-aminopropyl) the ammonia butyl of preparation formula II]-2,2-dihydroxyl ethanamide,
(R in the formula 1
1Representation hydroxy or amino, but two R
1Be not amino simultaneously, R
2Represent hydrogen atom, carboxyl or CONH (CH
2)
4NH (CH
2)
3NH
2), described oxicracking carries out in a solvent with Periodic acid, and cracking temperature is the boiling point of 0 ℃～solvent for use, and the cracking time is several minutes～several days, makes the ethanamide (II) and ω-guanidine radicals fatty amide (X VI) condensation that make then.
The n definition as above in the formula.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN85103298A CN1010944B (en) | 1984-02-29 | 1985-04-30 | Glyoxylylspermidine and the prepn. method |
| CN90101495A CN1014604B (en) | 1985-04-30 | 1985-04-30 | Method for producing glyoxylspermidine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59036263A JPS60181056A (en) | 1984-02-29 | 1984-02-29 | Preparation of n-(4-(3-aminopropylaminobutyl)-2,2- dihydroxyethanamide |
| CN85103298A CN1010944B (en) | 1984-02-29 | 1985-04-30 | Glyoxylylspermidine and the prepn. method |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN90101495A Division CN1014604B (en) | 1985-04-30 | 1985-04-30 | Method for producing glyoxylspermidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85103298A CN85103298A (en) | 1987-01-21 |
| CN1010944B true CN1010944B (en) | 1990-12-26 |
Family
ID=25741614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85103298A Expired CN1010944B (en) | 1984-02-29 | 1985-04-30 | Glyoxylylspermidine and the prepn. method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1010944B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4838537B2 (en) * | 2005-05-25 | 2011-12-14 | 株式会社 資生堂 | Inadequate keratinization inhibitor, pore-reducing agent, skin roughening preventive / improving agent, and composition for external use on skin |
-
1985
- 1985-04-30 CN CN85103298A patent/CN1010944B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CN85103298A (en) | 1987-01-21 |
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