JPS636071B2 - - Google Patents

Info

Publication number: JPS636071B2
Authority: JP; Japan
Prior art keywords: tetrahydrocamptothecin; nitro; camptothecin; chloroform; reduced pressure
Prior art date: 1982-03-05
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

Application number

JP3409482A

Other languages

English (en)

Japanese (ja)

Other versions

JPS58152888A (ja

Inventor

Sada Myasaka

Seigo Sawada

Kenichiro Nogata

Masahiko Mutai

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Yakult Honsha Co Ltd

Original Assignee

Yakult Honsha Co Ltd

Priority date (The priority date 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 date listed.)

1982-03-05

Filing date

1982-03-05

Publication date

1988-02-08

1982-03-05 Application filed by Yakult Honsha Co Ltd filed Critical Yakult Honsha Co Ltd

1982-03-05 Priority to JP3409482A priority Critical patent/JPS58152888A/ja

1982-09-01 Priority to US06/413,879 priority patent/US4473692A/en

1982-09-02 Priority to CA000410691A priority patent/CA1246576A/en

1982-09-03 Priority to DE8282304649T priority patent/DE3274351D1/de

1982-09-03 Priority to EP82304649A priority patent/EP0074256B1/de

1983-09-10 Publication of JPS58152888A publication Critical patent/JPS58152888A/ja

1984-07-18 Priority to US06/632,039 priority patent/US4545880A/en

1988-02-08 Publication of JPS636071B2 publication Critical patent/JPS636071B2/ja

Status Granted legal-status Critical Current

Links

VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 24
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 23
VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 22
KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 20
229940127093 camptothecin Drugs 0.000 claims description 20
238000004519 manufacturing process Methods 0.000 claims description 13
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
XLHNAFUKOSPOAT-UHFFFAOYSA-N 4-ethyl-4-hydroxy-9-nitro-(+-)-1h-pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4h,12h)-dione Chemical compound C1=C([N+]([O-])=O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 XLHNAFUKOSPOAT-UHFFFAOYSA-N 0.000 claims description 7
229910017604 nitric acid Inorganic materials 0.000 claims description 7
125000002252 acyl group Chemical group 0.000 claims description 5
239000003795 chemical substances by application Substances 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
230000007062 hydrolysis Effects 0.000 claims description 3
238000006460 hydrolysis reaction Methods 0.000 claims description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
239000011541 reaction mixture Substances 0.000 description 17
239000000243 solution Substances 0.000 description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
229910052943 magnesium sulfate Inorganic materials 0.000 description 10
235000019341 magnesium sulphate Nutrition 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
150000001875 compounds Chemical class 0.000 description 9
239000003054 catalyst Substances 0.000 description 8
238000010531 catalytic reduction reaction Methods 0.000 description 8
239000013078 crystal Substances 0.000 description 8
YSAMJAXLRIUOHA-SFVMKZFCSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),4,6,8,15(20)-pentaene-14,18-dione Chemical compound N1C2=CC=CC=C2CC(CN2C3=O)C1C2=CC1=C3COC(=O)[C@]1(O)CC YSAMJAXLRIUOHA-SFVMKZFCSA-N 0.000 description 7
239000005457 ice water Substances 0.000 description 7
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
238000000354 decomposition reaction Methods 0.000 description 6
238000000034 method Methods 0.000 description 6
MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 6
229910003446 platinum oxide Inorganic materials 0.000 description 6
238000010992 reflux Methods 0.000 description 6
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
229960000583 acetic acid Drugs 0.000 description 5
238000003756 stirring Methods 0.000 description 5
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
238000006243 chemical reaction Methods 0.000 description 4
239000000284 extract Substances 0.000 description 4
230000003647 oxidation Effects 0.000 description 4
238000007254 oxidation reaction Methods 0.000 description 4
238000010898 silica gel chromatography Methods 0.000 description 4
MVUUMBZAHAKPKQ-FQEVSTJZSA-N 10-aminocamptothecin Chemical compound C1=C(N)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 MVUUMBZAHAKPKQ-FQEVSTJZSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
125000003277 amino group Chemical group 0.000 description 3
238000001816 cooling Methods 0.000 description 3
229910052739 hydrogen Inorganic materials 0.000 description 3
239000000203 mixture Substances 0.000 description 3
238000006396 nitration reaction Methods 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
235000017557 sodium bicarbonate Nutrition 0.000 description 3
229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
235000010288 sodium nitrite Nutrition 0.000 description 3
239000002904 solvent Substances 0.000 description 3
239000000126 substance Substances 0.000 description 3
HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 2
KLFJSYOEEYWQMR-NRFANRHFSA-N 10-methoxycamptothecin Chemical compound C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-NRFANRHFSA-N 0.000 description 2
HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 2
229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
230000001093 anti-cancer Effects 0.000 description 2
MXIBGRFZFZXAKG-FQEVSTJZSA-N chembl2115019 Chemical compound C1=C(Cl)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 MXIBGRFZFZXAKG-FQEVSTJZSA-N 0.000 description 2
OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
229940045803 cuprous chloride Drugs 0.000 description 2
239000012954 diazonium Substances 0.000 description 2
150000001989 diazonium salts Chemical class 0.000 description 2
125000000524 functional group Chemical group 0.000 description 2
239000012362 glacial acetic acid Substances 0.000 description 2
125000005843 halogen group Chemical group 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
229910000042 hydrogen bromide Inorganic materials 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
125000004433 nitrogen atom Chemical group N* 0.000 description 2
230000000704 physical effect Effects 0.000 description 2
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
238000000746 purification Methods 0.000 description 2
238000006722 reduction reaction Methods 0.000 description 2
239000007858 starting material Substances 0.000 description 2
WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
FWFUSMMVFVVERM-UHFFFAOYSA-N 2-(1,4-dioxan-2-yl)acetic acid Chemical compound OC(=O)CC1COCCO1 FWFUSMMVFVVERM-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
XVMZDZFTCKLZTF-UHFFFAOYSA-N 9-methoxycamtothecin Natural products C1=CC(OC)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 XVMZDZFTCKLZTF-UHFFFAOYSA-N 0.000 description 1
KLFJSYOEEYWQMR-UHFFFAOYSA-N CPT-OMe Natural products C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-UHFFFAOYSA-N 0.000 description 1
241000759905 Camptotheca acuminata Species 0.000 description 1
241000196324 Embryophyta Species 0.000 description 1
206010028980 Neoplasm Diseases 0.000 description 1
206010034133 Pathogen resistance Diseases 0.000 description 1
206010039491 Sarcoma Diseases 0.000 description 1
ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
239000002253 acid Substances 0.000 description 1
229930013930 alkaloid Natural products 0.000 description 1
150000003797 alkaloid derivatives Chemical class 0.000 description 1
230000002152 alkylating effect Effects 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
239000002246 antineoplastic agent Substances 0.000 description 1
229940041181 antineoplastic drug Drugs 0.000 description 1
238000005899 aromatization reaction Methods 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
229960004926 chlorobutanol Drugs 0.000 description 1
239000002026 chloroform extract Substances 0.000 description 1
FIMJSWFMQJGVAM-UHFFFAOYSA-N chloroform;hydrate Chemical compound O.ClC(Cl)Cl FIMJSWFMQJGVAM-UHFFFAOYSA-N 0.000 description 1
238000004440 column chromatography Methods 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
230000000694 effects Effects 0.000 description 1
238000007336 electrophilic substitution reaction Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
125000000623 heterocyclic group Chemical group 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
230000010534 mechanism of action Effects 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
150000002739 metals Chemical class 0.000 description 1
VRWLBMGRSLQKSU-UHFFFAOYSA-N methanol;pyridine Chemical compound OC.C1=CC=NC=C1 VRWLBMGRSLQKSU-UHFFFAOYSA-N 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
238000001668 nucleic acid synthesis Methods 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
229910052697 platinum Inorganic materials 0.000 description 1
239000002994 raw material Substances 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
238000000926 separation method Methods 0.000 description 1
238000007086 side reaction Methods 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000007787 solid Substances 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
238000005406 washing Methods 0.000 description 1

Landscapes

Nitrogen Condensed Heterocyclic Rings (AREA)

JP3409482A 1981-09-04 1982-03-05 新規な１０−ニトロ−カンプトテシン誘導体の製造法 Granted JPS58152888A (ja)

Priority Applications (6)

Application Number	Priority Date	Filing Date	Title
JP3409482A JPS58152888A (ja)	1982-03-05	1982-03-05	新規な１０−ニトロ−カンプトテシン誘導体の製造法
US06/413,879 US4473692A (en)	1981-09-04	1982-09-01	Camptothecin derivatives and process for preparing same
CA000410691A CA1246576A (en)	1981-09-04	1982-09-02	Camptothecin derivatives and process for preparing same
DE8282304649T DE3274351D1 (en)	1981-09-04	1982-09-03	Camptothecin derivatives, processes for preparing same, formulations containing such derivatives and their use
EP82304649A EP0074256B1 (de)	1981-09-04	1982-09-03	Camptothecine Derivate, Verfahren zu ihrer Herstellung, Zusammensetzungen welche diese Derivate enthalten und ihre Anwendung
US06/632,039 US4545880A (en)	1981-09-04	1984-07-18	Photochemical process for preparing camptothecin derivatives

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
JP3409482A JPS58152888A (ja)	1982-03-05	1982-03-05	新規な１０−ニトロ−カンプトテシン誘導体の製造法

Publications (2)

Publication Number	Publication Date
JPS58152888A JPS58152888A (ja)	1983-09-10
JPS636071B2 true JPS636071B2 (de)	1988-02-08

Family

ID=12404681

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP3409482A Granted JPS58152888A (ja)	1981-09-04	1982-03-05	新規な１０−ニトロ−カンプトテシン誘導体の製造法

Country Status (1)

Country	Link
JP (1)	JPS58152888A (de)

1982
- 1982-03-05 JP JP3409482A patent/JPS58152888A/ja active Granted

Also Published As

Publication number	Publication date
JPS58152888A (ja)	1983-09-10

Publication	Publication Date	Title
EP0074256B1 (de)	1986-11-20	Camptothecine Derivate, Verfahren zu ihrer Herstellung, Zusammensetzungen welche diese Derivate enthalten und ihre Anwendung
JPH0312070B2 (de)	1991-02-19
JPH0310630B2 (de)	1991-02-14
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JP2005502670A (ja)	2005-01-27	１４−ヒドロキシノルモルフィノン誘導体の調製方法。
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US6743918B2 (en)	2004-06-01	Process for producing camptothecin
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