DK155518B - Fremgangsmaade til optisk resolvering af racemisk 1,4-dimethoxy-6-hydroxy-6-acetyltetralin - Google Patents
Fremgangsmaade til optisk resolvering af racemisk 1,4-dimethoxy-6-hydroxy-6-acetyltetralin Download PDFInfo
- Publication number
- DK155518B DK155518B DK020376AA DK20376A DK155518B DK 155518 B DK155518 B DK 155518B DK 020376A A DK020376A A DK 020376AA DK 20376 A DK20376 A DK 20376A DK 155518 B DK155518 B DK 155518B
- Authority
- DK
- Denmark
- Prior art keywords
- racemic
- dimethoxy
- hydroxy
- acetyltetraline
- procedure
- Prior art date
Links
- AGUPHKGJZBMPMX-UHFFFAOYSA-N 1-(2-hydroxy-5,8-dimethoxy-5,6,7,8-tetrahydro-1h-naphthalen-2-yl)ethanone Chemical compound C1C(O)(C(C)=O)C=CC2=C1C(OC)CCC2OC AGUPHKGJZBMPMX-UHFFFAOYSA-N 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 4
- 230000003287 optical effect Effects 0.000 title description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000002262 Schiff base Substances 0.000 claims description 2
- 150000004753 Schiff bases Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- -1 acetonitrile phenylethylamine Chemical compound 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VEPUKHYQNXSSKV-UHFFFAOYSA-N 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone Chemical compound C1CCCC2=CC(C(=O)C)=CC=C21 VEPUKHYQNXSSKV-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
DK 155518 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til optisk resolvering af racemisk 1,4-dimethoxy-6-hydroxy-
6-acetyltetralin, som har den almene formel II
5 r^V*”3 [01] “ OCH- 3 11
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i 10 kravets kendetegnende del angivne. Adskillelsen er skarp og totalt uventet, eftersom der ikke tidligere er registreret isomeradskillelse af ketoner via ketiminer (Eliel, Stereochemistry of Carbon Compounds, side 56 - McGraw-Hill, 1962), formentlig fordi Schiff-baser sædvanligvis er temme-15 lig ustabile og let sønderdeles under omkrystallisation. Desuden har det vist sig, at de optisk aktive ketoler II kan laves om til den racemiske ketol, og det er derfor muligt at omsætte den racemiske ketol II til den ønskede, optisk aktive form i meget højt udbytte ved isomeradskillelse 20 af den racemiske ketol II med (-)-1-phenylethylamin fulgt af en omsætning af den ikke ønskede isomer tilbage til den racemiske form og gentagelse af adskillelsen i optiske isomere .
25 De forbindelser, som kan fremstilles ifølge opfindelsen, udgør værdifulde udgangsstoffer for fremstilling af hidtil ukendte anthracyclinoner, som på sin side udgør værdifulde lægemidler til behandling af maligne sygdomme, i særdeleshed sarkom, brystcancer, lungekarcinom, maligne lymfomer, 30 neuroblastom, akut leukæmi og blærecancer.
Opfindelsen anskueliggøres nærmere ved hjælp af følgende eksempel.
2
DK 155518 B
Eksempel
Isomeradskillelse af 1.4-dimethoxy-6-hydroxv-6-ace-5 tvltetralin.
l/4-dimethoxy-6-hydroxy-6-acetyltetralin (13,6 g) i aceto-nitril (50 ml) og (-)-1-phenylethylamin (7,4 g) opvarmes i 5 minutter til 80°C; opløsningen køles langsomt til stue-10 temperatur, og efter 3 timer isoleres det krystallinske bundfald (6 g, smeltepunkt 190-192°, 0*-!- 38°, c = 1, CHC13) og opløses i methanol (50 ml), som indeholder 12 ml 2N HC1. Opløsningen opvarmes til 50°C i 10 minutter, fortyndes derefter med vand og ekstraheres med chloroform. Ek-15 strakten inddampes i vacuum, og remanensen omkrystalliseres af chloroform-ethylether til fremstilling af (-)-1,4-dime-thoxy-6-hydroxy-6-acetyltetralin (II) (4,3 g, smeltepunkt 130 til 132°, ΖΧ701 2 3 4 5 6 - 50° c = 1, CHC13) .
Acetonitrilmoderludene inddampes i vacuum, og remanensen 2 opløses i methanol (50 ml), som indeholder 14 ml 2N HC1.
3
Opløsningen opvarmes til 50°C i 10 minutter, fortyndes der 4 efter med vand og ekstraheres med chloroform. Ekstrakten 5 inddampes i vacuum, og remanensen omkrystalliseres af chlo- 6 roform-ethylether til fremstilling af (+)-1,4-dimethoxy-6-hydroxy-6-acetyltetralin (4,8 g, smeltepunkt 130 til 132° + 50° c = 1, CHClg). Fra moderludene genvindes en del racemisk l,4-dimethoxy-6-hydroxy-6-acetyltetralin (4,5 g) ved koncentration og recirkulering.
Claims (1)
- DK 155518 B Fremgangsmåde til optisk resolvering af racemisk 1,4-dime-thoxy-6-hydroxy-6-acetyltetralin, k_e_n_d_e_t_e_g_n_e_t 5 ved, at nævnte racemiske forbindelse i et passende organisk opløsningsmiddel, fortrinsvis acetonitril, omsættes med (-)-l-phenylethylamin til dannelse af diasteromere Schiff-baser, der adskilles ved omkrystallisation, hvorfra de en-antiomere ketoler genvindes ved behandling med fortyndet 10 mineralsyre i methanolisk opløsning ved en temperatur på 50°C i 10 minutter og derefter oprenses ved omkrystallisation fra en blanding af chloroform og ethylether.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB269175 | 1975-01-22 | ||
| GB2691/75A GB1500421A (en) | 1975-01-22 | 1975-01-22 | Optically active anthracyclinones |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK20376A DK20376A (da) | 1976-08-02 |
| DK155518B true DK155518B (da) | 1989-04-17 |
| DK155518C DK155518C (da) | 1989-08-28 |
Family
ID=9744103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK020376A DK155518C (da) | 1975-01-22 | 1976-01-20 | Fremgangsmaade til optisk resolvering af racemisk 1,4-dimethoxy-6-hydroxy-6-acetyltetralin |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4077988A (da) |
| JP (4) | JPS6033819B2 (da) |
| AT (1) | AT342035B (da) |
| AU (1) | AU500067B2 (da) |
| BE (1) | BE837756A (da) |
| CA (1) | CA1064920A (da) |
| CH (3) | CH622486A5 (da) |
| DE (2) | DE2660848C2 (da) |
| DK (1) | DK155518C (da) |
| ES (1) | ES444494A1 (da) |
| FR (4) | FR2320105A1 (da) |
| GB (1) | GB1500421A (da) |
| HK (1) | HK1082A (da) |
| MX (1) | MX4278E (da) |
| NL (1) | NL179724C (da) |
| SE (4) | SE435498B (da) |
| SU (5) | SU683613A3 (da) |
| ZA (1) | ZA76292B (da) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4070382A (en) * | 1975-11-18 | 1978-01-24 | Research Corporation | Intermediates for polycyclic quinoid antibiotics |
| GB1527050A (en) * | 1976-06-19 | 1978-10-04 | Farmaceutici Italia | Optically active anthracyclinones |
| US4134903A (en) * | 1976-08-07 | 1979-01-16 | Societa Farmaceutici Italia S.P.A. | Anthracycline ethers and their preparation |
| GB1573037A (en) * | 1977-05-05 | 1980-08-13 | Farmaceutici Italia | Anthracyclines |
| GB1573036A (en) * | 1977-05-05 | 1980-08-13 | Farmaceutici Italia | Anthracyclines |
| US4296105A (en) * | 1978-08-03 | 1981-10-20 | Institut International De Pathologie Cellulaire Et Moleculaire | Derivatives of doxorubicine, their preparation and use |
| NL8001417A (nl) * | 1979-03-17 | 1980-09-19 | Erba Farmitalia | Antitumorglycosiden. |
| US4259476A (en) * | 1979-04-02 | 1981-03-31 | Kende Andrew S | Novel heterocyclic anthracycline compounds |
| JPS5673039A (en) * | 1979-08-20 | 1981-06-17 | Hoffmann La Roche | Naphthacene derivative |
| GB2056443B (en) * | 1979-08-20 | 1984-01-18 | Hoffmann La Roche | Cyclic compounds |
| GB2071084B (en) * | 1980-01-22 | 1984-02-29 | Hoffmann La Roche | Polycylic compounds |
| JPS5756494A (en) * | 1980-09-22 | 1982-04-05 | Microbial Chem Res Found | New anthracyclin derivative |
| ES514486A0 (es) * | 1981-07-29 | 1983-08-16 | Sumitomo Chemical Co | Un procedimiento para la preparacion de derivados de aminonaftaceno. |
| BE896743A (fr) * | 1982-08-13 | 1983-09-16 | Erba Farmitalia | Synthese de naphtacenequinone. |
| US4489206A (en) * | 1983-05-13 | 1984-12-18 | Adria Laboratories, Inc. | Synthesis of (+)-4-demethoxydaunomycinone |
| US4831019A (en) * | 1983-10-31 | 1989-05-16 | Adria Laboratories, Inc. | Pharmaceutical preparations of 4-demethoxy-n-trifluoroacetyl anthracyclines |
| US4496485A (en) * | 1983-11-25 | 1985-01-29 | G. D. Searle & Co. | Asymmetric 7-O-(substituted acetyl)-4-demethoxydaunomycinones |
| GB8519452D0 (en) * | 1985-08-02 | 1985-09-11 | Erba Farmitalia | Injectable solutions |
| JP2736255B2 (ja) * | 1987-03-11 | 1998-04-02 | フアルマシア・エ・アツプジヨン・エツセ・ピー・アー | イムノグロブリン結合体 |
| NZ224252A (en) * | 1987-04-21 | 1991-09-25 | Erba Carlo Spa | An anthracycline glycoside and its preparation |
| GB8803301D0 (en) * | 1988-02-12 | 1988-03-09 | Erba Carlo Spa | Process for preparation of 4-demethoxy-daunomycinone aglycone of 4-demethoxy-daunorubicin |
| GB8824947D0 (en) * | 1988-10-25 | 1988-11-30 | Erba Carlo Spa | New 4-substituted anthracyclinones & process for preparing them |
| NL9001834A (nl) * | 1990-08-16 | 1992-03-16 | Pharmachemie Bv | Nieuwe antracyclineverbindingen met anti-tumorwerkzaamheid, nieuwe tussenverbindingen voor de bereiding van deze antracyclineverbindingen, alsmede preparaten die de aktieve antracyclineverbindingen bevatten. |
| GB9418260D0 (en) * | 1994-09-09 | 1994-10-26 | Erba Carlo Spa | Anthracycline derivatives |
| IT1317106B1 (it) * | 2000-11-16 | 2003-05-26 | Menarini Ricerche Spa | Processo per la sintesi di antracicline otticamente attive. |
| DE10155016A1 (de) * | 2001-11-07 | 2003-05-15 | Knoell Hans Forschung Ev | Neue Chinon-Verbindung, Verfahren zur Herstellung und deren Verwendung |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3904632A (en) * | 1972-05-08 | 1975-09-09 | Hoffmann La Roche | (')-di-o-isopropylidene-2-keto-l-gulonates |
| JPS5840556A (ja) * | 1981-09-04 | 1983-03-09 | Ricoh Co Ltd | 電子写真圧力定着転写紙及びその転写紙用原紙の製造法 |
-
1975
- 1975-01-22 GB GB2691/75A patent/GB1500421A/en not_active Expired
-
1976
- 1976-01-06 NL NLAANVRAGE7600075,A patent/NL179724C/xx not_active IP Right Cessation
- 1976-01-16 US US05/649,825 patent/US4077988A/en not_active Expired - Lifetime
- 1976-01-19 ZA ZA292A patent/ZA76292B/xx unknown
- 1976-01-19 AT AT30676A patent/AT342035B/de not_active IP Right Cessation
- 1976-01-19 MX MX763633U patent/MX4278E/es unknown
- 1976-01-20 JP JP51005803A patent/JPS6033819B2/ja not_active Expired
- 1976-01-20 DK DK020376A patent/DK155518C/da not_active IP Right Cessation
- 1976-01-20 DE DE2660848A patent/DE2660848C2/de not_active Expired
- 1976-01-20 DE DE2601785A patent/DE2601785C2/de not_active Expired
- 1976-01-20 CA CA243,860A patent/CA1064920A/en not_active Expired
- 1976-01-20 AU AU10432/76A patent/AU500067B2/en not_active Expired
- 1976-01-20 SE SE7600563A patent/SE435498B/xx not_active IP Right Cessation
- 1976-01-21 CH CH74276A patent/CH622486A5/de not_active IP Right Cessation
- 1976-01-21 BE BE163665A patent/BE837756A/xx not_active IP Right Cessation
- 1976-01-21 FR FR7601535A patent/FR2320105A1/fr active Granted
- 1976-01-21 ES ES444494A patent/ES444494A1/es not_active Expired
- 1976-01-21 SU SU762311601A patent/SU683613A3/ru active
- 1976-09-24 FR FR7628763A patent/FR2320085A1/fr active Granted
- 1976-09-24 FR FR7628762A patent/FR2333769A1/fr active Granted
- 1976-09-24 FR FR7628764A patent/FR2320086A1/fr active Granted
- 1976-12-03 SU SU762425700A patent/SU646914A3/ru active
-
1977
- 1977-10-11 SU SU772532447A patent/SU650498A3/ru active
- 1977-10-11 SU SU772530649A patent/SU724087A3/ru active
- 1977-10-11 SU SU772532450A patent/SU776557A3/ru active
-
1980
- 1980-01-07 CH CH7780A patent/CH624085A5/de not_active IP Right Cessation
- 1980-01-07 CH CH7880A patent/CH622530A5/de not_active IP Right Cessation
-
1982
- 1982-01-14 HK HK10/82A patent/HK1082A/xx unknown
- 1982-02-18 SE SE8201015A patent/SE461529B/sv not_active IP Right Cessation
- 1982-02-18 SE SE8201013A patent/SE453185B/sv not_active IP Right Cessation
- 1982-02-18 SE SE8201014A patent/SE461525B/sv not_active IP Right Cessation
-
1984
- 1984-04-13 JP JP59073134A patent/JPS59231098A/ja active Granted
- 1984-04-13 JP JP59073133A patent/JPS59231038A/ja active Pending
- 1984-04-13 JP JP59073132A patent/JPS59231037A/ja active Pending
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |