CS201009B2 - Bilek,walter,at - Google Patents
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- CS201009B2 CS201009B2 CS443978A CS443978A CS201009B2 CS 201009 B2 CS201009 B2 CS 201009B2 CS 443978 A CS443978 A CS 443978A CS 443978 A CS443978 A CS 443978A CS 201009 B2 CS201009 B2 CS 201009B2
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- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical class C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 3
- 238000003684 Perkin reaction Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 150000001907 coumarones Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 3
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 150000003232 pyrogallols Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 229960004469 methoxsalen Drugs 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- GOFQRLNJZFQDGG-UHFFFAOYSA-N 6-hydroxy-7-methoxy-1-benzofuran-5-carbaldehyde Chemical compound COC1=C(O)C(C=O)=CC2=C1OC=C2 GOFQRLNJZFQDGG-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- ZRGFVGWYWMJNOH-UHFFFAOYSA-N (5-formyl-7-methoxy-1-benzofuran-6-yl) acetate Chemical compound C(=O)C=1C(=C(C2=C(C=CO2)C=1)OC)OC(C)=O ZRGFVGWYWMJNOH-UHFFFAOYSA-N 0.000 description 5
- -1 2,4-diformyl-5-acetoxy-6-methoxyphenoxy Chemical group 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- MOKWZUTYQWEYSV-UHFFFAOYSA-N C(=O)C=1C(=C(C2=C(C=C(O2)C(=O)O)C1)OC)O Chemical compound C(=O)C=1C(=C(C2=C(C=C(O2)C(=O)O)C1)OC)O MOKWZUTYQWEYSV-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- PCWZKQSKUXXDDJ-UHFFFAOYSA-N Xanthotoxin Natural products COCc1c2OC(=O)C=Cc2cc3ccoc13 PCWZKQSKUXXDDJ-UHFFFAOYSA-N 0.000 description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(i) oxide Chemical compound [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 2
- WANKRKFIRRJAMD-UHFFFAOYSA-N C(=O)C=1C(=C(C2=C(C=C(O2)C(=O)O)C1)OC)OC(C)=O Chemical compound C(=O)C=1C(=C(C2=C(C=C(O2)C(=O)O)C1)OC)OC(C)=O WANKRKFIRRJAMD-UHFFFAOYSA-N 0.000 description 2
- MJGKDOBOYBLLEO-UHFFFAOYSA-N COC1=C(C(=CC(=C1OCC(=O)O)C=O)C=O)O Chemical compound COC1=C(C(=CC(=C1OCC(=O)O)C=O)C=O)O MJGKDOBOYBLLEO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241001435619 Lile Species 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 2
- 229940112669 cuprous oxide Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- SQBBOVROCFXYBN-UHFFFAOYSA-N methoxypsoralen Natural products C1=C2OC(=O)C(OC)=CC2=CC2=C1OC=C2 SQBBOVROCFXYBN-UHFFFAOYSA-N 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- PFTNSNIUPJYFRB-UHFFFAOYSA-N 4,6-dihydroxy-5-methoxybenzene-1,3-dicarbaldehyde Chemical compound OC1=C(C=C(C=O)C(=C1OC)O)C=O PFTNSNIUPJYFRB-UHFFFAOYSA-N 0.000 description 1
- BUNGCZLFHHXKBX-UHFFFAOYSA-N 8-methoxypsoralen Natural products C1=CC(=O)OC2=C1C=C1CCOC1=C2OC BUNGCZLFHHXKBX-UHFFFAOYSA-N 0.000 description 1
- 229940027041 8-mop Drugs 0.000 description 1
- HAGREJWEXYKQEV-UHFFFAOYSA-N 9-methoxy-7-oxofuro[3,2-g]chromene-6-carboxylic acid Chemical compound C1=C(C(O)=O)C(=O)OC2=C1C=C1C=COC1=C2OC HAGREJWEXYKQEV-UHFFFAOYSA-N 0.000 description 1
- RDJHCKHLMLNWND-UHFFFAOYSA-N CC(=O)OC1=C(C=C(C(=C1OC)OCC(=O)O)C=O)C=O Chemical compound CC(=O)OC1=C(C=C(C(=C1OC)OCC(=O)O)C=O)C=O RDJHCKHLMLNWND-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- LZLOFGMGFADIKQ-UHFFFAOYSA-N benzene;1,4-dioxane Chemical compound C1COCCO1.C1=CC=CC=C1 LZLOFGMGFADIKQ-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- VJBCBLLQDMITLJ-UHFFFAOYSA-N chromen-7-one Chemical compound C1=COC2=CC(=O)C=CC2=C1 VJBCBLLQDMITLJ-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cosmetics (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Tento vynález se týká způsobu výroby derivátů 9-methoxy-7H-furo(3,2-g)(1)benzopyran-7-onu obeoného vzorce IThis invention relates to a process for the preparation of 9-methoxy-7H-furo (3,2-g) (1) benzopyran-7-one derivatives of the formula I
* 12 skupinu. Sloučeniny, ve kterých alespoň jeden ze substituentů R a R je odlišný od vodíku, jsou nové.* 12 group. Compounds in which at least one of R and R is different from hydrogen are new.
Sloučeniny, které se dají získat podle vynálezu, jsou cenná farmaceutika, popřípadě meziprodukty, ze kterých se dá snadno vyrobit methoxsalen (sloučenina obecného vzorce I, kde r' a R2 znamenají vodík). Methoxsalen je sloučenina, kterou se může úspěšně léčit psori asis, chronické, tvrdošíjné onemocnění kůže, které se ve své četnosti přibližuje diabetes.The compounds obtainable according to the invention are valuable pharmaceuticals or intermediates from which methoxsalene (compound of formula I wherein r 1 and R 2 are hydrogen) can be readily prepared. Methoxsalen is a compound that can be successfully treated for psori asis, a chronic, stubborn skin disease that approaches diabetes in its frequency.
Léčení se může provádět ambulantně, není nebezpečné a nepotřebuje žádné lokální ošetřo vání mastmi. Toto spočívá v tom, že se methoxsalen podává perorálně a potom se psoriaticky změněná kůže ozařuje dlouhovlnovým ultrafialovým zářením. Tímto způsobem je možné zastavit kožní změny a následujícím léčením v časových odstupech se pacient může i velmi dlouhou dobu udržet bez příznaků tohoto onemocnění.The treatment can be performed on an outpatient basis, is not dangerous and does not require any local ointment treatment. This is because methoxsalen is administered orally and then the psoriatic skin is irradiated with long-wave ultraviolet radiation. In this way, it is possible to stop the skin changes and by following treatment at intervals, the patient can remain without symptoms for a very long time.
Methoxsalen, označený též jako 8-methoxypsoralen, 8-MOP, amoidin popřípadě xanthotoxin je přirozené látka, které se nachází v americkém stromě Phagara xanthoxyloides, v rúta gravoolens, v nmimajus, v andělském kořeni a v jiných okoličnatých rostlinách. Methoxsalen se dá z přirozených zdrojů získat jen těžce a nákladně v malých množstvích, takže vyvstává vel· 201009 ká potřeba vyrobit substanci, cennou pro léčení psoriasis, synteticky a laciněji. V principu se pro výrobu derivátů 9-methoxy-7H-furo(3,2-g)(1) benzopyran-7-onu nabízí tři různé cesty:Methoxsalen, also referred to as 8-methoxypsoralen, 8-MOP, amoidin or xanthotoxin, is a natural substance found in the American tree Phagara xanthoxyloides, in the rut gravoolens, in nmimajus, in the angel's root and in other surrounding plants. Methoxsalene can be obtained from natural sources only in a difficult and costly manner in small quantities, so that there is a great need to produce a substance valuable for the treatment of psoriasis, synthetically and cheaper. In principle, three different routes are available for the preparation of 9-methoxy-7H-furo (3,2-g) (1) benzopyran-7-one derivatives:
2.2.
3.3.
vychází se ze vychází vychází sloučeniny obsahující kumarinový skelet:compounds containing coumarin skeleton:
se ze sloučeniny obsahující skelet benzo(b)furanu se ze symetricky o,-o-substituovaného pyrogalolu:from a compound containing a benzo (b) furan skeleton from symmetrically o, -o-substituted pyrogalol:
v němžin which
R znamená vodík nebo organický zbytek.R is hydrogen or an organic radical.
Až dosud provedené laboratorní pokusy syntézy methoxsalenu probíhaly podle první nebo druhé cesty a poskytovaly pouze nepatrné výtěžky, takže byly prováděny předevěím z vědeckého zájmu, protože neposkytovaly praktickou možnost využití: E. Spáth a M. Pailer, Chem.To date, laboratory experiments on the synthesis of methoxsalene have followed either the first or second route and have yielded only minor yields, so that they have been carried out primarily from scientific interest because they did not provide practical application: E. Spath and M. Pailer, Chem.
Ber. 69. 767-70 (1936); G. Rodighiero a C. Antonello, Ann. Chim. (Rom), 46, 960-67, (1956), C. A. 51: 6 616 násl.; T. R. Seshadri a M. S. Sood, Indián J. Chem. 1 (7), 291-4 (1963),Ber. 69, 767-70 (1936); G. Rodighiero and C. Antonello, Ann. Chim. (Rom), 46, 960-67, (1956), C.A. 51: 6166 ff .; T. R. Seshadri and M. S. Sood, Indian J. Chem. 1 (7), 291-4 (1963).
N. J. de Souza, P. V. Nayak a E. Secco, J. Heterocy-clic Chem. 42-45 (1966); a D. K. Chatterjee a K. Sen, Tetrahedron Lett. 59. 5 223-4 (1969).NJ de Souza, P.V. Nayak and E. Secco, J. Heterocyclic Chem. 42-45 (1966); and D. K. Chatterjee and K. Sen, Tetrahedron Lett. 59, 5223-4 (1969).
V poslední době se proto v Indii a Saudské Arábii přeSlo k tomu, že se nastoupí polosyntetická cesta, podle níž se prekursory izolované z rostlinných extraktů převedou v principu známými postupy syntézy v methoxsalen.Recently, therefore, in India and Saudi Arabia, a semi-synthetic path has been adopted in which precursors isolated from plant extracts are converted in principle by known methoxsalene synthesis procedures.
Tyto způsoby vyžadují ale další závislost na druhu rostlin, které se v těchto zemích daří, které již nyní - ve spojení s malými výtěžky - vedou k tvorbě vysokých cen.However, these methods require further dependence on the type of plants that are doing well in these countries, which are already leading to high prices, coupled with low yields.
Nyní byl vyvinut nový způsob, který umožňuje poprvé technicky zhodnotitelnou syntézu methoxsalenu, nebol vychází od cenově výhodných surovin a v jednotlivých stupních až ke konečnému produktu vykazuje veskrze dobré výtěžky.A new process has now been developed which allows for the first time technically feasible synthesis of methoxsalene, since it starts from cost-effective raw materials and shows very good yields in individual steps up to the final product.
Způsob podle vynálezu spočívá nyní v tom, že se derivát pyrogalolu, obecného vzorce IIThe process according to the invention now consists in the preparation of a pyrogalol derivative of the general formula II
OHC Λ CHOOHC Λ CHO
R3CR 3 C
OCHj—COOHOCH3 — COOH
OCH, kde R^ znamená vodík nebo acetylovou skupinu, nechá reagovat za podmínek na deriváty kumaronu obecného vzorce III OHCOCH, where R 1 is hydrogen or acetyl, is reacted under conditions to coumarone derivatives of formula III OHC
X X / r1 r^o ι'Χ och3 (II)XX / r1 r ^ o Χ 'och 3 (II)
Perkinovy reakce (III) kde R1 mé shora uvedený význam a RJ znamená acetylovou skupinu a tento derivát kumaronu se 2 za podmínek Perkinovy reakce nechá dále reagovat na sloučeninu obecného vzorce I, kde R znamená vodík a r' mé shora uvedený význam, nebo se popřípadě sloučenina obecného vzorcePerkin reaction (III) wherein R 1 is as defined above and R J is acetyl and this coumarone derivative is further reacted under the Perkin reaction conditions to a compound of formula I wherein R is hydrogen and is as defined above, or optionally a compound of formula
33
III, kde R znamená acetylovou skupinu, nechá zmýdelnit na sloučeninu, kde R znamená vodík a tato sloučenina se potom nechá reagovat s kyselinou malonovou v přítomnosti alkalického katalyzátoru, například dimethylpyridinu, na derivát 9-methoxy-7H-furo(3,2-g)(1)-benzopyran-7-onu obecného vzorce I, kde r' a R2 mají shora uvedený význam, a popřípadě se odštěpí přítomná karboxylová skupina.III, where R is acetyl, is saponified to a compound where R is hydrogen and this compound is then reacted with malonic acid in the presence of an alkali catalyst such as dimethylpyridine to give a 9-methoxy-7H-furo derivative (3.2 g) (1) -Benzopyran-7-one of formula (I), wherein r 1 and R 2 are as defined above, and optionally the carboxyl group present is cleaved.
Vzorci lze princip způsobu podle vynálezu znázornit následovně:The formula of the method of the invention can be illustrated as follows:
Podmínky Perkinovy reakce jsou obšírně vyloženy Johnem R. Johnsonem na str. 210 a násl. knihy Organlc Reactions, sv. 1 (Bachraann-Johnson- Fieser-Snyder, nakladatelství John Wiley a Sons /1947/).The conditions of Perkin's reaction are broadly interpreted by John R. Johnson on page 210 et seq. Books Organlc Reactions, Vol. 1 (Bachraann-Johnson-Fieser-Snyder, John Wiley & Sons / 1947).
Následující příklady mají blíže vysvětlit předložený vynález, aniž by se tento omezoval pouze na ně.The following examples are intended to illustrate the present invention in more detail without limiting it to them.
Příklad 1Example 1
a) 2,4-Diformyl-5-methoxy-6-hydroxyfenoxyoctová kyselina (II, RJ = H)a) 2,4-diformyl-5-methoxy-6-hydroxyfenoxyoctová acid (II, R = H, J)
och3 och 3
OHCOHC
....
CHOCHO
OCH och2coohOCH och 2 cooh
IVIV
I la g (10,2 mmolu) 4,6-dihydroxy-5-methoxyisoftalaldehydu se rozpustí ve 20 al 2 N hydroxidu sodného, doplní 2,5 g (13,4 mmoly) kyseliny jodoctové a 2 hodiny míchají při 80 °C. Po ochlazení se reakční směs okyselí 2 N kyselinou chlorovodíkovou a extrahuje ethylacetátem. Organická fáze se desetkrát vytřepá 1% vodným roztokem pyridinu, spojené vodné fáze se znovu okyselí kyselinou chlorovodíkovou a opět extrahují ethylacetátem. Organické fáze se suší síranem sodným a rozpouštědlo se odpaří. (II; iP = Η): T. t. 192 až 193 °C (voda), b) 5-Formyl-6-hydroxy-7-methoxybenzofuran (III, R1» R3 = H)11 g (10.2 mmol) of 4,6-dihydroxy-5-methoxyisophthalaldehyde are dissolved in 20 [mu] l of 2N sodium hydroxide, made up to 2.5 g (13.4 mmol) of iodoacetic acid and stirred at 80 [deg.] C. for 2 hours. After cooling, the reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is shaken ten times with a 1% aqueous solution of pyridine, the combined aqueous phases are acidified again with hydrochloric acid and extracted again with ethyl acetate. The organic phases were dried over sodium sulfate and the solvent was evaporated. (II; IP = Η): mp. 192-193 ° C (water), b) 5-Formyl-6-hydroxy-7-methoxy-benzofuran (III, R 1 "R 3 = H)
0,2 g (0,79 mmolu) 2,4-diformyl-5-hydroxy-6-methoxyfenoxyootové kyseliny (III, R^ = H) se doplní 0,06 g (0,73 mmolu) bezvodého octanu sodného a 0,4 g (3,92 mmoly) aoetanhydridu a za stálého míchání se zahřeje na 170 °C, Při tom nejdříve vznikající 2,4-diformyl-5-aeetoxy-6-methoxyfenoxyoctová kyselina (II, R^ = COCH^), se nechá zreagovat dalším desetiminutovým zahříváním na 170 °C.0,2 g (0,79 mmol) of 2,4-diformyl-5-hydroxy-6-methoxyphenoxyootic acid (III, R R = H) is added to 0,06 g (0,73 mmol) of anhydrous sodium acetate and 0, 4 g (3.92 mmol) of acetic anhydride are heated to 170 [deg.] C. with stirring and the 2,4-diformyl-5-aethoxy-6-methoxyphenoxyacetic acid (II, R < 6 > = COCH3) is formed first. react by further heating to 170 ° C for 10 minutes.
Po ochlazení se rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ether a etherickou fázi s roztokem hydrogenuhličitanu sodného a potom se desetkrát extrahuje 2 N hydroxidem sodným, přičemž se vzniklý 5-formyl-6-acetoxy-7-methoxybenzofuran (III, r' = H, íP = COCHp zmýdelní na sloučeninu III (R1 = R^ = H). Spojené fáze, zalkalizované hydroxidem sodným se okyselí kyselinou chlorovodíkovou a extrahují etherem. Etherická fáze se suší síranem sodným a ether se odstraní (III, R1 = R^ = Η): T. t. 68 až 69 °C (petrolether).After cooling, it was partitioned between saturated sodium bicarbonate solution and ether and ethereal sodium bicarbonate solution, and then extracted 10 times with 2 N sodium hydroxide to give 5-formyl-6-acetoxy-7-methoxybenzofuran (III, r '= H, ip = COCHp hydrolyzed to compound III (R 1 = R = H). the combined phase basified with sodium hydroxide, acidified with hydrochloric acid and extracted with ether. the ethereal phase is dried over sodium sulfate and the ether is removed (III, R 1 = R f = Mp 68-69 ° C (petroleum ether).
Příklad 2Example 2
5-Formyl-6-acetoxy-7-methoxybenzofuran (III, r' = H, R^ = COCHj)5-Formyl-6-acetoxy-7-methoxybenzofuran (III, r 1 = H, R 2 = COCH 3)
Ha lilaHa lila
0,2 g (0,79 mmolu) sloučeniny (II, R^ = H) se doplní 0,06 g (0,73 mmoly) bezvodého octanu sodného a 0,4 g (3,92 mmolú) acetanhydridu a zahřívá, přičemž se nejdříve vzniklá 2,4-diformyl-5-acetoxy-6-methoxyfenoxyoctová kyselina (II, R^ = COCH^) nechá dále zreagovat 10minutovým zahříváním na 170 °C za míchání. Po ochlazení se rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ether, etherická fáze se suší a rozpouštědlo se odstraní, přičemž se získá v titulu uvedená sloučenina jako světležlutý olej; hodnota Rf = 0,7.0.2 g (0.79 mmol) of (II, R R = H) are added to 0.06 g (0.73 mmol) of anhydrous sodium acetate and 0.4 g (3.92 mmol) of acetic anhydride and heated while The 2,4-diformyl-5-acetoxy-6-methoxyphenoxyacetic acid (II, R R = COCH ^) initially formed was further reacted by heating to 170 ° C for 10 minutes with stirring. After cooling, it was partitioned between saturated sodium bicarbonate solution and ether, the ether phase was dried and the solvent was removed to give the title compound as a pale yellow oil; Rf = 0.7.
Eluční činidlo (benzen)ether (3:1); stabilní fáze : silikagel (GF Woelm DC, Art. Nr.Eluent (benzene) ether (3: 1); Stable phase: Silica gel (GF Woelm DC, Art. Nr.
556 Fa. Woelm, Esehwege /NSR/).556 Fa. Woelm, Esehwege (Germany).
Příklad 3Example 3
5-Formyl-6-hydroxy-7-methoxybenzofuran (III, r' + R3 = H)5-Formyl-6-hydroxy-7-methoxybenzofuran (III, R '+ R 3 = H)
lila lilelila lile
0,2 g (0,85 mmolu) 5-formyl-6-acetoxy-7-methoxybenzofuranu (III, r' = H, R3 = COCH^) se míchají společně s 5 ml 2 N hydroxidu sodného 1 hodinu při teplotě místnosti. Potom se převrství etherem, ether se vícekrát extrahuje 2 N hydroxidem sodným a spojené vodné fáze se okyselí kyselinou chlorovodíkovou a znovu se extrahují etherem.0.2 g (0.85 mmol) of 5-formyl-6-acetoxy-7-methoxybenzofuran (III, r '= H, R 3 = COCH 3 ) are stirred with 5 ml of 2 N sodium hydroxide for 1 hour at room temperature. . It is then layered with ether, extracted several times with 2N sodium hydroxide and the combined aqueous phases are acidified with hydrochloric acid and extracted again with ether.
Organická fáze se suší síranem sodným a rozpouštědlo se odstraní, přičemž se získá sloučenina uvedená v titulu; T. t. 68 až 69 °C (petrolether).The organic phase was dried over sodium sulfate and the solvent was removed to give the title compound; Mp 68-69 ° C (petroleum ether).
Příklad 4Example 4
5-Formyl-6-hydroxy-7-methoxybenzofuran-2-karboxylová kyselina (III, r' = COOH, R3 = H)5-Formyl-6-hydroxy-7-methoxybenzofuran-2-carboxylic acid (III, r '= COOH, R 3 = H)
))
0,5 g (1,97 mmolu) 2,4-diformyl-5-hydroxy-6-methoxyfenoxyoctové kyseliny (II, R = H), 0,15 g (1,83 mmolu) bezvodého octanu sodného a 1 g (9,8 mmolů) acetanhydridu se zahřívají za míchání na 150 °C.0.5 g (1.97 mmol) of 2,4-diformyl-5-hydroxy-6-methoxyphenoxyacetic acid (II, R = H), 0.15 g (1.83 mmol) of anhydrous sodium acetate and 1 g (9 (8 mmol) of acetic anhydride are heated to 150 ° C with stirring.
Zprvu vznikající 2,4-diformyl-5-acetoxy-6-methoxyfenoxyoctová kyselina (II, R3 = COCH^) se přitom cyklizuje. Po 10 minutách se nechá vychladnout a rozdělí se mezi ether a nasycený roztok hydrogenuhličitanu sodného.Initially formed 2,4-diformyl-5-acetoxy-6-methoxyphenoxy acid (II, R 3 = COCH ^), while the cyclized. After 10 minutes, allow to cool and partition between ether and saturated sodium bicarbonate solution.
Etherická fáze se extrahuje ještě třikrát nasyceným roztokem hydrogenuhličitanu sodného, přičemž se vznikající 5-formyl-6-acetoxy-7-methoxybenzofuran-2-karboxylové kyselina (III, R1 = COOH, R3 = COCH^) zmýdelní na 5-formyl-6-hydroxybenzofuran-2-karboxylovou kyselinu (III, R1 = COOH, R3 = H).The ether phase is extracted three times with saturated sodium bicarbonate, the resulting 5-formyl-6-acetoxy-7-methoxy-benzofuran-2-carboxylic acid (III, R 1 = COOH, R 3 = COCH ^) saponified to 5-formyl- 6-hydroxybenzofuran-2-carboxylic acid (III, R 1 = COOH, R 3 = H).
Spojené vodné fáze se okyselí kyselinou chlorovodíkovou a vyloučená karboxylová kyselina se odfiltruje. (III, R1 = COOH, R3 = Η): T. t. 275 až 278 °C (dioxan).The combined aqueous phases were acidified with hydrochloric acid and the precipitated carboxylic acid was filtered off. (III, R 1 = COOH, R 3 = Η): mp 275-278 ° C (dioxane).
Příklad 5Example 5
5-Formyl-6-hydroxy-7-methoxybenzofuran (III, R1 = R3 = H) a 5-formyl-6-hydroxy-7-methoxybenzofuran-2-karboxylová kyselina (III, r' = COOH, R3 = H).5-Formyl-6-hydroxy-7-methoxybenzofuran (III, R 1 = R 3 = H) and 5-formyl-6-hydroxy-7-methoxybenzofuran-2-carboxylic acid (III, r '= COOH, R 3 = H).
lid llld Hic θ>5 S (1)97 mmolu) 2,4-diformyl-5-hydroxy-6-methoxyfenox,yoctové kyseliny (II, R3 = H), 0,15 g (1,83 nunolu) bezvodého octanu sodného a 1 g (9,8 mmolů) acetanhydridu se zahřívají za míchání lOminutovým zahříváním na 170 °C se primárně vznikající 2,4-diformyl-5-acetoxy-6-methoxyfenoxyoctová kyselina (II, R3 = COOH) dále reaguje.IId (Hic (> 5 S (1) 97 mmol)) 2,4-diformyl-5-hydroxy-6-methoxyphenox, ylacetic acid (II, R 3 = H), 0.15 g (1.83 nunol) of anhydrous acetate sodium and 1 g (9.8 mmol) of acetic anhydride were heated with stirring lOminutovým heating at 170 ° C with the primarily formed of 2,4-diformyl-5-acetoxy-6-methoxyphenoxy acid (II, R 3 = COOH) is reacted further.
Po ochlazení se rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ether. Ve vodné fázi se přitom rozpustí 5-formyl-6-acetoxy-7-methoxybenzofuran~2-karboxylová kyselina (III, r’ = COOH, R3 = COCH^) za zmýdelnění acetoxyskupiny, takže při okyselení kyselinou chlorovodíkovou se získá 5-formyl-6-hydroxy-7-methoxybenzofuran-2-karboxylová kyselina (XII, R’ = COOH, R3 = Η). T. t. 275 až 278 °C (dioxan).After cooling, it was partitioned between saturated sodium bicarbonate solution and ether. In the aqueous phase while dissolved 5-formyl-6-acetoxy-7-methoxy-benzofuran-2-carboxylic acid (III, R = COOH, R 3 = COCH ^) after saponification of the acetoxy group so that upon acidification with hydrochloric acid to give 5-formyl 6-hydroxy-7-methoxybenzofuran-2-carboxylic acid (XII, R 1 = COOH, R 3 = Η). Mp 275-278 ° C (dioxane).
Etherická fáze se desetkrát extrahuje 2 N hydroxidem sodným, přičemž se 5-formyl-6-acetoxy-7-methoxybenzofuran (III, R1 = H, R3 = COCH^) zmýdelní na 5-formyl-6-hydroxy-7-methoxybenzofuran (III, R1 = R3 = H).The ether phase is extracted ten times with 2 N sodium hydroxide solution, with 5-formyl-6-acetoxy-7-methoxy-benzofuran (III, R 1 = H, R 3 = COCH ^) saponified to 5-formyl-6-hydroxy-7-methoxy-benzofuran (III, R 1 = R 3 = H).
Okyselením spojených vodných fází kyselinou chlorovodíkovou a novou extrakcí etherem, sušením a odpařením rozpouštědla se získá sloučenina (III, R' = R3 = Η): T. t. 68 až 69 °C (petrolether).Acidification of the combined aqueous phases with hydrochloric acid and re-extraction with ether, drying and evaporation of the solvent gave compound (III, R '= R 3 = Η): mp 68-69 ° C (petroleum ether).
Příklad 6Example 6
5-Formyl-6-hydroxy-7-methoxybenzofuran (III, R1 = R3 = H)5-Formyl-6-hydroxy-7-methoxy-benzofuran (III, R 1 = R 3 = H)
0,2 g (0,85 nunolu) 5-formyl-6-hydroxy-7-methoxybenzofuran 2-karboxylové kyseliny (III, r’ = COOH, R3 = H) se smísí za horka s 0,02 g jemně práškovaného kysličníku měánatého a 10 minut se zahřívá na 280 až 290 °C.0.2 g (0.85 nunol) of 5-formyl-6-hydroxy-7-methoxybenzofuran of 2-carboxylic acid (III, r '= COOH, R 3 = H) is mixed hot with 0.02 g of finely pulverized oxide The mixture was heated to 280-290 ° C for 10 minutes.
Po ochlazení se rozdělí mezi ether a nasycený roztok hydrogenuhličitanu sodného, kyslič nik měánatý se odfiltruje a organická fáze se suší a odpaří; T. t. 68 až 69 °C (petrolether)After cooling, it was partitioned between ether and saturated sodium bicarbonate solution, the copper (I) oxide was filtered off and the organic phase was dried and evaporated; Mp 68-69 ° C (petroleum ether)
Příklad 7Example 7
9-Methoxy-7-oxo-7H-furo(3,2-g)(1)benzopyran-2-karboxylová kyselina (I, R1 = COOH, R^ = H)9-methoxy-7-oxo-7H-furo (3,2-g) (1) benzopyran-2-carboxylic acid (I, R 1 = COOH, R = H)
llldllld
Ib[0057] Ib
0,2 g (0,85 mmolu) 5-formyl-6-hydroxy-7-methoxýbenzofuran-2-karboxylové kyseliny (III, r' = COOH, - H) se zahřívá s 0,064 g (0,78 «moly) bezvodého octěnu sodného a 0,8 g (7,84 mmoly) acetanhydridu za míchání 12 hodin pod zpětným chladičem. Po ochlazení se rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ethylacetétu, vodná fáze se okyselí kyselinou chlorovodíkovou a znovu se extrahuje eťhylacetétem.0.2 g (0.85 mmol) of 5-formyl-6-hydroxy-7-methoxybenzofuran-2-carboxylic acid (III, r '= COOH, - H) was heated with 0.064 g (0.78 mol) of anhydrous sodium acetate and 0.8 g (7.84 mmol) of acetic anhydride with stirring for 12 hours under reflux. After cooling, it was partitioned between saturated sodium bicarbonate solution and ethyl acetate, the aqueous phase was acidified with hydrochloric acid and extracted again with ethyl acetate.
Organická fáze se suší síranem sodným a odpaří, a zbytek (0,22 g) se podrobí sloupcové chromatografii) 20 g silikagelu (60 Merck, velikost zrna 0,063 až 0,2 mm), eluens:benzen (di— oxan) ledové kyselina octová:90:25:4; T. t. 255 až 260 °C (rozkl.).The organic phase was dried over sodium sulfate and evaporated, and the residue (0.22 g) was subjected to column chromatography) 20 g of silica gel (60 Merck, grain size 0.063-0.2 mm), eluent: benzene (di-oxane) glacial acetic acid : 90: 25: 5; Mp 255-260 ° C (dec.).
Příklad 8Example 8
0,1 S (0,38 mmolu) 9-methoxy-7-oxo-7H-furo(3,2-g) ( 1) benzpyran-2-karboxylové kyseliny (I, r' = COOH, R2 = H) se rozpustí v 0,5 ml chinolinu, doplní 0,01 g jemně práškovaného kysličníku měčínatého a vaří se 15 minut pod zpětným tokem.0.1 s (0.38 mmol) 9-methoxy-7-oxo-7H-furo (3,2-g) (1) benzopyran-2-carboxylic acid (I, R = COOH, R 2 = H) Dissolve in 0.5 ml of quinoline, make up to 0.01 g of finely powdered cuprous oxide and boil under reflux for 15 minutes.
Po ochlazení se rozdělí mezi 2 N kyselinu chlorovodíkovou a ether, kysličník měánatý se odfiltruje, ether se promyje nasyceným roztokem hydrogenuhličitanu sodného, suší síranem sodným a odpaří. T. t. 145 až 146 °C (benzen-petrolether).After cooling, it was partitioned between 2N hydrochloric acid and ether, the cuprous oxide was filtered off, the ether was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. Mp 145-146 ° C (benzene-petroleum ether).
Příklad9Example9
9-Methoxy-7H-furo(3,2-g)(1)benzpyran-7-on (i, R1 1 R2 = H)9-Methoxy-7H-furo (3,2-g) (1) benzpyran-7-one (1, R 1 R 2 = H)
0,15 g (0,78 mmolu) 5-formyl-6-hydroxy-7-methoxybenzofuranu (III, r' = R^ = H), 0,064 g (0,78 mmolu) bezvodého octanu sodného a 0,4 g (3,92 maolů) acetanhydridu se zahřívá 7 hodin za míchání na 170 °C. Po ochlazení se rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ether, etherická fáze se promyje studeným 1 N hydroxidem sodným a vodou, suší síranem sodným a odpaří. T. t. 145 až 146 °C (benzen-petrolether).0.15 g (0.78 mmol) of 5-formyl-6-hydroxy-7-methoxybenzofuran (III, r '= R = = H), 0.064 g (0.78 mmol) of anhydrous sodium acetate and 0.4 g ( 3.92 Maol) acetic anhydride was heated to 170 ° C with stirring for 7 hours. After cooling, it was partitioned between saturated sodium bicarbonate solution and ether, the ether phase was washed with cold 1 N sodium hydroxide and water, dried over sodium sulfate and evaporated. Mp 145-146 ° C (benzene-petroleum ether).
Příklad 10Example 10
lilalila
0,2 g (0,85 mmolu) 5-formyl-6-acetoxy-7-methoxybenzofuranu (III, r' = H, R^ = COCHj), 0,07 g (0,85 mmolu) bezvodého oetanu sodného a 0,43 g (4,25 mmolů) acetanhydridu se zahřívá 7 hodin za míchání na 170 °C.0.2 g (0.85 mmol) of 5-formyl-6-acetoxy-7-methoxybenzofuran (III, r '= H, R ^ = COCH 3), 0.07 g (0.85 mmol) of anhydrous sodium oetane and 0 43 g (4.25 mmol) of acetic anhydride were heated to 170 ° C with stirring for 7 hours.
Po ochlazení se rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ether, etherická fáze se promyje studeným 1 N hydroxidem sodným a vodou, suěí síranem sodným a odpaří. T. t. 145 až 146 °C (petrolether).After cooling, it was partitioned between saturated sodium bicarbonate solution and ether, the ether phase was washed with cold 1 N sodium hydroxide and water, dried over sodium sulfate and evaporated. Mp 145-146 ° C (petroleum ether).
Příklad 11Example 11
9-Methoxy-7H-furo(3,2-g)(1)benzopyran-7-on (I, r' = R2 = H)9-Methoxy-7H-furo (3,2-g) (1) benzopyran-7-one (1, R 1 = R 2 = H)
och3 och 3
lile Ic lalile Ic la
0,2 g (1,04 mmolu) 5-formyl-6-hydroxy-7-methoxybenzofuranu (III, R1 = R^ = H), 0,12 g (1,15 mmolu) kyseliny malonové a 0,0056 ml 2,4-lutidinu se zahřívá za míchání 12 hodin na 80 °C. Při tom vznikající 9-methoxy-7-oxo-7H-furo(3,2-g)(1)benzopyran-6-karboxylové kyseliny (I, R1 - H, R2 = COOH) (Hodnota R^ = 0,2, eluční činidlo benzen) dioxan/ledová kyselina octová 90:25:4, stabilní fáze:silikagel (GF Woelm DC, druh č. 4 556, Fa Woelm, Eschwege /NSR/) se rozpustí v 1 ml chinolinu, doplní 0,2 g měděné bronz! a vaří 15 minut pod zpětným tokem.0.2 g (1.04 mmol) of 5-formyl-6-hydroxy-7-methoxy-benzofuran (III, R 1 = R = H) 0.12 g (1.15 mmol) of malonic acid and 0.0056 ml The 2,4-lutidine was heated to 80 ° C with stirring for 12 hours. Removing the resulting 9-methoxy-7-oxo-7H-furo (3,2-g) (1) benzopyran-6-carboxylic acid (I, R 1 - H, R 2 = COOH) (Rf value = 0, 2, eluent benzene) dioxane / glacial acetic acid 90: 25: 4, stable phase: silica gel (GF Woelm DC, type # 4,556, Fa Woelm, Eschwege (NSR)) is dissolved in 1 ml quinoline, added to 0, 2 g copper bronze! and boil for 15 minutes under reflux.
Potom se zfiltruje a rozdělí mezi 2 N kyselinu chlorovodíkovou a ether, etherická fáze se promyje nasyceným roztokem hydrogenuhličitanu sodného, suší síranem sodným a odpaří. T. t. 145 až 146 °C (benzen-petrolether).It is then filtered and partitioned between 2N hydrochloric acid and ether, the ether phase is washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated. Mp 145-146 ° C (benzene-petroleum ether).
Příklad 12Example 12
9-Methoxy-7H-furo(3,2-g)(1 )benzopyran-7-on (I, R^ = R2 = H)9-Methoxy-7H-furo (3,2-g) (1) benzopyran-7-one (1, R 2 = R 2 = H)
OHC CHOOHC CHO
OCHjCOOH OCHiOCHjCOOH OCHi
<T O<T O
OCHqOCHq
HOHIM
Ha laHa la
0,2 g (0,79 mmolu) 2,4-diformyl-5-hydroxy-6-methoxyfenoxyoctové kyseliny (II, R^ = H) se doplní 0,32 g (3,16 mmoly) acetanhydridu a 0,07 g (0,85 mmolu) bezvodého oetanu sodného a 5 hodin míchá při 170 °C. Po ochlazení se reakčni směs rozdělí mezi nasycený roztok hydrogenuhličitanu sodného a ether, etherická fáze se vícekrát promyje 1 N hydroxidem sodným a vodou, suší síranem sodným a odpaří. T. t. 145 až 146 °C (benzen-petrolether).2,4 g (0,79 mmol) of 2,4-diformyl-5-hydroxy-6-methoxyphenoxyacetic acid (II, R R = H) are added to 0,32 g (3,16 mmol) of acetic anhydride and 0,07 g (0.85 mmol) of anhydrous sodium oetane and stirred at 170 ° C for 5 hours. After cooling, the reaction mixture was partitioned between saturated sodium bicarbonate solution and ether, the ether phase was washed several times with 1 N sodium hydroxide and water, dried over sodium sulfate and evaporated. Mp 145-146 ° C (benzene-petroleum ether).
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| Publication Number | Publication Date |
|---|---|
| CS201009B2 true CS201009B2 (en) | 1980-10-31 |
Family
ID=3572227
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS443978A CS201009B2 (en) | 1977-07-15 | 1978-07-04 | Bilek,walter,at |
Country Status (8)
| Country | Link |
|---|---|
| AT (1) | AT362369B (en) |
| CS (1) | CS201009B2 (en) |
| DD (1) | DD137587A5 (en) |
| HU (1) | HU175083B (en) |
| NL (1) | NL7807394A (en) |
| PL (1) | PL208406A1 (en) |
| SU (1) | SU876058A3 (en) |
| YU (1) | YU156378A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7279597B1 (en) | 1999-11-05 | 2007-10-09 | Emisphere Technologies, Inc. | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
| US7129274B1 (en) | 1999-11-05 | 2006-10-31 | Emisphere Technologies Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
| RU2282633C9 (en) * | 2005-04-04 | 2007-01-20 | Государственное образовательное учреждение высшего профессионального образования "Кубанский государственный технологический университет" (ГОУВПО "КубГТУ") | Method for preparing 1,11-dialkyl-3,5-dihydrofuro-[2',3':3,4]-cyclohepta[c]isochromens |
-
1977
- 1977-07-15 AT AT512877A patent/AT362369B/en not_active IP Right Cessation
-
1978
- 1978-06-30 YU YU156378A patent/YU156378A/en unknown
- 1978-07-04 CS CS443978A patent/CS201009B2/en unknown
- 1978-07-07 NL NL7807394A patent/NL7807394A/en not_active Application Discontinuation
- 1978-07-10 HU HU78GE1036A patent/HU175083B/en unknown
- 1978-07-14 DD DD20672878A patent/DD137587A5/en unknown
- 1978-07-14 SU SU782636897A patent/SU876058A3/en active
- 1978-07-14 PL PL20840678A patent/PL208406A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| YU156378A (en) | 1982-10-31 |
| ATA512877A (en) | 1980-10-15 |
| HU175083B (en) | 1980-05-28 |
| AT362369B (en) | 1981-05-11 |
| DD137587A5 (en) | 1979-09-12 |
| SU876058A3 (en) | 1981-10-23 |
| PL208406A1 (en) | 1979-06-04 |
| NL7807394A (en) | 1979-01-17 |
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