CS216979B1 - Dihydroxypropyl all-trans -9/4-methoxy-2,3,6-trimethyl-phenyl/-3,7-dimethyl-2,4,6,8-nonatetraenoat and method of preparation thereof - Google Patents
Dihydroxypropyl all-trans -9/4-methoxy-2,3,6-trimethyl-phenyl/-3,7-dimethyl-2,4,6,8-nonatetraenoat and method of preparation thereof Download PDFInfo
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- CS216979B1 CS216979B1 CS32680A CS32680A CS216979B1 CS 216979 B1 CS216979 B1 CS 216979B1 CS 32680 A CS32680 A CS 32680A CS 32680 A CS32680 A CS 32680A CS 216979 B1 CS216979 B1 CS 216979B1
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- Czechoslovakia
- Prior art keywords
- trans
- methoxy
- dimethyl
- dihydroxypropyl
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- -1 Dihydroxypropyl Chemical group 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- IUEMQUIQAPPJDL-UHFFFAOYSA-M sodium;2,3-dihydroxypropanoate Chemical compound [Na+].OCC(O)C([O-])=O IUEMQUIQAPPJDL-UHFFFAOYSA-M 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims 1
- 101150065749 Churc1 gene Proteins 0.000 claims 1
- 102100038239 Protein Churchill Human genes 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- 206010020648 Hyperkeratoses Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000005775 Parakeratosis Diseases 0.000 description 1
- 206010037575 Pustular psoriasis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 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
- 210000003608 fece Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Vynález se týká 2,3-dihydroxypropyl all-trans-9-(4-metoxy-2,3,6-trimetylfenyl)-3,7-dime tyl-2,4,6,8-nonate traenoátu.The invention relates to 2,3-dihydroxypropyl all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonate traenoate.
Etylester all-trans-9-(4-metoxy-2,3,6-trimetylfenyl)-3,7-dimetyl-2,4,6,8-nonatetraenové kyseliny je účinnou látkou, používanou při perorální terapii řady kožních chorob, doprovázených nadměrnou keratinizací, jako je erythródermické a pustulózní psoriasis a různé dys-, para- a hyperkeratózy (Experientia, 34, 1 105, 1978). Ukazuje se, že látky tohoto typu mohou být využity k prevenci transformace normálních buněk na buňky rakovinné (tamtéž).All-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester is an active ingredient used in the oral therapy of a number of skin diseases accompanied by excessive keratinization, such as erythroderma and pustular psoriasis and various dys-, para- and hyperkeratoses (Experientia, 34, 1 105, 1978). It appears that substances of this type can be used to prevent the transformation of normal cells into cancer cells (ibid.).
Nízká resorbovatelnost uvedeného etylesteru vede k tomu, že se převážná část léčiva vylučuje in feces.The low resorbability of said ethyl ester results in the bulk of the drug being excreted in feces.
Tuto nevýhodu odstraňuje nový derivát, a to 2,3-dihydroxypropylester all-trans-9-(4-metoxy-2,3,6-trimetylfenyl)-3,7-dimetyl-2,4,6,8-nonatetraenové kyseliny vzorce IThis disadvantage is overcome by a new derivative, 2,3-dihydroxypropyl all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, of the formula AND
(I) který je předmětem vynálezu. Tato sloučenina obsahuje dvě volné OH-skupiny, čímž se zvyšuje rozpustnost a resorbovatelnost. Další výhodou je chemická příbuznost s přirozenými monoglyceridy, což ji činí blízkou živým organismům.(I) which is the subject of the invention. This compound contains two free OH groups, thereby increasing solubility and resorbability. Another advantage is chemical kinship with natural monoglycerides, which makes it close to living organisms.
Předmětem vynálezu je dále způsob přípravy této látky, tj. 2,3-dihydroxypropyl all-trans-9-(4-metoxy-2,3,6-trimetylfenyl)-3,7-dimetyl-2,4,6,a-nonatetraenoátu vzorce I, jehož podstatou je, že se na 1 mol chloridu kyseliny all-trans-9-(4-metoxy-2,3,6-trimetylfenyl)-3,7-dimetyl-2>416,8-nonatetraenové vzorce IIThe present invention further provides a process for the preparation of 2,3-dihydroxypropyl all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6, α- nonatetraenoátu formula I which is characterized in that 1 mol of the acid chloride of all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2> 4 1 6,8-nonatetraenoic of formula II
(II) působí 10 až 50 moly glycerolu v přítomnosti 1 až 1,1 molu glycerétu sodného nebo 10 až 20 molů pyridinu, a to za teploty 0 až 30 °C po dobu 50 až 70 minut.(II) treats 10 to 50 moles of glycerol in the presence of 1 to 1.1 moles of sodium glycerate or 10 to 20 moles of pyridine at a temperature of 0 to 30 ° C for 50 to 70 minutes.
Způsob přípravy podle vynálezu je novým jednostupňovým přístupem k přípravě 1-acylglycerolů, které se podle dosavadní techniky připravují třístupňovým postupem podle schématu: glycerol -► 2,3-isopropylidenglycerol -» 1-acyl-2,3-isopropylidenglycerol -► 1-acylglycerol. (Advances in Lipid Research, 14, 213, 1976.) Jednostupňový postup podle vynálezu je ekonomicky výhodnější.The process according to the invention is a novel one-step approach to the preparation of 1-acylglycerols, which according to the prior art are prepared by a three-step process according to the scheme: glycerol-2,3-isopropylidene glycerol-1-acyl-2,3-isopropylidene glycerol-1-acylglycerol. (Advances in Lipid Research, 14, 213, 1976.) The one-step process of the invention is more economical.
Příprava se provádí přidáním roztoku chloridu kyseliny vzorce II v inertním rozpouštědle (dioxan, tetrahydrofuran) ke směsi glycerolu a zásady. Jako zásady se použije glycerátu' sodného nebo terciárního aminu, např. pyridinu. Molární poměr chloridu vzorce II ku glycerolu je 1:10 až 50. Molární poměr chloridu vzorce II ku glycerátu sodnému je 1:1 až 1,1, ivlolární poměr chloridu vzorce II ku terciárnímu aminu je 1:1 až 100. Reakce se provádí za teplot 0 až 30 °C, s výhodou za teploty místnosti, kdy je reakce ukončena přibližně po 20 hodinách. Produkt se izoluje po zředění reakční směsi vodou extrakcí do chloroformu a zbaví vedlejších produktů chromatografií na sloupci silikagelu. Způsob přípravy podle vynálezu je ilustrován následujícími příklady provedení.The preparation is carried out by adding a solution of the acid chloride of formula II in an inert solvent (dioxane, tetrahydrofuran) to a mixture of glycerol and a base. The base used is sodium glycerate or a tertiary amine such as pyridine. The molar ratio of the chloride of formula II to glycerol is 1:10 to 50. The molar ratio of the chloride of formula II to sodium glycerate is 1: 1 to 1.1, the ivolar ratio of the chloride of formula II to the tertiary amine is 1: 1 to 100. 0 to 30 ° C, preferably at room temperature, when the reaction is complete after about 20 hours. The product is isolated after dilution of the reaction mixture with water by extraction into chloroform and freed from by-products by silica gel column chromatography. The process according to the invention is illustrated by the following examples.
Příklad 1Example 1
K roztoku 0,7 g glycerátu sodného v 15 g glycerolu se při 20 °C za míchání přidá roztok 2,06 g chloridu kyseliny vzorce II v 15 ml dioxanu a směs se míchá 20 hodin. Směs se zředí 30 ml vody a 10 ml etanolu a extrahuje se nejprve 30 ml a potom 10 ml chloroformu. Chloroformové extrakty se vysuší 2 g bezvodého síranu hořečnatého a odpaří. Zbytek se rozpustí v 5 ml chloroformu a nanese na 3,5 x 7 cm na silikagelovou kolonku. Kolonka se promyje 150 ml chloroformu, který eluuje vedlejší produkty. Hlavní produkt se potom vymyje 300 ml chloroformu a získá se odpařením eluátu. Získá se 1,6 g (67 %) látky vzorce I ve formě oleje, který zvolna krystalicky tuhne.To a solution of 0.7 g of sodium glycerate in 15 g of glycerol at 20 ° C is added, with stirring, a solution of 2.06 g of the acid chloride of formula II in 15 ml of dioxane, and the mixture is stirred for 20 hours. The mixture is diluted with 30 ml of water and 10 ml of ethanol and extracted first with 30 ml and then with 10 ml of chloroform. The chloroform extracts were dried (2 g anhydrous magnesium sulfate) and evaporated. Dissolve the residue in 5 ml of chloroform and apply to 3.5 x 7 cm onto a silica gel column. The column is washed with 150 ml of chloroform, which elutes the by-products. The main product is then washed with 300 ml of chloroform and recovered by evaporation of the eluate. 1.6 g (67%) of (I) are obtained in the form of an oil which crystallizes slowly.
Teplota tání 48 až 49 °C, Rf = 0,47 (Silufol UV 254, Chloroform-metanol 9:1).Mp 48-49 ° C, R f = 0.47 (Silufol UV 254, Chloroform-methanol 9: 1).
P ř í k 1 a ά 2Example 1 and 2
Ke směsi 15 g glycerolu a 6 g pyridinu se při 0 °C za míchání přidá roztok 2,06 g chloridu kyseliny vzorce II v 10 ml dioxanu. V míchání se pokračuje při 20 °C 20 hodin. Reakční směs se zpracuje a produkt se izoluje stejně jako v příkladu 1. Výtěžek 1,55 g (65 %) látky vzorce I.To a mixture of 15 g of glycerol and 6 g of pyridine is added at 0 ° C with stirring a solution of 2.06 g of the acid chloride of formula II in 10 ml of dioxane. Stirring was continued at 20 ° C for 20 hours. The reaction mixture was worked up and the product isolated as in Example 1. Yield 1.55 g (65%) of the compound of formula I.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS32680A CS216979B1 (en) | 1980-01-16 | 1980-01-16 | Dihydroxypropyl all-trans -9/4-methoxy-2,3,6-trimethyl-phenyl/-3,7-dimethyl-2,4,6,8-nonatetraenoat and method of preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS32680A CS216979B1 (en) | 1980-01-16 | 1980-01-16 | Dihydroxypropyl all-trans -9/4-methoxy-2,3,6-trimethyl-phenyl/-3,7-dimethyl-2,4,6,8-nonatetraenoat and method of preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS216979B1 true CS216979B1 (en) | 1982-12-31 |
Family
ID=5335172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS32680A CS216979B1 (en) | 1980-01-16 | 1980-01-16 | Dihydroxypropyl all-trans -9/4-methoxy-2,3,6-trimethyl-phenyl/-3,7-dimethyl-2,4,6,8-nonatetraenoat and method of preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS216979B1 (en) |
-
1980
- 1980-01-16 CS CS32680A patent/CS216979B1/en unknown
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