PL236557B1 - 1'-(3,7,11-Trimethyl-3-vinyldodeca-6,10-dienyl)-2'-hydroxy-sn-glycero-3'-phosphocholine and method for obtaining it - Google Patents
1'-(3,7,11-Trimethyl-3-vinyldodeca-6,10-dienyl)-2'-hydroxy-sn-glycero-3'-phosphocholine and method for obtaining it Download PDFInfo
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- PL236557B1 PL236557B1 PL419069A PL41906916A PL236557B1 PL 236557 B1 PL236557 B1 PL 236557B1 PL 419069 A PL419069 A PL 419069A PL 41906916 A PL41906916 A PL 41906916A PL 236557 B1 PL236557 B1 PL 236557B1
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Abstract
Zgłoszenie dotyczy fosfolipidowej pochodnej kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego, o wzorze 1 oraz sposobu jej otrzymywania na drodze reakcji sn-glicero-3-fosfocholiną (GPC) i tlenku dibutylocyny (DBTO), rozpuszczonych w bezwodnym 2-propanolu z chlorku kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego, w obecności trietyloaminy (TEA). Zgłoszenie może znaleźć zastosowanie w przemyśle kosmetycznym i farmaceutycznym.The application concerns the phospholipid derivative of 3,7,11-trimethyl-3-vinyldeca-6,10-dienoic acid of formula 1 and the method of its preparation by the reaction of sn-glycero-3-phosphocholine (GPC) and dibutyltin oxide (DBTO), dissolved in anhydrous 2-propanol from 3,7,11-trimethyl-3-vinyldeca-6,10-dienoic acid chloride, in the presence of triethylamine (TEA). The application may find application in the cosmetics and pharmaceutical industries.
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest 1’-[3,7,11-trimetylo-3-winylododeka-6,10-dienylo]-2’-hydroksy- sn -glicero-3’-fosfocholina, o wzorze 1, przedstawionym na rysunku oraz sposób jej otrzymywania.The present invention relates to 1 '- [3,7,11-trimethyl-3-vinylododeca-6,10-dienyl] -2'-hydroxy-sn-glycero-3'-phosphocholine of the formula 1, as shown in the figure, and the method of its receiving.
Przedmiotem wynalazku jest także sposób otrzymywania 1’-[3,7,11-trimetylo-3-winylododeka-6,10-dienylo]-2’-hydroksy- sn-glicero-3’-fosfocholiny o wzorze 1.The invention also relates to a method for the preparation of 1 '- [3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl] -2' -hydroxy-sn-glycero-3 '-phosphocholine of formula 1.
Wynalazek może znaleźć zastosowanie w przemyśle kosmetycznym, farmaceutycznym oraz jako środek w terapii chorób nowotworowych.The invention may find application in the cosmetics and pharmaceutical industries as well as in the treatment of neoplastic diseases.
Dotychczas znany jest ze zgłoszenia patentowego P.418653 fosfolipid zwierający dwie cząsteczki kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego jednocześnie w pozycji sn -1 i sn-2 fosfatydylocholiny. Z kolei z opisu wynalazku P.418943 znana jest fosfatydylocholina zawierająca cząsteczkę kwasu palmitynowego w pozycji sn-1 i cząsteczkę kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego w pozycji sn-2.So far, a phospholipid containing two 3,7,11-trimethyl-3-vinylododeca-6,10-diene acid molecules simultaneously in the sn -1 and sn-2 positions of phosphatidylcholine is known from the patent application P.418653. In turn, from the description of the invention P.418943 there is known phosphatidylcholine containing a palmitic acid molecule in the sn-1 position and a 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene acid molecule in the sn-2 position.
Nie jest znana lizofosfatydylocholina zawierająca kwas 3,7,11-trimetylo-3-winylododeka-6,10-dienowego w pozycji sn-1.There is no known lysophosphatidylcholine containing 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene acid in the sn-1 position.
Istotą wynalazku jest 1’-[3,7,11-trimetylo-3-winylododeka-6,10-dienylo]-2’-hydroksy- sn-glicero-3’-fosfocholina przedstawiona na rysunku oraz sposób jej otrzymywania.The essence of the invention is the 1 '- [3,7,11-trimethyl-3-vinylododeca-6,10-dienyl] -2'-hydroxy-sn-glycero-3'-phosphocholine shown in the figure and the method of its preparation.
Istotą sposobu otrzymywania lizofosfatydylocholiny z cząsteczką kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego jest to, że mieszaninę sn-glicero-3-fosfocholiny (GPC) i tlenku dibutylocyny (DBTO) rozpuszczonych w bezwodnym 2-propanolu poddaje się reakcji z chlorkiem kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego, również rozpuszczonym w propan-2-olu, w obecności trietyloaminy (TEA). Całość miesza się przez co najmniej 1 godzinę w temperaturze wrzenia rozpuszczalnika, a następnie wydziela powstały produkt i oczyszcza go za pomocą chromatografii kolumnowej.The essence of the method of obtaining lysophosphatidylcholine with a molecule of 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene is that a mixture of sn-glycero-3-phosphocholine (GPC) and dibutyl tin oxide (DBTO) dissolved in anhydrous 2- propanol is reacted with 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene chloride, also dissolved in propan-2-ol, in the presence of triethylamine (TEA). The mixture is stirred for at least 1 hour at the reflux temperature of the solvent, and then the resulting product is isolated and purified by column chromatography.
Sposób, według wynalazku, objaśniony jest bliżej na przykładzie wykonania.The method according to the invention is explained in more detail using an exemplary embodiment.
Przykład 1Example 1
Do kolby okrągłodennej zawierającej 8 cm3 2-propanol dodaje się 300 mg (1,16 mmol) osuszonej sn-glicero-3-fosfocholiny (GPC) oraz 290 mg (1,17 mmol) tlenku dibutylocyny (DBTO) i całość ogrzewa się w temperaturze wrzenia rozpuszczalnika przez 1 godzinę. Po tym czasie mieszaninę reakcyjną ochładza się i dodaje 242 mg (2,4 mmol) trietyloaminy (TEA) oraz 678 mg (2,4 mmol) chlorku kwasu 3,7,11-trimetylo-3-winylododeka-6,10-dienowego rozpuszczonego w 4 cm3 bezwodnego 2-propanolu. Zawiesinę miesza się intensywnie w temperaturze pokojowej w atmosferze N2 przez 1 godzinę. Po tym czasie mieszaninę poreakcyjną odsącza się pod zmniejszonym ciśnieniem na lejku Schotta przez warstwę celitu, a następnie odparowuje się rozpuszczalnik pod zmniejszonym ciśnieniem. Surowy produkt oczyszcza się za pomocą chromatografii kolumnowej na żelu krzemionkowym stosując jako eluent mieszaninę rozpuszczalników CHCh : MeOH : H2O, 65 : 25 : 4 (v/v/v). Otrzymuje się 305 mg (0,61 mmol) 1’-[3,7,11-trimetylo-3-winylododeka-6,10-dienylo]-2’-hydroksy- sn-glicero-3’-fosfocholiny z wydajnością 52% w postaci mazistej substancji o czystości >97% (wg HPLC).To a round bottom flask containing 8 cm 3 of 2-propanol was added 300 mg (1.16 mmol) of dried sn-glycero-3-phosphocholine (GPC) and 290 mg (1.17 mmol) of dibutyltin oxide (DBTO) and the mixture heated at the boiling point of the solvent for 1 hour. After this time, the reaction mixture is cooled and 242 mg (2.4 mmol) of triethylamine (TEA) and 678 mg (2.4 mmol) of dissolved 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene chloride are added. in 4 cm 3 of anhydrous 2-propanol. The suspension is vigorously stirred at room temperature under N2 atmosphere for 1 hour. After this time, the reaction mixture was filtered under reduced pressure on a Schott funnel through a celite pad, and then the solvent was evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel using a solvent mixture of CHC3: MeOH: H2O 65: 25: 4 (v / v / v) as the eluent. 305 mg (0.61 mmol) of 1 '- [3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl] -2'-hydroxy-sn-glycero-3'-phosphocholine are obtained with a yield of 52% as a greasy substance, purity> 97% (by HPLC).
Dane spektroskopowe otrzymanego związku są następujące:The spectroscopic data of the obtained compound are as follows:
1H NMR (600 MHz, ODOI3/OD3OD 2 : 1 (v/v)), δ: 0.91 (s, 6H, CH3-15 (A), CH3-15 (B)), 1.18-1.21 (m, 4H, CH2-4 (A), CH2-4 (B)), 1.35, 1.44 (dwa s, 12H, CH3-12 (A), CH3-12 (B), CH3-17 (A), CH3-17 (B)), 1.36 (s, 3H, CH3-16 (A), CH3-16 (B)), 1.67-1.71 (m, 4H, CH2-5 (A), CH2-5 (B)), 1.72-1.74 (m, 2H, CH2-8 (A), CH2-8 (B)), 1.80-1.84 (m, 2H, CH2-9 (A), CH2-9 (B)), 2.12-2.18 (dwa d, J = 14,4 Hz, 4H, układ AB, CH2-2 (A), CH2-2 (B)), 2.98 (s, 18H, -N(CH3)3 (A), -N(CH3)3 (B)), 3.38 (m, 4H, CH2-3 (A), ΟΚ2-β), 3.61-3.66 (m, 2H, jeden z CH2-3’ (A), jeden z CH2-3’ (B)), 3.70-3.75 (dwa m, 4H, jeden z CH2-3’ (A), jeden z CH2-3’ (B), H-2’ (A), H-2’ (B)), 3.84-3.90 (dwa m, 4H, OH2-1’ (A), CH2-1’ (B)), 4.01-4.06 (szeroki m, 4H, OH2-a (A), OH2-a (B)), 4.74 (d, J = 17.4 Hz, 2H, szeroki OH2-14 (A), jeden z OH2-14 (B)), 4.80 (d, J = 10.8 Hz, 2H, jeden z OH2-10 (A), jeden z OH2-10 (B)), 4.84-4.86 (m, 4H, H-6 (A), H-6 (B), H-10 (A), H-10 (B)), 5.59 (dd, J = 17,4, 10.8 Hz, 2H, H-13 (A), H-13 (B));1H NMR (600 MHz, ODOI3 / OD3OD 2: 1 (v / v)), δ: 0.91 (s, 6H, CH3-15 (A), CH3-15 (B)), 1.18-1.21 (m, 4H, CH2-4 (A), CH2-4 (B)), 1.35, 1.44 (two s, 12H, CH3-12 (A), CH3-12 (B), CH3-17 (A), CH3-17 (B )), 1.36 (s, 3H, CH3-16 (A), CH3-16 (B)), 1.67-1.71 (m, 4H, CH2-5 (A), CH2-5 (B)), 1.72-1.74 (m, 2H, CH2-8 (A), CH2-8 (B)), 1.80-1.84 (m, 2H, CH2-9 (A), CH2-9 (B)), 2.12-2.18 (two d, J = 14.4 Hz, 4H, AB system, CH2-2 (A), CH2-2 (B)), 2.98 (s, 18H, -N (CH3) 3 (A), -N (CH3) 3 ( B)), 3.38 (m, 4H, CH2-3 (A), ΟΚ2-β), 3.61-3.66 (m, 2H, one from CH2-3 '(A), one from CH2-3' (B)) , 3.70-3.75 (two m, 4H, one with CH2-3 '(A), one with CH2-3' (B), H-2 '(A), H-2' (B)), 3.84-3.90 (two m, 4H, OH2-1 '(A), CH2-1' (B)), 4.01-4.06 (broad m, 4H, OH2-a (A), OH2-a (B)), 4.74 (d , J = 17.4 Hz, 2H, broad OH2-14 (A), one of OH2-14 (B)), 4.80 (d, J = 10.8 Hz, 2H, one of OH2-10 (A), one of OH2- 10 (B)), 4.84-4.86 (m, 4H, H-6 (A), H-6 (B), H-10 (A), H-10 (B)), 5.59 (dd, J = 17 , 4, 10.8 Hz, 2H, H-13 (A), H-13 (B));
13C MMR (151 MHz, ODOI3/OD3OD 2 : 1 (v/v)) δ: 15.22, 24.97 (O-12 (A), O-12 (B), O-17 (A), O-17 (B)), 16.95 (O-16 (A), O-16 (B)), 22.25 (O-5 (A), O-5 (B)), 22.27 (O-15 (A), O-15 (B)), 26.21 (O-9 (A), O-9 (B)), 38.77 (O-3 (A), O-3 (B)), 39.22 (O-8), 40.43, 40.46 (O-4 (A), O-4 (B)), 44.49, 44.52 (O-2 (A), O-2 (B)), 53.60 (t, J = 3.8 Hz, -N(CH3)3 (A), -N(CH3)3 (B)), 58.61,58.65 (d, J = 4.8 Hz, O-α (A), O-a (B)), 64.31, 64.32 (O-1’ (A), O-1’ (B)), 66.00 (m, O-β (A), O-β (B)), 66.51 (d, J = 5.4 Hz, O-3’ (A), C-3’ (B)), 68.28 (d, J = 6.5 Hz, O-2’ (A), C-2’ (B)), 111.75 (O-14 (A), O-14 (B)), 123.78 (O-10 (A), O-10 (B)), 13 C MMR (151 MHz, ODOI3 / OD3OD 2: 1 (v / v)) δ: 15.22, 24.97 (O-12 (A), O-12 (B), O-17 (A), O-17 ( B)), 16.95 (O-16 (A), O-16 (B)), 22.25 (O-5 (A), O-5 (B)), 22.27 (O-15 (A), O-15 (B)), 26.21 (O-9 (A), O-9 (B)), 38.77 (O-3 (A), O-3 (B)), 39.22 (O-8), 40.43, 40.46 ( O-4 (A), O-4 (B)), 44.49, 44.52 (O-2 (A), O-2 (B)), 53.60 (t, J = 3.8 Hz, -N (CH3) 3 ( A), -N (CH3) 3 (B)), 58.61.58.65 (d, J = 4.8 Hz, O-α (A), Oa (B)), 64.31, 64.32 (O-1 '(A), O-1 '(B)), 66.00 (m, O-β (A), O-β (B)), 66.51 (d, J = 5.4 Hz, O-3' (A), C-3 '( B)), 68.28 (d, J = 6.5 Hz, O-2 '(A), C-2' (B)), 111.75 (O-14 (A), O-14 (B)), 123.78 (O -10 (A), O-10 (B)),
PL 236 557 Β1PL 236 557 Β1
123.84 (C-6 (A), C-6 (B)), 130.80 (C-11 (A), C-11 (B)), 134.61 (C-7 (A), C-7 (B)), 144.87 (C-13 (A), C-13 (B)), 171.75 (C-1 (A), C-1 (B));123.84 (C-6 (A), C-6 (B)), 130.80 (C-11 (A), C-11 (B)), 134.61 (C-7 (A), C-7 (B)) , 144.87 (C-13 (A), C-13 (B)), 171.75 (C-1 (A), C-1 (B));
31P NMR (243 MHz, CDCI3/CD3OD 2 : 1 (ν/ν)) δ: 0.00; 31 P NMR (243 MHz, CDCl3 / CD3OD 2: 1 (ν / ν)) δ: 0.00;
(α, β) - oznacza sygnały pochodzące od choliny(α, β) - indicates choline-derived signals
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