Method of producing triphenylmethyl derivatives of sn-glycero-3-phosphocholine and sn-glycero-3 phos

专利摘要:
The invention relates to organo-organic compounds, in particular to the preparation of triphenylmetallic compounds. derivatives of Sn-glycero-3-phosphocholine and Sn-glycero-3-phosphoethanolamine of the formula HjC-0-T nos 0HjC-OpO-CHjCH NF, where l is not substituted or one- or. multiple-substituted With C-alkyl, C, - Cg-alkoxy or halogen of a triphenylmethyl group, R, - R2,; Rj-triphenylmethyl, unsubstituted or substituted by 4-alkoxy- (), 2-chloro, which are used in the synthesis of biologically active substances. The goal is to develop a simpler way to obtain the target compounds. Preparation of yarn vedUT from Sn-glycero-3-phosphocholine or correspondingly tsi S p-glycero-3-phospho (C-triphenylmethyl) -tanololine as a base or cadmium or zinc complex and a reactive triphenylmethyl derivative of the formula T- X, where T is indicated above, X is C1, Br, I, in an inert organic solvent at 20-135 s in the presence of protons of a tertiary amine or a heterocyclic base as an acceptor. i and y to cd with
公开号:SU1422999A3
申请号:SU853898601
申请日:1985-05-14
公开日:1988-09-07
发明作者:Пальтауф Фридрих；Херметтер Альбин
申请人:Хеми Линц Аг (Фирма)；
IPC主号:

专利说明:


SP
The invention relates to a method for producing triphenylmethyl derivatives of Sn-glycero-3-phosphocholine and Sn - glycero-3-phosphoethanolamine - new compounds that can be used as medical intermediates for the synthesis of biologically active mixed glycero-phosphocholines and glycerophosphoethanolamines. chemistry
The purpose of the invention is to obtain new triphenylmethyl derivatives of Sn-glycero-3-phosphocholine and Sn-glycero-3-phosphoethanolamine, the use of co-as-intermediate products in the synthesis of biologically active mixed glycerophosphocholines and lycerophosphoethanolamines allows to simplify the process of obtaining last.
 Sn-glycero-3-phosphocholic. N or 5n-glycero-3-phospho- (H-triphenylmethyl) -thanololine is used as starting materials in the described synthesis. Sn-glycero-3-phosphocholine can be obtained by alkaline hydrolysis of natural lecithin.
5p-glycero-3-phospho- (K-tripheny 1) - ethanolamines can be easily obtained by N-tritylation of 5p-g Lycero-3-phospho-ethanolamine. Particularly preferable and simple by preparation of Sn-glycero-3-phospho- (K Methyl-Methanolamine triphenyl is a trityl phosphation of phosphatidyl ethanol amine in a mixture of the phospholipids of vegetable, animal microbial origin of a reactive, halogenated trifeshvdmetil, preferably trifenilmetilbromid.
From this mixture, 8n-glycero-3-phospho- (L-triphenylethyl) -ethanolamine can be isolated by extraction with a solvent that is not miscible with water, preferably chloroform in the presence of methanol, water-soluble cleavage products and then can be obtained in its pure form by washing fatty acids from an alkaline aqueous phase, if appropriate adding methanol.
Get 5N-glycero-3-phospho- (H-gripenilmetsh1) -ethanolamine as follows
1.5 g of soybean phospholipids and 1.4 g of trinfentemethyl bromide are dissolved in 50 MJI of chloroform. After adding 1.1 g of triethylamine, the reaction mixture
0
stirred for 12 h at 20 ° C. After that, 30 ml of chloroform and 100 ml of a 0.5N solution of sodium hydroxide in methanol are added and stirring is continued for 30 minutes at 20 seconds. Then 100 MP of chloroform is added, the organic phase is separated and washed three times with alkaline aqueous phase, then
The IQ organic solvent is distilled off in vacuo. The residue, which contains 8n-glycero-3-phospho- (. K-triphenylmethyl) ethanolamine, can be used directly in the subsequent 0-tritylation by JII. The pure compound, which is obtained by chromatography of the crude product through silica gel with a mixture of chloroform-methanol, is shown on a silica gel thin-layer chromatograph (eluent: chloroform; methanol: 25% Sd: 50: 25: 6). R. {0.3.
EXAMPLE 1. 1-0-Triphenylmethyl-Sn-glycero-triphosphocholine.
5 5 g of Sn-glycero-tripho-choline and CaC complex and 4.6 g of triphenylmethyl chloride are dissolved in 50 ml of anhydrous dimethylformamide at 70 ° C. After addition of 2.3 mp of triethylamine, the mixture is stirred for 30 minutes at 70 ° C in the absence of moisture. After cooling the reaction mixture, 5 g of powdered NaHCO was added and the mixture was stirred for 20 minutes at room temperature. temperature Then the reaction rast ™
5 The thief is filtered and 300 ml of ethyl ether are added. The resulting oil is separated by centrifugation, once washed with diethyl ether, then dissolved in 150 ml of methanol. 11 After adding 300 ml of chloroform, washed with 90 ml of solvent mixture: the upper phase consists of CH OH / HjO 3:48:47, and the lower phase is diluted There are 150 MP of CHC13 / CH, OH 2: 1 mixture. Then 3 ml of a 20% aqueous solution of ammonia are added and the mixture is held for 3 15 minutes at room temperature, after which the colorless formed is separated by centrifugation.
0 sediment. After distilling off the solvent in vacuo, the oily residue is treated three times with 50 ml of diethyl ether to obtain 5.5 g of a yellowish solid (98X from
S theory), which, when processed by a thin layer of silica gel chromatography (mobile phase CHCl / CH OH / 25% NHj 65: 35: 5), gives the value of R.f
0
0
five
15
 0.15 and contains only very small amounts of impurities. The pure substance is obtained by chromatography under medium pressure over silica gel. A gradient is used for elution. / CHjOH, and the eluent contains 0,5ob.% 25% aqueous solution of ammonia. Thus, 2.93 g, (53.3% of theory) of pure substance are obtained. The reduced yield is due to the partial cleavage of the 1-0-triphenylmethyl group during the purification process over silica gel. For thin-layer chromatography on silica gel (mobile phase is the same as for the analysis of the crude product) the purified substance gives one spot at RI O, 15.
NMR spectrum - n, S ppm; (CIClj / 1E01, 2: 1), 3.1 (N-CH,), 3 (choline and glycerin); 7.25 (CH-triphenylmethyl),
Example 2. 1-0-triphene shmetil-5n-glycero-3-phospho- (H-triphenylmethyl) - ethanolamine.
946 mg of Sn-glycero-triphospho- (N-immunoethylmethyl) ethanolamine and 1.735 g of triphenyl chloromethane in 32 ml of anhydrous pyridine are stirred for 48 hours in the absence of moisture at room temperature. The mixture is then poured into ice water. The product is extracted with three portions of diethyl ether. The combined ether extracts are washed twice with water, after which the suaat over
(61.8% of theory) of a pure substance. The lower yield is due to the partial elimination of the 1 0-triphenylmethyl group during the purification process with silica gel.
NMR-H spectrum, y ppm (DMCO-D); .3.5-4.3 (glycerol and ethanolamine CH are blurred); 7.25 (C-H-triphenylmethyl, 0 is average).
Example Using the method described in Example 1, the following compound was obtained: 1-0- (4, dimethoxytriphenylmethyl) -5p-glycerolothosphosphocholine. Output 94% of theory. A thin-layer chromatogram on silica gel (mobile phase: CHCl j mixture: CH: OH: 25% aqueous NHj 65: 35: 5) represents one spot with R 0.15.
Nuclear Magnetic Resonance Spectrum НH, ppm (SVBOV): 3.1 (N-CH,); 3.8 (phenyl-0-CH,); 3.3-4.3 (choline and glycerin); 7.23 - (aromatic).
PRI me R 4. 1-0- (4,4 -Dimethoxy 25 triphenylmethyl) -Sn-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine.
A solution of 2.4 g of Sn-glycero-3-fo.Sfo- (K-triphenylmethyl) -ethanolamine and 4.5 g of 4,4-dimethoxytriphenylchlrmethane in 80 ml of anhydrous pyridine is stirred at room temperature for 72 hours. distilling off the pyridine in vacuo the residue is dissolved in 200 ml
20
thirty
mixtures of CHC1, and CHjGH 2: 1. The resulting solution is rinsed twice with 40 ml of the mixture.
sodium sulfate. After distillation, the plant is 5 CHC1,: CH, OH: H20 (3: 48: 471, after which the solvent left in vacuum is left to remove the pyri solvent in vacuum. In
five
(61.8% of theory) of a pure substance. The lower yield is due to the partial elimination of the 1 0-triphenylmethyl group during the purification process with silica gel.
NMR-H spectrum, y ppm (DMCO-D); .3.5-4.3 (glycerol and ethanolamine CH are blurred); 7.25 (C-H-triphenylmethyl, 0 medium).
Example Using the method described in Example 1, the following compound was obtained: 1-0- (4, dimethoxytriphenylmethyl) -5p-glycerolothosphosphocholine. Output 94% of theory. A thin-layer chromatogram on silica gel (mobile phase: CHCl j mixture: CH: OH: 25% aqueous NHj 65: 35: 5) represents one spot with R 0.15.
Nuclear Magnetic Resonance Spectrum НH, ppm (SVBOV): 3.1 (N-CH,); 3.8 (phenyl-0-CH,); 3.3-4.3 (choline and glycerin); 7.23 - (aromatic).
PRI me R 4. 1-0- (4,4 -Dimethoxy-5 triphenylmethyl) -Sn-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine.
A solution of 2.4 g of Sn-glycero-3-fo.Sfo- (K-triphenylmethyl) -ethanolamine and 4.5 g of 4,4-dimethoxytriphenylchlrmethane in 80 ml of anhydrous pyridine is stirred at room temperature for 72 hours. distilling off the pyridine in vacuo the residue is dissolved in 200 ml
0
the din is removed by evaporation of the residue in vacuo in the presence of toluene. The resulting residue is introduced into 30 ml of a mixture of chloroform and methanol 1: 1 and the solution is left overnight at 4 ° C. After filtration of the precipitated triphenylcarbonyl and subsequent distillation of the mixture of solvents, 1.7 g (100.9%
40
A brown oil is obtained, from which, after treatment with diethyl ether in portions of 80 and 30 ml, 2.5 g (62% of theory) of the crude product are obtained in the form of a colorless amorphous powder. According to silica gel thin layer chromatography, the mobile phase: a mixture of GHCIj: CH50H 6: 4.
from the theory of) an impure product, which This product contains more than 90% is used without additional treatment in a subsequent acylation. This product contains small amounts, and triphenylcarbonyl. Chromatography on silica gel for subsequent acylation. Chromatography on silica gel with a gradient of chloroform with methanol gives a pure compound that exhibits one spot at R 0.6 when analyzed by thin-layer chromatography on silica gel (mobile phase: a mixture of chloroform and methanol 6: 4). So get 1.05 g
50
product (R 0, -6), which can be used without further purification to obtain pure enantiomeric 1,2-diacyl-5n-glycero-3-phosphoethane, with various substituents.
A pure substance is obtained by chromatography at medium pressure on silica gel with a gradient (in the presence of 0.5% by volume of aqueous ammonia). On a thin-layer chromatogram, there is one spot of it at R = 0.6 (conditions are similar to Example 3). Output
40
As a result, a brown oil is obtained, from which, after treatment with diethyl ether in portions of 80 and 30 ml, 2.5 g (62% of theory) of the crude product are obtained in the form of a colorless amorphous powder. According to silica gel thin layer chromatography, the mobile phase: a mixture of GHCIj: CH50H 6: 4.
 This product contains more than 90% cel
product (R 0, -6), which can be used without further purification to obtain pure enantiomeric 1,2-diacyl-5n-glycero-3-phosphoethane, with various substituents.
A pure substance is obtained by chromatography at medium pressure on silica gel with a gradient (in the presence of 0.5% by volume of aqueous ammonia). On a thin-layer chromatogram, there is one spot of it at R = 0.6 (conditions are similar to Example 3). Output
5142
pure product 1.93 g (48% of the- |) ii). The reduced yield is due to the partial removal of the 1 0-triphenyl-methyl group during the purification process over silica gel.
: CneKTj NMR-H, ppm (CICI, / C1.01 a: 1); 3.1 (,); 3.8 (phenyl-0 CH3); 3.3-4.3 (choline and glycerin); 7.23 (aromatic).
Thin-layer chromatograms in examples 5-21 were obtained on silica gel
Yield: 83.5%, Rj 0.18, H-NMR (mobile phase: chloroform /
1 Methanol / 25% aqueous ammonia 65: 35: 5), spectrum, S ppm: 0.95 (3N, -CH); 1.1
i NMR spectra -H were recorded in solution
|; CDCD / CDaOD 2 mix: 1).
 Using the method described in the examples. 1-4, the following are obtained
Compound.
 PRI me R 5. The reaction temperature 2Q foholin.
In dimethylformamide 120 C. Exit: 81% of theory, R 0.20
: 1-0- (4,4,4 -Trimethoxytripeschme n-NMR spectrum, (In ppc; 0.9 (ZN, -CHj):
Thyl) -3p-glycero-3-phosphocholin.1.1-1-1.5 (8H, middle, -CHj-); 3.1
, 5 1.4 () 5 3.1 (9Hj N — CHj); 3.3 - 4.3 (9H, choline and glycerin); 7.3 (14K5 aromatic.).
EXAMPLE 11 1-0- (4-n-Hex11p-oxytriphenylmethyl) -En-glycero-3-fosj Yield: 82% of theory, R.J. 0.15, as shown, H-NMR spectrum, S ppm; LH, N-CH,); 3.3-4.3 (9H, avg., Media: | solin and glycerin), 3.8 (9H, 0-CHj) | 7.3 (12H average, aromatic)
PRI me R 6. 1-0- (4-Methoxytriphe nylmethyl) -8n-glycero-3-phosphocholine.
Output 87% of theory, K. 0.15, One spot. n-NMR spectrum, 5 ppm; 3.1 (9H, N-CHj) 3.3-4.3 (9H, medium. Medium, choline and glycerin), 3.8 (3H, 0-CHj), 7.3 (14 medium aromatic).
Example 7. The process is carried out in DOPA at 135 ° C.
I-0- (4-Metsh1Triphenylmethyl) -Sn-g gatsero-Z-phosphocholine.
Output 63.5% of theory, R. 0.17, one point. n-NMR spectrum, S ppm: 2.25 (3N,.-CHj) | 3.1 (9H, N-CH,) 3.3-4.3 (9H, medium, choline and glycerin), 7.3 (14 aromatic).
Example 8.1-0- (4-n-Hexyltrife nibmatyl) -5n glycero 3-phosphocholine,
Output: 74% of theory of the crude product, of the theory of the product, purified using preparative column chromatography). R | 0.20, one spot. H-NMR spectrum, S ppm; 0.9 (3N, -SI); 1.2-1.5 (8H,) | 2.6 (2H, aryl-CHF-); 3.1 (9H, N-CH ,,); 3.3-4.3. (911, middle, choline and glycerin) ,. 7.3 (14H, -aromatic.).
PRI me R 9. 1-0- (2-Isoproxy1-phenylmethyl) -8n-glycero-3-phosphocholine.
25
thirty
40
(9H, N —CH,); 3.3-4.3 (9H, choline and glycerin; 3.95 (2H, -OCH); 3.3-3.3 (9H, choline and glycerin); (2H, -OCHN); 7.3 ( 14H, aromatic.).
Take p12. 1-0- (4-Bromotriphenyl methyl) -Sn-glycero-3-phosphocholine.
Yield: 92% of crude product theory: 67% of the theory of the product purified by preparative column chromatography, R-f 0.16, one H-NMR spectrum ,. Ppm: 3.1 (9H., N-CHjJ 3.3-4.3 (9H, choline and glycerin); 35 (14H, aromatic).
Example 13. 1-0- (5-ChlC p-2-me-tox-triphensh1metsh1) -5n-glycero-3 phosphocholine.
Yield: 71.5%, R 0.15, H-Ya1-1R-spectrum, ppm: 3.1 (9H, N-CH,), 3.3-4.3 (9H, choline to glycerol); 3.85 (5H.5) j - 7.3 (13H, aroma,).
Example 14. 1-0- (3-Bromo-4-methoxytriphenylmethyl;) -Sn-glycero-3-phosphocholine.
Yield: 71.5% of theory, R. O ,, 15. H-NMR spectrum, S ppm 5 3.1 (9H, N - CH,) 3.3-4.3 (9H, choline and glycerin ), 3.85 (3N, G-CHj), 7.3 (13H, aromatic).
Example 15 of 1-0-Trifen Sh1methyl-Zp-glycer o-3-phospho- (K 4-a-but-shstriphenylmethyl) ethanol: 1F1n.
Yield: 97% of the theory of non-effusion of the product, 34.5% of the theory of purified by preparative column xpoi-iai-c product diffusion (partial decomposition on the silnagel). R - O 5.68, one spot. n-NMR spectrum, ppm: 1.1-155
50
55
Output 63.5% of the theory of the crude product, 48.5% of the theory of the product purified by preparative column chromatography, R 0.17, one n t
but. H-NMR spectrum, S ppm; 1.6 (6H, CHj) j2.9 (1H, 3.1 (9H, N-CHj); 3.3-4.3 (9H, choline and glycerin), 7.3 C14H, aromatic).
Example 10. 1-0- (4-n-Butoxytriphenylmethyl) 5n-glycero-3-phosphocholine.
Yield: 83.5%, Rj 0.18, H-NMR spectrum, S ppm: 0.95 (3N, -CH); 1.1
spectrum, S ppm: 0.95 (3N, -CH); 1.1
1.4 () 5 3.1 (9Hj N-CHj); 3.3 - 4.3 (9H, choline and glycerin); 7.3 (14K5 aromatic.).
EXAMPLE 11 1-0- (4-n-Hex11p-oxytriphenylmethyl) -En-glycero-3-fos5
0
0
(9H, N —CH,); 3.3-4.3 (9H, choline and glycerin; 3.95 (2H, -OCH); 3.3-3.3 (9H, choline and glycerin); (2H, -OCHN); 7.3 ( 14H, aromatic.).
Take p12. 1-0- (4-Bromotriphenyl methyl) -Sn-glycero-3-phosphocholine.
Yield: 92% of crude product theory: 67% of the theory of the product purified by preparative column chromatography, R-f 0.16, one H-NMR spectrum ,. Ppm: 3.1 (9H., N-CHjJr 3.3-4.3 (9H, choline and glycerin); 5 (14H, aromatic).
Example 13. 1-0- (5-ChlC p-2-me-tox-triphensh1metsh1) -5n-glycero-3 phosphocholine.
Yield: 71.5%, R 0.15, H-Ya1-1R-spectrum, ppm: 3.1 (9H, N-CH,), 3.3-4.3 (9H, choline to glycerol); 3.85 (5H.5) j - 7.3 (13H, aroma,).
Example 14. 1-0- (3-Bromo-4-methoxytriphenylmethyl;) -Sn-glycero-3-phosphocholine.
Yield: 71.5% of theory, R. O ,, 15. H-NMR spectrum, S ppm 5 3.1 (9H, N - CH,). 3.3-4.3 (9H, choline and glycerin), 3.85 (3N, G-CHj), 7.3 (13H, aromatic).
Example 15 of 1-0-Trifen Sh1methyl-Zp-glycer o-3-phospho- (K 4-a-but-shstriphenylmethyl) ethanol: 1F1n.
Yield: 97% of the theory of non-effusion of the product, 34.5% of the theory of purified by preparative column xpoi-iai-c product diffusion (partial decomposition on the silnagel). R - O 5.68, one spot. n-NMR spectrum, ppm: 1.1-155
0
five
71A22999
(4H,), 2.6 (2H, -CH-Ar11l); 3.3-4.3 (9H, quinoline and glycerin), 7.3 (29H, aromatic.).
The starting 5p-glycero-3-phospho- (M-A-n-butyl-triphenylmethyl) -ethanolamine was obtained by N-tritylation of Sn-glycerol-3-phosphoethanolamine A-n-butyltriphenylmethyl bromide. R- |. 0.36
The output of 73.2% from Teopmi, R 0,6 ii-NMR spectrum, S ppm; 3.1 (, N-CH 3.3-4.3 (9H, choline and glycerin); 3, (3N, G-CFI); 7.3 (28H, medium, artic.).
Original Sn-glycepo-3-foxo- (N-3-bromo-4-methoxy-triphenylmethyl) -etholamine was obtained by N-tritylation
Example 16. 1-0-Triphenylmethyl-0 phospholipid soybean 3-bromo-4-methoxy-5n-glycero-3-phospho- (M-2-chlorotriphenyl-triphenylmethylbromide. Methyl) -ethanolamine.
Output 82.5% of the theory of the crude product, 61.5% of the theory of purified
Example 20. 1-0- (4-n-Hexyl phenylmethyl) -5n-glycero-3-phospho- (4-isopropoxytriphenylmethyl) -ethanol min.
preparative column chromatography of the product. RI 0.62, one spot. H-NMR spectrum, S PLM: 3.3-4.3
15
Example 20. 1-0- (4-n-Hexyltriphenylmethyl) -5n-glycero-3-phospho- (4-isopropoxytriphenylmethyl) -ethanolamine.
Exit 74% of theory, R 0.74, n-NMR spectrum, 5 ppm: 0.9 (3N, CHj),
(9H, choline and glycerin), 7.3 (29H,
aromatic.).
The original Sn-glycepo-3-foxo- (N-2-
chlorotriphenylmethyl) ethanolamine was obtained by N-tritylation of phospholipids
soy 2-chloro-triphenylmethyl chloride,
Rf 0.30o
Example 17. 1-0- (4-n-Butoxy- 25 Soybean 4-isopropoxy-trifetriphenylmethyl) -pn-glycero-3-phospho-nylmethyl chloride soybean flipid.
(N-4-metsh1-triphenstmetsh1) -ethanolamine. Output: 76.2% of theory, R 0.72.
H-NMR spectrum, S ppm: 0.95 (BZ, -CH,)
1.1-1.5 (4Nu-CH, -), 2.25 (MN, aryl-
CHj) 3.3-4.3 (9H, choline and glycerin);
4.0 (2H, -OCHj), 7.3 (28H, medium
arom.)
Source 5p-glycero-3-phospho- (H7
4-methyl-triphenylmethyl) -ethanol amine.
obtained by N-tritylation of phospholipi-35 Sn-glycero-3-phosphocholine.
Soybean 4-methyltriphenylmethylbromide with 110.18 g (0.28 mol) Sn-glycero3-phosphocholine (EPXX complex) and 117.08 g (0.42 mol) of triphenylmethyl chloride dissolved in 900 ml of dimethylformamide at 60 C. While stirring, 58.2 MP (0.42 mol) of triethylamine are added and alternated at 70 ° C for 35 minutes. Recycling of the reaction product
1.4 (6H, izlopropoxy-CH,); 1.1-1.5 (8H, -CH), 2.6 (2H, CH, -aryl), 3.3-20.33 (9H, choline and glycerin), 4.6 (1H, CH) 7.3 (28H, aromatic.).
The starting 5p-glycero-3-phospho- (K-4-isopropoxy-triphenylmethyl) ethanolamine was obtained by N-tritylolane phosPamide 21. 1-0-Triphenylmethyl-8p-glycero-3-phospho- (K -4-n-hexyloxy-triphenylmethyl) -ethanolamine.
Yield 69.3% of theory. R 0.67, n-NMR spectrum, S ppm: 0.9 (3N, SI,), 1.1-1.6 (8H, middle, -CHj-); 3.3 - 4.3 (9H, choline and glycerin), 3.95 (2H, -OCH,), 7.3 (29H, middle aromatic.).
PRI me R 22. 1-0-Triphenylmethyl R .J 0.30.
Example 18. 1-0- (4-Bromotrifinemethyl) -5n-glycero-3-phospho- (H4-n-hexyphenylmethyl) -ethanolamine. .
Yield: 92% of theory of the crude product, 39.4% of the theory of purified preparative column chromatography (partial decomposition on silica gel).
R 0.71, one spot. H-NMR spectrum, S ppm: 1.1-1.5 (8H, -CH), 2.6 (2H, aryl-CH), 3.3-4.3. (9H, Kalin: and glycerin), 7.3 (28,, medium, aromatic,).
The starting 5n-glycero-3-phospho- (H-4-n-hexyltriphenylmethyl) -e tanolamine was obtained by N-tritylation of phospholipi40
produced as in example 1.
5 Get 79.66i g (56.95% of theory) of the pure product.
/ (- nr-l
H-NMR, S ppm: (SOS1, / SOZOV 2: 1):
3, t (N-CHj); 3.3-4.3 (choline and glycerol), 7.25 (triphenylmethyl C – H). 50 Example 23 A. A. 1-0-Triphenylmetsh1-2-oleoyl-5p-glycero-3-phosphocholine.
1.26 g of oleic acid are reacted with 794 g of carbonyl1; 26 g of oleic acid are introduced into interaction with 794 g of soybean carbonilds 4-n-hexyltriphenylmethyl chloride .55 of diimvdazole in 25 ml of tetrahydrofuran
Example 19. | -0-Triphensh1metsh1- for 45 min at room temperature — Sn-glycero-.3-phos-pho- (N-3-bromo-4-meter-temperature) and then the solvent is removed in sitriphenylmethyl) -ethanolamine. vacuum. After that the residue that
Yield 73.2% of Teopmi, R 0.60. ii-NMR spectrum, S ppm; 3.1 (, N-CH,),: 3.3-4.3 (9H, choline and glycerin); 3.85 (GH, G-CFI); 7.3 (28H, medium, aromatic.).
Original Sn-glycepo-3-foxo- (N-3-bromo-4-methoxy-triphenylmethyl) -ethanolamine was obtained by N-tritylation
soybean phospholipids Z-bromo-4-methoxy-triphenylmethyl bromide.
Example 20. 1-0- (4-n-Hexyltriphenylmethyl) -5n-glycero-3-phospho- (4-isopropoxytriphenylmethyl) -ethanolamine.
Exit 74% of theory, R 0.74, n-NMR spectrum, 5 ppm: 0.9 (3N, CHj),
1.4 (6H, izlopropoxy-CH,); 1.1-1.5 (8H, -CH), 2.6 (2H, CH, -aryl), 3.3- 4.3 (9H, choline and glycerin), 4.6 (1H, CH), 7.3 (28H, aromatic.).
The starting 5p-glycero-3-phospho- (K-isopropoxy-triphenylmethyl) ethanolamine was obtained by N-tritylolane phosPamide 21. 1-0-Triphenylmethyl-8p-glycero-3-phospho- (K- 4-n-hexyloxy-triphenylmethyl) -ethanolamine.
Yield 69.3% of theory. R 0.67, n-NMR spectrum, S ppm: 0.9 (3N, SI,), 1.1-1.6 (8H, middle, -CHj-); 3.3 - 4.3 (9H, choline and glycerin), 3.95 (2H, -OCH,), 7.3 (29H, middle aromatic.).
Example 22 1-0-Triphenylmethyl was produced as in Example 1.
5 Get 79.66i g (56.95% of the theory of pure product.
/ (- nr-l
H-NMR, S ppm: (SOS1, / SOZOV 2: 1):
3, t (N-CHj); 3.3-4.3 (choline and glycerol), 7.25 (triphenylmethyl C – H). 50 Example 23 A. A. 1-0-Triphenylmetsh1-2-oleoyl-5p-glycero-3-phosphocholine.
1.26 g of oleic acid are reacted with 794 g of carbonyl
Contains the formation of imidazole-CuG; fatty acid, mixed with a solution of 1.1 g of the crude product 1-0-trifeschmethyl-8n-glycero-3-phosphocholine (according to example 1) in .28 ml of dimethyl sulfoxide. After the addition of the catalyst, which is obtained by dissolving 1: D8 mg of metallic sodium. In 11.5 ml of dimethyl sulfoxide, the reaction mixture is allowed to stand shaking occasionally for L0 min at. Then add to a mixture of 64 MP 0.1 n, aqueous acetic | isl-oty. Extract twice with an oroform mixture with methanol 2: 1 (v / v ly) and wash the combined organic bases twice with a 1: 1 mixture of methanol and water (v / v). After evaporation of the solvent in vacuo, the crude product is dissolved in chloroform and sediment t per column with silica gel | 1 pure compound (1.1 g) eluted with s-chloroform-methanol gradients to thin-layer chromatography on silica (barely (solvent chloroform: nol: 25% W in the ratio: 5) shows a single spot, Ri 0 ,four
B. 2-Oleoyl-8p-glycevro-3-phosphocholine,
A solution of 500 mg of 1-0-triphenylmethyl-2-oleoyl-8n-glycero-3-phosphocholine in 30 nM of methylene chloride is mixed with 0.5 ml of a 20% aqueous solution of boron trifluoride in methanol and then stirred for 30 minutes at 0 ° C. Then i5 ml of methanol and 9 mg of water are added, shaken and the organic phase is separated. The solvent is removed by distillation under high vacuum at room temperature.
B, 1-Palmitoyl-2-oleoyl-8n-glycero-3-phosphocholine.
The residue, the extrusion, contains the selective 2-oleoyl-Sn-glycero-3-phosphocholine, dissolves in 30 mp of anhydrous chloroform. Then, 820 mg of phthalic anhydride and 200 mg of dimethylaminopyridine were added to this solution and the reaction mixture was stirred for 20 hours at 20 ° C. After that, 15 ml of methanol is added and shaken first with 0.1N.HC1 and then c. After removing the organic solvent in vacuo, the substance is purified by chromatography on silica gel using chloroform-metaiolic gradients. Purified compound (400 g) in the case of thin-layer chromatography on silica
.
50
five
gel (solvent - chloroform: methanol: 25% NHj in the ratio 65: 35: 5) gives a single PETNO. 0.4.
PRI me R 24. 1-Stearoyl-2-oleoyl-3n-glycero-3-phosphocholine ..
JacTBOp 2-oleoyl-8p-glycero-3-phosphocholine obtained from 700 mg of 1-0-triphenylmethyl-2-al: eoyl-5p-glycero-3-phosphocholine according to example 23 (stage A and B) is reacted with 1 2 g of stearic anhydride according to the procedure described in Example 23 (Step B) are chromatographed and analyzed. 550 g (76% yield, calculated on 1-0-triphenylmethyl-8n-glycero-3-phosphocholine) 1-stearoyl-2-oleoyl-5n-glycero-3-phosphochaline, which is obtained in a thin layer silica gel chromatogram (solvent - chloroform: methanol: 25% water solution 65: 35: 5 shows a single spot, R | - 0.4.
Example 25. A. 1-0-Triphenylmethyl-2-linoleone-8n-glycero-3 phosphox choline.
600 mg of 1-0-triphenylmethyl-8n-glycerol-3-phosphochrlin are acylated using linoleylimidazolide, which is obtained from 690 mg of linoleic acid and 440 mg of carbonyldiimidazole, as described in Example 23 (step A). under a moderate (moderate) pressure of silica gel, the pure compound (690 MI-J yield 75% of theory) in a thin-layer chromatogram on silica gel shows a single spot, Rr 0.3 (solvent - chloroform: methanol: 25% aqueous solution of NHj 65 : 35: 5).
B, 2-Linoleoyl-5p-glycero-3-phosphocholino
A solution of 1 g of 1-0-Triphenylmethyl-2-linoleoyl-Bp-glycero-3-phosphocholine in 60 ml of methyl chloride to remove 1 ™ 0 - triphenylmethyl residue, as described in Example 23 (Stage B), Bathe with a 20% solution of trifto-boron boron in methanol.
Century 1 -Stearsi, noleoyl-Zn-gly-cero-Z-phosphrcholine
The 2-linearoyl-3p glycero-3-phosphocholine obtained in stage B is reacted with 1.6 g of antspida stearic acid according to the procedure described in Example 23 (step B) and chromatographically purified, 820 mg are filtered (yield 80 %, based on 1-0-trif {| P142299
nilmethyl-2-linoleoyl-5p-glycero-3-- phosphocholine) of pure product, which in a thin-layer chromatogram on silica gel (chloroforM methanol solvent: 25% aqueous ammonia in the ratio 65: 35: 5) shows a single spot, R = 0.7.
Example 26. A. 1-0-Triphenylmethyl-2-acetyl-8n-glycero-3-phosphohog
LIN.
320 mg of 1-0-triphenylmethyl-5p-glycero-3-phosphocholine is reacted with 0.7 mg of acetic anhydride in A ml of anhydrous pyridine overnight at room temperature. The reaction mixture is then drunk in ice water, extracted twice with a mixture of chloroform and methanol (2: 1). The combined organic phases are washed twice with 2 ml of a mixture of chloroform, methanol and water (3: 48: A7, by volume), dried over sodium bicarbonate and brought to dryness.
15
From the 1-O-triphenylmethyl-2-methoxy-acetyl-5p-glycero-3-phosphocholine as specified in example 23 (step B), the 1-0-triphenylmethyl group is cleaved off and the 2-methoxyacetyl formed by this, the crude product is purified by
Chromatography under moderate (medium) js Sn-glycero-3-phosphocholine, as in the prescription on silica gel using chloroform-methanol gradients. Pure product (180 mg, 51% yield) on a silica gel thin-layer chromatogram (chloroform: meta- solvent.
thirty
Measure 2 was reacted with steric acid anhydride to obtain 1-stearosh-2-methoxyacetyl-5n-glycero-3-phosphocholine and chromatographically purified.
thirty
nol: 25% aqueous ammonia solution in a ratio of 65: 35: 5 by volume) a single spot, R 0.6.
NMR-H spectrum, dm.d. (, 2: 1 by volume); 2.13 (NzS-SO, singlet, ZN); 3.16 (, singlet, 9H), 3.3-35 interaction with 2-ethylhexanoyl-A, 4 (glycerol and choline-CH2); 5.23 (glidazolid, which is obtained from 114 mg of cerol-C-H, 1H); 7.33 (aromatic, 2-ethylhexanoic acid and 178 mg
15H).
B. 2-Acetyl-8p-glycero-3-phosphocho Example 28 A. A. 1-0-Trifensh-1-methyl-2- (2-ethylhexanoyl) -Sn-glycero-3-phosphocholine.
A solution of 250 mg of 1-0-triphenylmethyl-Sn-glycero-3-phosphocholine is administered in
40
carbonyldiimidazole, as indicated in example 23 (stage A) method Rabolin.
B. 1-Palmitoyl-2-acetal 1-8p-glycero-3-phosphocholine.
From 1-0-triphenylmethyl-2-acetyl-5p-glycero-3-phosphocholine according to the procedure described in example 23 (step B), the 1-0-triphenylmethyl group and 2-acetyl-3p-glycero-3 formed -phosphocholine is injected with so-interaction with palmitic anhydride according to the method of working in Example 23 (Stage B) to produce 1-palmitoyl-2-acetyl-8n-glycero-3-phosphocholine,
Example27 „A. 1-0-Trifone shl nl-2-methoxy-acetyl-8n-glycero-3 phosphocholine,
316 mg of 1-0-triphene1methyl-Zp-glidero-3-phosphocholic is administered in vakakmo1 2
g
P
five
fission with methoxyacetylamide, which is obtained from 90 mg of methoxyacetic acid and 178 mg of carbonyldiimidazole, according to the procedure described in Example 23 (step A) and processed. Obtain 250 mg (69% vkod) of pure 1-0-triphenylmethyl-2-metoxyacet 1-5p-glycero-3-phosphocholine, which in the thin-layer chromatogram (solvent - chloroform: methanol: 25% aqueous solution of ammonia, 65: 35: 5 shows a single spot, R 0.25.
B. 2-Methoxy-acetyl-5n-glycero-3-foSfocholine.
B. 1-Stearoyl-2-methoxyacetyl-Sn-glycero-3-phosphocholine.
From the 1-O-triphenylmethyl-2-methoxy-acetyl-5p-glycero-3-phosphocholine as specified in Example 23 (step B), the 1-0-triphenylmethyl group and the 2-methoxyacetylSn-glycero-3 formed are cleaved phosphocholine, as in
interaction with 2-ethylhexanoyl-azolide, which is obtained from 114 mg of 2-ethylhexanoic acid and 178 mg
Measure 2 was reacted with steric acid anhydride to obtain 1-stearosh-2-methoxyacetyl-5n-glycero-3-phosphocholine and chromatographically purified.
Example 28. A. 1-0-Trifensh-1-methyl-2- (2-ethylhexanoyl) -Sn-glycero-3-phosphocholine.
A solution of 250 mg of 1-0-triphenylmethyl-Sn-glycero-3-phosphocholine is administered in
carbonyldiimidazole specified in example 23 (stage A) method of operation and process. 200 mg (69% yield) of pure 1-O-triphenylmethyl-2- (2-ethylhexanoyl) -5p-glycero-3-phosphocholine are obtained, which in the thin layer chromatogram (chloroform: methanol: 25% aqueous solution ammonia, 65: 35: 5) shows a single spot. R 0.24).
B. 2- (2-Ethylhexanoyl) -8n-glycero-3-phosphocholine.
B. 1-Oleoyl-2- (2-ethylhexanoyl) - Bp-glycero-3-phosphocholine.
The 1-0-triphenylmethyl group and the resulting 2- (2-ethylhexanosh1) -8n-glycero-3 phosphochol are cleaved from the 1-0-triphensh1methyl-2- (2-ethyl-hexane-15p-glycero-3-phosphocholine) - Lin is reacted with oleic anhydride to obtain Shem 1-oleoyl-2- (2-ethylhexanoyl) -Sjn-glycero-3-phosphocholine and chromatographically purified.
j. EXAMPLE 29 A. A. 1-0-Triphenyl-1 ethyl-2- (1-C) dodecanoyl-8n-gly-Cero-3-phosphocholine.
: 100 kg (1 - C) -dodecanoic acid (lpci / mmol) and 90 mg of carbonyldi-Cmidazole are reacted for 45 minutes in 30 ml of anhydrous ethehydrofuran at 20 ° C. A solution of the resulting adylimidazolide is added to about 127 mg of 1-0-triphenyl-methyl-8p-lycro-3-phosphocholine. After removal
the solvent in vacuo is dissolved in 1 ml of dimethyl sulfoxide and reacted by adding a catalytically active acid-binding agent, which is obtained by dissolving 23 g of sodium tiecKoro sodium in 18 ml of dimethyl sulfo 0ide. The reaction mixture was shaken for 10 minutes at shaking at 20 ° C and then neutralized with 10 ml of aqueous acetic acid. Then, 1 is extracted twice with 15 ml of a mixture of shoroform with methanol (2: 1 by volume), the combined organic phases are washed successively with 6 ml of a solution of chloroform-methanol-aqueous NH (3:48:47 by volume) and chloroform with methanol and water (3:48:47 by volume). After removal of the solvent in vacuo and vacuum in the presence of benzene, the crude product is obtained, which is purified by chloroform-methanol gradients by chromatography under moderate (moderate) pressure on sy.i-gel, with 110. mg of pure substance (82% yield) being eluted with a ratio of chloroform to methanol 6: 4 (by volume).
A pure substance in a thin layer chromatogram on silica gel (solvent: chloroform with methanol and a 25% aqueous solution of ammonia, 65: 35: 5 by volume) shows a single spot, R {0.25. The radioactivity is 1 (Uci (mmol). NMR spectrum is 8 ppm (CDCl, -CD, OD 2: 1, by volume): 0.90 (acyl-CH, MN); 1.2 4CHi ), singlet, 16H), 1.66 (C-CO, multiplet, 2H); 3.16 (HjC-N, singlet, 9H); 3.3-4.4 (glycerol and choline-CHg, 8H); 3.23 (glycerol-CH, multiplet, 1H), 7.33 (aromatic, 15H).,
Q
five
0
0 5 5
0 5
0
B, 2- (1- C) -Dodecanoyl-5n-glycero-3-phosphocholine.
B. 1-Oleoyl-2- (1-) -dodecano-yl-8n-glycero-3-phosphocholine.
From 1-0-triphenme1-methyl- 2- (1-C) dodecanoyl-5n-glycero-3-phosphocholine, 1-0 triphene: a methyl group and the resulting ol: 2-() -dodecanoyl-8n-glycero-3- phosphocholine is reacted with oleic anhydride with 1H-1-oleoyl-2- (1-) -co-docanoyl-8n-glycero-3-phosphocholine pol1D1enium and chromatographically purified.
Example 30 A. A. 1-0-Trifensh1methyl2- (9 -10-dibromostearoyl) -8n-glycevro-3-phosphocholine.
300 mg of 1-0-triphenylmethyl-8p-glycero-3-phosphocholine is introduced into the reaction with 1.3 g of 9,10-dibromostearic acid anhydride in the presence of 300 mg of 4-K, K-dimeshtinaminopyridine in 20 ml of chloroform for 5 hours at 20 ° C and treated. 460 mg (82% yield) of pure 1-0-triphenylmethyl-2- (9, 10-dibromostearosh 1-8p-glycero-3 phosphocholine, which in the thin-layer chromatogram (solvent is chloroform: methanol: 25% aqueous ammonia, is obtained , 65: 35 ;; 5 by volume) shows a single spot. Rr 0.3.
B. 2- (9, 10-Dipfromostaroil) -8n-glycepo-3-phosphofoxoline,
B. 1-Stearoyl-2- 9 10 -dibromostearoyl) -Sn-glycero-3-phosphocholine,
From the 1-0-triphenylmethyl-2- (9 i 10-dibromostearoyl) -8p-: glycero-3-phosphocholine, the 1-0-triphenylmethyl group was split off and the resulting 2- (9, 10-dibromosterooyl) 8n-glycero-RO-3-phosphocholine is reacted with stearic anhydride to produce 1-stearosh-2- (9, 10-dibromo stearoyl) -8n-glycero-3-phosphocholine and chromatographically purified.
Example 31, A. 1 0-Trifé1 Shlmethyl-2-arihi, coenoyl-5 P-glycero-3-phosphocholine,
550 .mg 1-0-trifb1NSh1methyl - 8p-glycero-3-4 OSfocholine (according to example 1) specified in example 8, the method of operation is injected into the interaction with x- 1.50 g of anhydride arachidonic acid in an argon atmosphere. After addition of 15 MP of methanol, Proz-Shalot with 9 ml of chloroform-methanol-water (3:48:47 by volume) and then the bottom of the mixture is dried and purified by chromatography under medium (moderate) pressure.
750 mg (80% yield) of pure 1-O-triphenylmethyl-2-arachidonoyl Sn-glycero-3-phosphoscholine is obtained, which is thin layer chromatogram (solvent: chloroform; methanol: 25% aqueous ammonia 65: 35: 5 volume) across ™ is one spot. R - 0} 3.
B. 2-Arachidonoyl-3n-glycero-3-phosphocholine.
B. 1-Stearosh1-2-arahidonoiL-5n-glycero-3-phosphocholine.
From the 1-0-triphenylmethyl-2-arachidonoyl-8n-glycero-3-phosphocholine, the 1-0-triphenylmethyl group is cleaved off and the 2-arachidonoyl-Sn-glycero-3-phosphocholine formed thereby reacts with the anhydride stearic acid to obtain 1-stearoyl-2-arachidonoyl-8n-glycero-3-phosphocholine and chromatographically purified.
PRI, ME 32. A. 1-0-Triphenylmethyl-2-tetracosanoyl-Sn-glycero-3-phosphocholine.
316 mg of 1-0-triphenylmethyl-8n-glycero-3-phosphocholine is introduced into the action with tetracosanoylimide.zolide, which is obtained from 1.7 g of tetracosano boi acid and 356 mg of carbonyl imidazole, and processed. 850 mg (62% yield) of pure 1-0-triphenyl-methyl-2-tetracosanoyl-3n-glycero 3 phosphocholine 5 are obtained, which in a thin layer
chromatogram (solvent: a solution of 35 phenylmetsh1) -thanolamine in a mixture of
chloroform with methanol and 25% aqueous ammonia, 65: 35: 5 by volume, shows a single spot, R 0.3.
B. 2-Tetracosanoyl-8n-glOnO-3 phosphochrlin.
B. 1-Oleoyl-2-tetracosanoyl-8n-glycero 3-phospholin.
From 1-0-triphenylmethyl 2-tetraco-zanoyl-8n-glycero-3-phosphocholine, the t-0-trimstilmethyluk) group was split off to form a 2-tetracanoyl-8n-glycero 3-phosphocholine reacted with oleic acid anhydride to produce
1-oleoyl 2-tetracosano-l-8n-glycera 3 -phosphocholium and chromatographically purified.
PRI me R 33, A. 1-0-Tripheny.eptil-2 - oleoyl-8n-glycero-3-phosphorus- (M-Trnfeki.pma g Lin) -ethanol amine,
386 mg of oleic acid and 255 carc) -schmidazole in 10 ml of tetrahydrofuran are transferred over






,,
299916

45 min at room temperature in the absence of moisture. After the introduction of 480 mg of 1-0-triphenylmethane 1-5p-glycero 3-phospho- (H-triphenylmethyl) -thanolamine, 3.1 mg of a solution of 41 mg of metallic sodium in dilethyl sulfoxide is added to the oleoimimidazolide solution. Leave to react for 20 minutes.
Q at room temperature and neutralize. Then 17.8 ml O, 1 n. aqueous acetic acid. The mixture is placed in ice water, extracted three times with diethyl ether, the combined organic phases are washed twice with water, dried with N32864 dried and then the solvent is removed in vacuo. After purification of the crude product by chromatography on silica gel using gradients
2Q petroleum ether-chloroform gives 633 mg of the pure title compound. Thin layer chromatography of the product on silica gel (chloroform-methanol solvents 9: 1) shows:, g single spot. R 0.6.
NMR-H-spectrum, 5 ppm (AHSC): 0.88 (-CH,); 1.26 (-CHj-); 1.8-2.3 (-CHN-CHg-C C-, -CHN-CHg-CH-C 0); 351-4.3 (glycerol and ethanolamine CH); 5.1 (glycerol C2-C-H, oleoyl) j 7.25 (triphenylmethyl, C-H).
B. 2-Oleoyl-5n-glycero-3-phospho- (N-triphenylmethyl) ethanolamine.
A solution of 406 mg of 1-O-triphenylmethyl-2-oleoyl-8n-glycero-3 phospho- (H-tri30
30 ml of methylene chloride and 1 mp of a 20% solution of boron trifluoride in methanol are stirred for 30 minutes at. Then 30 ml of methylene chloride is added, washed three times with water and the organic phase is dried over Na, j, 804. B, 1-Palmitoyl-2-oleoyl-8n-glycerol-po-3-foxo- (N-triphenylmethyl) ethanolamine.
tilaminopyridine
To the solution of the obtained 2-oleoyl-8n-glycero-3-phospho- (M-triphenylmethyl) -ethanolamine, 1.3 g of palmitic anhydride and 230 mg of dimethyl reaction are added
stir for 6 hours at 20 ° C. Then the solvent is removed in vacuo. After chromatography of the residue on silica gel using gradients of petroleum ether — chloroform, 361 mg of pure acylated product are obtained. Connection in the case of fine-layer chromatography on silica gel (solvent:
chloroform - methanol .9: 1 shows Ri 0.6,
(CDCl):
0.88 (-CHj); 1.22 (-CHN-); 1.55 (-CH-G-CO); 1.8-2.3 (-CH. ,, - C.)
single spot.
NMR-H-spectrum, S ppm
3.1-4.3 (glycerol and ethanolamine C-H) 5.1 (glycerol C-H, oleoyl); 7.23 (triphenylmethyl C-H).
G. 1-11 almitoyl-2-oleoyl-8n-glyzro-3-phosphoethanolamine. : A solution of 190 mg of 1-palmitoyl-2-ole-Oyl-3p-3-glycero- (N-triphenylmethyl) - e | tanolamine in 12 ml of a mixture of 6 ml of methylene chloride and trifluoroacetic
Rf
acids in the absence of moisture are left to stand for 5 minutes at 0 ° C. After that, they are neutralized with 23 5J% -Horo aqueous ammonia solution. The phase is separated and extracted with a mixture of chloroform and methanol 2: 1. The drained organic phases are washed in the | rdoy. After removing the solvent in | Vacuum The crude product is purified by chromatography on silica gel using chloroformine-methanol gradients. Compound-1 in the case of thin-layer chromatography on silica gel (solvent: chloroform — methanol — 25% ammonia solution, 50–25; 6 shows a single spot. –0.5.
PRI me R 34. A. 1-0-Triphenylmethyl-2 linoleoyl-3n-glycero-3-phosph (H triphenylmethyl-1-sh) -ethanolamine
464 mg of linoleic acid and 365 mg of carbonyldiimidazole. In .15 ml of tetrahydrofuran are introduced into the reaction E for 45 minutes at 20 ° C. The solution of the resulting acyl imidazole is added ™ to 530 mg of the 1-0-trifu shlmethyl-8n-glycero-3-phospho- (N-triphenylmethyl) ethanolamine. After removing the solvent in vacuo, the residue is dissolved in 15 ml of dimethyl sulfoxide, and the reaction is carried out by adding a catalytically active acid binder, which is obtained by dissolving 49 mg of metallic sodium in 3.7 ml of dimethyl sulfoxide. The reaction mixture at
shake occasionally for 20 minutes at 20 ° C and then. H (3) neutralized with 10.14 ml of aqueous 0.1 N acetic acid solution. Then extracted twice with 20 ml of a mixture of chloroform and methanol 2O1 (by volume) The combined organic phases are washed successively.
8 ml of a mixture of chloroform - methanol. - water NH (3:48:47 volumes) and chloroform with methanol and water (3: 48:47. by volume). After removal of the solvent in vacuo and evaporation

in the presence of benzene, a crude product is obtained which, after purification by chromatography under moderate (moderate) pressure on silica gel using chloroform-methanol gradients, gives 670 mg (yield 92%) of pure compound. A pure compound in the thin-layer chromatogram on silica gel (solvent; methanol – chloroform 8; 3 by volume) shows a single spot. RI 0.61.
B. 2-Linoleoyl-5p-glycero-3-fss-pho- (M-triphenylmethane 1) -ethanolamine.
From 435 mg of 1-0-triphenylmethyl-1-5n-glycero-3-phospho- (H-tr | Ifenylmethyl) -ethanolamine, the 1-Og-triphenyl methyl group is cleaved from 0.5 ml of a 20% solution of boron trifluoride in methanol,
B. 1-Oleoyl-2-linoleoyl-5n-glycero-3-phospho- (N-triphenylmethyl) -tranolamine.
G. 1-Oleoyl-2-linsleoyl-5n-glycero-3-phosphoethanolamine.
2 Linoleoyl-8n-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine, by reaction with oleic acid anhydride, is further adylated to 1-oleoyl-2-linoleoyl-5n-glycero-3-phospho- (N-triphenylmethyl) -ethanol an N-triphenylmethyl group is cleaved onto and from it.
Example 35 A. A. 1-0-Triphenylmethyl-2-stearo.sh1-8p-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine.
380 mg of 0-triphenylmethyl-5n-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine is obtained by reacting 350 mg of stearoylimidazolide. B 2-Stearoyl-5 p-glycero-3-phosphorus- (N-sulfate I-methyl) -ethanolamine.
Obtained by crushing a 1–0-trifegalgalilny group obtained from the product obtained in stage A
B 1.-Oleosh1-2-stea: royl-8n-glycera o-3-fox- (N-type: yl-methyl) -eta.- nolamine ..
G, 1-Oleoyl-2-stearosh1-Zn-glycero-3-phosphoethanolamine.
The 2-stearosh-1-8p-glycero-3-phospho (M trife 1-1ylmethyl) ethanol obtained in stage B is reacted with 1.5 g of oleic anhydride to give 340 mg of 1 oleoyl-2-stea 1422999
royl-Sn-glycero-3-phospho- (N-triphenylmethyl) ethanolamine. Distillation yields 250 mg of 1-oleoyl-2-stearoyl-5n-glycero-3-phosphoethanolamine, from which by chromatography on silica gel using gradients of chloroform - 140 mg of pure methanol is obtained in methanol in the TB layer chromatogram (solvent: chloroform - methanol - 25% aqueous ammonia, 50: 25: 6 by volume) in a single spot. Rjt 0.5
PRI me R 36. 1-0-Triphenylmethyl-2-acetyl-5p-glutsero-3-phospho- (K-triphe10
nilmethyl) -ethanolamine.
300 mg of 1-0-triphenylmethyl-3n-glycene-po-3-foxo- (N-triphenylmethyl) -ethanolamine are reacted with 500 mg of acetic anhydride in 5 mp anhydrous. pyridine for 20 h at. Then add to 50 ml of ice water and extract twice with a 2: 1 mixture of chloroform and methanol (by volume). The combined organic phases are washed twice with a mixture of chloroform, methanol and water 3:48:47 (by volume), dried over sodium bicarbonate and brought to dryness in vacuo. Residual pyridine is removed by evaporation in the presence of 20
450 mg of 1-0-triphenylmelsh1-5n-glycero-3-phospho- (H-triphene-shmet1sh) -ethano- (according to example 2) are brought into contact with 900 mg of propionic anp-schrid in 10 mg of pyridine at 30 ° C to obtain 1-0-triphenylmethyl-2-propionyl-5n-lycero-3-phospho- (K-triphensh1-methyl) -e anolamic, process and. clear. Yield 220 mg (45% of theory). Oh, 5.-The resulting product is converted to the following compounds:
2-propionyl-8n-glycero-3-phospho- (H-triphenylmethyl) -ethanolamine;
1-palmitokp-2-propionyl-5p-gly25
cero-3-ospho- (N-triphenylmethyl) -tetapam11n;
1-Palmktoz-sh-2-propionyl-8n-glycero-3-phosphoethanolamine.
PRI me R 38. 1-0-Triphenylmethyl-2-butyr1-1l-8n-glccero-3-phospho- (K-triphenol-1m1p) -ethanolamine.
500 mg of 1-0-triphenylmethyl-5p-glycero-3-phospho- (K-triphenylmethyl) -ethanolamine are acylated with butyrylimidazolide, which is obtained from 132 mg of butyric acid and 267 mg of carbonyldiazole, treated, and purified. The resulting product (300 mg, yield 56%. RJ, - 0.52, on silica gel, solvent: chlorine of toluene, the crude product of purification — methanol 8: 2, by volume) is converted by chromatography under average (moderate) pressure on silica gel using gradients chloroform - methanol. The obtained pure substance (128 mg, 40% yield) on a thin layer of silica gel on silica gel (solvent: chloroform - methanol 8: 2 by volume) shows a single spot: K / - 0.50 ..
NMR n-spectrum, S ppm (CDC1, -CD, OD S 2: 1, by volume): 2.0 (HjC-CG, singlet, 3FI) I 2.8-4.2 (glycaryl and choline - СЬ%) | 3.16 (gliderol-CH, multiplet, 1H) f 7.23 (aromatic, 30 N).
35
1 0-triphene Rl-Imethyl-2-acetyl-Sn-glyamine 45 acylate isobutyryl imidazoles 1dero 3 phospho- (M-triphenylmethyl) -ethanolamine into the following further products:
2-acetyl, l-3p-glycero-3-foxo- (N-triphenylmethyl) ethanolamine;
1 - palyFP 01-sh-2-acetyl-5p-glycero-3-foxo- (N-triphenylmethyl) -ethanolamine
1 - pali {Itoyl-2 acetsh: -5p-glycero Z-phosphate ethanol-iH,
PRI me R 37., 1-0-Triphenyl-chetyl 2 propionyl-3n-glycero-3-phospho- (N-hydrogenphenylismethy. Rt) Ethanolamia.
0
20
450 mg of 1-0-triphenylmelsh1-5n-glycero-3-phospho- (H-triphene-shmet1sh) -ethano- (according to example 2) are brought into contact with 900 mg of propionic anp-schrid in 10 mg of pyridine at 30 ° C to obtain 1-0-triphenylmethyl-2-propionyl-5n-lycero-3-phospho- (K-triphensh1-methyl) -e anolamic, process and. clear. Yield 220 mg (45% of theory). Oh, 5.-The resulting product is converted to the following compounds:
2-propionyl-8n-glycero-3-phospho- (H-triphenylmethyl) -ethanolamine;
1-palmitokp-2-propionyl-5n-gly.
five
cero-3-ospho- (N-triphenylmethyl) -tetapam11n;
1-Palmktoz-sh-2-propionyl-8n-glycero-3-phosphoethanolamine.
PRI me R 38. 1-0-Triphenylmethyl-2-butyr1-1l-8n-glccero-3-phospho- (K-triphenol-1m1p) -ethanolamine.
500 mg of 1-0-triphenylmethyl-5p-glycero-3-phospho- (K-triphenylmethyl) -ethanolamine are acylated with butyrylimidazolide, which is obtained from 132 mg of butyric acid and 267 mg of carbonyldiazole, treated, and purified. The product obtained (300 mg, 56% yield. R.J., - 0.52, on silica gel, solvent: chlorine is further incorporated into the following compounds: 2 butyryl-3n-glycero-3-phospho- (Ctriphenylmethyl) -ethanolamine;
1-palmitosh 1-2-butyryl-5p-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine;
1 palmitoyl-2-butyryl-Zp-glycero-3-phosphoethanolamine.
PRI mime 39. 1-0-Triphenylmetsh1-2-isobutyryl 5n-glycero-3-phospho- (H-triphenylmethyl) -ethanolamine.
500 mg of 1-0-triphesh1lmethyl-Zp-glycero-3-phospho- (K-triphenylmethyl) -etheno0
five
The house, which is obtained from 132 mg of iso-butyric acid and 267 mg of carbonyldiimide ol, is processed and purified. The resulting product (272 mg, 50% yield, RJ 0.53, on silica gel, solvent: chloroform-methanol 8: 2 , by volume) has the following spectroscopic data:
NMR n-spectrum, S ppm (AHSC-CDjOD, 2: 1 by volume): 1.2 (CH, 6H); 2.5-359 (glycerol and choline - CE, 8H) J 5j.26 (glycerol-CH, multiplet, 1H) | 7523 (aromatic, ZON).
21
1-0-Triphenylmethyl-2-isobutyryl 8th glycero-3-phospho- (N-triphenylmetn.) - ethanolamine is converted to the following compounds:
2-isobutyryl-811-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine;
: 1-oleoyl - 2-isobutyryl-3n-glycerol-3-phospho- (K-triphenylmethyl) -ethanol- aH; ten
1-oleoyl 2-isobutyrs 1-8p-glycero-ZN osfoethanolamine.
: EXAMPLE 40. 1-O-Triphenylmethyl- 2- (3; trifluoromethylbutyryl) -Sn-glyce- | pb-3-phospho- (H-triphenylmethyl) -ethanol-mHe,
; 900 mg of 1-0-triphenylmethyl 8p-glycrro-3-phospho- (K-triphenylmethyl) -etha-i-nrlamine and 500 mg of 3-trifluoromethyl-20-tiriline hydride in 50 ml of methylene chloride after the addition of 300 mg of 4-H, The N-dimethylaminopirndine is stirred for 4 hours at 20 Cc. After adding water, the organic phase is dried over and evaporated in vacuo. After purification of the crude product by rty chromatography under medium (moderate) pressure on silica gel using chloroform-methanol Q in the presence of 0.5% by volume aqueous solution of NH, 820 mg is obtained (yield 76%, R | - 0.50, on silica gel, solvent; chloroform - methanol 8: 2, by volume) - 1-p-triphenylmethyl-2- (3-trifluoromethyl-butyryl) -Sn-glycero-3-phospho- (N-triphenyl-1-methyl 1) -ethanolamine. This product is converted to the following compounds:
 . 2-Cz-trifluoromethylbutyrsh1) -8n-glycero-3-frsfo- (K-triphenylmethyl) zanolamine;
1-papmitoyl-2- (3-trifluorometh-1-butyryl) -Sn-gly-dero-3-phospho- (N-triphenylmethyl) -ethanols n |
1-palyshtosh1-2- (3-trifluoromethyl-butyr1sh) -Sn-glycero-3-phosphoethanol- -
min
EXAMPLE 41. 1-O-Triphenylmethyl-2- (2-butyl exanoyl) -Sn-glider O-3-phospho- (H-triphenylmethyl) -e-tanolamine.
420 mg of 1 0-triphene1-methyl-5n-glycene-50 ro-3-phospho- (H-trifensh1methyl) -ethanol amine are acylated with 2-butylhexanosilimimidozolide, obtained from 200 mg of 2-butylhexanoic acid and 210 mg of carbonyldiimidazole. - 55 wallow and clean. The obtained product (370 mg, yield 70, 0.55, on silica gel, solvent: chloroform - me142299922
Tacol 8: 2, by volume is converted to the following compound:
2- (2-butylhexanesyl) -5n-glydero-3-phospho (N-triphenylmethyl) -ethanol-amine;
1-palmitoyl-2- (2-butylhexanoyl) -5n-glycero-3-phosph6- (M-triphenylmethyl) -ethanolamine;
1-palmitoyl-2- (2-butylhexanoyl) - Sn-glycero-3-phosphoethanolamine.
PRI me R. 42. 1--0-Trifensh1methyl-2-arachidonoyl-5n-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine.
500 mg of 1-0-triphenylmethyl-5p-glycero-3-phospho- (H-triphenylmethyl) -e-tanolamine and 890 mg of arachidonic anhydride in 50 ml of methylene chloride after the addition of 300 mg of 4-H, The N-methylaminopyridine is stirred for 4 hours at 20 ° C. After the addition of water, it is shaken, the organic phase is dried over and evaporated in vacuo. After purification, the crude product by medium pressure chromatography on silica gel using gradients of chloroform - methanol in the presence of 0.5% by volume of aqueous NHj gives 520 mg (yield 82%, Ri 0.61, silica gel: e, solvent: chloroform - methanol 8: 2, by volume) 1-0-triphenylmethyl-2-arachidonoyl-5n-glydero-3-phospho- (N-triphenylmethyl) - ethanolamine. This product is converted to the following compounds:
2-arachidonoyl-5n-glycero-3-fss- (L-triphenylmethyl) -e: ganolamine;
1-palmitoyl-2-arachidonoyl-Ep-glycero-3-phospho- (H-triphenylmethyl) -ethanolamine;
1-palmitoyl - 2-a rachidonoyl-8n- glycero-3-phosphoethanolamine,
 EXAMPLE 43 1-O-Triphenylmethyl-2-tetracosanoyl-8n-glycero-3-phospho- (N-triphenylmethyl) ethanolamine.
500 mg of -1-0-triphenylmethyl-Zp-glycero-3-phospho- (N-triphenylmethyl) -ethanolamine (according to Example 2) are acylated with tetracosanoylimidazolide, which is obtained from 1.7 g of tetracosanoic acid and 267 mg of carbonyldiimide- ash is treated, and cleaned. The product obtained (640 mg, yield 90%, R 0.6, on silica gel, solvent: chloroform — methanol 8: 2, by volume) is converted to the following compound:
2-tetracosanoyl-8n-glycero-3-phosphorus- (Hn tphenylmeth:) - ethanolamine;
40
1-palmitoyl-2-tetrax) zanosht-5p-glycepo-3-phospho- (N-triphenylmethyl) -ethanolamine;
1-palmitoyl-2-tetracosanoyl-5n-glycero-3-phosphoethanolamine.
EXAMPLE 44. 1-Stearoyl-2-oleoyl-Sn-glycero-3-phosph-(N-triphenyl-methyl) -ethanolamine.
To a solution of 2-oleoyl-5p-glycero-3-phospho- (H-triphenylmethyl) -ethanolamine, which is obtained from 1.1 g of 1-0-triphenylmethyl-1-oleoyl-5p-glycero-3-phospho- (5 H-triphenylmethyl) -ethanolamine in 150 ml of methylene chloride, 3.5 g of stearic anhydride and 625 mg of 4-K, M-dimethylaminopyridine are added. The reaction mixture is stirred for 3 hours at 20 ° C and then mixed with 45 MP of chloroform-methanol-water (3:48:47 by volume) and 75 ml of methanol. After shaking, the lower phase is separated and washed twice more with 45 MP with a mixture of chloroform - methanol - aqueous ammonia (3:48:47 in volume), and once with a mixture of chloroform - methanol - water (3:48:47 volumes). After removing the solvent in the vacuum, the crude product is purified by medium pressure chromatography on silica gel using gradients of chloroform — methanol, and 990 mg are obtained (yield 89%, R 0.6, on silica gel, solvent; chloroform — methanol 9 : 1, by volume) of a substance.
G. 1-Stearoyl-2-oleo1-8p-glycero-3-phosphoethanolamine.
1 t of 1-stearoyl-2-oleoyl-5p-glycero 3-phospho- (N- triphenylmethyl) - | tanolamine in 30 MP of trifluoroacetic acid is defended for 5 min at OS, then it is processed and 550 mg of pure substance is obtained (yield 72% ), which on a thin-layer chromatogram on silica gel (solvent: chloroform - metaol - 25% MMi-j-iK 50: 25: 6, by volume) shows one:; the second spot. R 0
Example 45. B. 1g Stearosh1-2-linoleoyl-3n-glycero-3-phospho- (K-triphenylmethyl) -ethanogtmin.
G. 1-Stearosh1 2-linoleoyl-8n-glycero-3-phosphoethanol-shn.
2 Linoleoyl-5n-gpitsero-3-phospho- (N-triphenklemetsh) -ethanolamine, obtained from 700 to; 1 H) -trifenylmethyl-2-pnolleoc-g ;; ito 3-phospho- (K-tr ife-sh-methyl) ethanolamine in methylene chloride de, mixed with 2, g of anhydride


stearic acid and 390 mg of 4-N, N-dimethylaminopyridine and stirred for 3 hours at ambient temperature. The resulting product is reacted with trifluoroacetic acid and purified. Thus, 250 mg of pure 1-stearosh1-2-linole-ogl-5p-glycero-3-phosphoethanolamine, which, on a thin-layer chromatogram on silica gel (solvent: chloroform-methanol, as in Example 26), gives a single spot. . 0.5
Thus, the shattering method allows obtaining new triphenylmethyl-derivatives of Sn-glycero-3-phosphonic focholine and 5n-glycero-3-h5 bosfo-ethanol-amine, the use of which in the synthesis of biologically active phospholipids simplifies the process of obtaining the latter.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining triphenylmethyl derivatives of Sn-glycero-3-phosphocholine and Sn-glycero-3-phosphozthanolamine of the general formula
NgS-O-T
NOS-N O
II + / Rf
H2C-0-P-0-CH2CH2N B2
where T is not substituted or mono- or multiple substituted by C, - Cg-alkyl. C, - Sat - alkoxy or halogen of a triphenylmethyl group; R, RJ R, CH ,; R, H, RJ-triphenylmethyl, unsubstituted or substituted by -alkyl (Cf-Cb), 2-chloro, 3-bromo, 4-alkoxy-C (-C -group, denoted by the fact that Sn -glycero-3-phosphocholine or Sn-glycero-3-phospho- (L-trifecylmethyl) -ethanolamine of the general formula
I wear about
H2C-0-P-OCH2CH2N Rl
ABOUT
R.
where R (-Rj have the indicated meanings, in the form of a base or a cadmium or zinc complex, is reacted with the reactive tri2142299926
phenylmethyl derivative of total for-in inert organic solvent
Tsulypri 20-135 C in the presence of a quality: X, ve proton acceptor tertiary
. T has | the indicated values; amine or heterocyclic base X is chlorine, bromine, iodine; 5kI.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

DE2820893C2|1978-05-12|1986-02-20|A. Nattermann & Cie GmbH, 5000 Köln|Structural analogs of natural phospholipids and processes for making these compounds|

---

IT1123187B|1979-09-17|1986-04-30|Lpb Ist Farm|PROCESS FOR THE PREPARATION OF L-ALPHA-GLYCERYLPHOSPHORYLCHOLINE|

---

DE3130867A1|1981-08-04|1983-02-24|Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen|INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF GLYCERINE DERIVATIVES|

---

AT383130B|1984-05-15|1987-05-25|Chemie Linz Ag|METHOD FOR THE PRODUCTION OF PHOSPHATIDYLCHOLINES AND PHOSPHATIDYLETHANOLAMINES SUBSTITUTED DIFFERENTLY AT C1 AND C2 OVER THE NEW COMPOUNDS 1-0-TRITYLGLYCEROPHOSPHOCHOLIN OR RELATED |AT383130B|1984-05-15|1987-05-25|Chemie Linz Ag|METHOD FOR THE PRODUCTION OF PHOSPHATIDYLCHOLINES AND PHOSPHATIDYLETHANOLAMINES SUBSTITUTED DIFFERENTLY AT C1 AND C2 OVER THE NEW COMPOUNDS 1-0-TRITYLGLYCEROPHOSPHOCHOLIN OR RELATED |

---

DE3638687A1|1986-11-13|1988-05-19|Lentia Gmbh|ONE-STEP METHOD FOR PRODUCING MIXED SUBSTITUTED 1,2-DI-ACYL-SN-GLYCERO-3-PHOSPHOCHOLINES|

---

AT388165B|1986-12-10|1989-05-10|Chemie Linz Ag|One-stage process for the preparation of 1,2-diacyl-SN- glycero-3-phosphocholines with mixed substituents|

---

JP2657486B2|1987-02-20|1997-09-24|花王株式会社|Detergent composition|

---

US5144045A|1990-11-13|1992-09-01|American Cyanamid Company|Phosphocholine derivative inhibitors of phospholipase A2|

---

US5698537A|1996-06-18|1997-12-16|Clarion Pharmaceuticals Inc.|Method of lowering the viscosity of mucus|

---

US6838452B2|2000-11-24|2005-01-04|Vascular Biogenics Ltd.|Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis|

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US7964641B2|2003-08-18|2011-06-21|Btg International Limited|Treatment of neurodegenerative conditions|

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US9006217B2|2007-01-09|2015-04-14|Vascular Biogenics Ltd.|High-purity phospholipids|

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US7807847B2|2004-07-09|2010-10-05|Vascular Biogenics Ltd.|Process for the preparation of oxidized phospholipids|

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US8569529B2|2007-01-09|2013-10-29|Vascular Biogenics Ltd.|High-purity phospholipids|

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GB0425932D0|2004-11-25|2004-12-29|Btg Int Ltd|Structured phospholipids|

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NZ592357A|2008-11-06|2013-09-27|Vascular Biogenics Ltd|Oxidized lipid compounds and uses thereof|

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ES2855299T3|2014-11-26|2021-09-23|Vascular Biogenics Ltd|Oxidized lipids and fibrosis treatment or prevention|

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US9771385B2|2014-11-26|2017-09-26|Vascular Biogenics Ltd.|Oxidized lipids|

---

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---

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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AT0159084A|AT383130B|1984-05-15|1984-05-15|METHOD FOR THE PRODUCTION OF PHOSPHATIDYLCHOLINES AND PHOSPHATIDYLETHANOLAMINES SUBSTITUTED DIFFERENTLY AT C1 AND C2 OVER THE NEW COMPOUNDS 1-0-TRITYLGLYCEROPHOSPHOCHOLIN OR RELATED |

---