Method of obtaining derivatives of beta-d-phenylthioxylozides

专利摘要:
The invention relates to heterocyclic substances, in particular the production of β-D-phenylthioxy-amide derivatives of the total type, where RH, CL, NO 2 , CN A-sulfur or oxygen B- -CH 2 - -CH (OH) - C-O Y-H, acetyl group, or their epimers, when B = -CH (OH) -group with antithrombotic activity, which can be used in medicine. The goal is to create new, more active substances of the specified class. Synthesis is carried out by the reaction of the corresponding diphenyl compound with chloroacetylthioxyloside or acetylthioxylose ip II, III, IV where Y is the acetyl group HAL-CL, BR A and B - see above. The process is conducted in an inert solvent at a molar ratio of compounds II: III or IV-1: (1.1-1.2) in the presence of an acid or Lewis acid acceptor. If necessary, remove the acetyl group at a temperature from room temperature to reflux of the reaction mixture in a C 1 -C 4 alcohol medium (preferably in methanol) in the presence of a metal alcoholate, for example sodium methoxide. New compounds are 2–16 times higher in activity than known substances, and their toxicity is higher in D 50 in mice and rats when administered orally and is equal to 5 g / kg. 3 tab.
公开号:SU1567124A3
申请号:SU884355706
申请日:1988-05-03
公开日:1990-05-23
发明作者:Самрет Сот；Беллами Франсуа；Миллет Жан
申请人:Фурнье Инновасьон Э Синержи (Фирма)；
IPC主号:

专利说明:

where Y is an acetyl group; Br; A and B - see above. The process is carried out in an inert solvent at a molar ratio of compounds 11: 111 or IV-1: (1.1-1.2) in the presence of an acid or Lewis acid acceptor. If necessary, remove the acetyl group at a temperature from room temperature to boiling the reaction mixture under reflux in a C-C alcohol (ray in methanol) in the presence of a metal alcoholate, for example sodium methoxide. The novel compounds are 2–16 times higher in activity than known substances, and their toxicity is higher in LD50 in mice and rats when administered orally and is 5 g / kg. 3 tab.
eight
 04
This invention relates to a process for the preparation of -U-phenylthio-xyloside derivatives of the general formula
YO HN-S
Jrtnk
YO OY
where R is hydrogen, chlorine, nitro or cyano;
A - sulfur or oxygen;
In SNg, SNON or CO-group;
Y is hydrogen or acetyl group, when B is CHOH-group,
are in the form of epimers with antithrombotic activity.
The purpose of the invention is to obtain new thioxylosid derivatives possessing increased antithrombotic venous activity in comparison with analogues.
Example 1: Preparation of 0-4- (4-nitrobenzoyl) -Phenyl-dimethylthiocarbo- 25 mate.
To a suspension of L, 4 g (0.0224 mol) (4-hydroxyphenyl) - (4-nltrophenyl) -methanol in 60 ml of water was added 1.4 g (0.025 mol) of the tableted hydro-jin eid.
9.5 g (0.030 mol) of the product obtained in example 2 is dissolved in 90 dioxane. 0.039 mol of sodium methane (8% solution in methyl) is added and monitored by thin layer chromatography, eluted with a mixture of hexane and ethyl acetate (1: 1 by volume), the initial product disappears. After stirring for 1 hour at room temperature the reaction mixture is acidified, hydrolyzed with 1 hydrochloric acid solution at 0 ° C. The target product is extracted with ethyl acetate. The resulting organic phase is washed with water until neutral pH, dried over sulfate m
35
potassium oxide The reaction mixture is heated at 50 ° C for two hours with vigorous stirring. The mixture was brought to 0 ° C and a solution of 3.5 g (0.029 mol) of dimethylthiocarbamoyl chloride in 15 ml of tetrahydrofuran (TF) was added dropwise. After the addition is complete, the reaction mixture is stirred at 0 ° C for 15 minutes, then at 20 ° C for 1 hour. The reaction medium is then hydrolyzed in 25 ml. 1n. NaOH at Q ° C. The resulting precipitate is filtered and washed with water until neutral pH. After drying, it is recrystallized from a mixture of methy-
nor, filtered and the solvent is evaporated. Receive 3 g (yield 93% of the desired product, melting at 116-117 ° C.
Example. Preparation of f (4 nitrobenzoyl) -phenyl -2,3,4-t ri-O-acetyl-1, 5-dithio-ft-1) xylo-pyran
A mixture of 150 ml of anhydrous benzene, 150 ml of nitromethane and 30 g of a 0.4 nm molecular sieve was stirred at room temperature for 15 minutes, then 14.2 g (0.0552 mol) of mercury cyanide (Hg (CN) After stirring, were added to the 19.6 g (0.0552 mol) of 2,3,4-tri-0-acetyl-1-bromo-5-thio-o (, - and-xyloiranoside, then 13 g (0.050 mol) (4-merkaitophenyl) - (4-nitrophenyl) -methanol in small portions. At the end of dolenchloride with dioxane. 5.9 g 4s of boiling are obtained. the reaction mixture is heated
/ / - h. ,
(yield 84%) of the desired product, melting at 168 C.
Example 2. Preparation of S-4- (4-nitrobenzoyl) phenyl-dimethylthiocarbamate.
Under nitrogen and with stirring, 5 g of the product obtained in Example 1 is heated at 200-210 ° C for three hours. The disappearance of the starting product is monitored by thin layer chromatography, by diluting a mixture of toluene with ethyl acetate (4: 9 by volume). Get 5 g (yield - the number
50
55
at 40–50 ° C for four hours, then filtered through Celite (diatomaceous silica
for filtering).
i
The residue is washed several times with ethyl acetate. The resulting organic phase is washed successively with a saturated solution of sodium chloride, 1N. NaOH solution, sodium chloride solution, then with water until neutral pH. The magnesium oxide is dried over a gland and the solvent is evaporated. The resulting yellowish oil is dissolved in 50 ml of ester and allowed to stand.
ten
15
20 671244
quality of the target product, melting at 198-199 C.
Example J. Preparation of (4-mercaptophenyl) - (4-nitrophenyl) -methanol under nitrogen.
9.5 g (0.030 mol) of the product obtained according to example 2 is dissolved in 90 ml of dioxane. 0.039 mol of sodium methylate (8% solution in methanol) is added and monitored by thin layer chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1 by volume), the disappearance of the starting product. After stirring for 1 hour at room temperature, the reaction mixture is acidified, hydrolyzing with 1N. hydrochloric acid solution at 0 ° C. The target product is extracted with ethyl acetate. The resulting organic phase is washed with water until neutral pH, dried over magheid sulphate.
nor, is filtered off and the solvent is evaporated. 3 g (yield 93%) of the desired product is obtained, melting at 116-117 ° C.
Example. Preparation of f (4 nitrobenzoyl) -phenyl -2,3,4-t ri-O-acetyl-1, 5-dithio-ft-1) xylo-pyran
eida.
l
A mixture of 150 ml of anhydrous benzene, 150 ml of nitromethane and 30 g of 0.4 nm molecular sieve was stirred at room temperature for 15 minutes, then 14.2 g (0.0552 mol) of mercury cyanide (Hg (CN) 2) was added. . After stirring for the 10 minutes at room temperature, 19.6 g (0.0552 mol) of 2,3,4-tri-0-acetyl-1-bromo-5-thio-o (, - and xyloiranoside, then 13 g (0.050 mol) (4-merkaitophenyl) - (4-nitrophenyl) -methanol in small portions. After the addition is complete, the reaction mixture is heated
/ / - h. ,
at 40–50 ° C for four hours, then filtered through celite (diatomized silica
for filtering).
i
The residue is washed several times with ethyl acetate. The resulting organic phase is washed successively with a saturated solution of sodium chloride, 1N. NaOH solution, sodium chloride solution, then with water until neutral pH. The magnesium is dried over a gallon, filtered and the solvent is evaporated. The resulting yellowish oil is dissolved in 50 ml of ester and allowed to stand.
The reaction time is 4 hours. The product crystallizes. After filtering, 17.2 g of the desired product of configuration ft are obtained. The mother liquors are then evaporated and the products they contain are separated by flash chromatography, eluting with a mixture of toluene and ethyl acetate (8: 1 by volume). Finally, 18.6 g of isomer ft (yield 70%), melted at 166-169 ° C, -p + 92 °,, 5 (CHCl1), and 3.9 g of isomer v (yield 15%) are obtained as foam 286, 5 (SNSC).
PRI me R 5. Obtaining H (4-nitrobenzoyl) fenshG -1, 3-dithio- -D-xylopyranoside.
In a nitrogen atmosphere, 18 g (0.0337 mol) obtained in example 4 product
tri-O-acetyl-1, 5-dithio-p-1) xyleneolanoside.
In a nitrogen atmosphere, 7 g (0.0131 mol) of 4- (4-nitrobenzoyl) -fenhG - 2, 3,4-tri-O-acetyl-1, 5-dithio-p-1) xylene glycine, obtained by Example 4, is dissolved in 70 ml of methanol, and then 0.5 g (0.0131 mol) of sodium tetrachlorohydride is added to the reaction mixture at room temperature. Stir for 30 minutes, then the reaction mixture is acidified by adding Amberlite 1R 120 (H) to resin. After-) 5 After filtration, the filtrate is evaporated. 6.3 g of the desired product are obtained (yield 90%) as a yellow foam, about ™ +29, with (), 15 (methanol).
Formula 8. Preparation of 4- (4-dissolved in a mixture of 100 ml of ethyl acetate 20 nitrobenzyl) phenyl -2,3,4-tri-O-acetone with 300 ml of methanol, then added tyl-1, 5-dithio-P-and-xylopyranoids.
8.5 ml of sodium methoxide as a 3% solution in methanol. After keeping for two hours while stirring at room temperature, the precipitate formed is filtered off and washed twice with 50 ml of methanol. The resulting filter is neutralized with Amberlite 111 120 (H) resin until then after filtration the solvent is evaporated and the evaporation residue thus obtained is combined with the previously obtained precipitate. 13.8 g of the expected product are obtained (quantitative yield), melting at 183 ° C, 5, (DMSO).
EXAMPLE 6 Preparation of 4- (4-nitrophenyl) oximeshG - phenyl-1, 5-dithio p 0-xylopyranoside.
Under nitrogen atmosphere, 1.2 g (0.0315 mol) of sodium tetraborogilride was added to a suspension of 11.2 g (0.0275 mol) of the product obtained in Example 5. The solution became homogeneous after two hours of stirring at 0 ° C. The reaction mixture is neutralized with Amberlite R 120 (H) resin before, and after filtration the solvent is evaporated. Thus, the resulting evaporation residue is purified on a silica column, eluting with ethyl acetate. 11.2 g (quantitative) of the desired product is obtained, melting at 80 ° C, oip +8, 5 (methanol).
PRI me R 7. Preparation of (4-nitrophenyl) oxymethyl-phenyl-2,3,4 In a nitrogen atmosphere 3.3 g (0.00616 mol) of 4- (4-nitrophenyl) -hydroxy-phenyl -2 , 3,4-tri-0-acetyl-
25 1,5-dithio-DCH) -xylopyranoside, obtained in example 7, are suspended in 17 ml of methylene chloride. The reaction medium is cooled to 0 ° C, then 17 ml of trifluoroacetic acid are added at once.
30 acids and 470 mg (0.0123 mol) of sodium tetrachlorohydride are added in small portions. Stirring of the medium is continued at 0 ° C for 1.5 hours. The reaction medium is hydrolyzed with ice and extracted with methylene chloride. The resulting organic phase is washed with a saturated solution of bicarbonate, then with water until neutral pH. The organic phase is dried, filtered, then evaporated. Get
35
40
45 i
2.77 g (yield 87%) of the desired product, obtained as a foam.
Example 9. Preparation of 4- (4-nitrobenzyl) -phenyl -1,5-dithio-B-U-xylopyranoside.
50
55
2.79 g (0.00537 mol) of 4- (4-nitrobenzyl) phenyl -2,3,4-tri-0-acetyl-1,5-dithio-i-xylopyranoside prepared according to example 8, suspended in 40 ml of methanol, then with stirring at room temperature, 0.15 ml of sodium methoxide is added as an 8% solution in methanol. After stirring for 12 hours at room temperature, sodium methoxide is neutralized with Amberlitk 1R 120 (H) resin. The reaction medium is filtered, evaporated, then the evaporation residue obtained in this way
Under a nitrogen atmosphere, 3.3 g (0.00616 mol) of 4- (4-nitrophenyl) -oxyl-phenyl -2,3,4-tri-0-acetyl-
5 1,5-dithio-DCH) -xylopyranoside, obtained in example 7, are suspended in 17 ml of methylene chloride. The reaction medium is cooled to 0 ° C, then 17 ml of trifluoroacetic acid are added at once.
0 acid and 470 mg (0.0123 mol) of sodium tetrachlorohydride are added in small portions. Stirring of the medium is continued at 0 ° C for 1.5 hours. The reaction medium is hydrolyzed with ice and extracted with methylene chloride. The resulting organic phase is washed with a saturated solution of bicarbonate, then with water until neutral pH. The organic phase is dried, filtered, then evaporated. Get
five
0
5 i
2.77 g (yield 87%) of the desired product, obtained as a foam.
Example 9. Preparation of 4- (4-nitrobenzyl) -phenyl -1,5-dithio-B-U-xylopyranoside.
0
five
2.79 g (0.00537 mol) of 4- (4-nitrobenzyl) phenyl -2,3,4-tri-0-acetyl-1,5-dithio-i-xylopyranoside prepared according to example 8, suspended in 40 ml of methanol, then with stirring at room temperature, 0.15 ml of sodium methoxide is added as an 8% solution in methanol. After stirring for 12 hours at room temperature, sodium methoxide is neutralized with Amberlitk 1R 120 (H) resin. The reaction medium is filtered, evaporated, then the evaporation residue obtained in this way
ten
15
25
thirty
purify by flash chromatography, eluting with a mixture of methylene chloride and methanol (95: 5 by volume). 1.3 g of the expected product are obtained (yield 60%), melting at 163 ° C., 5, (methanol).
PRI me R 10. Preparation of 4- (4-nitrobenzyl) phenyl -2,3,4-tri-0-acetyl-5-thio-1 $ -U-K strength of oprosnoside.
In a nitrogen atmosphere at 3 ° C, 4.5 g (0.01965 mol) of 4- (4-nitrobenzyl) phenol, 3 ml of 2,4,6-trimethylpyridine, / 0 ml of a mixture of toluene and nitromethane (1: 1 by volume) and 10 grams of 0.4 nm molecular sieve. The reaction medium is stirred vigorously for 20 minutes, then 5.8 g (0.0225 mol) of silver triflate is introduced, and 8.7 g (0.0245 mol) of 1-bromo-2,3,4 tri-0-acetyl 5-thio-6-and-xylopyranoside is added in portions of 2.17 g, in total over 30 minutes. The mixture is stirred in the absence of light and at 3 ° C. for 20 hours. The reaction medium is filtered through Celite and the precipitate is washed three times with 200 ml of ethyl acetate. The obtained filtrate is washed with 1N. HC1, then with water until neutral pH. After drying over magnesium sulphate, filtration and evaporation, the resulting yellowish oil is purified by flash chromatography, eluting with a mixture of hexane and ethyl acetate. 3 g (yield 30%) of isomer 3, melted at 1340 ° C, oiJJ -25, 5, (CHC1,), and 3 go6-isomer, o (.d +284, 4, (CHC1E)) are obtained.
II p having p 11. Preparation of Ј4- (4-nitrobenzyl) phenyl-5-thio-y-xylopyranoside.
Under nitrogen at 0 ° C, 2.5 g (0.005 mol) of the product obtained according to example 10 are suspended in 150 ml of methanol, then 0.5 ml of sodium methyl acetate is added as an 8% solution. ra in methanol. The reaction mixture is stirred for two hours;
about
Amberlite 111 120 (H) is added. When the pH becomes neutral, the methanol is evaporated under reduced pressure and the residue after evaporation lio 55 is then filized. 1.9 g (quantitative) of the desired product is obtained, melting at 16b ° C, cx -21, 5 (methanol).
15671248
Example 12. Preparation of 4 (4-nitrobenzoyl) fenshG -2,3,4-tri-O-acetyl-5-thio-p-D-xylopyranoside.
Under nitrogen, 1.1 g (0.0028 mol) of the product obtained according to example 10 are mixed sequentially, with 50 ml of anhydrous methylene chloride, 0.66 g (0.043 mol) of chromium oxide (12) and 12 ml of pyridine. The resulting mixture is heated at 60 ° C for 24 hours, then 0.66 g of chromium oxide is added and heating is continued for 24 hours. The organic phase is separated from the insoluble residue by decantation. The insoluble precipitate is treated with sodium bicarbonate solution and iso-propyl alcohol, then extracted three times with methylene chloride. The organic phases are combined and washed with sodium bicarbonate solution, with water until neutral pH, 1N. hydrochloric acid, then with water until neutral pH. Dry over magnesium sulfate, filter, and evaporate. Thus, the resulting residue after evaporation is purified by flash chromatography, eluting with a mixture of chloroform and ethyl acetate (1: 1 by volume). Obtain 0.720 g of the original product and 0.260 g (yield 24%) of the target product, melting at, o
45
-47, 3 (SNSC).
Example 13. Preparation of J4- (435 nitrophenyl) oxymethyl | phenyl} -1, 5-lithio- | 3B-xylopyranoids.
Under a nitrogen atmosphere, 5.33 g (0.01 mol) of the product obtained in Example 4 is dissolved in 50 ml of anhydrous methano-
40 la, then 0.5 ml of sodium methoxide solution is added as an 8% solution in methanol. The mixture was measured for 1 h, and the disappearance of the starting product was monitored by thin layer chromatography. When the disappearance of the starting product is complete, 0.4 mg (0.0105 mol) of sodium tetraborohydride (NaSCh) is added in small portions and the disappearance of the resulting intermediate acetylated product is monitored. Amberlite R-1R 120 (H) resin is added to the resulting mixture to neutralize the medium. After filtration, the filtrate is you-. soar to dryness. The residue after evaporation, obtained as a foam, is treated with bidistilled water, then lyophilized. 4 g of the desired product are obtained (yield quantitative
0
five
Under nitrogen, 1.1 g (0.0028 mol) of the product obtained according to example 10 are mixed sequentially, with 50 ml of anhydrous methylene chloride, 0.66 g (0.043 mol) of chromium oxide (12) and 12 ml of pyridine. The resulting mixture is heated at 60 ° C for 24 hours, then 0.66 g of chromium oxide is added and heating is continued for 24 hours. The organic phase is separated from the insoluble residue by decantation. The insoluble precipitate is treated with sodium bicarbonate solution and iso-propyl alcohol, then extracted three times with methylene chloride. The organic phases are combined and washed with sodium bicarbonate solution, with water until neutral pH, 1N. hydrochloric acid, then with water until neutral pH. Dry over magnesium sulfate, filter, and evaporate. Thus, the resulting residue after evaporation is purified by flash chromatography, eluting with a mixture of chloroform and ethyl acetate (1: 1 by volume). Obtain 0.720 g of the original product and 0.260 g (yield 24%) of the target product, melting at, o
five
-47, 3 (SNSC).
Example 13. Preparation of J4- (45 nitrophenyl) oxymethyl | phenyl} -1, 5-lithio- | 3B-xylopyranoids.
Under a nitrogen atmosphere, 5.33 g (0.01 mol) of the product obtained in Example 4 is dissolved in 50 ml of anhydrous methano-
0, then 0.5 ml of sodium methoxide solution is added as an 8% solution in methanol. The mixture was measured for 1 h, and the disappearance of the starting product was monitored by thin layer chromatography. When the disappearance of the starting product is complete, 0.4 mg (0.0105 mol) of sodium tetraborohydride (NaSCh) is added in small portions and the disappearance of the resulting intermediate acetylated product is monitored. Amberlite R-1R 120 (H) resin is added to the resulting mixture to neutralize the medium. After filtration, the filtrate is you-. soar to dryness. The residue after evaporation, obtained as a foam, is treated with bidistilled water, then lyophilized. 4 g of the desired product are obtained (yield quantitative
melting), melting at 80 ° С, о г ° +8,, 5 (methanol).
Example 14. Getting | 4- (4-nitrophenyl) oximetc G phenyl g-5-thio-fi-D-xylopyranoside.
According to the method of example 13, 4- (4-nitrobenzoyl) fenshG -2, 3-tri-O-acepsh-thio-p-and-xylopnranoside obtained in example 12, is obtained with a quantitative yield of the target product with S.pl. 108-118 ° CXr 7, (methanol).
Example 15. Obtaining (4-mer captophenyl) -3-nitrophenyl methanone.
According to the method of Example 1, of 18 g (0.07407 mol) of (4-hydroxyphenyl) (3-nitrophenyl) methanol and 12.3 g (0.0992 mol) of dimethylthiocarbamoyl chloride, 20.5 g are obtained (yield 84%) 0-4- (3-nitrobenzoyl) phenyl-dimethylthio carbamate.
According to the method of Example 2, 20.5 g (0.062 mol) (quantitative yield) of S-4 - (3-nitro) are obtained from 20.5 g (0.062 mol) and-4 (3-nitrobenzoyl) phenyl-dimethylthiocarbamate. be n c ogt) -phenyl-dimethylthiocarbamate.
According to the method according to example 3 of
20.5g (0.062 mol) of 8-4- (3-nitrobenzoyl) -phenyl-dimethylcarbamate I get
, 15.6 g (yield 96%) (4-Mercaptophenyl) (3-nitrophenyl) -methanone, melted at 114 ° C.
Er im 16. Production of (4-cyanophenyl) (- 4-mercapto-phenyl) -methanone.
According to the method of Example 1, 5.6 g are obtained from 5 g (0.0224 mol) of (4-hydroxyphenyl) (-3-nitrophenyl) methanone and 3.6 g (0.0312 mol) of dimethylthiocarbamoyl chloride (yield 76% ) 0-4- (4-cyanobenzoyl) -phenyl-dimethyl-thiocarbamate, melting at 162 C.
According to the method of Example 2, out of 5.2 g (0.0167 mol) of 0-4- (4-cyano-benzoyl) phenyl-dimethylthiocarbamate, 5.2 g (quantitative) of S-4- (4-cyanobenzoyl) - phenyl-dnmethyl-thiocarbamate, melted at 174 C,
According to the method according to example 3 of
18.6g (0.059 mol) of 8-4- (4-cyanobenzoyl) phenyl-dimethylthiocarbamate give 12.5 g (yield 92%) of (4-mercaptophenyl) (-4-cyanophenyl) methanone, melting at 156 C.
Example 17. Hojr / 4 4- (4-cyanobenzoyl) phen1 HG | -2, 3, 4-tri-0-acetyl-1, 5-dithio-p -1) xylopyranoside.
five
0
five
0
Q
five
"
five
five
According to the method of operation on irimera 4 of 6 g (0.0251 mol) (4-mercaptophenyl) (4-cyanophenyl) methanone obtained in Example 16 9.8 g (0.0276 mol) 2.3 , 4-tri-0-acetyl-1-bromo-5-thio-pt, β-D-xylopyranoside, and 7.1 g (0.0276 mol) of mercury cyanide, are obtained. 7.3 g (yield 52%) of the p-isomer, melting at 172 C, oi +50,, 15 (СНС1,).
EXAMPLE 18, Preparation of 4- (4-cyanobenzoyl) phenyl -1,5-dithio-hydroxypyranoside.
According to the method of Example 5 out of 2 g (0.0356 mol) of the product obtained according to Example 17 and 0.75 ml of sodium methyl acetate as an 8% solution, 1.38 g (quantitative) of the desired product is obtained, melted at 164 ° С, xLp +53,, 197 ().
EXAMPLE 19 Preparation of G 4-Ј (4-cyanophenyl) oximePPhenylt -1,5-dithio-A-B-xylopyrano.
According to the method according to example 7 of 3.7. g (0.0095 mol) of the product obtained in Example 18 and 0.370 g (0.0097 mol) of sodium tetraborhydride, 3 g (yield 81%) of the desired product are obtained, melting at 70-85 ° C., 8,, 598 ( CH3OH).
PRI me R 20. The separation of two epimers of | 4- t (4-nitrophenyl) -oximethyl-phenyl | 1,5-dithio-0-D-xylopyranoside.
1. Preparation of (+) - | 4- (4-nitrophenyl) oxymethyl phenyl -1, 5-dithio-L-D-xylopyranoside.
11.2 g of a mixture of epimers, Ј $ +8, ..., 5 (methanol) obtained in Example 6, are recrystallized from 80 ml of saturated ethyl acetate. Obtain 7.85 g of crystals (C,) +4, 4, (methanol), and the filtrate (F). The crystals (C,) are recrystallized from 150 ml of ethyl acetate containing 1% water (by volume). Obtain 3.15 g of crystals (C), oL +17.6, 45 (methanol).
The crystals (C2) are recrystallized from 40 ml of ethyl acetate, saturated with water. Obtain 1.78 g of crystals (C5),, 2, 45 (methanol).
The crystals (Ce) are recrystallized again from 16 ml of ethyl acetate saturated with water. 1.43 g of oii + 25,, 4 (methanol) (+) - isomer crystals melting at 141 ° C are obtained.
2. Preparation of (-) - {4- (4-Nitrophenyl) oxymethyl-phenyl-1,5-dithio-1) xylopyranoside
The filtrate (F, i) is evaporated under vacuum and treated with ethyl acetate containing less than 100 ppm of water. After crystallization, 3.9 g of crystals (Cg), Y.Ј −4.6, 45 (methanol) are obtained. (
Crystals {Su) are recrystallized from 130 ml of this lattice containing less than 100 ppm of water. Obtain 1.44 g of crystals (C),, 4,, 35 (methanol) .i
The crystals (C) are recrystallized from 60 ml of ethyl acetate containing less than 100 rrp of water. 0.96 g of crystals are obtained: i -1 5,., 4 (methanol) (-) - isomer, melting at 157-163 ° C.
Example21. Preparation of (2-cyanophenyl) (4-mercaptophenyl) methanol.
According to the method of Example 1, from 13.3 g (0.059 mol) (2-cyanophenyl (4-hydroxyvinyl) methanol and 8.5 g (0.068 mol) of dimethylthiocarbamoyl chloride), 16.5 g are obtained (yield 89) 0-4 - (2-cyanobenzoyl) phenyl-dimethylthiocarbamate, melting at 138 C.
According to the method of Example 2, of 16 g (0.052 mol) of 0-4- (2-cyanobenzoyl) phenyl-dimethylthiocarbamate, 10.9 g (68% yield) of 5-4- (2-cyanobenzoyl) phenyldimethylthiocarbamate are obtained. , melted at 112 ° C.
According to the method of Example 3, out of 10.6 g (0.034 mol) of 8-4- (2-cyanobenzoyl) phenyl-dimethylthiocarbamate, 9 g (80% yield) of (2-cyanophenyl) - (4-mercaptophenyl) methanol is obtained, melted at 102 ° C.
Example2. Preparation of (3-cyano-phenyl) (4-mercaptophenyl) -methanol.
According to the method of Example 1, out of 27 g (0.0121 mol) of (3-cyanophenyl) (4-hydroxyphenyl) methanone and 17.2 g (0.138 mol) of dimethylthiocarbamoyl chloride, 35 g are obtained (yield 88%) 0- 4- (3-cyanobenzoyl) -phenyl-dimethylthiocarbamate, melting at 160 ° C.
According to the method of Example 2, out of 33 g (0.106 mol) of 0-4- (3-cyanobenzoyl) phenyl-dimethylthiocarbamate, 25 g (yield 9%) of I-4- (3-cyanobenoyl) phenyl-dimethylthiocarbamate, melt shakos at 150 ° C.
According to the method according to example 3 of 22.6 g (0.073 mol) 5-4- (3-cyano

with
0
five
0
five
0
five
0
five
benzoyl) phenyldimethylthiocarbamate gives 16.5 g (yield 94.9%) of (3-cyanophenyl) (4-merkaitophenyl) methanol, melting at 126 ° C.
In tab. 1 and 2 are physical
characteristics of the proposed compounds.
The antithrombotic activity of the products according to the proposed method is shown on venous thrombosis.
Venous stasis (congestion) is realized during hypercoagulation according to the method described by WESSBR et al. (J.Applied Physiol. 1959, p. 943-946). The hypercoagulating agent used is (J. Havpraan et al. Thrombosis and Haemostasis 43/2, 198U, p. 118) activated factor X solution, supplied by Flow Laboratories, 71 KPa per 12.5 ml (physiological serum).
The study was carried out on male Wistar rats, not fasting, weighing 250-280 g (batches of 10 animals). The test products are orally administered as a suspension in PEG 400. Thrombosis is induced and 4 hours after this treatment, the resulting clot is removed and weighed. Obtained at a dose of 12.5 mg / kg orally (with the exception of the opposite indication), as well as the results obtained with the well-known products of the prior art, are given in Table. 3
The proposed compounds are poorly toxic, in particular the compounds of Examples 3 and 12 have a DL50 in mice and rats (oral administration) exceeding 5 g / kg.
The products according to the invention have antithrombotic venous activity 2-16 times higher than the activity of the known products.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives} - I) -phenylthioxy-amides of the general formula I
„
where R is hydrogen, chlorine, nitro or cyanogruip;
A - sulfur or oxygen;
In SNg-, SNOP or CO-group;
Y is hydrogen or acetyl group.
or their epimers, when B is a CHON-group, I differ by the fact that the compound is of formula II
ft
ON-ЈVB
where A, B and K have the indicated meanings,
are injected into the reaction with chloroacetylthioxysucide or acetylthioxyloside of the general formulas III or IV, respectively.
YO TV-G5
0
where Y is an acetyl group;
Hal - chlorine, bromine,
in an inert solvent at a molar ratio of compound II: compound III or, 1-1.2 in the presence of an acid or Lewis acid acceptor, if necessary, deacetylation is carried out at a temperature from room temperature to the boiling point of the reaction mixture with a refluxing refrigerator in a low alcohol such as methanol in the presence of an alcohol of a metal such as sodium methoxide.
Table 1
Note, a - residual solvent 2.3% H20; b - residual
2.5% HgO solvent; c - lyophilized product; d is a mixture of epimers.
2
A mixture of diastereoisomers.
Note. A is the comparative product described in Example 1 A-0133103; B is the comparative product described in Example 97 EP. B-0051023.
Editor V. Bugrenkova
Compiled by I. Fedoseeva
Tehred L.Serdyukova Proofreader V.Kabaniy
Order 1231
Circulation 295
VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
- :.
Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
Table3
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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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FR8706237A|FR2614893B1|1987-05-04|1987-05-04|NOVEL B-D-PHENYL-THIOXYLOSIDES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS|

---