Method for producing omeprasol salts

专利摘要:
Novel salts of omeprazole with Li+, Na+, K+, Mg2+, Ca2+, Ti4+, N+(R1)4 as cation; processes for their preparation thereof, pharmaceutical compositions containing such salts and their use in medicine.
公开号:SU1314953A3
申请号:SU843710408
申请日:1984-03-02
公开日:1987-05-30
发明作者:Элоф Брэндстрем Арне
申请人:Актиеболагет Хессле (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the production of new salts of omeprazole, which can be used to provide gastrointestinal cytoprotective effect in mammals and humans, as well as to prevent and treat gastrointestinal inflammatory diseases in humans and mammals,
Example 1, Preparation of the sodium salt of 5-methoxy-2- (A-methoxy-3, 5-dimethyl-2-pyridinyl) methyl sulfonyl -1 H-benzimidazole (sodium salt of omeprazole).
Omeprazole (1000 g, 2.90 mol) is added to a solution of NaOH (116 g, 2.90 mol) in deionized water (25 L). After stirring for 5 minutes, 5 liters of methylene chloride were added and the stirring process continued for another 10 minutes. Next, the two phases were separated. The aqueous phase was washed with 5 L of methylene chloride, filtered through Celite to give a clear solution as a result, and then evaporated to concentrate under reduced pressure to a total volume equal to l. Then 6 l of absolute ethanol was added and the evaporation process was continued until a dry product was obtained. After adding 7 L of ethyl acetate, the resulting mixture was refluxed with stirring for 30 minutes. After cooling and settling overnight, the resulting slurry was stirred with an additional amount (2 L) of ethyl acetate and filtered. The cake was washed with diethyl ether and dried under reduced pressure at 40 ° C overnight.
Got the sodium salt of omeprazole (975 g, 92% of theoretical yield), so pl. 208-210 s.
NMR spectrum (f (D, 0) (S;: 1.85 (singlet, 3N); 2.1 (singlet, 3N); 3.5 (singlet, 3N); 3.85 (singlet, 3N ); 4.75 (singlet, 2H) j 6.85 (double doublet, 1H); 7.2 (doublet, 1H); 7.55 (doublet, 1H); 8.15 (doublet, 1H).
PRI mme R 2. Obtaining the sodium salt of omeprazole.
Omeprazole (1300 g, 3.77 mol) was added with vigorous mechanical stirring to a mixture of 13 l of tetrahydrofuran and 296 g (3, 7 mol of 50% NaOH, and the stirring process was continued for 45 minutes. Then 5.7 liters of trichloroethylene and the stirring process continued for another 45 minutes. After adding
5.7 L of trichlorostillean the stirring process was continued overnight at room temperature. The resulting mixture was cooled to 5 ° C and then stirred for 3 hours. Sediment
was filtered, the filter cake was washed with 5 l of trichlorethylene and then dried under reduced pressure and 50 ° C.
Got the sodium salt of omeprazole
(1314 g, 95% of theoretical yield), so pl. 208-210 ° C.
PRI me R 3. Getting the potassium salt of omeprazole.
Omeprazole (10.0 g, 0.0290 mol)
KOH (1.60 g) was added to the solution;
0.0285 mol) in deionized water, and then 50 ml of methylene chloride was added. The resulting mixture was subjected to intensive stirring for
15 minutes. The resulting phases were separated, the aqueous phase was washed with 50 ml of methylene chloride and filtered on celite until a clear solution was obtained. After evaporation to dryness was obtained
crystalline residue.
As a result of recrystallization from ethyl acetate, the potassium salt of omeprazole was obtained, mp. 148-150 s (soluble in water).
First Preparation of diomeprazole calcium will dihydrate. Anhydrous CaCl (17.9 g; 0.161 mol) was dissolved in deionized water (200 ml), obtained
the solution was added dropwise with vigorous stirring to a solution of the sodium salt of omeprazole (125 g, 0.340 mol) in 1250 ml of deionized water and stirred for
1 hour at room temperature. The precipitate was separated by centrifugation and washed with deionized water until C1 ions were removed from the solution, determined with AgNOj. After air drying and grinding, the crystals of the product obtained were dried in vacuum at 40 ° C for 20 hours.
As a result, oneprazole calcium salt dihydrate was obtained (104 g; 80% of theoretical ngcode), m.p. 182-184 sec.
NMR spectrum, S (CDClI-H drop DMSO-Dg); 2.0 (singlet, SN); 2.15 (singlet, 3N); 3.6 (singlet, SN); 3.7 (singlet, SN); 4.5 (singlet, 2H); 6.7 (double doublet, 1H); 7.1 (doublet, 1H); 7.6 (doublet, 1H); 8.15 (singlet, 1H).
PRI me R 5. Getting dihydrate magnesium salt of diomepraeol,
Anhydrous MgCP, (16, 2 g, O, 1 7 mol) was dissolved in 625 ml of deionized water, the resulting solution was added dropwise with vigorous stirring to a solution of omeprazole sodium salt (125 g, 0.340 mol) in 1560 ml deionized water. The resulting solution was further stirred for 1 hour at room temperature. The precipitate was separated by centrifugation and then washed with deionized water until the CP ions were removed from the solution, which was determined with AgNOj.
As a result of air drying, grinding and drying in vacuum at 40 ° C for 24 hours, the dihydrate magnesium salt of omeprazole was obtained (111 g, 87% of the theoretical yield), m.p. 117-178 C.
PRI me R 6. Preparation of a diomeprazole magnesium salt.
As a result of the reaction between magnesium (0.35 g, 0.0145 mol) and absolute methanol (10 ml) in the presence of one drop of carbon tetrachloride, a solution () of a solution of methanol was obtained. After adding 10 ml of methanol, the resulting solution was added dropwise to a solution of omeprazol (10 g, 0.029 mol) in methanol (200 ml). The resulting mixture was stirred at room temperature for 30 minutes. After evaporation, a solid crystalline product was obtained, which is the magnesium salt of diomeprazole, m.p. 178-180 C.
PRI me R 7. Preparation of omeprazole tetrabutyl ammonium salt.
Omeprazole sodium (3.8 g, 0.010 mol) was added to a mixture consisting of tetrabutyl ammonium acid sulfate (3.5 g, 0.010 mol) and NaOH (0.42 g, 0.0105 mol) in 15 ml deionized water. Then 10 ml of methylene chloride was added and the mixture was shaken in a separatory funnel. After separation of the phases, dry




the organic phase was dried and the solvent was separated by evaporation.
As a result, omeprazole tetrabutyl ammonium salt was obtained (3.5 g, 60% of the theoretical yield).
NMR spectrum, S (): 0.8-1.5 (multiplet, 12H); 1.15-1.6 (multiplet, 16H); 2.25 (singlet, SN); 2.3 (singlet, SN); 2.75-3.15 (multiplet, 8H), - 3.75 (singlet, 3N); 3.9 (singlet, SN); 4.7 (doublet, 1H); 5.05 (doublet, 1H); 6.8 (double doublet, 1H); 7.3 (doublet, 1H); 7.7 (doublet, 1H); 8.35 (singlet, 1H).
PRI me R 8. Preparation of guanidine (C (NH).) Omeprazole salts.
A solution of guanidine (0.0029 mol) obtained from guanidine nitrate and KOH in 50 ml of ethanol was added to a solution of omeprazole (180 g, 0.0029 mol), the resulting solution was stirred for 15 minutes, and then the solvent was evaporated.
Got the guanidine salt of omeprazole (so pl. 110-112 C, soluble in water).
PRI me R 9. Obtaining titanium salt tetraomenrazole.
Titanium tetraisopropylate (1.03 g, 0.0036 mol) was added to a solution of omeprazole in anhydrous isopropanol (250 ml) and the resulting mixture was stirred under nitrogen at room temperature for 4 hours. A white precipitate was obtained. Next, the solvent was evaporated, followed by washing three times with petroleum ether and drying in vacuo.
The result is a white crystalline powder, which is a titanium salt of tetraomeprazole, so pl. more than 260 C.
PRI me R 10. Obtaining lithium salt of omeprazole.
Omeprazole (3.0 g, 0.0087 mol) was added to 0.207 g (0.00865 mol) LiOH in deionized water, and then 25 ml of methylene chloride was added. The resulting mixture was vigorously stirred for 15 minutes. Thereafter, the phases were separated, the aqueous phase was washed with 25 ml of methylene chloride and then filtered through celite to obtain a clear solution. Evaporation to dryness allowed to obtain a crystalline lithium salt of omeprazole so pl. 198-200 s, soluble in water).
513
NMR spectrum, (CDCIj): 1.65 (singlet, 3N); 1.8 (singlet, 3H) j 3.45 (singlet, GN); 3.4 (singlet, SN); 4.2 (singlet, 2H); 6.6 (double doublet, 1H); 6.95 (doublet, 1H); 7.45 (doublet, 1H); 7.75 (singlet, 1H).
The NMR spectrum data given in Examples 1, 4, 7 and 10 are determined at a frequency of 90 MHz.
Test for the stability of omeprazole salts.
The stability of the sodium salt of omeprazole, obtained in accordance with Example 1, is compared with the stability of the neutral form of omeprazole. Both compounds were stored for 6 months at 37 ° C and 80% relative humidity. Next, the amount of degradation products formed was measured.
Studies have shown that the amount of degradation products formed as a result of storage of neutral omeprazole and sodium salt of omeprazole was 6 and 0.4% (from the initial amount of omeprazole), respectively.
The table shows the total amount of by-products found after storage of omeprazole and salts of omeprazole.
As can be seen from this study, the stability of omeprazole and its salts
49536
a significantly smaller amount of decomposed product compared to the neutral form of omeprazole, i.e.; have higher stability.
five

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining salts of omeprazole of the general formula
P
CAT
Jti
where, 2 or 4;
  , Na, K,,, N (K) - / or
where R is lower alkyl,
characterized in that the interaction of omeprazole form-2S mules
  j t, CH, -S.
I
OSSN
with a base capable of separating cation CAT | with the separation of the target product.
+50
+37/80 + 50 +37/80
Magnesium and calcium salts were investigated after 1.5 months of storage.
Editor A, Veselovska
Compiled by G. Zhukov
Tehred L. Serdyukova Proofreader A. Tsko
Order 2224/58 Circulation 372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4

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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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SE8301182A|SE8301182D0|1983-03-04|1983-03-04|NOVEL COMPOUNDS|LV930867A| LV5503A3|1983-03-04|1993-06-30|Suffering for the acquisition of omeprazole islands|

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LTRP947A| LT2253B|1983-03-04|1993-09-06|THE CAPACITY OF RECEIVING OMEPRAZOL SALTS|