CN110396084B - Method for preparing high-purity trityl olmesartan medoxomil - Google Patents
Method for preparing high-purity trityl olmesartan medoxomil Download PDFInfo
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- CN110396084B CN110396084B CN201810373175.5A CN201810373175A CN110396084B CN 110396084 B CN110396084 B CN 110396084B CN 201810373175 A CN201810373175 A CN 201810373175A CN 110396084 B CN110396084 B CN 110396084B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The invention relates to a method for preparing high-purity trityl olmesartan medoxomil, which is characterized in that an inorganic salt solution is used for cooling and crystallization, the purity of the trityl olmesartan medoxomil prepared by the method is high, the use of a large amount of organic solvents is avoided, the operation is simple, and the cost is low.
Description
Technical Field
The invention relates to the technical field of a medicine preparation method, in particular to a method for preparing high-purity trityl olmesartan medoxomil.
Background
4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, an important intermediate for the drug olmesartan medoxomil for treating hypertension. Olmesartan Medoxomil (Olmesartan Medoxomil) is a prodrug of Olmesartan, a potent and specific angiotensin ii receptor antagonist, which acts selectively AT the AT1 receptor. Olmesartan medoxomil, developed by Sankyo corporation of japan and Forest Laboratories in the united states, was marketed in the united states in 5 months in 2002 and in germany in 10 months in the same year.
CN102206208A discloses a method for purifying trityl olmesartan medoxomil, which is to dissolve a crude trityl olmesartan medoxomil in acetone, and then cool and crystallize to obtain trityl olmesartan medoxomil. According to the method, high-purity trityl olmesartan medoxomil can be obtained only when the content of trityl olmesartan medoxomil is low, but when the content of trityl olmesartan medoxomil is high, the purification effect is not obvious, or multiple times of purification are needed, acetone is used as a crystallization solvent, and the product yield is not high.
WO2014036686 discloses a preparation method and a purification method of trityl olmesartan medoxomil:
the purification method comprises the following steps: extraction with ethyl acetate and multiple recrystallizations.
The above purification method requires a large amount of organic solvent, and particularly, extraction is not suitable for industrial mass production. Therefore, the development of a method for preparing high-purity trityl olmesartan medoxomil with simple operation and environmental protection is of great significance.
Disclosure of Invention
The invention aims to provide a method for purifying trityl olmesartan medoxomil, which has high yield and solves the problem of industrial preparation and purification of trityl olmesartan medoxomil.
In order to solve the problems, the invention adopts the following technical scheme:
dissolving the crude product of trityl olmesartan medoxomil in an organic solvent, wherein the organic solvent is selected from any one or more of DMF, DMSO, 1-methyl-2 pyrrolidone, methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran, and ethanol is preferred; adding inorganic salt solution, stirring, cooling and crystallizing, wherein the inorganic salt is selected from one or more of sodium chloride, potassium chloride, sodium bromide and potassium bromide, preferably sodium chloride, to obtain high-purity trityl olmesartan medoxomil. The mass of the added inorganic salt solution is 15 to 30 times, preferably 20 to 25 times of the mass of the crude product of trityl olmesartan medoxomil; the concentration range of the inorganic salt solution is 10-25% (m/m), preferably 20-25% (m/m). The crystallization temperature range is-15 to 0 ℃, and the optimal selection is-5 to 0 ℃; the crystallization time is 2 to 10 hours, preferably 4 to 6 hours.
Further, another object of the present invention is to provide a process for preparing trityl olmesartan medoxomil with high purity:
the method comprises the following steps:
(a) Hydrolyzing the compound shown in the formula II in tetrahydrofuran and purified water in the presence of lithium hydroxide to obtain a compound shown in the formula III; after the reaction is finished, adding ethyl acetate and a sodium chloride solution, stirring and layering, collecting an organic phase, drying anhydrous sodium sulfate, filtering, and concentrating the filtrate to be dry to obtain a compound shown in the formula III;
(b) Reacting a compound shown in a formula III in DMF (dimethyl formamide) in the presence of anhydrous potassium carbonate, potassium iodide and a compound shown in a formula IV to obtain a compound shown in a formula I, namely trityl olmesartan medoxomil;
(c) And (c) filtering the reaction liquid in the step (b), adding the filtrate into an inorganic salt solution, cooling, stirring and crystallizing to obtain high-purity trityl olmesartan medoxomil.
The method for preparing trityl olmesartan medoxomil does not generate trityl olmesartan medoxomil, and solves the problem that trityl olmesartan medoxomil is difficult to remove in CN 102206208A.
In the step c, the inorganic salt is selected from one or more of sodium chloride, potassium chloride, sodium bromide and potassium bromide, preferably sodium chloride. The mass of the added inorganic salt solution is 15 to 30 times, preferably 20 to 25 times of the mass of the crude product of trityl olmesartan medoxomil; the concentration of the added inorganic salt solution is in the range of 10-25% (m/m), preferably 20-25% (m/m). When in crystallization, the crystallization temperature range is-15 to 0 ℃, and the preferable temperature range is-5 to 0 ℃; the crystallization time is 2 to 10 hours, preferably 4 to 6 hours.
The chemical name of the trityl olmesartan medoxomil is as follows: 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester.
The purity of trityl olmesartan medoxomil obtained by the preparation method is not lower than 98.0%, and the yield is as high as more than 95%.
The invention has the advantages that:
(1) The operation is simplified, and the requirement on equipment is low;
(2) The purification yield and the product purity are both high, and the method is suitable for industrial production;
(3) The purification method does not need solvent extraction, avoids column chromatography and is more environment-friendly to operate.
Detailed Description
The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention.
Example 1
Adding 52kg of crude trityl olmesartan medoxomil into 150kg of ethanol, heating to reflux, carrying out hot filtration, gradually cooling the filtrate to 20 ℃, adding the filtrate into a sodium chloride solution (338.0 kg of sodium chloride is added into 940.0kg of purified water, stirring and dissolving), stirring for 4 hours at the temperature of-5-0 ℃, carrying out swing filtration, and putting the filter cake into an oven drying tray, wherein the oven temperature is 40 +/-5 ℃, and carrying out forced air drying for 8 hours. 50.49kg trityl olmesartan medoxomil was obtained with a retention time of 33.2min, a purity of 98.1% and a yield of 97.1%.
HPLC conditions:
flow rate: f =1.0ml/min, column temperature: t =40 ℃, detection wavelength: λ =210nm, column: tima C8 (250 mm. Times.4.6 mm,5 μm). Solvent: a =0.015mol/L potassium dihydrogen phosphate solution (2.04 g potassium dihydrogen phosphate was taken and dissolved in 1000ml water, and pH was adjusted to 3.5 with phosphoric acid (1 → 5)), and B = acetonitrile.
Example 2
Into a glass-lined reaction vessel were charged 188.0kg of tetrahydrofuran, 54.0kg of ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylate, 92.0.0kg of purified water and 4.0kg of lithium hydroxide monohydrate. After the addition, the reaction was stirred at 20 ℃ for 18 hours, the reaction temperature was recorded every 2 hours, and TLC was followed until the starting material was substantially reacted. After the reaction, 240.0kg of ethyl acetate and a sodium chloride solution (20.0 kg of sodium chloride was added to 180.0kg of purified water and dissolved by stirring) were added, and the mixture was stirred for 10 minutes and allowed to stand for 20 minutes to separate into layers. The organic phase was washed with a sodium chloride solution (32.0 kg of sodium chloride was added to 288.0kg of purified water, stirred and dissolved) in 2 equal portions, each for 10 minutes with stirring, and left to stand for 20 minutes. The organic phase was collected, dried over anhydrous sodium sulfate with stirring for over 4 hours. Filtering, concentrating the filtrate under reduced pressure until ethyl acetate is removed (the water bath temperature is controlled at 45 +/-5 ℃, and the vacuum degree is controlled at-0.1 to-0.06 MPa), adding 188.0kg of N, N-dimethylformamide, adding 15.3kg of anhydrous potassium carbonate, 2.7kg of potassium iodide, slowly adding 14.5kg of 4-chloromethyl-5-methyl-1,3-dioxol-2-one at the temperature of 20 +/-10 ℃ under stirring, heating, and stirring and reacting for 2 hours at the temperature of 40 +/-2 ℃ of the feed liquid. After the reaction is finished, the temperature of the feed liquid is reduced to 15 +/-5 ℃, the filtrate is subjected to swing filtration, the filtrate is added into a sodium chloride solution (338.0 kg of sodium chloride is added into 940.0kg of purified water, and the mixture is stirred and dissolved) for 4 hours at the temperature of-5 to 0 ℃, the filter cake is subjected to swing filtration, and the filter cake is put into an oven drying tray and is subjected to air blast drying for 8 hours at the oven temperature of 40 +/-5 ℃. 58.2kg of trityl olmesartan medoxomil were obtained with a yield of 96.5%.
And (3) HPLC (high performance liquid chromatography) of a product: the purity is 98.9%; the retention time of the compound of formula II was 23.5min,0.04%.
Claims (1)
1. A process for preparing trityl olmesartan medoxomil comprising the steps of:
(a) Hydrolyzing the compound shown in the formula II in tetrahydrofuran and purified water in the presence of lithium hydroxide to obtain a compound shown in the formula III; after the reaction is finished, adding ethyl acetate and a sodium chloride solution, stirring and layering, collecting an organic phase, drying anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness to obtain a compound shown in the formula III;
(b) Reacting a compound shown in a formula III in DMF (dimethyl formamide) in the presence of anhydrous potassium carbonate, potassium iodide and a compound shown in a formula IV to obtain a compound shown in a formula I, namely trityl olmesartan medoxomil;
(c) And (c) filtering the reaction liquid in the step (b), adding the filtrate into a sodium chloride solution, wherein the concentration range of the sodium chloride solution is 10-25% by mass, the mass of the sodium chloride solution is 20-25 times of the mass of the crude product of trityl olmesartan medoxomil, cooling, stirring and crystallizing, the crystallization temperature range is-5-0 ℃, and the crystallization time is 2-10 hours, so that the high-purity trityl olmesartan medoxomil is obtained.
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