JP5301348B2 - Method for producing pravastatin sodium salt - Google Patents

Abstract

The invention discloses a preparation method of sodium salt of pravastatin, which comprises the following steps: adding inorganic alkaline or organic alkaline containing sodium ions as positive ions into organic solution containing the pravastatin until pH is more than 7 and obtaining sodium pravastatin; the organic solution containing the pravastatin comprises the pravastatin and first solvent, wherein the first solvent is selected from one or a plurality of methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate and tert-butyl acetate.

Description

  The present invention relates to a method for producing a sodium salt of pravastatin.

Pravastatin sodium is a kind of statin drug and its chemical name is {1S- [1α (βs *, δs *), 2α, 6α, 8β (R *), 8aα]}-1,2, 6,7,8,8a-Hexahydro-β, δ, 6-trihydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -1-naphthaleneheptanoic acid monosodium salt. Pravastatin sodium and lovastatin, simvastatin, atorvastatin, fluvastatin and its derivatives and analogs are all hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which can cause hypercholesterolemia and atherosclerosis Used to treat.

  Pravastatin sodium exerts its hypolipidemic action in two ways. One is reversibly suppressing the activity of HMG-CoA reductase, blocking the biosynthesis of cholesterol in the liver, lowering the amount of intracellular cholesterol to some extent, and stimulating LDL receptors on the cell surface to compensate. Increase the degradation metabolism of LDL and removal of blood LDL by the receptor. The other is to suppress the production of LDL by inhibiting the synthesis of VLDL, which is a precursor of LDL, in the liver. Pravastatin sodium is administered in its water-soluble active form and has higher reversibility and selectivity for the liver than other statins in the biosynthesis of cholesterol. This characteristic of pravastatin is that it exerts the strongest HMG-CoA reductase inhibitory effect on hepatocytes and its distribution in the brain and other glands is very low, since the liver is the main place for cholesterol synthesis. To ensure. Because pravastatin sodium has outstanding low toxicity and effective hypolipidemic action, its therapeutic effect is remarkable, its tolerance is good, and it is recognized as one of the most developed of these drugs.

  In the prior art, pravastatin sodium is generally produced by a method of crystallization in an organic solvent. In order to precipitate pravastatin sodium from a saturated dissolved state to a supersaturated state, the usual method uses a temperature difference and makes it supersaturated.In this case, after dissolving at a high temperature, the temperature is lowered. Otherwise, the precipitation method must be used. Otherwise, dissolution at room temperature would cause the concentration to be too low and increase the loss in the mother liquor after cooling, and thus cannot be industrialized. Alternatively, after dissolving at room temperature, the solution is heated and concentrated in vacuo to obtain a pravastatin sodium solution having a high concentration, and then pravastatin sodium is precipitated by cooling. Since the latter also requires a temperature rise and further has a vacuum concentration step, the demand for equipment and facilities is high.

  In the prior art, both methods have great ill effects. For example, the amount of the organic solvent used is very large, it is disadvantageous for safety, the consumption of resources is large, and the influence on the environment is large. On the other hand, in any method, the temperature of the solvent is raised so that pravastatin sodium is easily dissolved, and then the temperature is lowered to crystallize and precipitate pravastatin sodium. The temperature rise in them causes a large amount of organic solvent to volatilize, so that severe results such as explosions are likely to occur, the requirements for equipment and production environment are extremely high, and it is also disadvantageous for the health of the operator. Furthermore, pravastatin sodium becomes unstable at high temperatures, which promotes the biodegradation of pravastatin sodium into other structural analogs. Moreover, an extra cooling facility is required for temperature reduction, which increases input and operating energy consumption.

  Therefore, in the industrial production of pravastatin sodium, there is a strong demand in this field for a safe, simple and efficient method that uses less organic solvent, can be carried out at room temperature, has low demands on equipment and facilities. .

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel method for producing pravastatin sodium salt.

The first of the present invention is
(1) Pravastatin, methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate, acetic acid a step of adding an inorganic base or an organic base whose cation is a sodium ion to a pravastatin-containing organic solution comprising a first solvent selected from the group consisting of tert-butyl and a first solvent selected from the group, and a pH> 7. A method for producing pravastatin sodium salt is provided.

  In another preferred example, the aforementioned production method is performed at room temperature.

  In another preferred example, the concentration of pravastatin in the organic solution is 1-300 g / L.

  In another preferred example, the concentration of pravastatin in the aforementioned organic solution is 30-120 g / L.

  In another preferred example, the inorganic base or organic base whose cation is sodium ion is a solution, and is selected from an inorganic base or organic base whose cation is sodium ion and a C1-4 aliphatic alcohol or a combination thereof. A second solvent. The aforementioned C1-4 aliphatic alcohol is preferably methyl alcohol, ethyl alcohol or a combination thereof.

  In another preferred example, the inorganic or organic base wherein the cation is a sodium ion is selected from sodium hydroxide or a C1-4 sodium aliphatic alkoxide. The aforementioned C1-4 sodium aliphatic alkoxide is preferably sodium methoxide, sodium ethoxide or a combination thereof.

In another preferred example, before step (1),
(1 ′) including a step of mixing pravastatin and a first solvent to obtain a pravastatin-containing organic solution.

  In another preferred example, in step (1 ′) described above, pravastatin is dissolved in a first solvent to form a pravastatin-containing organic solution.

  In another preferred example, in step (1 ′) described above, pravastatin and / or a salt thereof is transferred to the first solvent by extraction to form a pravastatin-containing organic solution.

In another preferred example, the aforementioned method is
(a) by dissolving or extracting pravastatin and / or a salt thereof, methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, Transferring to a first solvent that is one or more selected from the group consisting of sec-butyl acetate, isobutyl acetate, and tert-butyl acetate to form a pravastatin-containing organic solution;
(b) adding an inorganic base or an organic base whose cation is a sodium ion to the organic solution obtained in step (a) to obtain a precipitate;
(c) A step of obtaining pravastatin sodium from the precipitate obtained in step (b) by repeating steps (a)-(b) 1-5 times, preferably 1-3 times;
including.

The second of the present invention is
(1) pravastatin sodium obtained by the aforementioned production method;
(2) a pharmaceutically acceptable carrier;
A pharmaceutical composition containing

The third aspect of the present invention is
A therapeutic method for treating atherosclerosis, hypercholesterolemia or hyperlipidemia is provided by administering to a patient a therapeutically effective amount of the pharmaceutical composition described above.

  As a result, the present invention provides a method for producing pravastatin sodium salt, which uses an organic solvent in a small amount, can be carried out at room temperature, has low demands on facilities and facilities, is safe, simple and efficient.

Specific Embodiments As a result of extensive investigations, the present inventors have surprisingly found that pravastatin sodium is precipitated from a solution by adding sodium ions to a pravastatin-containing organic solution to change the pH of the solution. A method for efficiently obtaining sodium at room temperature has been found and the present invention has been completed.

In the present invention, “pravastatin” and “pravastatin free acid” may be used interchangeably, and both mean the free acid of “pravastatin sodium”. The chemical name of pravastatin is {1S- [1α (βs *, δs *), 2α, 6α, 8β (R *), 8aα]}-1,2,6,7,8,8a-hexahydro-β, δ, 6-trihydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -1-naphthaleneheptanoic acid.

  In the present invention, normal temperature is a temperature range well known to those skilled in the art, and is 15-30 ° C, preferably 15-25 ° C.

  As used herein, “organic solution” means a solution that uses a non-aqueous substance as a solvent. Among them, the water content is <10 v / v%, preferably <5 v / v%, more preferably <1 v / v%. The non-aqueous substance as the above-mentioned solvent is preferably an organic solvent.

  As used herein, “first solvent” is an organic solvent that forms a pravastatin-containing organic solution, pravastatin sodium is less soluble, and its solubility is less than 30 g / L, preferably more than 10 g / L Small, most preferably less than 1 g / L. The first solvent is methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate. From tert-butyl acetate, one or more selected from the group is preferable, and ethyl acetate is more preferable.

  As used herein, “second solvent” means an organic solvent that is compatible with the first solvent, but is different from the first solvent, and pravastatin sodium is easily soluble in the solvent. Greater than 100 g / L, preferably greater than 200 g / L, most preferably greater than 300 g / L. The aforementioned second solvent is selected from lower aliphatic alcohols, and one kind selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol or tert-butyl alcohol. Alternatively, various C1-4 aliphatic alcohols are preferable, and methyl alcohol, ethyl alcohol, or a combination thereof is more preferable.

  In the present invention, “pravastatin sodium structural analog” means a substance having a structure similar to pravastatin sodium. They are present in the fermentation broth, which is the source of pravastatin, or are the biodegradation products of pravastatin. These, for example, 3α-pravastatin sodium are mixed with pravastatin sodium and become impurities.

  In the present invention, Na + is added to a pravastatin-containing organic solution to adjust the pH to 7 or more, and a solid matter is precipitated. The resulting precipitate has a pravastatin sodium content of 90% or more, preferably 95% or more, more preferably 98% or more.

In one preferred example of the present invention, the method for producing pravastatin sodium comprises:
(a) mixing pravastatin with a first solvent to obtain a pravastatin-containing organic solution;
(b) adding to the organic solution obtained in step (a) an inorganic or organic base whose cation is sodium ion until pH> 7 to obtain pravastatin sodium;
including.

In another preferred embodiment of the present invention, the method for producing pravastatin sodium as described above comprises
(a) Extracting pravastatin salt to extract methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, acetic acid Transferring to a first solvent that is one or more selected from the group consisting of isobutyl and tert-butyl acetate to form a pravastatin-containing organic solution;
(b) adding an inorganic base or an organic base whose cation is a sodium ion to the organic solution obtained in step (a) to obtain a precipitate;
(c) A step of obtaining pravastatin sodium from the precipitate obtained in step (b) by repeating steps (a)-(b) 1-5 times, preferably 1-3 times;
including.

  In the present invention, a pravastatin-containing organic solution can be obtained by a method known in the relevant field, which includes, but is not limited to, a method obtained by mixing pravastatin with a first solvent. The concentration of pravastatin in the pravastatin-containing organic solution of the present invention is 1-300 g / L, preferably 30-120 g / L, more preferably 50-100 g / L.

  In one preferred form of the invention, pravastatin is dissolved in the first solvent. The above-described dissolution is well known to those skilled in the art, and the present invention shows a process of uniformly dispersing pravastatin in a first solvent to form a solution.

  In another preferred form of the invention, pravastatin and / or a salt thereof is transferred to the first solvent by extraction to form a pravastatin-containing organic solution. The above extraction is well known to those skilled in the art, and includes a method of adding a first solvent to an aqueous solution of pravastatin salt, transferring pravastatin to the first solvent, discarding the aqueous phase, and obtaining a pravastatin-containing organic solution. included. The aforementioned pravastatin salt is selected from pravastatin sodium and pravastatin potassium, and is preferably pravastatin sodium. It is preferable to add an acidic substance dropwise to an aqueous solution of pravastatin salt so that the pH is 7 or less, preferably 5 or less, more preferably 3 or less, and then add a first solvent to extract. The aforementioned acidic substance is selected from an organic base or an inorganic base, and is preferably an inorganic base, which includes, but is not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.

  While searching for an improved method of the prior art, the present inventors made the pravastatin solution enter a supersaturated state from a saturated dissolved state by making the pH change a driving force that becomes a supersaturated state. I noticed that it could be deposited. Pravastatin sodium may exist as pravastatin free acid, that is, pravastatin, but the difference between the chemical structures of the two is only the difference between hydrogen ion and sodium, that is, hydrogen ion is used instead of sodium. However, only the use of hydrogen ions in place of sodium makes a major distinction between the solubility of pravastatin and pravastatin sodium, ie pravastatin is readily soluble in a first solvent (eg ethyl acetate), but pravastatin sodium It is difficult to dissolve in a first solvent (eg ethyl acetate), so pravastatin can be converted to pravastatin sodium by dissolving pravastatin in the first solvent (eg ethyl acetate) and then raising the pH. The latter precipitates because it is difficult to dissolve in the first solvent (for example, ethyl acetate).

  When a Na + -containing substance is added to the pravastatin-containing organic solution and the pH is 7 or more, preferably pH 7-10, more preferably pH 7-9, precipitates are generated.

In one preferred form of the invention, to the pravastatin-containing organic solution is added a solution comprising a Na ⁺ -containing substance and a second solvent. The aforementioned Na ⁺ -containing substance is easily dissolved in the second solvent. The aforementioned Na ⁺ -containing substance is an inorganic base or an organic base whose cation is a sodium ion, is selected from NaOH or a C 1-4 sodium aliphatic alkoxide, and is preferably NaOH. Said C1-4 sodium aliphatic alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium sec-butoxide or sodium tert-butoxide. It is preferable to use sodium methoxide, sodium ethoxide, or a combination thereof. The second solvent is selected from C1-4 aliphatic alcohols or combinations thereof. The aforementioned C1-4 aliphatic alcohol is preferably methyl alcohol, ethyl alcohol or a combination thereof.

  In another preferred embodiment of the present invention, the pravastatin-containing organic solution is added with a methyl alcohol solution of NaOH and / or an ethyl alcohol solution of NaOH to increase the pH, thereby precipitating pravastatin sodium.

  In another preferred form of the invention, the pravastatin-containing organic solution is directly added with an inorganic or organic base whose solid cation is sodium ion, such as, for example, NaOH, sodium ethoxide, or sodium methoxide. .

Pharmaceutical Composition The present invention further provides a drug formulation containing pravastatin sodium salt. Drug formulations exist in oral and non-gastrointestinal forms, respectively, and can be used to treat hypercholesterolemia and hyperlipidemia. The drug formulation of the present invention may be a tablet, capsule, granule, suppository or suspension.

  In addition to pravastatin sodium salt, the drug formulation of the present invention includes one or more fillers such as microcrystalline cellulose, lactose, sucrose, starch, modified starch; lactose, starch, modified starch, microcrystalline cellulose, One or more binders such as sucrose, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, gelatin, gum arabic, polyvinylpyrrolidone; crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl starch, starch, One or many disintegrants such as microcrystalline cellulose, magnesium aluminum silicate, potassium polyacrylate; magnesium stearate, calcium stearate, stearic acid One or many different flow aids such as calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax, silica; sodium citrate, potassium citrate, sodium phosphate, phosphorus One or many kinds of buffers such as disodium oxyhydrogen, calcium carbonate, hydrogen phosphate, phosphate, sulfate, sodium carbonate, magnesium carbonate, benzoate, sodium bicarbonate, potassium bicarbonate, lauryl sulfate or the like May contain a mixture of these buffering agents.

  The drug formulation can be produced by a conventional compounding method known to those skilled in the art.

  The features described in the present invention or the features described in the embodiments may be arbitrarily combined. All features disclosed herein may be used in combination with any form of composition, and each feature disclosed in the specification is similarly replaced by an alternative feature serving an equivalent or similar purpose. May be. Unless otherwise stated, the disclosed features are only examples of a general series of equivalent or similar features.

The main advantages of the present invention are as follows.
(1) The amount of organic solvent (first solvent, for example, ethyl acetate) was greatly reduced.
(2) Can be carried out at room temperature, reducing the demand for equipment and facilities,
(3) Impurities are efficiently removed, and the removal effect of pravastatin sodium structural analog is particularly high.

  Hereinafter, the present invention will be further described with reference to specific examples. These examples are used to illustrate the present invention and are understood not to limit the scope of the invention. Experimental methods that do not describe specific conditions in the following examples are performed under normal conditions or conditions recommended by the manufacturer. Unless otherwise stated, all percentages and parts are by weight.

  Unless otherwise defined, all technical and scientific terms used in the sentence have the same meanings as are well known to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. The preferred embodiments and materials described in the text are for listing only.

Determination of optical rotation, purity and structural analogues of pravastatin sodium Measurement method and equipment:
Optical rotation measurement: Perkin Elmer POL341
Determination of purity and structural analogs: HPLC (Waters), C18 reverse phase column, fluid phase: methyl alcohol: water: glacial acetic acid: triethylamine = 450: 550: 1: 1, normal temperature, detection wavelength 238 nm.

Example 1
After completely dissolving 35 g of pravastatin (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd.) in 750 mL of ethyl acetate at 20 ° C, a methyl alcohol solution containing 1M NaOH is added until the pH reaches 7 or more. Added. The precipitate was collected by filtration and vacuum dried to obtain 31 g of pravastatin sodium white crystalline powder.
The specific rotation of pravastatin sodium was + 157 ° and the purity was 99.95%, among which the content of the structural analog 3α-pravastatin sodium was 0.03%.

Example 2
After completely dissolving 350 g of pravastatin crude product in 2 L of water at 20 ° C, add 4 L of ethyl acetate, stir, adjust the pH with 0.5 M H ₂ SO ₄ so that the pH is 4 or less, and Then, the aqueous phase was discarded, and an ethyl alcohol solution containing 1 M NaOH was added until the pH reached 8 or more, and a total of 800 mL was added. The precipitate was collected by filtration and vacuum-dried to obtain 330 g of purified pravastatin sodium white crystalline powder.
The measurement results and the contrast data of the purity of the pravastatin sodium crude product are as follows.

  All documents according to the present invention are cited in this application as a reference, so that each document is individually cited. In addition, after reading the above description of the present invention, engineers in this field can make various changes and modifications to the present invention, but those equivalent aspects are within the scope of the present invention. It is understood that it is included.

Claims (10)

(1) Pravastatin, methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate and acetic acid the first solvent is one or various selected from the group consisting of tert- butyl, pravastatin-containing organic solution consisting comprising the step of adding an inorganic base cation is a sodium ion until pH> 7 at ambient temperature ,
The inorganic base whose cation is sodium ion is a solution, and the solution is composed of an inorganic base whose cation is sodium ion and a second solvent selected from C1-4 aliphatic alcohols or combinations thereof. A method for producing pravastatin sodium salt, characterized in that:   The method according to claim 1, wherein the concentration of pravastatin in the organic solution is 1 to 300 g / L.   The method according to claim 2, characterized in that the concentration of pravastatin in the organic solution is 30-120 g / L. Aliphatic alcohol C1-4 before mentioned is characterized in that methyl alcohol, ethyl alcohol or a combination thereof The method of claim 1.   The method according to claim 1, wherein the inorganic base in which the cation is a sodium ion is sodium hydroxide. Before step (1)
(1 ') The method of Claim 1 including the process of mixing pravastatin and a 1st solvent at normal temperature, and obtaining the pravastatin containing organic solution.   The method according to claim 6, wherein in the step (1 ′), pravastatin is dissolved in a first solvent to form a pravastatin-containing organic solution.   The method according to claim 6, wherein in the step (1 ′), pravastatin and / or a salt thereof is transferred to a first solvent by extraction to form a pravastatin-containing organic solution. (a) by dissolving or extracting pravastatin and / or a salt thereof, methyl formate, n-propyl formate, isopropyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, Transferring to a first solvent that is one or more selected from the group consisting of sec-butyl acetate, isobutyl acetate and tert-butyl acetate , and forming a pravastatin-containing organic solution at room temperature ;
(b) a step of adding an inorganic base whose cation is sodium ion to the organic solution obtained in step (a) to obtain a precipitate at room temperature ;
(c) From the precipitate obtained in step (b), repeating steps (a)-(b) 1-5 times to obtain pravastatin sodium at room temperature ;
The method of claim 1, comprising:   The method according to claim 9, wherein in step (c), steps (a)-(b) are repeated 1-3 times.