CN111362856B - Method for producing atorvastatin calcium by utilizing micro-reaction device - Google Patents
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Abstract
The application discloses a method for continuously producing atorvastatin calcium by utilizing a micro-reaction device, which has simple process, can continuously produce atorvastatin calcium, and has higher operation safety and selectivity; in addition, the reaction volume is small, the reaction time is short, and the corrosion to equipment is small; meanwhile, the microchannel reactor has the characteristics of high-efficiency heat transfer capacity and easy direct amplification, has high reaction conversion rate, and the obtained product has good quality and low energy consumption, and is a green environment-friendly and efficient method for synthesizing atorvastatin calcium.
Description
Technical Field
The application relates to the field of synthesis of drug intermediates, in particular to a production process for preparing an antihyperlipidemic drug atorvastatin calcium by utilizing a microreaction device.
Background
Atorvastatin calcium (Atorvastatin calcium), having the chemical name (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid calcium salt (2:1) trihydrate, the product on the market being its hemicalcium salt trihydrate, marketed by the company Warner-Lambert in the United states under the trade name Lipritol (LIPITOR), having the structural formula:
atorvastatin calcium is an angiotensin ii (angiotenin ii) AT1 receptor antagonist capable of lowering plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and enhancing LDL uptake and metabolism by increasing hepatic LDL receptors on the cell surface. The traditional Chinese medicine has the advantages of small side effect, unique action mechanism, good tolerance and convenient administration, and becomes the first choice medicine in the aspect of the anti-hyperlipoidemia medicines in the century.
The preparation method of atorvastatin mainly comprises a racemate resolution method, a diastereoselective condensation method, a Paal-Knorr synthesis method, a cycloaddition method, a dicarbonyl asymmetric reduction method and the like, and the synthesis methods can be divided into 2 types: linear synthesis and convergent synthesis. The linear synthesis method is to synthesize the substituted pyrrole ring first and then condense with the side chain to obtain the target product, which mainly comprises a phenethylamine resolution method and a chiral Aldol condensation method. The main problems of these two methods in the synthesis of pyrrole rings are that 2- (N-isobutyryl-N-2- (1, 3-dioxolan-2) ethyl) amino-p-fluorophenylacetic acid and N, 3-diphenylpropynylamide form isomers when they are closed, and that the two isomers are similar in nature and are difficult to separate by recrystallization. Column chromatography can be separated but is not suitable for industrial production. The convergent synthesis is more economical and practical than the linear synthesis. The main ring and the side chain are respectively synthesized, the quality is easy to control, the operation is simple and easy to implement, and the target product is easy to separate and purify.
The atorvastatin calcium synthesized by the convergent synthesis method has a common intermediate L1, and the method for synthesizing the atorvastatin calcium bulk drug through the intermediate has a plurality of reported documents at home and abroad, and the synthesis route is as follows:
the intermediate L1 is subjected to acid deprotection, the generated atorvastatin tert-butyl ester is hydrolyzed under alkaline conditions, and then calcium acetate is used for forming calcium salt, so that crude atorvastatin calcium salt is obtained.
Microreactors, also known as microchannel reactors, are three-dimensional structural elements that can be used to carry out chemical reactions, manufactured in solid substrates by means of special micromachining techniques. Microreactors generally contain small channel dimensions (equivalent diameters less than 500 μm) and channel diversity, in which fluids flow, and in which the desired reactions are required to occur. This results in a very large surface area to volume ratio in the microstructured chemical device. Compared with the traditional reaction equipment, the microchannel reactor has the following advantages:
1. control of reaction temperature by microchannel reactor: the great specific surface area of the micro-reaction device determines that the micro-channel reactor has great heat exchange efficiency, and even if a great amount of heat is released instantaneously during the reaction, the micro-channel reactor can timely guide out the heat and maintain the stable reaction temperature. In contrast, the strongly exothermic reactions in conventional reactors often occur as a result of insufficient heat exchange efficiency. Local overheating tends to result in the formation of by-products, which leads to reduced yields and selectivity. In addition, if a large amount of heat generated by violent reaction in production cannot be timely conducted out, a material flushing accident and even explosion can be caused.
2. Control of the reaction time: conventional batch reactions often employ gradual dropwise addition of reactants to prevent the reaction from becoming too vigorous. This makes the residence time of a portion of the material too long. In many reactions, the reaction yield is reduced because of the formation of byproducts resulting from the long residence time of the reactants, products, or intermediate transition state products under the reaction conditions. The microchannel reactor technology adopts continuous flow reaction in a microchannel, so that the residence time of materials under the reaction condition can be controlled. Once the optimal reaction time is reached, the materials are immediately transferred to the next reaction or the reaction is stopped, so that byproducts caused by long reaction time are effectively avoided.
3. The materials are mixed instantaneously and evenly in proportion: in those rapid reactions with strict requirements on the proportion of reaction materials, if the mixing is not good enough, local excessive proportion occurs, so that byproducts are produced, which is difficult to avoid in batch reactors, and the reaction channels of the microchannel reactors are generally only tens of micrometers, so that the materials can be rapidly and uniformly mixed according to the proportion, and the formation of the byproducts is avoided.
4. The structure ensures safety: unlike batch reactors, microchannel reactors employ continuous flow reactions, so the amount of chemicals retained in the reactor is always small and the extent of hazard is very limited, even in the event of runaway. In addition, the micro-channel reactor has extremely high heat exchange efficiency, and can be rapidly led out even if the reaction suddenly releases a large amount of heat, so that the stability of the reaction temperature is ensured, and the possibility of safety accidents and quality accidents is reduced. Therefore, the micro-channel reactor can easily cope with the harsh process requirements, and realizes safe production.
5. No amplification effect: batch reactors are used for fine chemical production. Because of the difference of heat and mass transfer efficiency between large production equipment and small test equipment, a period of fumbling is generally required when the small test process is amplified. The general flow is as follows: small-pilot-large production. When the technology of the micro-channel reactor is utilized for production, the process amplification is realized by increasing the number of micro-channels instead of the characteristic size of the micro-channels, so that the small-scale optimal reaction condition can be directly used for production without any change, the difficult problem of amplification of a conventional batch reactor does not exist, and the time of products from a laboratory to the market is greatly shortened by the micro-channel reactor.
In summary, the present application aims to provide a method for producing atorvastatin calcium by utilizing the characteristics and advantages of a microreactor.
Disclosure of Invention
The technical problem to be solved by the application is to provide a method for producing atorvastatin calcium by utilizing a micro-reaction device, which uses an atorvastatin calcium intermediate L1 as a raw material to rapidly and safely synthesize atorvastatin calcium, thereby greatly improving the yield, reducing the side reaction, having good application prospect and greatly reducing the production cost.
In order to solve the technical problems, the application adopts the following technical scheme:
the application provides a method for producing atorvastatin calcium by utilizing a micro-reaction device, which comprises the following steps:
(1) Dissolving hydrochloric acid in distilled water to obtain a homogeneous phase solution A;
(2) Atorvastatin calcium intermediate L1Dissolving in methanol water solution to obtain homogeneous solution B;
(3) Dissolving sodium hydroxide in distilled water to obtain a homogeneous phase solution C;
(4) Pumping the homogeneous solution A prepared in the step (1) and the homogeneous solution B prepared in the step (2) into a first micro-mixer in a micro-channel reaction device respectively at the same time, mixing and then introducing into the first micro-reactor;
(5) Simultaneously pumping the homogeneous solution C prepared in the step (3) and the effluent of the first micro-reactor into a second micro-mixer in a micro-channel reaction device respectively while the step (4) is carried out, and introducing the mixed solution into the second micro-reactor;
(6) And collecting effluent liquid of the second micro-reactor, and then dropwise adding calcium acetate to react to obtain crude atorvastatin calcium.
1. In some embodiments of the present application, the method for producing atorvastatin calcium by using a micro-reaction device described above, wherein in the step (1), the concentration of hydrochloric acid in the homogeneous solution a is 0.1 to 0.5mol/L.
In other embodiments of the present application, the method for producing atorvastatin calcium using a microreaction device as described above, wherein in step (2), a homogeneous solution B is obtained, and the ratio of water to methanol is 1:1 to 9, the concentration of the atorvastatin calcium intermediate L1 is 0.1 to 1.0g/ml.
In other embodiments of the present application, the above method for producing atorvastatin calcium using a microreaction device, wherein in the step (3), the concentration of sodium hydroxide in the homogeneous solution C is 0.002 to 0.1g/ml.
In some embodiments of the present application, the method for producing atorvastatin calcium using a microreaction device as described above, wherein in the step (4), the reaction molar ratio of atorvastatin calcium intermediate L1 to hydrochloric acid is controlled to be 1:5-10, and wherein the reaction molar ratio of hydrochloric acid to sodium hydroxide is 1:2.2 to 3.
In other embodiments of the present application, the above method for producing atorvastatin calcium using a micro-reaction device, wherein in the step (4), the flow rate of the homogeneous solution a pumped into the first micro-mixer in the micro-channel reaction device is 0.1 to 1.0mL/min; the flow rate of the homogeneous phase solution B pumped into the first micro mixer in the micro channel reaction device is 0.1-1.0 mL/min; in the first micro-reactor, the reaction temperature is 0-60 ℃, and the reaction residence time is 20-30 min.
In some embodiments of the present application, the above method for producing atorvastatin calcium using a micro-reaction device, wherein in the step (5), the flow rate of the homogeneous solution C pumped into the second micro-mixer in the micro-channel reaction device is 0.06-0.15 mL/min; in the second micro-reactor, the reaction temperature is 0-60 ℃, and the reaction residence time is 20-30 min.
The application provides a microchannel reaction device for producing atorvastatin calcium, which comprises a first feed pump, a second feed pump, a third feed pump, a first micro-mixer, a second micro-mixer, a first micro-reactor, a second micro-reactor and a receiver; the first feeding pump and the second feeding pump are connected to the first micro-mixer in a parallel manner through pipelines, the first micro-mixer is connected with the first micro-reactor in series, the discharge port of the first micro-reactor is connected to the second micro-mixer in a parallel manner with the third feeding pump, the second micro-mixer is connected with the second micro-reactor and the receiver in series in sequence, and the connection is through pipelines. In some preferred embodiments, the first micromixer is a Y-type mixer and the second micromixer is a T-type mixer. In other preferred embodiments, the inner diameter of the conduit is 0.5 to 1mm; the volume of the first micro-reactor is 5-15 mL, and the volume of the second micro-reactor is 5-15 mL.
The atorvastatin calcium production method provided by the application has the advantages of simple process, continuous production, high operation safety, high selectivity, small reaction volume, short reaction time and less corrosion to equipment; meanwhile, the high-efficiency heat mass transfer capability and the characteristic of easy direct amplification of the microchannel reactor are utilized, the conversion rate is higher, more than 90%, the product quality is good, the energy consumption is low, and the method is a green environment-friendly and high-efficiency method for synthesizing atorvastatin calcium.
Drawings
FIG. 1 is a schematic structural view of a microreaction device according to the present application.
Detailed Description
The application will be better understood from the following examples. However, it will be readily understood by those skilled in the art that the specific material ratios, process conditions and results thereof described in the examples are illustrative of the present application and should not be construed as limiting the application described in detail in the claims.
Wherein, each part of the microchannel reaction device has the following model:
the first, second and third feed pumps are Lei Fu feed pumps, and are purchased from Baoding Lei Fu fluid technology Co., ltd, and the model is TYD01-01-CE;
the first micromixer is a Y-type mixer, available from south kyo moisturizing fluid control devices limited;
the second micromixer is a T-type mixer, available from south kyo moisturizing fluid control devices inc;
the first microreactor and the second microreactor are Teflon tubes, purchased from Nanjing wetting fluid control equipment Co., ltd., and have an inner diameter of 0.5-1 mm, and the pipeline is made of polytetrafluoroethylene. The reagents used in the experiments were AR, and were purchased from the chemical sciences of the United states of America.
Example 1
20mL of a 0.5mol/L hydrochloric acid solution was weighed and stirred at room temperature to be uniformly mixed to prepare a homogeneous solvent A. 1.0g of atorvastatin calcium intermediate L was weighed and dissolved in 20ml of aqueous methanol solution (methanol: water=7:3), and stirred at room temperature to be uniformly mixed to prepare a homogeneous solution B. 0.8g of sodium hydroxide was weighed and dissolved in 20mL of water, and the mixture was stirred at room temperature to prepare a homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution B into a Y-type mixer at a flow rate of 0.868mL/min respectively, mixing, and then introducing the mixed solution into a first microreactor with a coil pipe inner diameter of 1mm, wherein the volume of the first microreactor is 5mL, the reaction temperature is controlled at 40 ℃, and the reaction residence time is 20min; simultaneously pumping the homogeneous solution C into a T-type mixer at a flow rate of 0.12mL/min, mixing, and introducing into a second microreactor, wherein the volume of the second microreactor is 5mL, the reaction temperature is controlled at 35 ℃, and the residence time is 25min. Collecting effluent liquid of the second micro-reaction device, and dropwise adding a calcium acetate aqueous solution to obtain a product atorvastatin calcium crude product; conversion was calculated by HPLC and was 91.5%.
Example 2
20mL of a 0.5mol/L hydrochloric acid solution was weighed and stirred at room temperature to be uniformly mixed to prepare a homogeneous solvent A. 1.0g of atorvastatin calcium intermediate L was weighed and dissolved in 20ml of aqueous methanol solution (methanol: water=7:3), and stirred at room temperature to be uniformly mixed to prepare a homogeneous solution B. 0.8g of sodium hydroxide was weighed and dissolved in 20mL of water, and the mixture was stirred at room temperature to prepare a homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution B into a Y-type mixer at a flow rate of 0.428mL/min respectively, mixing, and then introducing the mixed solution into a first microreactor with a coil pipe inner diameter of 1mm, wherein the volume of the first microreactor is 10mL, the reaction temperature is controlled at 50 ℃, and the reaction residence time is 20min; simultaneously pumping the homogeneous solution C into a T-type mixer at a flow rate of 0.12mL/min, mixing, and introducing into a second micro-reactor, wherein the volume of the reactor is 10mL, the reaction temperature is controlled at 45 ℃, and the residence time is 25min. Collecting effluent liquid of the second micro-reaction device, and dropwise adding a calcium acetate aqueous solution to obtain a product atorvastatin calcium crude product; conversion was calculated by HPLC and was 91.5%. .
Example 3
20mL of a 0.5mol/L hydrochloric acid solution was weighed and stirred at room temperature to be uniformly mixed to prepare a homogeneous solvent A. 1.0g of atorvastatin calcium intermediate L was weighed and dissolved in 20ml of aqueous methanol solution (methanol: water=7:3), and stirred at room temperature to be uniformly mixed to prepare a homogeneous solution B. 0.8g of sodium hydroxide was weighed and dissolved in 20mL of water, and the mixture was stirred at room temperature to prepare a homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution B into a Y-type mixer at a flow rate of 0.428mL/min respectively, mixing, and then introducing the mixed solution into a first microreactor with a coil pipe inner diameter of 1mm, wherein the volume of the first microreactor is 15mL, the reaction temperature is controlled at 60 ℃, and the reaction residence time is 20min; simultaneously pumping the homogeneous solution C into a T-type mixer at a flow rate of 0.12mL/min, mixing, and introducing into a second microreactor, wherein the volume of the second microreactor is 15mL, the reaction temperature is controlled at 55 ℃, and the residence time is 25min. Collecting effluent liquid of the second micro-reaction device, and dropwise adding a calcium acetate aqueous solution to obtain a product atorvastatin calcium crude product; conversion was calculated by HPLC method and was 92.8%.
Example 4
20mL of a 0.5mol/L hydrochloric acid solution was weighed and stirred at room temperature to be uniformly mixed to prepare a homogeneous solvent A. 1.0g of atorvastatin calcium intermediate L was weighed and dissolved in 20ml of aqueous methanol solution (methanol: water=5:5), and stirred at room temperature to be uniformly mixed to prepare a homogeneous solution B. 0.8g of sodium hydroxide was weighed and dissolved in 20mL of water, and the mixture was stirred at room temperature to prepare a homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution B into a Y-type mixer at a flow rate of 0.428mL/min respectively, mixing, and then introducing the mixed solution into a first microreactor with a coil pipe inner diameter of 1mm, wherein the volume of the first microreactor is 10mL, the reaction temperature is controlled at 50 ℃, and the reaction residence time is 20min; simultaneously pumping the homogeneous solution C into a T-type mixer at a flow rate of 0.08mL/min, mixing, and introducing into a second microreactor, wherein the volume of the second microreactor is 10mL, the reaction temperature is controlled at 45 ℃, and the residence time is 25min. Collecting effluent liquid of the second micro-reaction device, and dropwise adding a calcium acetate aqueous solution to obtain a product atorvastatin calcium crude product; conversion was calculated by HPLC method to give 90.5%.
Example 5
20mL of 0.6mol/L hydrochloric acid solution is weighed and stirred at room temperature to be uniformly mixed to prepare a homogeneous phase solvent A. 1.0g of atorvastatin calcium intermediate L was weighed and dissolved in 20ml of aqueous methanol solution (methanol: water=5:5), and stirred at room temperature to be uniformly mixed to prepare a homogeneous solution B. 1.0g of sodium hydroxide was weighed and dissolved in 20mL of water, and the mixture was stirred at room temperature to prepare a homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution B into a Y-type mixer at a flow rate of 0.428mL/min respectively, mixing, and then introducing the mixed solution into a first microreactor with a coil pipe inner diameter of 1mm, wherein the volume of the first microreactor is 10mL, the reaction temperature is controlled at 50 ℃, and the reaction residence time is 30min; simultaneously pumping the homogeneous solution C into a T-type mixer at a flow rate of 0.08mL/min, mixing, and introducing into a second microreactor, wherein the volume of the second microreactor is 10mL, the reaction temperature is controlled at 50 ℃, and the residence time is 30min. Collecting effluent liquid of the second micro-reaction device, and dropwise adding a calcium acetate aqueous solution to obtain a product atorvastatin calcium crude product; conversion was calculated by HPLC and was 91.8%.
Example 6
20mL of 0.12mol/L hydrochloric acid solution is weighed and stirred at room temperature to be uniformly mixed to prepare a homogeneous phase solvent A. 0.2g of atorvastatin calcium intermediate L1 was weighed and dissolved in 20ml of aqueous methanol solution (methanol: water=5:5), and stirred at room temperature to be uniformly mixed to prepare a homogeneous solution B. 0.2g of sodium hydroxide was weighed and dissolved in 20mL of water, and the mixture was stirred at room temperature to prepare a homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution B into a Y-type mixer at a flow rate of 0.428mL/min respectively, mixing, and then introducing the mixed solution into a first microreactor with a coil pipe inner diameter of 1mm, wherein the volume of the first microreactor is 10mL, the reaction temperature is controlled at 50 ℃, and the reaction residence time is 30min; simultaneously pumping the homogeneous solution C into a T-type mixer at a flow rate of 0.08mL/min, mixing, and introducing into a second microreactor, wherein the volume of the second microreactor is 10mL, the reaction temperature is controlled at 50 ℃, and the residence time is 30min. Collecting effluent liquid of the second micro-reaction device, and dropwise adding a calcium acetate aqueous solution to obtain a product atorvastatin calcium crude product; conversion was calculated by HPLC method to give 90.1%.
The above-described embodiments are only illustrative embodiments for the full description of the application, and the scope of the application is defined by the claims and is not limited to the above-described embodiments. All matters disclosed in the specification, including the abstract and drawings, and all methods and steps disclosed, may be combined in any combination, unless the features and/or steps are in mutually exclusive combinations. Each feature disclosed in the specification, including the abstract and drawings, may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Equivalent substitutions and modifications which do not depart from the gist of the application will now be within the scope of the application for those skilled in the art. Such modifications are also within the scope of the present application. Each reference cited herein is incorporated by reference in its entirety.
Claims (6)
1. A method for producing atorvastatin calcium by utilizing a micro-reaction device, which is characterized by comprising the following steps: (1) dissolving hydrochloric acid in distilled water to obtain a homogeneous solution A; in the step (1), a homogeneous phase solution A is obtained, and the concentration of hydrochloric acid is 0.1-0.5 mol/L;
(2) Atorvastatin calcium intermediate L1Dissolving in methanol water solution to obtain homogeneous solution B; in the step (2), a homogeneous solution B is obtained, wherein the ratio of water to methanol is 1:1 to 9, the concentration of the atorvastatin calcium intermediate L1 is 0.1 to 1.0g/mL;
(3) Dissolving sodium hydroxide in distilled water to obtain a homogeneous phase solution C;
(4) Pumping the homogeneous solution A prepared in the step (1) and the homogeneous solution B prepared in the step (2) into a first micro-mixer in a micro-channel reaction device respectively at the same time, mixing and then introducing into the first micro-reactor; in the step (4), the flow rate of the homogeneous solution A pumped into a first micro mixer in a micro channel reaction device is 0.1-1.0 mL/min; the flow rate of the homogeneous phase solution B pumped into the first micro mixer in the micro channel reaction device is 0.1-1.0 mL/min; in the first micro-reactor, the reaction temperature is 0-60 ℃, and the reaction residence time is 20-30 min;
(5) Simultaneously pumping the homogeneous solution C prepared in the step (3) and the effluent of the first micro-reactor into a second micro-mixer in a micro-channel reaction device respectively while the step (4) is carried out, and introducing the mixed solution into the second micro-reactor; in the step (5), the flow rate of the homogeneous solution C pumped into the second micro mixer in the micro channel reaction device is 0.06-0.15 mL/min; in the second micro-reactor, the reaction temperature is 0-60 ℃ and the reaction residence time is 20-30 min;
(6) And collecting effluent liquid of the second micro-reactor, and then dropwise adding calcium acetate to react to obtain crude atorvastatin calcium.
2. The method for producing atorvastatin calcium by use of a micro-reaction apparatus of claim 1 wherein in the step (3), a homogeneous solution C is obtained, wherein the concentration of sodium hydroxide is 0.002-0.1 g/mL.
3. The process according to claim 1, wherein in step (4), the reaction molar ratio of atorvastatin calcium intermediate L1 to hydrochloric acid is controlled to be 1:5-10, wherein the reaction molar ratio of hydrochloric acid to sodium hydroxide is 1:2.2 to 3.
4. The method of claim 1, wherein the microchannel reactor comprises a first feed pump, a second feed pump, a third feed pump, a first micromixer, a second micromixer, a first microreactor, a second microreactor, and a receiver; the first feeding pump and the second feeding pump are connected to the first micro-mixer in a parallel manner through pipelines, the first micro-mixer is connected with the first micro-reactor in series, the discharge port of the first micro-reactor is connected to the second micro-mixer in a parallel manner with the third feeding pump, the second micro-mixer is connected with the second micro-reactor and the receiver in series in sequence, and the connection is through pipelines.
5. The method of claim 4, wherein the first micromixer is a Y-type mixer and the second micromixer is a T-type mixer.
6. The method of claim 4, wherein the inner diameter of the pipe is 0.5-1 mm; the volume of the first micro-reactor is 5-15 mL, and the volume of the second micro-reactor is 5-15 mL.
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| CN112375801A (en) * | 2020-10-22 | 2021-02-19 | 复旦大学 | Micro-reaction system and method for continuously preparing (R) -3-hydroxy-5-hexenoic acid ester by using same |
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| CA2499047A1 (en) * | 2005-03-01 | 2006-09-01 | Apotex Pharmachem Inc. | Process for producing atorvastatin hemicalcium |
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