CN108586427B - Preparation method of atorvastatin calcium intermediate - Google Patents
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Abstract
The invention belongs to the field of pharmaceutical chemistry, in particular relates to the field of pharmacy, and particularly relates to a preparation method of an atorvastatin calcium intermediate. The reagent adopted in the whole preparation process is safe and environment-friendly, and the preparation method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, particularly relates to the field of pharmacy, and particularly relates to a preparation method of an atorvastatin calcium intermediate.
Background
Atorvastatin Calcium (Atorvastatin Calcium) was developed by Warner-Lambert (now incorporated into pfeiri), approved by the FDA in 1996 to be marketed in the united states for the treatment of hypercholesterolemia and mixed hyperlipidemia.
(4R-Cis) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxolane-tert-butyl hexanoate (125995-13-3) (Compound I) is a key intermediate compound in the synthesis of atorvastatin calcium.
At present, the preparation method of the compound I basically follows the synthetic process route as follows:
therefore, the compound VI serving as a key intermediate compound for synthesizing the compound I has important research significance in the process of research and development of the preparation process of atorvastatin calcium, and the synthesis method and the synthesis process of the compound VI are hot problems in the existing synthesis research of atorvastatin calcium.
At present, the preparation method of the compound VI mainly comprises two types, wherein the first type adopts cyano substitution and then dihydroxy protection, and the second type adopts dihydroxy protection and then cyano substitution.
It can be seen that although the two preparation processes differ in terms of yield and reaction conditions, for example, the yield can reach 81% for the first process and only 11% for the second process, while the reaction temperature in the second process requires 100 ℃ and the reaction time even 30 hours. However, both methods have in common in the synthesis process that both methods require the use of NaCN. In addition, during the synthesis process, solvents such as hydrocyanic acid and the like are also needed to be used as reaction media.
For those skilled in the art, hydrocyanic acid, hydrochloride, etc. are all very toxic substances. These substances are not only extremely harmful to human bodies, but also severely pollute the environment. Hydrocyanic acid and hydrohalite are used as reaction raw materials, which not only does not meet the current national environmental protection trend, but also is difficult to purchase. This further increases the cost of preparation of compound vi and thus of atorvastatin calcium.
Therefore, it is important to research and develop how to prepare and obtain the compound VI without using highly toxic substances such as hydrocyanic acid, hydrochloride and the like.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel preparation method of an atorvastatin calcium intermediate on the premise of not using hydrocyanic acid and hydrochloride, and the synthetic route of the method is as follows:
further preferably, the preparation method can be specifically described as comprising the following steps:
the first step is as follows: reacting the compound II with a lithium metal reagent to obtain a compound III;
the second step is that: mixing methyl chloroformate with compound III at low temperature, raising the temperature to room temperature, and reacting the compound III with the methyl chloroformate to obtain compound IV;
the third step: under the alkaline condition, reacting the compound IV with a methanol solution of ammonia to obtain a compound V;
the fourth step: and dehydrating the compound V to generate a compound VI under the action of a dehydrating agent.
Preferably, the first step reaction is carried out in one solution of diethyl ether, tetrahydrofuran, 1, 4-dioxane, dichloromethane, toluene and xylene or a mixed solvent obtained by optionally mixing two or more of the above in any mixing ratio.
More preferably, the first reaction is carried out in a solution of diethyl ether or tetrahydrofuran.
When the first step reaction solvent is diethyl ether or tetrahydrofuran, the reaction temperature is-5-10 ℃.
The preferable technical scheme is that the mode for mixing the methyl chloroformate and the compound III is to dropwise add the compound III into the methyl chloroformate solution.
Preferably, after the second step reaction is completed, quenching, extraction, drying and concentration are also included.
The further preferable technical scheme is that the low-temperature condition is-30 ℃ to 0 ℃.
The further preferable technical scheme is that the solvent of the methyl chloroformate solution is a mixed solvent formed by mixing one or more than two of diethyl ether, tetrahydrofuran, 1, 4-dioxane, dichloromethane, toluene and xylene according to any mixing ratio.
The room temperature is 15-25 ℃.
More preferably, the low temperature condition is-20 ℃.
And further preferably, the solvent of the methyl chloroformate solution is diethyl ether or tetrahydrofuran.
In a preferred embodiment, the third step is to add ammonia in methanol to the organic solution of compound IV for reaction.
Preferably, after the third step of reaction is completed, the method further comprises removing the solvent, extracting, drying and concentrating.
The methanol solution of ammonia referred to herein may be a saturated methanol solution of ammonia obtained by dissolving ammonia gas in a methanol solution, or may be a methanol solution of ammonia obtained by mixing ammonia water with a methanol solution.
More preferably, the reaction temperature of the third step is 15-100 ℃.
The further preferable technical proposal is that the compound V is dissolved in an organic solvent and dehydrated to generate the compound VI under the action of an alkaline substance and a dehydrating agent.
The organic solvent is preferably one or a mixture of more than two of dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, benzene, toluene and xylene in any proportion. Wherein the alkaline substance is preferably at least one of pyridine, 4-dimethylamino pyridine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. Wherein the dehydrating agent is one of thionyl chloride and phosphorus oxychloride or a mixture obtained by mixing thionyl chloride and phosphorus oxychloride in any proportion.
Further, the invention also discloses a method for preparing the compound I by the compound VI, which comprises the following steps: and dissolving the compound VI in an organic solvent, and reacting with hydrogen under the action of a catalyst to obtain a compound I.
Further preferably, the reaction is described as the hydrogenation reaction by adding an organic solvent solution of the catalyst to an organic solvent solution of the compound VI, after the reaction is completed, filtering, concentrating, diluting with water, adjusting pH with liquid ammonia, extracting, drying, and concentrating to obtain the corresponding compound I.
Wherein, the catalyst is preferably one or a mixture of more than two of palladium carbon, platinum carbon and Raney nickel in any proportion. The organic solvent is a mixture of one or more than two of alcohols such as methanol, ethanol, propanol and the like, formic acid, acetic acid and propionic acid which are mixed according to any mixing ratio.
In a preferred embodiment, the catalyst is preferably palladium on carbon or platinum on carbon.
In another preferred embodiment, the organic solvent is preferably acetic acid.
Furthermore, the invention also discloses that the preferable compound VI reacts with hydrogen under the action of a catalyst and at the temperature of 20-30 ℃.
The invention breaks through the dilemma that hydrocyanic acid, hydrochloride and other highly toxic substances are required to be used in the traditional preparation process of the atorvastatin calcium intermediate. By the brand-new preparation method of the atorvastatin calcium intermediate, the compound VI can be prepared and synthesized on the premise of not using virulent substances such as hydrocyanic acid, hydrochloride and the like, and the compound I can be prepared by using the compound VI. The reagent adopted in the whole preparation process is safe and environment-friendly, and the preparation method is more suitable for industrial production.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
The reagents used in the examples are all commercially available products unless otherwise specified.
Example 1
Metallic lithium (0.18 g) was dissolved in 40mL of anhydrous ether at 0 ℃, 10mL of an ether solution of Compound II (2.79 g,0.01 mol) was slowly added dropwise thereto, and the mixture was stirred at 0 ℃ with generation of a white precipitate, and after completion of the reaction of lithium, the mixture was allowed to stand, and the supernatant containing Compound III was used for the next reaction.
Methyl chloroformate (1.09 g, 0.012 mol) was dissolved in 10ml of anhydrous ether, and the supernatant containing compound iii (ether solution of compound iii) obtained in the preceding step was added dropwise thereto at-20 ℃, and after completion of the addition, the temperature was raised to room temperature (15 to 25 ℃), followed by stirring until the reaction was completed. Then theThe temperature was reduced to 0 ℃ and 6.5mL of a saturated ammonium chloride solution was added to the reacted solution, followed by 2.2mL of 10% by mass hydrochloric acid, and the organic layer was retained, washed with 5% sodium bicarbonate, and the ether was removed by rotary evaporation to give 2.11g of Compound IV (purity 93%, yield 70%). Product characterization data were as follows:1H-NMR (400 MHz,CDCl3) 4.49 – 4.37 (m, 2H), 3.70 (s, 3H), 2.62-2.53 (m, 2H), 2.40-2.32 (m,2H), 1.86-1.77 (m, 2H), 1.42 (s, 9H), 1.21 (s, 6H).13C-NMR (100 MHz, CDCl3)172.92, 171.80, 100.80, 81.86, 69.53, 51.87, 42.07, 41.03, 35.33, 28.33,26.21 .
the compound IV (6.25 g, 0.02 mol) is reacted with NH3H2O (200 mL)/MeOH (200 mL) solution was stirred at room temperature for about 16 h, and after the reaction was complete, most of the MeOH was removed, diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give compound v (1.45 g, 85%). Product characterization data were as follows:1H-NMR(400 MHz, CDCl3) 5.61 (s, 2H), 4.49 – 4.36 (m, 1H), 4.16 – 4.04 (m, 1H),2.65 –2.56 (m, 1H), 2.56 – 2.47 (m, 1H), 2.43 – 2.36 (m, 1H), 2.34-2.26 (m,1H), 1.83 – 1.70 (m, 1H), 1.57-1.52 (m, 1H), 1.42 (s, 9H), 1.21 (s, 6H).13C-NMR (100 MHz, CDCl3) 175.73, 172.92, 100.80, 81.86, 73.66, 69.53, 45.59,41.03, 35.33, 28.33, 26.21。
compound V (4.31 g,0.015 mol) was dissolved in toluene (25 mL), pyridine (0.5 mL) and thionyl chloride (0.5 mL) were added, stirred at room temperature overnight, then washed with water, aqueous sodium bicarbonate and brine, respectively, dried and concentrated. Compound VI (3.23 g, 80%) was obtained. Product characterization data were as follows:1H-NMR (400 MHz, CDCl3) 4.47-4.44 (m,2H), 2.92-2.88(m, 1H), 2.77-2.70 (m, 1H), 2.60-2.56 (m, 1H), 2.40-2.32 (m,1H), 2.00-1.92 (m, 1H), 1.82-1.74 (m, 1H), 1.42 (s, 9H), 1.21 (s, 6H).13C-NMR(100 MHz, CDCl3) 172.92, 171.80, 100.80, 81.86, 69.53, 51.87, 42.07, 41.03,35.33, 28.33, 26.21。
in the reaction kettle, chemical combination is firstly addedObject VI (5 g), acetic acid 50ml, then adding 10% palladium carbon (0.5 g) acetic acid solution (5 ml), 20-30 ℃ hydrogenation reaction for 8 h. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was rotary evaporated to give an oil. The oil was dissolved in 30ml of water, the pH was adjusted to 8-9 with liquid ammonia, and then extracted with dichloromethane. The dichloromethane layer was separated and dried over anhydrous sodium sulfate and rotary evaporated to give compound i (4.62 g, 91%). Product characterization data were as follows:1H-NMR (400 MHz,CDCl3): 4.23-4.19 (m, 1H),3.99-3.95 (m, 1H), 2.74 (t,J=7.1 Hz, 2H), 2.40-2.36 (m, 1H),2.27-2.22 (m,1H), 1.58-1.41 (m, 2H),1.40 (s, 9H), 1.31 (s, 6H),0.89 (s, 9H).13C-NMR (100 MHz, CDCl3) 172.92, 100.80, 81.86, 69.53, 67.23,41.03, 40.00, 39.23, 35.55, 28.33, 26.21。
example 2
Metallic lithium (0.18 g) was dissolved in 40mL of anhydrous tetrahydrofuran at 0 ℃, 10mL of a tetrahydrofuran solution of Compound II (2.79 g,0.01 mol) was slowly added dropwise thereto, and the mixture was stirred at 0 ℃ with generation of a white precipitate, and after completion of the reaction of lithium, the mixture was allowed to stand, and the supernatant containing Compound III was used for the next reaction.
Methyl chloroformate (1.09 g, 0.012 mol) was dissolved in 10ml of anhydrous tetrahydrofuran. The supernatant containing compound III (tetrahydrofuran solution of compound III) obtained in the previous step was added dropwise thereto at-20 ℃ and warmed to room temperature (15 to 25 ℃), stirred, and after completion of the reaction, 6.5mL of a saturated ammonium chloride solution was added at 0 ℃ followed by 2.2mL of 10% hydrochloric acid, the organic layer was retained, washed with 5% sodium bicarbonate, and the tetrahydrofuran was removed by rotary evaporation to obtain 2.05g of compound IV (purity 92%, yield 68%).
The compound IV (6.25 g, 0.02 mol) is reacted with NH3H2O (200 mL)/MeOH (200 mL) solution was stirred at room temperature for about 16 h, and after the reaction was complete, most of the MeOH was removed, diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give compound v (1.45 g, 85%).
Compound V (4.31 g,0.015 mol) was dissolved in toluene (25 mL), pyridine (0.5 mL) and thionyl chloride (0.5 mL) were added, stirred at room temperature overnight, then washed with water, aqueous sodium bicarbonate and brine, respectively, dried and concentrated. Compound VI (3.23 g, 80%) was obtained.
In a reaction kettle, firstly adding a compound VI (5 g) and 50ml of acetic acid, then adding a 10% platinum carbon (0.5 g) acetic acid solution (5 ml), and carrying out hydrogenation reaction at 20-30 ℃ for 8 h. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was rotary evaporated to give an oil. The oil was dissolved in 30ml of water, the pH was adjusted to 8-9 with liquid ammonia, and then extracted with dichloromethane. The dichloromethane layer was separated and dried over anhydrous sodium sulfate and rotary evaporated to give compound i (4.57 g, 90%).
Example 3
Metallic lithium (0.18 g) was dissolved in 40mL of anhydrous ether at 0 ℃, 10mL of an ether solution of Compound II (2.79 g,0.01 mol) was slowly added dropwise thereto, and the mixture was stirred at 0 ℃ with generation of a white precipitate, and after completion of the reaction of lithium, the mixture was allowed to stand, and the supernatant containing Compound III was used for the next reaction.
Methyl chloroformate (1.09 g, 0.012 mol) was dissolved in 10ml of anhydrous ether. The supernatant containing compound III (ether solution of compound III) obtained in the previous step was added dropwise thereto at-20 ℃ and the mixture was warmed to room temperature (15 to 25 ℃), stirred, and after completion of the reaction, a saturated ammonium chloride solution was added thereto at 0 ℃, followed by addition of 2.2ml of 10% hydrochloric acid, followed by retention of the organic layer, washing with 5% sodium bicarbonate, and removal of ether by rotary evaporation to obtain 2.11g of compound IV (purity 93%, yield 70%).
To compound IV (6.25 g, 0.02 mol) was added an excess of saturated NH3The MeOH solution was stirred at room temperature for about 16 h, and after the reaction was complete, most of the MeOH was removed, diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give compound v (1.42 g, 83.3%).
Compound V (4.31 g,0.015 mol) was dissolved in toluene (25 mL), pyridine (0.5 mL) and thionyl chloride (0.5 mL) were added, stirred at room temperature overnight, then washed with water, aqueous sodium bicarbonate and brine, respectively, dried and concentrated. Compound VI (3.23 g, 80%) was obtained.
In a reaction kettle, firstly adding compound VI (5 g) and 50ml of formic acid, then adding 10 percent platinum carbon (0.5 g) formic acid solution (5 ml), and carrying out hydrogenation reaction for 8h at the temperature of 20-30 ℃. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was rotary evaporated to give an oil. The oil was dissolved in 30ml of water, the pH was adjusted to 8-9 with liquid ammonia, and then extracted with dichloromethane. The dichloromethane layer was separated and dried over anhydrous sodium sulfate and rotary evaporated to give compound i (4.62 g, 91%).
Example 4
The tests were carried out in the manner disclosed in examples 1 to 3, except for examples 1 to 3. In this example, the solvent and the reaction temperature in the first reaction step were replaced, respectively.
The diethyl ether or tetrahydrofuran in examples 1-3 was replaced by 1, 4-dioxane, dichloromethane, toluene, xylene, and mixed solution of diethyl ether and tetrahydrofuran in equal ratio, such as 1:100 (volume ratio) of diethyl ether to tetrahydrofuran, 100:1 (volume ratio) of diethyl ether to tetrahydrofuran, 1:100 (volume ratio) of toluene to dichloromethane, and 100:1 (volume ratio) of toluene to dichloromethane, and the results show that the solutions disclosed in the present invention can be used as the solvent for the first reaction.
We have carried out the reaction at-5 deg.C, -2 deg.C, 5 deg.C, 8 deg.C and 10 deg.C instead of 0 deg.C in the first step, and the results show that the reaction can be carried out under the conditions of-5 deg.C to 10 deg.C.
Example 5
The tests were carried out in the manner disclosed in examples 1 to 3, except for examples 1 to 3. In this example, the solvent and the reaction temperature in the second reaction step were replaced, respectively.
We respectively replace-20 ℃ in the second step with-30 ℃, -28 ℃, -25 ℃, -15 ℃, -13 ℃, -10 ℃, -8 ℃, -5 ℃ and 0 ℃.
The results show that reactions are possible in the range of-30 ℃ to 0 ℃.
According to the reagent added in the first step, 1, 4-dioxane, dichloromethane, toluene, xylene and mixed solution of diethyl ether and tetrahydrofuran in equal proportion are correspondingly added in the second step, and the diethyl ether and tetrahydrofuran are replaced by the diethyl ether or tetrahydrofuran in the form of solution of 1:100 (volume ratio), 100:1 (volume ratio), 1:100 (volume ratio), 100:1 (volume ratio) and the like, and the solution of toluene and dichloromethane is shown to be used as the solvent for the second step reaction.
Example 6
The tests were carried out in the manner disclosed in examples 1 to 3, except for examples 1 to 3. In this example, the reaction temperature in the third reaction step was replaced.
In this example, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ and 100 ℃ were examined, respectively.
The result shows that the reaction can be realized within the range of 15-100 ℃.
Example 7
The tests were carried out in the manner disclosed in examples 1 to 3, except for examples 1 to 3. In this example, the reaction temperature in the fourth reaction step was replaced.
Methylene dichloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, benzene, xylene, a mixed solution of methylene dichloride and toluene, a mixed solution of acetonitrile and toluene and the like are respectively used for replacing toluene for dissolving the compound V. The results show that the solutions disclosed in the present invention can be used for the dissolution of compound v.
Pyridine is replaced by 4-dimethylamino pyridine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide respectively. The results show that the solutions disclosed in the present invention can all be used to form the basic reaction environment for compound v.
The thionyl chloride is replaced by phosphorus oxychloride and a mixture of thionyl chloride and phosphorus oxychloride in any proportion as a dehydrating agent, and the result shows that the compound VI can be obtained.
Example 8
The tests were carried out in the manner disclosed in examples 1 to 3, except for examples 1 to 3. In this example, the reaction conditions for preparing compound I from compound VI are replaced.
Platinum carbon, Raney nickel, a mixture of palladium carbon and platinum carbon and a mixture of palladium carbon and Raney nickel are respectively used as catalysts for preparing the compound I from the compound VI. The results show that the catalyst disclosed by the invention can be used for preparing the compound I from the compound VI.
The results show that the solutions disclosed by the invention can be used for preparing the compound I from the compound VI.
What has been described above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (5)
1. The preparation method of the atorvastatin calcium intermediate is characterized by comprising the following steps: the synthetic route of the method is as follows:
the preparation method comprises the following steps:
the first step is as follows: reacting the compound II with a lithium metal reagent to obtain a compound III;
the second step is that: mixing methyl chloroformate with compound III at low temperature, raising the temperature to room temperature, and reacting the compound III with the methyl chloroformate to obtain compound IV;
the third step: under the alkaline condition, reacting the compound IV with a methanol solution of ammonia to obtain a compound V;
the fourth step: dehydrating the compound V to generate a compound VI under the action of a dehydrating agent;
dissolving the compound V in an organic solvent, and dehydrating to generate a compound VI under the action of an alkaline substance and a dehydrating agent;
wherein, the organic solvent A is one or a mixture of more than two of dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, benzene, toluene and xylene which are mixed in any proportion;
B. the alkaline substance is at least one of pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide;
C. the dehydrating agent is one of thionyl chloride and phosphorus oxychloride or a mixture obtained by mixing thionyl chloride and phosphorus oxychloride according to any proportion.
2. The process for the preparation of atorvastatin calcium of claim 1, wherein: in the first step of the process,
the first step is reaction in one solution of diethyl ether, tetrahydrofuran, 1, 4-dioxane, dichloromethane, toluene and xylene or a mixed solvent obtained by optionally mixing two or more of the two or more according to any mixing ratio;
the reaction temperature is-5-10 ℃.
3. The process for the preparation of atorvastatin calcium of claim 1, wherein: in the second step, the first step is carried out,
A. the mode of mixing the methyl chloroformate with the compound III is to drop the compound III into the methyl chloroformate solution;
B. after the second step reaction is finished, quenching, extracting, drying and concentrating are also included;
C. the low temperature condition is-30-0 ℃;
D. the solvent of the methyl chloroformate solution is a mixed solvent formed by mixing one or more than two of diethyl ether, tetrahydrofuran, 1, 4-dioxane, dichloromethane, toluene and xylene according to any mixing ratio.
4. The process for the preparation of atorvastatin calcium of claim 1, wherein: in the third step, the first step is carried out,
A. in the third step, adding a methanol solution of ammonia into the organic solution of the compound IV for reaction;
B. after the third step of reaction is finished, removing the solvent, extracting, drying and concentrating;
C. the methanol solution of ammonia is a methanol solution of saturated ammonia formed by dissolving ammonia gas in a methanol solution, or a methanol solution of ammonia obtained by mixing ammonia water with a methanol solution;
D. the reaction temperature of the third step is 15-100 ℃.
5. The process for preparing atorvastatin calcium of claim 1 further comprising the step of preparing compound I from compound vi: dissolving the compound VI in an organic solvent, and reacting with hydrogen under the action of a catalyst to obtain a compound I, wherein the structural formula of the compound I is as follows;
adding an organic solvent solution of a catalyst into an organic solvent solution of a compound VI for hydrogenation reaction, filtering after the reaction is finished, concentrating, adding water for dilution, adjusting the pH value of liquid ammonia, extracting, drying and concentrating to obtain a corresponding compound I;
the catalyst A is one or a mixture of more than two of palladium carbon, platinum carbon and Raney nickel in any proportion;
B. the organic solvent is a mixture of one or more than two of alcohols such as methanol, ethanol, propanol and the like, formic acid, acetic acid and propionic acid which are mixed according to any mixing ratio;
C. and reacting the compound VI with hydrogen at the temperature of 20-30 ℃ under the action of a catalyst.
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