KR20160120532A - Method for preparing of chiral intermediate and method for the preparing of HMG-CoA reductase inhibitor using chiral intermadiate - Google Patents
Method for preparing of chiral intermediate and method for the preparing of HMG-CoA reductase inhibitor using chiral intermadiate Download PDFInfo
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- KR20160120532A KR20160120532A KR1020150049724A KR20150049724A KR20160120532A KR 20160120532 A KR20160120532 A KR 20160120532A KR 1020150049724 A KR1020150049724 A KR 1020150049724A KR 20150049724 A KR20150049724 A KR 20150049724A KR 20160120532 A KR20160120532 A KR 20160120532A
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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Abstract
The present invention relates to a process for preparing a chiral compound and a process for preparing an HMG-CoA reductase inhibitor using the same, and more particularly, to a process for producing a statin compound, which is an HMG-CoA reduction inhibitor, The present invention relates to a method for producing a chiral compound capable of producing a high-purity statin compound on a commercial scale, and a method for producing an HMG-CoA reduction inhibitor using the same.
Description
The present invention relates to a process for preparing a chiral compound and a process for preparing an HMG-CoA reduction inhibitor using the chiral compound thus prepared.
The first generation of drugs that are known as "statins" are cholesterol-inhibiting effects of HMG-CoA reductase inhibitors. Simvastatin, lovastatin, Pravastatin and the second generation of synthetic medicines include atorvastatin, fluvastatin, rosuvastatin, and pitavastatin.
The structure of the main products is as follows.
Dual fluvastatin, rosuvastatin and pitavastatin have a common structure of 1,3-syn-diol carboxylic acids linked by a trans double bond, as can be seen above.
One of the main methods of preparing these compounds is to make two racemates of 1,3-syn-diol by various methods, then separating the two and using chiral intermediates.
As a method for producing fluvastatin in a commercially available manner, there have been known a method for producing fluvastatin (USP 5354772) from Sandoz, a method for producing rosuvastatin (USP 5260440) from Shionogi and the like, The racemate is prepared and separated by the following reaction equation.
According to the above method, a trans-cinnamaldehyde group is first prepared, and then a di-anion is formed using a base equivalent to at least 2 equivalents of a beta- ketoester and then introduced into aldehyde. Then, two syn-1,3-diols are prepared according to the chirality of the alcohol, and the two racemates are separated by various methods, for example, chemical resolution, enzymatic resolution, Separate.
However, the method of separating the racemate after the racemate has the following serious problems.
First, since a 50:50 racemic mixture of A and B requires a resolution of 98% or more to a desired target optical activity, it is required to undergo a complicated resolution process, and a yield of 50% or less is obtained only by the separation process, .
Second, the opposite isomer remains in the product and acts as an impurity, thereby deteriorating the quality of the product.
Thus, methods using chiral intermediates may be advantageous and are described in Heathcock (J. Am. Chem. Soc. 1985, 107, 3731), Bayer (USP 5849749), Bristol Meyers (J. Org. 56, 3744), Shionogi (USP 5354879) and the like.
[Compound I]
The following reaction formula is shown by plotting the example of Bristol Meyers Quibs (J. Org. Chem. 1991, 56, 3744), which introduces the method for producing the compound I above.
However, the chiral intermediates of the above scheme have the following problems during the production process.
First, an expensive chiral resolving agent such as S-1-phenylethylamine should be used. Even when resolution is performed at a low temperature of -78 ° C, a mixture of diastereomers having a maximum ratio of 79:21 is obtained Loses. Therefore, it is necessary to separate the desired isomers, so that in this case there is a yield reduction of at least 20% and a counter-isomer removal and burden of disposal.
Second, hazardous reactions such as N 2 O 4 oxidation reaction and high-pressure hydrogen reaction must be performed in order to cleave the amine group used as a resolving agent.
Third, since a dimethylphosphinyl functional group is to be introduced into the carboxylate of the compound (E), a strong base such as normal butyllithium in an amount of 3.0 to 4.5 equivalents in total, such as 1.0 or more equivalents of normal butyllithium, should be used .
Fourth, in order to obtain the final compound (2) from the carboxylic acid, the diazo reaction must be carried out in an ether solvent.
Fifth, a reduction reaction using hydrogen requires an expensive palladium catalyst, which results in poor economical efficiency and lowers the quality of the resulting product because it may contain heavy metals.
Sixth, the overall manufacturing process is complicated, the yield is low and the economic efficiency is low. It is not suitable for commercial production processes such as explosive and toxic materials.
In order to solve the problems of the prior art as described above, the present invention provides chiral intermediates which can be used in the production of statin compounds, which are HMG-CoA reduction inhibitors, in a high yield and high purity, And a method for producing the compound.
It is another object of the present invention to provide a process for producing a chiral compound capable of producing a high-purity statin compound economically on a commercial scale, and a process for producing the HMG-CoA reduction inhibitor using the same.
In order to achieve the above object,
(S1) a step of selectively hydrolyzing a compound of the formula (2) to produce a compound of the formula (3);
(S2) condensing a compound of the formula (3) with t-butanol in the presence of a solvent and a condensing agent to prepare a compound of the formula (4);
(S3) reacting a compound of the following formula (4) with a compound having a hydroxy-protecting group in the presence of a solvent and a base compound to prepare a compound of the formula (5);
(S4) hydrolyzing the compound of formula (5) in the presence of a solvent and a base compound to prepare a compound of formula (6);
(S5) reacting a compound of formula (6) with a compound of formula R 3 OH, wherein R 3 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene, To obtain a compound of the formula (7); And
(S6) reacting a compound of formula (7) with a compound of formula (8) in the presence of a solvent and a base compound to prepare a chiral compound of formula (1);
Wherein R < 1 > and R < 2 >
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
(7)
[Chemical Formula 8]
In the above Chemical Formulas 1 to 8,
X is selected from the group consisting of P (= O) (R 1 ) 2, S (= O) R 1, or SO 2 R 1 wherein R 1 is hydrogen, lower alkyl, substituted lower alkyl, , Aryl, or substituted aryl),
P is a hydroxy protecting group,
R < 2 > is lower alkyl or substituted lower alkyl of methyl, ethyl or propyl,
R 3 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene.
In the above formulas 5 to 7, the hydroxy protecting group (P) may be t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl, aryl and the like.
The solvent of step (S2), (S3), (S4), (S5) or (S6) may be selected from the group consisting of methanol, ethanol, 2-propanol, t-butanol, benzene, toluene, xylene, tetrahydrofuran, But are not limited to, 1,4-dioxane, petroleum ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dimethoxyethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachlorethylene, tetrachloroethane, Examples of the solvent include dichlorobenzene, trichlorobenzene, dimethoxyethane, dialkylformamide, dimethylformamide, dialkyl acetamide, dimethylacetamide, hexamethylphosphoramide, dialkylsulfoxide and dimethylsulfoxide.
The condensing agent of the step (S2) or (S5) may be at least one selected from the group consisting of SOCl 2 , SO 2 Cl 2 , SOBr 2 , SO 2 Br 2 , PCl 3 , PCl 5 , POCl 3 , methyl chloroformate, ethyl chloroformate, Chloroformate, isobutyl chloroformate, dichlorohexylcarbodiimide and the like can be used.
The compound having a hydroxy-protecting group in step (S3) may be t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl, aryl or the like.
The base compound of the step (S3), (S4), (S5) or (S6) may be a trialkylamine, a dialkylamine, Calcium, an alkali metal hydroxide, an alkali metal hydride, an alkali metal alkoxide, an alkali metal alkyl compound, an alkaline earth metal hydroxide, an alkaline earth metal hydride, an alkaline earth metal alkoxide, an alkaline earth metal alkyl Compounds and the like may be used.
The present invention also provides a method for preparing an HMG-CoA reduction inhibitor, which comprises reacting an aldehyde-based compound and a chiral compound of the formula (1).
Specifically, the HMG-CoA reduction inhibitor is
(S1) condensing the aldehyde-based compound of Formula 9 and the chiral compound of Formula 1 to prepare a trans compound of Formula 10;
(S2) deprotecting the hydroxy group of the trans compound of Formula 10 to prepare a compound of Formula 11
(S3) reducing the ketone group of the compound of Formula 11 to prepare cis-1,3-diol of Formula 12;
(S4) separating the t-butyl group from the cis-1,3-diol of Formula 12 to prepare an HMG-CoA reduction inhibitor of Formula 13;
: ≪ RTI ID = 0.0 >
[Chemical Formula 9]
[Chemical formula 10]
(11)
[Chemical Formula 12]
[Chemical Formula 13]
In the above formulas (9) to (13)
A is
P is a hydroxy protecting group.
The HMG-CoA reduction inhibitor may be a compound represented by the following formula (13a), (13b) or (13c).
[Chemical Formula 13a]
[Chemical Formula 13b]
[Chemical Formula 13c]
According to the present invention, chiral intermediates which can be used in the production of statin compounds, which are HMG-CoA reduction inhibitors, can be produced in a high yield and high purity by a mild and simple method without a dangerous reaction step, Scale production.
Hereinafter, the present invention will be described in detail.
The present invention relates to a method for mildly producing a chiral compound represented by the following formula (1), which is an intermediate capable of producing a statin compound, which is an HMG-CoA reduction inhibitor, without complicated and troublesome processes.
[Chemical Formula 1]
In Formula 1,
X is selected from the group consisting of P (= O) (R 1 ) 2, S (= O) R 1, or SO 2 R 1 wherein R 1 is hydrogen, lower alkyl, substituted lower alkyl, , Aryl, or substituted aryl),
P is a hydroxy protecting group, more preferably t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl or aryl.
The process for preparing the chiral compound represented by the above formula (1) of the present invention comprises the following steps.
(S1) a step of selectively hydrolyzing a compound of the formula (2) to produce a compound of the formula (3);
(S2) condensing a compound of the formula (3) with t-butanol in the presence of a solvent and a condensing agent to prepare a compound of the formula (4);
(S3) reacting a compound of the following formula (4) with a compound having a hydroxy-protecting group in the presence of a solvent and a base compound to prepare a compound of the formula (5);
(S4) hydrolyzing the compound of formula (5) in the presence of a solvent and a base compound to prepare a compound of formula (6);
(S5) reacting a compound of formula (6) with a compound of formula R 3 OH, wherein R 3 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene, To obtain a compound of the formula (7); And
(S6) reacting a compound of formula (7) with a compound of formula (8) in the presence of a solvent and a base compound to prepare a chiral compound of formula (1);
Wherein X is selected from the group consisting of P (= O) (R 1 ) 2, S (= O) R 1 or SO 2 R 1 wherein R 1 is hydrogen, lower alkyl, substituted lower alkyl, lower alkoxy, lower alkoxy, aryl, or substituted aryl), P is a hydroxy protecting group, R 2 is methyl, ethyl or a lower alkyl or substituted lower alkyl profile, R 3 is phenyl, substituted phenyl, naphthyl, Substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene.
Hereinafter, the process for preparing the chiral compound of Formula 1 of the present invention will be described in more detail.
(S1): Preparation of the compound of formula (3)
A monoester compound represented by the following formula (3) is prepared by selective ester hydrolysis of a diester compound represented by the following formula (2) with a microorganism.
Wherein R < 2 > is lower alkyl or substituted lower alkyl of methyl, ethyl or propyl.
Since the monoester compound of formula (3) starts from a diester compound of formula (2), which is a meso compound, it has a yield of more than 50% based on hydrolysis using general microorganisms and a quantitative yield close to 100% and a yield of 99% Lt; / RTI > of optical purity.
The type of microorganism is not limited as long as it is a general esterase or microorganism, and specifically, lipase, protease, esterase and the like can be used. In addition, the microorganism can be used at a high concentration of 10% or more to carry out the reaction.
(S2) Step: Preparation of compound of formula (4)
A monoester compound of the following formula (3) and t-butanol are subjected to a condensation reaction under a solvent and a condensing agent to prepare a diester compound of the following formula (4).
Wherein R < 2 > is lower alkyl or substituted lower alkyl of methyl, ethyl or propyl.
Examples of the solvent include lower alcohol solvents such as methanol, ethanol, 2-propanol, and t-butanol; Aromatic solvents such as benzene, toluene and xylene; Ether solvents such as tetrahydrofuran, dioxane, 1,4-dioxane, petroleum ether, diethyl ether, diisopropyl ether, t-butyl methyl ether and dimethoxyethane; Halogen solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachlorethylene, tetrachloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene; Dimethylformamide, dialkylformamide, dialkyl acetamide, dialkyl sulfoxide and the like can be used. Particularly, in this step, aromatic solvents such as benzene, toluene and xylene; Ether solvents such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butyl methyl ether and dimethoxyethane; Halogen solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachlorethylene, tetrachloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene; Polar solvents such as dimethoxyethane, dialkylformamide, dimethylformamide, dialkyl acetamide, dimethylacetamide, hexamethylphosphoramide, dialkylsulfoxide and dimethylsulfoxide may be used. The solvent is preferably used in an amount of 1.0 to 100 equivalents relative to the compound of formula (3).
The condensing agent is SOCl 2, SO 2 Cl 2, SOBr 2, SO 2 Br 2, PCl 3, PCl 5, POCl 3, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate , Dichlorohexylcarbodiimide and the like can be used. The condensing agent is preferably used in an amount of 1.0 to 10.0 equivalents based on the compound of formula (3).
Also, the reaction is preferably carried out at a temperature of 30 ° C or less, preferably -30 to 30 ° C. If the reaction temperature is lower than -30 ° C, the reaction rate may be slower, and if it is higher than 30 ° C, by-products may occur.
(Step S3): Preparation of the compound of Chemical Formula 5
A diester compound represented by the following formula (4) is reacted with a compound having a hydroxy protecting group in the presence of a solvent and a base compound to prepare a compound represented by the formula (5).
Wherein R 2 is lower alkyl or substituted lower alkyl of methyl, ethyl or propyl and P is a hydroxy protecting group and more specifically t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl Or aryl.
For example, when the hydroxy protecting group (P) in the compound of Chemical Formula 5 is t-butyldimethylsilyl, the diester compound of Chemical Formula 4 is stirred in the presence of t-butyldimethylsilyl chloride, a solvent and a base compound, Compounds of formula 5 may be prepared wherein the Roxy protecting group is t-butyldimethylsilyl.
As the solvent, the same solvent as in the step (S2) may be used. In particular, aromatic solvents such as benzene, toluene and xylene; Halogen solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachlorethylene, tetrachloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene; Dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like are preferably used. The solvent is preferably used in an amount of 1.0 to 50.0 equivalents based on the compound of formula (IV).
Examples of the basic compound include amines such as trialkylamines, dialkylamines, alkylamines, and imidazoles; Inorganic materials such as sodium hydroxide, potassium hydroxide, gallium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate; A hydroxide of an alkali metal, an alkoxide of an alkali metal, an alkyl compound of an alkali metal, a hydroxide of an alkaline earth metal, a hydride of an alkaline earth metal, an alkoxide of an alkaline earth metal, an alkyl compound of an alkaline earth metal, etc. Can be used. Particularly, in this step, it is preferable to use inorganic materials such as trialkylamines, dialkylamines, alkylamines, imidazoles and like amines, sodium hydroxide, potassium hydroxide, gallium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate. The base compound is preferably used in an amount of from 1.0 to 10.0 equivalents based on the compound of formula (IV).
The reaction is preferably carried out at a temperature of 60 ° C or lower, preferably 40 to 10 ° C. If the reaction temperature is lower than 10 ° C, the reaction rate may be lowered. If the reaction temperature is higher than 40 ° C, by-products may be generated.
(S4): Preparation of compound of formula (6)
A compound of the following formula (5) is hydrolyzed in the presence of a solvent and a base compound to prepare a compound of the formula (6).
Wherein R 2 is lower alkyl or substituted lower alkyl of methyl, ethyl or propyl and P is a hydroxy protecting group and more specifically t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl Or aryl.
As the solvent, the same solvent as in the step (S2) may be used. In particular, a lower alcohol solvent such as methanol, ethanol, 2-propanol or t-butanol; Aromatic solvents such as benzene, toluene and xylene; And ether solvents such as tetrahydrofuran and 1,4-dioxane are preferably used. The solvent is preferably used in an amount of 1.0 to 50.0 equivalents based on the compound of Chemical Formula (5).
As the basic compound, the same basic compound as in the step (S3) may be used. In particular, it is preferable to use an inorganic material such as sodium hydroxide, potassium hydroxide, gallium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate. The base compound is preferably used in an amount of 1.0 to 10.0 equivalents based on the compound of formula (5).
The reaction is preferably carried out at a temperature of 60 ° C or lower, preferably 50 to 20 ° C. If the reaction temperature is lower than 20 ° C, the reaction rate may be slower, and if it is higher than 50 ° C, by-products may occur.
(Step S5): Preparation of the compound of formula (7)
Reacting a compound of formula 6 with R 3 OH, wherein R 3 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene, A compound represented by the following general formula (7) is prepared.
Wherein P is a hydroxy protecting group and more specifically t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl or aryl, and R 3 is phenyl, substituted phenyl, naphthyl, substituted Naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene.
As the solvent, the same solvent as in the step (S2) may be used. In particular, aromatic solvents such as benzene, toluene and xylene; Ether solvents such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, diisopropyl ether, t-butyl methyl ether and dimethoxyethane; Halogen solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachlorethylene, tetrachloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene; Dialkylformamide, dialkyl acetamide, dialkyl sulfoxide and the like are preferably used. The solvent is preferably used in an amount of 1.0 to 100.0 equivalents based on the compound of formula (6).
The condensing agent may be the same condensing agent as in the step (S2), and its content is preferably 1.0 to 10.0 equivalents based on the compound of the formula (6).
The basic compound may be the same basic compound as in step (S3) described above. In particular, basic compounds such as trialkylamines, dialkylamines, alkylamines and imidazoles, amines such as sodium hydroxide, potassium hydroxide, gallium hydroxide, It is preferable to use inorganic materials such as potassium and calcium carbonate. The base compound is preferably used in an amount of 1.0 to 10.0 equivalents based on the compound of the formula (6).
The reaction is preferably carried out at a temperature of 50 ° C or lower, preferably -10 to 30 ° C. If the reaction temperature is lower than -10 ° C, the reaction rate may be slower, and if it exceeds 30 ° C, by-products may occur.
(S6) Step: Preparation of the compound of formula (1)
The compound of formula (7) is reacted with a compound of formula (8) in the presence of a solvent and a base compound to prepare a chiral compound of formula (1).
Wherein P is a hydroxy protecting group and more specifically t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl or aryl, and R 3 is phenyl, substituted phenyl, naphthyl, substituted Naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene.
Specifically, in this step, by reacting a compound represented by the following formula (7) with a compound represented by the following formula (8) under a base compound, nucleophilic substitution proceeds selectively only in the lower ester among the two esters, Lt; / RTI > can be obtained.
In particular, esters derived from R 3 OH in the compound of Formula 7, or R 3 is a nucleophilic compound falling off during the substitution reaction with the case aryl group compound of formula (8) Since the alkali salts of aryloxy than the alkali salt of an alkoxy alkaline The side reaction such as the beta-cleavage reaction and the like can be suppressed, so that the chiral compound of the formula (1) can be produced with high purity and high yield.
In the case of the compound of formula (I), which is an existing chiral intermediate, the addition reaction proceeds only in the ester side by giving selectivity to the salt form of the carboxylic acid in the production process, and in this case, a base compound of 1.0 equivalent or more is further required. In the present invention, however, it is possible to reduce the amount of the base compound (1.0 equivalent) used in this step by finding the reaction selectivity that the nucleophilic substitution proceeds only in the lower ester among the two different esters, i.e., the lower ester and the t-butyl ester.
In the compound of Formula 8 X may be a P (= O) (R 1 ) a phosphorus compound or a, S (= O) R 1, an organic sulfur-based compound of the SO 2 R 1 2, wherein R 1 is hydrogen, lower Alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, or substituted aryl.
The compound of formula (8) is preferably used in an amount of 2.0 to 10.0 equivalents relative to the compound of formula (7).
As the solvent, the same solvent as in the step (S2) may be used. In particular, aromatic solvents such as benzene, toluene and xylene; Ether solvents such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, diisopropyl ether and t-butyl methyl ether; It is preferable to use a polar solvent such as dimethoxyethane, dimethylformamide, dimethylacetamide or hexamethylphosphoramide. The solvent is preferably used in an amount of 1.0 to 100.0 equivalents based on the compound of formula (7).
The basic compound may be the same basic compound as in the step (S3) described above. In particular, a basic compound such as a hydroxide of an alkali metal, a hydride of an alkali metal, an alkoxide of an alkali metal, an alkyl compound of an alkali metal, Hydroxides of alkaline earth metals, alkoxide of alkaline earth metals, and alkyl compounds of alkaline earth metals. The base compound is preferably used in an amount of 2.0 to 10.0 equivalents based on the compound of formula (VII).
The reaction is preferably carried out at a temperature of -100 ° C or higher, preferably -78 ° C to -40 ° C. When the reaction temperature is lower than -78 ° C, the reaction rate may be slower, and when it is higher than -40 ° C, side reactions may occur.
The process for preparing a chiral compound represented by the formula (1) of the present invention requires a complicated process of 8 or more steps and a racemate must be separated, and the yield is low, and the N 2 O 4 oxidation reaction, the high pressure hydrogenation reaction, Unlike the process for preparing the compound of formula (I), which is an existing chiral intermediate which is not economically feasible and which is not economical due to the use of a strong base such as n-butyllithium in an amount of 3.0 equivalents or more, It is suitable for commercial production because it is short in stage, high in overall yield, does not have to go through a dangerous reaction step, and only one isomer can be obtained with an enantio excess of 99% or more, There is no problem according to the present invention.
According to the present invention, it is possible to prepare chiral compounds which are intermediates for the production of statins more effectively than those obtained by conventional chemical resolution at a yield of 50 ~ 80% and an optical purity of 95 ~ 98% . That is, according to the present invention, a chiral compound can be produced with a quantitative yield close to 100% and a high optical purity at a level of 99%.
The chiral compound represented by formula 1 of the present invention can be used as an intermediate in the preparation of various chiral drugs, particularly HMG-CoA reduction inhibitors.
Specifically, an HMG-CoA reduction inhibitor, that is, a statin compound, may be prepared by reacting an aldehyde compound and a chiral compound of formula (1) as shown in the following reaction formula.
[Reaction Scheme]
A is
P is a hydroxy protecting group, more specifically t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl or aryl.
According to the above reaction scheme, a trans compound (compound of formula 10) is prepared by the condensation reaction of each aldehyde compound and the chiral compound of formula 1 according to the kind of the statin compound to be finally prepared, and the hydroxy group is deprotected to obtain the compound of formula 11 And then the ketone group is reduced to prepare cis-1,3-diol (compound of formula (12)). Then, the statin compound can be prepared by separating the t-butyl group from the cis-1,3-diol.
As described above, the HMG-CoA reduction inhibitor prepared using the chiral compound of Formula 1 of the present invention may be fluvastatin of Formula 13a, rosuvastatin of Formula 13b, or pitavastatin of Formula 13c.
[Chemical Formula 13a]
[Chemical Formula 13b]
[Chemical Formula 13c]
Hereinafter, the present invention will be described in more detail with reference to examples. These embodiments are for purposes of illustration only and are not intended to limit the scope of protection of the present invention.
Example 1. Preparation of compound of formula 4 (R2 is ethyl)
262.68 g of the monoester compound (compound of formula (III)) and 787.09 g of dichloromethane were introduced into a 3,000 mL round flask equipped with a stirrer and a thermometer. 266.09 g of SOCl 2 was added while maintaining the temperature of the reaction at 0 ° C, and then the temperature of the reaction was raised to 20 ° C and 552.59 g of t-butanol was added to the reaction product. At this time, the progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 1/1). When the reaction was completed with stirring at this temperature, 1,000 g of distilled water was slowly added to the reaction product. The reaction product was stirred for 15 minutes and then the water layer and the organic layer were separated. The solvent and the low boiling point organic matter were recovered by distillation from the organic layer and distilled under reduced pressure to obtain a diester compound (yield: 76.5%, purity: 98.0% Chiral purity: 99.8%).
Rf = 0.8 (n-hexane / ethyl acetate, 1/1)
Example 2. Preparation of compound of formula 5 (R2 is ethyl, P is t-butyldimethylsilyl)
176 g of diester compound (compound of formula (IV)) and 1,300 g of dichloromethane were added to a 3,000 mL round flask equipped with a stirrer and a thermometer. 62 g of imidazole and 125 g of t-butyldimethylsilyl chloride were added while maintaining the temperature of the reaction solution at room temperature and with stirring. The progress of the reaction after the addition was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 2/1). When the reaction was completed with stirring at room temperature, 1,500 g of distilled water was added to the reaction product. The reaction mixture was stirred for 15 minutes and then the water layer and the organic layer were separated. The solvent and the low-boiling organic compound were recovered by distillation and distilled under reduced pressure to obtain the compound of Compound 5 (yield: 90.8%, purity: 99.0%, chiral purity: 99.8% ).
Rf = 0.8 (n-hexane / ethyl acetate, 2/1)
Example 3. Preparation of compound of formula 6 (P is t-butyldimethylsilyl)
In a 2,000 mL round flask equipped with a stirrer and a thermometer, 57.6 g of the compound of Chemical Formula 5 and 150 g of methanol were added. 79.8 g of a 10% aqueous solution of sodium hydroxide was added while maintaining the temperature of the reaction solution at room temperature and stirring. The progress of the reaction after the addition was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 4/1). When the reaction was completed with stirring at room temperature, 400 g of ethyl acetate, 200 g of distilled water and 120 g of 10% hydrochloric acid aqueous solution were added to the reaction product. Then, the reaction product was stirred for 15 minutes, and the water layer and the organic layer were separated. The solvent and the low boiling point organic compound were separated from the organic layer by distillation and recovered to obtain the compound of Formula 6 (yield: 88.3%, purity: 98.0%, chiral purity: 99.8%).
Rf = 0.2 (n-hexane / ethyl acetate, 4/1)
Example 4. Preparation of compound of formula 7 (R 3 Is phenyl, P is t-butyldimethylsilyl)
30.0 g of the compound of Formula 6 and 90 g of dichloromethane were added to a 2,000 mL round flask equipped with a stirrer and a thermometer. The temperature of the reaction mixture was maintained at room temperature, and 8.9 g of phenol was added thereto while stirring. After cooling the temperature of the reaction product to 0 캜, DCC (Dicyclohexanecarbodiimide) was added, and the temperature of the reaction product was raised to 25 캜. The progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 4/1). After the reaction was completed, the reaction product was filtered, and the solvent and low-boiling organic compounds were recovered by distillation from the filtered organic layer and distilled under reduced pressure to obtain the compound of Formula 7 (yield: 85.0%, purity: 99.0%, chiral purity: 99.8%).
Rf = 0.7 (n-hexane / ethyl acetate, 4/1)
Example 5. Preparation of chiral compound of formula (1) wherein P is t-butyldimethylsilyl, X is P (= O) (OMe) 2,
In a 1,000 mL round flask equipped with a stirrer and a thermometer, 17.8 g of dimethyl methylphosphonate and 150 mL of tetrahydrofuran were added under a nitrogen atmosphere. The temperature of the reaction was maintained at -78 ° C and 82.5 mL of a 1.6 M normal butyl lithium in n-hexane solution was slowly added over 15 minutes. After the addition, the reaction product was stirred at this temperature for 1 hour, and 21.7 g of the compound of formula (7) was added thereto. The progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 1/1). After the reaction was completed, 200 g of a 5% hydrochloric acid aqueous solution and 400 mL of ethyl acetate were added to the reaction product. Subsequently, the reaction product was stirred for 15 minutes, and the water layer and the organic layer were separated. The solvent and the low boiling point organic compound were recovered by distillation from the organic layer and the product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 1/1) (Yield: 92.6%, purity: 99.5%, chiral purity: 99.8%).
Rf = 0.3 (n-hexane / ethyl acetate, 1/1)
Example 6: Preparation of statin compound (when statin is rosuvastatin, compound (1) is P-t-butyldimethylsilyl and X is P (= O) (OMe) 2)
4.15 g of potassium carbonate and 50 ml of dimethylformamide were placed in a 500 ml round flask equipped with a stirrer and a thermometer under a nitrogen atmosphere at room temperature. 4.24 g of the compound of Formula 1 obtained in Example 6, that is, tert-butyl (3R) -3- (tert-butyldimethylsilyloxy) -6-dimethoxyphosphinyl-5-oxohexanate, After the addition, the reaction mixture was stirred at room temperature for 1 hour.
To the reaction solution, 3.24 g of 4- (4-fluorophenyl) -3-formyl-2-isopropyl-5-methyl-1-methylsulfonylpyrimidine was added at room temperature under a nitrogen atmosphere and the reaction mixture was stirred at room temperature. The progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 7/1). After the reaction was completed, the solvent was removed by distillation under reduced pressure, and then 100 g of a 10% hydrochloric acid aqueous solution and 100 mL of ethyl acetate were added to the reaction product.
After the reaction was stirred for 15 minutes, the water layer and the organic layer were separated, and the solvent and the low boiling point organic matter were recovered by distillation from the organic layer and the product, tert-butyl 7- [4- (4- fluorophenyl) -2- -3-tert-butyldimethylsilyloxy) -5-oxo-6-heptanate (Rf = 0.4 (n-hexane / ethyl acetate, 7/1) . The compound was added to a 250 mL round-bottomed flask equipped with a stirrer and a thermometer without purification, and a tetrahydrofuran solution of 20 mL of tetrahydrofuran and 12 mL of 1.0 M tetrabutylammonium fluoride was added under a nitrogen atmosphere, followed by stirring at room temperature Respectively. The progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: n-hexane / ethyl acetate, 1/1). At the end of the reaction, 100 g of 10% sodium carbonate solution and 100 mL of ethyl acetate were added to the reaction mixture.
After the reaction was stirred for 15 minutes, the water layer and the organic layer were separated, and the solvent and the low boiling point organic matter were recovered by distillation from the organic layer and the product, tert-butyl 7- [4- (4- fluorophenyl) -2- -3-hydroxy-5-oxo-6-heptanate was subjected to silica gel column chromatography (eluent: (Step 2).
4.97 g of the compound was placed in a 100-mL round-bottomed flask equipped with a stirrer and a thermometer, and 20 mL of tetrahydrofuran and 5 mL of methanol were added thereto under a nitrogen atmosphere, followed by stirring at room temperature. The reaction temperature was maintained at -78 < 0 > C and 13.3 mL of a 1.0 M solution of triethylborane in tetrahydrofuran was slowly added over 15 minutes. After the addition, the reaction mixture was stirred at this temperature for 0.5 hours and 0.42 g of sodium borohydride was added. The progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: dichloromethane / ethyl acetate, 2/1). After the completion of the reaction, 14 mL of acetic acid was added to the reaction mixture, followed by stirring for 0.5 hour.
Then, the reaction mixture was poured into 200 g of 10% sodium carbonate solution, and the reaction mixture was extracted with 200 mL of ethyl acetate. The water layer and the organic layer were separated, and the solvent and low boiling point organic matter were recovered from the organic layer by distillation. Methanol was added to the thus-obtained concentrate, and the resulting mixture was stirred at room temperature for 15 minutes and concentrated. The product was then subjected to silica gel column chromatography (Eluent: dichloromethane / ethyl acetate, 3/1) to give 90.6% yield (Rf = 0.3 (dichloromethane / ethyl acetate, 3/1).
2.35 g of the obtained 1,3-syn-diol compound was added to a 100 mL round flask equipped with a stirrer and a thermometer, 10 mL of formic acid was added, and the mixture was stirred at room temperature. The progress of the reaction was confirmed by TLC (Thin Layer Chromatography; Eluent: dichloromethane / methanol, 4/1). After the reaction was completed, the reaction mixture was concentrated, 40 mL of ethanol and 50 mL of 0.1 N sodium hydroxide were added thereto, and the mixture was stirred at room temperature for 10 minutes.
After the reaction was concentrated, 20 mL of ethanol was added, stirred for 10 minutes, and then concentrated. Then, 50 mL of ether was added to the concentrate, followed by stirring at room temperature for 1 hour. The white crystals thus formed were filtered through filter paper, washed with 10 mL of ether three times, and dried to give rosuvastatin sodium salt in a yield of 89.7%.
1 H NMR (CDCl 3, 200 MHz)?: 7.15 (m, 4H); 6.62 (d, 1 H, J = 16 Hz); 4.99 (dd, 1H, J = 16 Hz, 7 Hz); 4.22 (m, 1 H), 3.72 (m, 2 H); 3.36 (s, 3 H); 2.24 (m, 2 H) 2.13 (s, 3 H); 1.37 (s, 3 H); 1.34 (s, 3 H)
[?] D = + 29.0 (C = 1.0, water)
Although the present invention has been described in terms of the preferred embodiments mentioned above, it is possible to make various modifications and variations without departing from the spirit and scope of the invention. It is also to be understood that the appended claims are intended to cover such modifications and changes as fall within the scope of the invention.
Claims (9)
(S2) condensing a compound of the formula (3) with t-butanol in the presence of a solvent and a condensing agent to prepare a compound of the formula (4);
(S3) reacting a compound of the following formula (4) with a compound having a hydroxy-protecting group in the presence of a solvent and a base compound to prepare a compound of the formula (5);
(S4) hydrolyzing the compound of formula (5) in the presence of a solvent and a base compound to prepare a compound of formula (6);
(S5) reacting a compound of formula (6) with a compound of formula R 3 OH, wherein R 3 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene, To obtain a compound of the formula (7); And
(S6) reacting a compound of formula (7) with a compound of formula (8) in the presence of a solvent and a base compound to prepare a chiral compound of formula (1);
Wherein R < 1 > and R < 2 >
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
(7)
[Chemical Formula 8]
In the above Chemical Formulas 1 to 8,
X is selected from the group consisting of P (= O) (R 1 ) 2, S (= O) R 1, or SO 2 R 1 wherein R 1 is hydrogen, lower alkyl, substituted lower alkyl, , Aryl, or substituted aryl),
P is a hydroxy protecting group,
R < 2 > is lower alkyl or substituted lower alkyl of methyl, ethyl or propyl,
R 3 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene or substituted pyrene.
Wherein the hydroxy protecting group (P) is at least one selected from the group consisting of t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, alkyl, alkoxyalkyl and aryl.
The solvent of step (S2), (S3), (S4), (S5) or (S6) may be selected from the group consisting of methanol, ethanol, 2-propanol, t-butanol, benzene, toluene, xylene, tetrahydrofuran, But are not limited to, 1,4-dioxane, petroleum ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dimethoxyethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachlorethylene, tetrachloroethane, Is at least one selected from the group consisting of dichlorobenzene, trichlorobenzene, dimethoxyethane, dialkylformamide, dimethylformamide, dialkyl acetamide, dimethylacetamide, hexamethylphosphoramide, dialkylsulfoxide and dimethylsulfoxide ≪ / RTI >
The condensing agent of the step (S2) or (S5) may be at least one selected from the group consisting of SOCl 2 , SO 2 Cl 2 , SOBr 2 , SO 2 Br 2 , PCl 3 , PCl 5 , POCl 3 , methyl chloroformate, ethyl chloroformate, Wherein the chiral compound is at least one selected from chloroformate, isobutyl chloroformate and dichlorohexylcarbodiimide.
The compound having a hydroxy-protecting group in step (S3) is at least one selected from t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, trimethylsilyl chloride, benzyl chloride and methoxymethyl chloride. ≪ / RTI >
The base compound of the step (S3), (S4), (S5) or (S6) may be a trialkylamine, a dialkylamine, Calcium, an alkali metal hydroxide, an alkali metal hydride, an alkali metal alkoxide, an alkali metal alkyl compound, an alkaline earth metal hydroxide, an alkaline earth metal hydride, an alkaline earth metal alkoxide and an alkaline earth metal alkyl Wherein the compound is at least one selected from the group consisting of compounds represented by the following formulas.
[Chemical Formula 1]
In Formula 1,
X is selected from the group consisting of P (= O) (R 1 ) 2, S (= O) R 1, or SO 2 R 1 wherein R 1 is hydrogen, lower alkyl, substituted lower alkyl, , Aryl, or substituted aryl),
P is a hydroxy protecting group.
The HMG-CoA reduction inhibitor
(S1) condensing the aldehyde-based compound of Formula 9 and the chiral compound of Formula 1 to prepare a trans compound of Formula 10;
(S2) deprotecting the hydroxy group of the trans compound of Formula 10 to prepare a compound of Formula 11
(S3) reducing the ketone group of the compound of Formula 11 to prepare cis-1,3-diol of Formula 12;
(S4) separating the t-butyl group from the cis-1,3-diol of Formula 12 to prepare an HMG-CoA reduction inhibitor of Formula 13;
Wherein the HMG-CoA reductase inhibitor is selected from the group consisting of:
[Chemical Formula 9]
[Chemical formula 10]
(11)
[Chemical Formula 12]
[Chemical Formula 13]
In the above formulas (9) to (13)
A is
P is a hydroxy protecting group.
Wherein the HMG-CoA reduction inhibitor is a compound represented by the following Formula 13a, 13b or 13c:
[Chemical Formula 13a]
[Chemical Formula 13b]
[Chemical Formula 13c]
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| KR100529703B1 (en) | 2002-09-23 | 2005-11-17 | 임광민 | Chiral intermediate, process for the production thereof, and process for the production of atorvastatin |
| KR20090018964A (en) * | 2007-04-18 | 2009-02-24 | 테바 파마슈티컬 인더스트리즈 리미티드 | A process for preparing intermediates of hmg-coa reductase inhibitors |
| KR100945763B1 (en) * | 2005-02-22 | 2010-03-08 | 테바 파마슈티컬 인더스트리즈 리미티드 | Preparation of rosuvastatin |
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| KR100529703B1 (en) | 2002-09-23 | 2005-11-17 | 임광민 | Chiral intermediate, process for the production thereof, and process for the production of atorvastatin |
| KR100945763B1 (en) * | 2005-02-22 | 2010-03-08 | 테바 파마슈티컬 인더스트리즈 리미티드 | Preparation of rosuvastatin |
| KR20090018964A (en) * | 2007-04-18 | 2009-02-24 | 테바 파마슈티컬 인더스트리즈 리미티드 | A process for preparing intermediates of hmg-coa reductase inhibitors |
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