WO2003087112A1 - Chiral intermediate and process for the production thereof - Google Patents

Chiral intermediate and process for the production thereof Download PDF

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Publication number
WO2003087112A1
WO2003087112A1 PCT/KR2003/000707 KR0300707W WO03087112A1 WO 2003087112 A1 WO2003087112 A1 WO 2003087112A1 KR 0300707 W KR0300707 W KR 0300707W WO 03087112 A1 WO03087112 A1 WO 03087112A1
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formula
compound
optionally substituted
carbon atoms
group
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PCT/KR2003/000707
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French (fr)
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Kwang-Min Lim
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Cls Laboratories, Inc.
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Priority to AU2003219592A priority Critical patent/AU2003219592A1/en
Publication of WO2003087112A1 publication Critical patent/WO2003087112A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • C07D239/28—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new chiral intermediates, process for the production thereof, and p rocess for the production of HMG-CoA reductase inhibitors using the same. More specifically, the present invention relates to new chiral intermediates which can be used for the preparation of HMG-CoA reductase inhibitors, a process for simply producing them under mild conditions with high yields, and a process for the production of HMG-CoA reductase inhibitors using the same.
  • statin Drugs having the effect of suppressing the biosynthesis of cholesterol by inhibiting the activity of HMG-CoA(3-hydroxy-3 -methyl- glutaryl coenzyme A) reductase are normally called "statin.”
  • the first generation of the statin includes simvastatin, lovastatin, and pravastatin, which are fermentation products, and the second generation of the statin includes atovastatin, fluvastatin, rosuvastatin, and pitavastain, which are synthetic drugs.
  • the chemical structures of the main statins are as follows:
  • U.S. Patent No. 5,354,772 discloses a process for the production of fluvastatin, which used the method of preparing racemates and then separating them as shown in the following reaction scheme.
  • the trans-cinnamyl aldehyde was first prepared, the beta-ketoester which had been converted to a di-anion with at least two equivalents of base was introduced to the trans-cinnamyl aldehyde, and then the selective reduction reaction was carried out to obtain two chirally different syn-l,3-diols (A) and (B), which were separated by chemical, enzymatic, or chromatographic method.
  • a diazo reaction should be carried out in ether solvent in order to obtain the final compound of formula (F) from the carboxylic acid.
  • An object of the present invention is to provide a process for simply producing chiral intermediates which can be used for the preparation of HMG-CoA reductase inhibitors under mild conditions with high yields, without the above mentioned complex and dangerous steps.
  • Another object of the present invention is to provide new intermediates produced by the above process. Further object of the present invention is to provide a process for the production of HMG-CoA reductase inhibitors using the above chiral intermediates.
  • the present invention relates to the chiral compound of formula (I), process for the production thereof, and process for the production of HMG-CoA reductase inhibitors using the same.
  • P is a hydroxy protecting group
  • the present process for the production of the chiral compound of formula (I) comprises the steps of:
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and P is a hydroxy protecting group, for example silyl group.
  • the . compound of formula (III) is prepared from the compound of formula (II) by selective hyrolysis using a microorganism:
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms.
  • lipase, protease, or esterase, etc. can be used, preferably with high substrate concentration of at least 10%.
  • the compound of formula (III) is prepared with high yield reaching 100% and high optical purity of about 99% starting from the compound of formula (II) which is a meso compound. Therefore, this step is very effective compared to the prior chemical resolution which has the yield of about 50 to 80% and the optical purity of 95 to 98%.
  • the compound of formula (IN) is prepared by the addition reaction of the compound of formula (HI) with isobutylene under acidic catalyst:
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms.
  • the acidic catalyst hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, polyphosphoric acid, silica having impregnated metal such as titanium, or zeolite, etc. can be used.
  • the acidic catalyst is preferably used in the amount of 0.000005-0.5 equivalents based on the compound of formula (Ifl).
  • the addition reaction can be carried out in aromatic solvent such as benzene, toluene, and xylene, ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, or halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • aromatic solvent such as benzene, toluene, and xylene
  • ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane
  • halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon
  • the reaction temperature is preferably less than 30°C, more preferably —30-10 °C. If the temperature is below -30 °C, the reaction rate slows down, and if the temperature is above 10 °C, isobutylene is vaporized so that an excessive amount of isobutylene should be used.
  • the compound of formula (V) is prepared by protecting the hydroxy group of the compound of formula (IN):
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and P is a hydroxy protecting group, for example silyl group such as t- butyldimethylsilyl group. If the hydroxy protecting group is a silyl group, for example t- butyldimethylsilyl group, the compound of formula (IN) is reacted with silyl halide, for example t-butyldimethylsilyl chloride in the presence of base.
  • silyl group such as t- butyldimethylsilyl group
  • the reaction solvent includes aromatic solvent such as benzene, toluene, and xylene, and halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • aromatic solvent such as benzene, toluene, and xylene
  • halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • the reaction temperature is preferably less than 60°C, more preferably 10-40 °C. If the temperature is below 10 °C, the reaction rate slows down, and if the temperature is above 40 °C, by-products occur.
  • amines such as trialkylamine, dialkylamine, alkylamine and imidazole, or inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate, etc. can be used, preferably in the amount of 1.0-10.0 equivalents based on the compound of formula (IN).
  • the compound of formula (I), the target product, is prepared by reacting the compound of formula (N) with the compound of formula (NI) in the presence of base.
  • X is or S(O)R ⁇ , wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl; P2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and
  • the reaction solvent includes ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, and polar solvent such as dimethylformamide, dimethylacetamide, and hexamethylphosphoamide, etc.
  • the reaction temperature is preferably less than 100°C, more preferably -78-40 °C. If the temperature is below -78 °C, the reaction rate slows down, and if the temperature is above 40 °C, side reactions proceed.
  • the compound of formula (NI) is preferably used in 2.0-10.0 equivalents based on the compound of formula (V).
  • the present invention introduced the step of preparing the compound of formula (I) based on the fact that the nucleophilic substitution occurs selectively at the lower ester group of 1 to 3 carbon atoms among the lower ester group of 1 to 3 carbon atoms and t-butyl ester group.
  • the above-mentioned Bristol-Myers Squibb's prior method imposed the selectivity by using the ester group and carboxylate group, h this case, the addition reaction occurred only at the ester group, but at least 1.0 equivalent of base was further required.
  • the present invention can reduce the used amount of base by using two different ester groups.
  • the present chiral compound of formula (I) can be used as an intermediate for preparing various chiral medicaments, particularly HMG-CoA reductase inhibitors.
  • HMG-CoA reductase inhibitors for example, representative HMG-Co A reductase inhibitors, fluvastatin, rosuvastatin and pitavastatin of formula (XI) can be prepared, as shown in the below reaction scheme, by reacting the aldehyde compound of formula (Nil) with the chiral compound of formula (I), deprotecting the hydroxy group of the trans compound of formula (NIII), reducing the ketone group of the compound of formula (IX), and cleaving the t-butyl group of the 1,3-dihydroxyester of formula (X).
  • P is a hydroxy protecting group
  • the condensation reaction of the aldehyde compound of formula (NH) with the chiral compound of formula (I) is c arried out in the presence of base.
  • base alkali metal carbonate, hydroxide, hydride, alkoxide, or alkyl, or alkaline earth metal carbonate, hydroxide, hydride, alkoxide, or alkyl, etc. can be used.
  • the base is preferably used in the amount of 1.0-5.0 equivalents based on the compound of formula (I), and the aldehyde is preferably used in the amount of 1.0-2.0 equivalents.
  • the reaction solvent includes lower alcohol such as methanol, ethanol, and isopropanol, ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, and polar solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoamide, and acetonitrile, etc.
  • lower alcohol such as methanol, ethanol, and isopropanol
  • ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane
  • polar solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoamide, and acetonitrile, etc.
  • the deprotecting reaction of the hydroxy group of the trans compound of formula (NIII) can be simply carried put, in the presence of fluoride compound such as tetraalkylamonium fluoride and hydrofluoride in ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, etc.
  • fluoride compound such as tetraalkylamonium fluoride and hydrofluoride in ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, etc.
  • the fluoride compound is preferably used in the amount of 1.0-5.0 equivalents based on the compound of formula (NHT).
  • the reduction of the ketone group of the compound of formula (IX) is carried out using alkali metal borohydride, cyanoborohydri.de, alkoxyborohydride, aluminiumhydride, alkylaluminiumhydride, or alkoxyaluminiumhydride, or alkaline earth metal borohydride, cyanoborohydride, alkoxyborohydride, aluminiumhydride, alkylaluminiumhydride, or alkoxyaluminiumhydride, etc. as a reducing agent.
  • a chelatmg agent such as trialkyborane, alkoxydialkylborane, dialkoxyalkylborane, and trialkoxyborane is used.
  • the reducing agent and chelating agent are used preferably in the amount of 1.0-10.0 equivalents based on the compound of formula (IX).
  • the reaction solvent includes ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, etc.
  • (X) is carried out preferably in the presence of acid, for example formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, alkylsulfonic acid, and toluenesulfonic acid.
  • acid for example formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, alkylsulfonic acid, and toluenesulfonic acid.
  • the acid is used preferably in the amount of 0.001-100 equivalents based on the compound of formula (X).
  • the reaction solvent includes organic acid such as formic acid and acetic acid, aromatic solvent such as benzene, toluene, and xylene, and halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • organic acid such as formic acid and acetic acid
  • aromatic solvent such as benzene, toluene, and xylene
  • halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • halogen solvent such as dichloromethane, dichloroethane, chloro
  • the process for the production of HMG-CoA reductase inhibitors using the chiral intermediates of the present invention does not have problem of removing by-products and disposing the waste, and therefore is suitable for being used industrially and commercially.
  • Rf 0.8 (n-hexane/ethyl acetate, 2/1)
  • rosuvastatin sodium salt 2.35g of the compound obtained in the above step was added to 100ml of round-bottomed flask equipped with a stirrer and thermometer, and 10ml of formic acid was added and stirred at room temperature. After the reaction was completed, the reactants were concentrated, and 40ml of ethanol and 50ml of 0.1N sodium hydroxide solution were added and stirred for 10 minutes at room temperature. Then, the reactants were concentrated, and 20ml of ethanol was added and stirred for 10 minutes, 5 times repeatedly. Afterwards, 50ml of ether was added to the resulting residue, and stirred for 1 hour at room temperature. The resulting white crystals were filtered through a filter paper, washed with 10ml of ether three times, and dried to give rosuvastatin sodium salt(yield: 89.7%).

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Abstract

The present invention relates to a new chiral intermediate, process for the production thereof, and process for the production of a HMG-CoA reductase inhibitor using the chiral intermediate.

Description

Chiral intermediate and process for the production thereof
Technical Field
The present invention relates to new chiral intermediates, process for the production thereof, and p rocess for the production of HMG-CoA reductase inhibitors using the same. More specifically, the present invention relates to new chiral intermediates which can be used for the preparation of HMG-CoA reductase inhibitors, a process for simply producing them under mild conditions with high yields, and a process for the production of HMG-CoA reductase inhibitors using the same.
Background Art
Drugs having the effect of suppressing the biosynthesis of cholesterol by inhibiting the activity of HMG-CoA(3-hydroxy-3 -methyl- glutaryl coenzyme A) reductase are normally called "statin." The first generation of the statin includes simvastatin, lovastatin, and pravastatin, which are fermentation products, and the second generation of the statin includes atovastatin, fluvastatin, rosuvastatin, and pitavastain, which are synthetic drugs. The chemical structures of the main statins are as follows:
Figure imgf000002_0001
Simvastatin Lovastatin Pravastatin
Figure imgf000003_0001
Atovastatin Fluvastatin
Figure imgf000003_0002
Rosuvastatin Pitavastatin
Since all of the above compounds have optical activity, the prior processes for the production thereof used the method of preparing two racemates followed by separating them, and the method of using chiral intermediates.
U.S. Patent No. 5,354,772 discloses a process for the production of fluvastatin, which used the method of preparing racemates and then separating them as shown in the following reaction scheme.
Figure imgf000004_0001
According to the above process, the trans-cinnamyl aldehyde was first prepared, the beta-ketoester which had been converted to a di-anion with at least two equivalents of base was introduced to the trans-cinnamyl aldehyde, and then the selective reduction reaction was carried out to obtain two chirally different syn-l,3-diols (A) and (B), which were separated by chemical, enzymatic, or chromatographic method.
However, the above process had problems as follows. Firstly, since complicated resolution procedures were needed for the achievement of desired optical purity, particularly more than 98% of optical purity from the racemates wherein compounds (A) and (B) are mixed in the ratio of 50 to 50, the yield decreased to below 50%), which increased the production costs. Secondly, the undesired isomer remaining in the product acted as an impurity to deteriorate the quality of the product.
Therefore, the method of using chiral intermediates has been variously studied [Heathcock, C.H., J. Am. Chem. Soc, 1985, 107, 3731, U.S. Patent No. 5,849,749, Karanewsky D. S., J. Org. Chem., 1991, 56, 3744, U.S. Patent No. 5,354,879]. The most commonly used method was that of Bristol-Myers Squibb, which used the intermediate of formula (F) prepared as shown in the following reaction scheme [J. Org. Chem., 1991, 56, 3744].
Figure imgf000005_0001
(C7(D) = 79/21
Figure imgf000005_0002
(C)
Figure imgf000006_0001
(F)
However, the above method had the following problems. Firstly, an expensive chiral resolving agent such as S-1-phenylethylamine must be used, and diastereomers were obtained at most in the ratio of 79:21, although the reaction was carried out at the low temperature of -78°C. Therefore, the desired isomer should be isolated from the mixture, which reduced the yield by at least 20%>. Also, the undesired isomer should be recovered and discarded.
Secondly, dangerous reactions such as N2O4 oxidation reaction and high- pressure hydrogenation reaction should be carried out to cleave the amine group of the resolving agent.
Thirdly, since an expensive palladium catalyst must be used during the reduction reaction with hydrogen, the method was economically disadvantageous, and the heavy metal could remain in the final product to deteriorate the quality of the product. Fourthly, since at least 1.0 equivalent of n-butyl lithium, etc. must be additionally used to introduce dimethylphosphinyl group to the carboxylate compound of formula (E), a total of 3.0 to 4.5 equivalents of strong base such as n-butyl lithium must be used.
Fifthly, a diazo reaction should be carried out in ether solvent in order to obtain the final compound of formula (F) from the carboxylic acid.
Lastly, since the method wholly included at least eight steps, it was complex and its yield was low, and the method included steps which were explosive and used toxic materials. Therefore, the method was not suitable for being used industrially and commercially.
Summary of the Invention
An object of the present invention is to provide a process for simply producing chiral intermediates which can be used for the preparation of HMG-CoA reductase inhibitors under mild conditions with high yields, without the above mentioned complex and dangerous steps.
Another object of the present invention is to provide new intermediates produced by the above process. Further object of the present invention is to provide a process for the production of HMG-CoA reductase inhibitors using the above chiral intermediates.
Detailed Descriptions of the Invention
The present invention relates to the chiral compound of formula (I), process for the production thereof, and process for the production of HMG-CoA reductase inhibitors using the same.
Figure imgf000007_0001
(I) wherein,
X is P(=O)(Rι)2 or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl; and
P is a hydroxy protecting group.
The present process for the production of the chiral compound of formula (I) comprises the steps of:
(i) selectively hydrolyzing the compound of formula (II) with a microorganism to give the compound of formula (El):
Figure imgf000008_0001
(13) (m)
(ii) reacting the compound of formula (III) with isobutylene under acidic catalyst to give the compound of formula (IN):
Figure imgf000008_0002
(m) (rv) (iii) protecting the hydroxy group of the compound of formula (IN) to give the compound of formula (V):
Figure imgf000008_0003
(IN) (N)
(iv) reacting the compound of formula (N) with the compound of formula (NT) under base to give the compound of formula (I) :
Figure imgf000009_0001
(V) (NI) (I) wherein,
X is P(=O)(Rι)2 or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl;
R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and P is a hydroxy protecting group, for example silyl group.
The present process for the production of the chiral compound of formula (I) is, hereinafter, described in detail.
Preparation of the compound of formula (III)
The. compound of formula (III) is prepared from the compound of formula (II) by selective hyrolysis using a microorganism:
Figure imgf000009_0002
(π) (m) wherein,
R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms. As the microorganism, lipase, protease, or esterase, etc. can be used, preferably with high substrate concentration of at least 10%.
The compound of formula (III) is prepared with high yield reaching 100% and high optical purity of about 99% starting from the compound of formula (II) which is a meso compound. Therefore, this step is very effective compared to the prior chemical resolution which has the yield of about 50 to 80% and the optical purity of 95 to 98%.
Preparation of the compound of formula (IV)
The compound of formula (IN) is prepared by the addition reaction of the compound of formula (HI) with isobutylene under acidic catalyst:
Figure imgf000010_0001
(HI) (IN) wherein,
R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms. As the acidic catalyst, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, polyphosphoric acid, silica having impregnated metal such as titanium, or zeolite, etc. can be used. The acidic catalyst is preferably used in the amount of 0.000005-0.5 equivalents based on the compound of formula (Ifl).
The addition reaction can be carried out in aromatic solvent such as benzene, toluene, and xylene, ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, or halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
The reaction temperature is preferably less than 30°C, more preferably —30-10 °C. If the temperature is below -30 °C, the reaction rate slows down, and if the temperature is above 10 °C, isobutylene is vaporized so that an excessive amount of isobutylene should be used. Preparation of the compound of formula (V)
The compound of formula (V) is prepared by protecting the hydroxy group of the compound of formula (IN):
Figure imgf000011_0001
(IN) (N) wherein,
R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and P is a hydroxy protecting group, for example silyl group such as t- butyldimethylsilyl group. If the hydroxy protecting group is a silyl group, for example t- butyldimethylsilyl group, the compound of formula (IN) is reacted with silyl halide, for example t-butyldimethylsilyl chloride in the presence of base.
The reaction solvent includes aromatic solvent such as benzene, toluene, and xylene, and halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
The reaction temperature is preferably less than 60°C, more preferably 10-40 °C. If the temperature is below 10 °C, the reaction rate slows down, and if the temperature is above 40 °C, by-products occur. As the base, amines such as trialkylamine, dialkylamine, alkylamine and imidazole, or inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate, etc. can be used, preferably in the amount of 1.0-10.0 equivalents based on the compound of formula (IN). Preparation of the compound of formula (I)
The compound of formula (I), the target product, is prepared by reacting the compound of formula (N) with the compound of formula (NI) in the presence of base.
Figure imgf000012_0001
(N) (VI) (I) wherein,
X is
Figure imgf000012_0002
or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl; P2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and
P is a hydroxy protecting group, for example silyl group. As the base, alkali metal hydroxide, hydride, alkoxide, or alkyl, or alkaline earth metal hydroxide, hydride, alkoxide, or alkyl, or their mixtures, etc. can be used, preferably in the amount of 2.0-10.0 equivalents based on the compound of formula (V). The reaction solvent includes ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, and polar solvent such as dimethylformamide, dimethylacetamide, and hexamethylphosphoamide, etc.
The reaction temperature is preferably less than 100°C, more preferably -78-40 °C. If the temperature is below -78 °C, the reaction rate slows down, and if the temperature is above 40 °C, side reactions proceed.
The compound of formula (NI) is preferably used in 2.0-10.0 equivalents based on the compound of formula (V).
The present invention introduced the step of preparing the compound of formula (I) based on the fact that the nucleophilic substitution occurs selectively at the lower ester group of 1 to 3 carbon atoms among the lower ester group of 1 to 3 carbon atoms and t-butyl ester group. The above-mentioned Bristol-Myers Squibb's prior method imposed the selectivity by using the ester group and carboxylate group, h this case, the addition reaction occurred only at the ester group, but at least 1.0 equivalent of base was further required. However, the present invention can reduce the used amount of base by using two different ester groups.
The present chiral compound of formula (I) can be used as an intermediate for preparing various chiral medicaments, particularly HMG-CoA reductase inhibitors. For example, representative HMG-Co A reductase inhibitors, fluvastatin, rosuvastatin and pitavastatin of formula (XI) can be prepared, as shown in the below reaction scheme, by reacting the aldehyde compound of formula (Nil) with the chiral compound of formula (I), deprotecting the hydroxy group of the trans compound of formula (NIII), reducing the ketone group of the compound of formula (IX), and cleaving the t-butyl group of the 1,3-dihydroxyester of formula (X).
Figure imgf000013_0001
(IX) (X)
Figure imgf000013_0002
(XI) wherein, X is P(=O)(Rι)2 or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl;
P is a hydroxy protecting group; and
A is
Figure imgf000014_0001
The present process for the production of HMG-CoA reductase inhibitors is, hereinafter, described in detail referring to the above reaction scheme.
The condensation reaction of the aldehyde compound of formula (NH) with the chiral compound of formula (I) is c arried out in the presence of base. As the base, alkali metal carbonate, hydroxide, hydride, alkoxide, or alkyl, or alkaline earth metal carbonate, hydroxide, hydride, alkoxide, or alkyl, etc. can be used. The base is preferably used in the amount of 1.0-5.0 equivalents based on the compound of formula (I), and the aldehyde is preferably used in the amount of 1.0-2.0 equivalents. The reaction solvent includes lower alcohol such as methanol, ethanol, and isopropanol, ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, and polar solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoamide, and acetonitrile, etc. If the protecting group is a silyl group, the deprotecting reaction of the hydroxy group of the trans compound of formula (NIII) can be simply carried put, in the presence of fluoride compound such as tetraalkylamonium fluoride and hydrofluoride in ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, etc. The fluoride compound is preferably used in the amount of 1.0-5.0 equivalents based on the compound of formula (NHT).
The reduction of the ketone group of the compound of formula (IX) is carried out using alkali metal borohydride, cyanoborohydri.de, alkoxyborohydride, aluminiumhydride, alkylaluminiumhydride, or alkoxyaluminiumhydride, or alkaline earth metal borohydride, cyanoborohydride, alkoxyborohydride, aluminiumhydride, alkylaluminiumhydride, or alkoxyaluminiumhydride, etc. as a reducing agent. Also, in order to prepare syn-l,3-diol, a chelatmg agent such as trialkyborane, alkoxydialkylborane, dialkoxyalkylborane, and trialkoxyborane is used. The reducing agent and chelating agent are used preferably in the amount of 1.0-10.0 equivalents based on the compound of formula (IX). The reaction solvent includes ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, etc.
The cleavage reaction of the t-butyl group of the 1,3-dihydroxyester of formula
(X) is carried out preferably in the presence of acid, for example formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, alkylsulfonic acid, and toluenesulfonic acid. The acid is used preferably in the amount of 0.001-100 equivalents based on the compound of formula (X). The reaction solvent includes organic acid such as formic acid and acetic acid, aromatic solvent such as benzene, toluene, and xylene, and halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc. According to the present invention, new chiral intermediates which can be used for preparing chiral medicaments such as HMG-CoA reductase inhibitors can be simply prepared without dangerous reaction steps with high yields and high optical purity of at least 98%. Therefore, since chiral medicaments such as HMG-CoA reductase inhibitors can be produced economically with high purity via the chiral intermediates of the present invention, the process for the production of HMG-CoA reductase inhibitors using the chiral intermediates of the present invention does not have problem of removing by-products and disposing the waste, and therefore is suitable for being used industrially and commercially.
Examples
The following examples are intended to illustrate the present invention, however these examples are not to be construed to limit the scope of the invention.
Example 1 :
Preparation of ethyl-(3S -3-hvdroxyglutaric acid To 2,000ml of round-bottomed flask equipped with a stirrer and thermometer,
400. Og of diethyl-3-hydroxyglutaric acid and 400ml of water were added. Then, 20.0g of esterase(code number: CLS-BC-14011) was added and stirred at 37°C. After the reaction was completed, the esterase was separated using a filter paper, and 400ml of ethyl acetate was slowly added to the filtrate and stirred for 15 minutes. Then, aqueous phase and organic phase were separated, and the organic phase was distillated to give ethyl-(3S)-3-hydroxyglutaric acid(yield: 99.7%), purity: 98.0%), chiral purity: 99.5%).
Rf = 0.2(n-hexane/ethyl acetate, 1/1) 1H NMR (CDCb, 200MHz) δ: 4.40~4.35(m, 1H); 4.10(q, 2H, J=7Hz); 3.45(bs, 1H); 2.50-2.41(d, 4H, J=6Hz); 1.26(t, 3H, J=7Hz).
Preparation of ethyl t-butyl-(3R)-3-hydroxyglutaric acid To 2,000ml of round-bottomed flask equipped with a stirrer and thermometer,
211.3g of ethyl-(3S)-3-hydroxyglutaric acid and 400ml of dichloromethane were added. Afterwards, 67.3g of isobutylene gas and 12.8ml of sulfuric acid were added and stirred at -10°C. After the reaction was completed, 400ml of distilled water was slowly added and stirred for 15 minutes. Then, aqueous phase and organic phase were separated, and the organic phase was distiUated under reduced pressure to give ethyl t-butyl-(3R)- 3-hydroxyglutaric acid(distillation range: 115~116°C/2.0mmHg, yield: 74.5%, purity: 98.0%, chiral purity: 99.2%).
Rf = 0.8 (n-hexane/ethyl acetate, 1 / 1 ) '
1H NMR (CDCb, 200MHz) δ: 4.41~4.36(m, 1H); 4.16(q, 2H, J=7Hz); 3.55(bs, 1H); 2.53~2.44(d, 4H, J=6Hz); 1.46(s, 9H); 1.27(t, 3H, J=7Hz).
Preparation of ethyl t-butyl-(3R)-3-(t-butyldimethylsilyloxy glutaric acid
To 500ml of round-bottomed flask equipped with a stirrer and thermometer, 17.6g of ethyl t-butyl-(3R)-3-hydroxyglutaric acid and 100ml of dichloromethane were added. Afterwards, 6.2g of imidazole and 12.5g of t-butyldimethylsilyl chloride were added and stirred at room temperature. After the reaction was completed, 200ml of distilled water was added and stirred for 15 minutes. Then, aqueous phase and organic phase were separated, and the organic phase was distiUated. The resulting residue was subjected to silica gel c olumn chromatography(eluent: n-hexane/ethyl acetate, 4/1) to give ethyl t-butyl-(3R)-3-(t-butyldimethylsilyloxy)glutaric acid(yield: 94.8%, purity: 99.0%, chiral purity: 99.0%).
Rf = 0.8 (n-hexane/ethyl acetate, 2/1)
1H NMR (CDCb, 200MHz) δ: 4.54-4.36(m, 1H); 4.12(q, 2H, J=6Hz); 2.55 - 2.44(dd, 4H, J=6Hz, J=2Hz); 1.45(s, 9H); 1.25(t, 3H, J=7Hz); 0.85(s, 9H); 0.06(s, 6H).
Preparation of t-butyl (3R)-3-(t-butyldimethylsilyloxy -6-dimethoxyphophinyl-
5-oxohexanate To 1,000ml of round-bottomed flask equipped with a stirrer and thermometer,
17.8g of dimethyl methylphosphonate and 150ml of tetrahydrofuran were added under nitrogen atmosphere. Afterwards, 82.5ml of 1.6M n-butyllithium in n-hexane was slowly added for 15 minutes and stirred for 1 hour at -78°C, and 19. lg of ethyl t-butyl-
(3R)-3-(t-butyldimethylsilyloxy)glutaric acid was added and stirred. After the reaction was completed, 200g of 5% HCl aqueous solution and 400ml of ethyl acetate were added and stirred for 15 minutes. Then, aqueous phase and organic phase were separated, and the organic phase was distiUated. The resulting residue was subjected to silica gel column chromatography(eluent: n-hexane/ethyl acetate, 1/1) to give t-butyl
(3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphophinyl-5-oxohexanate(yield: 77.6%, purity: 99.5%, chiral purity: 99.1%).
Rf = 0.3(n-hexane/ethyl acetate, 1/1)
1H NMR (CDCb, 200MHz) δ: 4.54~4.45(m, 1H); 3.76(d, 6H, J=llHz); 3.10(d, 2H, J-23Hz); 2.85(d, 2H, J=6Hz); 2.39(d, 2H, J=6Hz); 1.42(s, 9H), 0.83(s, 9H), 0.06(d, 6H, J=5Hz).
Example 2:
Preparation of t-butyl 7- 4-(4-fluorophenyl)-6-isopropyl-2-πSf-methyl-N- methylsulfonylamino pyrimidine-5-yl]-(3R -3-(t-butyldimethylsilyloxy -5-oxo- 6-heptenate
To 500ml of round-bottomed flask equipped with a stirrer and thermometer, 4.15g of potassium carbonate and 50ml of isopropanol were added at room temperature under nitrogen atmosphere. Afterwards, 4.24g of t-butyl (3R)-3-(t- butyldimethylsilyloxy)-6-dimethoxyphopl inyl-5-oxohexanate prepared in Example 1 was added at room temperature under nitrogen atmosphere and stirred for 1 hour, and then 3.24g of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde was added at room temperature under nitrogen atmosphere and stirred. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and lOOg of 10% HCl aqueous solution and 100ml of ethyl acetate were added and stirred for 15 minutes. Then, aqueous phase and organic phase were separated, and the organic phase was distiUated to give t-butyl 7-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-yl]-(3R)- 3 -(t-butyldimethylsilyloxy)-5-oxo-6-heptenate. Rf = 0.4(n-hexane/etιiyl acetate, 7/1)
Preparation of t-butyl 7-r4-(4-fluorophenyl -6-isopropyl-2-flSf-methyl-N- methylsulfonylamino)pyrimidine-5-yl]-(3R)-3-hvdroxy-5-oxo-6-heptenate The compound obtained in the above step was added to 250ml of round- bottomed flask equipped with a stirrer and thermometer without purification, and 20ml of tetrahydrofuran and 12ml of 1.0M tetrabutylammonium fluoride in tetrahydrofuran were added under nitrogen atmosphere and stirred at room temperature. After the reaction was completed, lOOg of 10% sodium carbonate solution and 100ml of ethyl acetate were added and stirred for 15 minutes. Then, aqueous phase and organic phase were separated, and the organic phase was distiUated. The resulting residue was subjected t o s ilica g el c olumn c hromatography(eluent: n -hexane/ethyl a cetate, 1 /l) t o give t-butyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidine-5-yl]-(3R)-3-hydroxy-5-oxo-6-heptenate(yield: 76.6%). Preparation of t-butyl 7-r4-("4-fluorophenyl -6-isopropyl-2-(N-methyl-N- methylsulfonylamino^pyrimidine-S-yll-rSR^S^-S.S-dihvdroxy-ό-heptenate
4.97g of the compound obtained in the above step was added to 100ml of round-bottomed flask equipped with a stirrer and thermometer, and 20ml of tetrahydrofuran and 5ml of methanol were added under nitrogen atmosphere and stirred at room temperature. Afterwards, 13.3ml of 1.0M triethylborane in tetrahydrofuran was slowly added for 15 minutes and stirred for 0.5 hours at -78°C, and then 0.42g of sodium borohydride was added and stirred. After the reaction was completed, 14ml of acetic acid was added and stirred for 0.5 hours, and then 200g of 10% sodium carbonate solution and 200ml of ethyl acetate were added. Then, aqueous phase and organic phase were separated, and the organic phase was distiUated. Afterwards, 20ml of methanol was added to the resulting residue, stirred for 15 minutes at room temperature, and concentrated, 5 times repeatedly. The resulting residue was subjected to silica gel column chromatography(eluent: dichloromethane/ethyl acetate, 3/1) to give t-butyl 7-[4- (4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-yl]-
(3R,5S)-3,5-dihydroxy-6-heptenate(yield: 90.6%).
Rf = 0.3 (dichloromethane/ethyl acetate, 3/1)
Preparation of rosuvastatin sodium salt 2.35g of the compound obtained in the above step was added to 100ml of round-bottomed flask equipped with a stirrer and thermometer, and 10ml of formic acid was added and stirred at room temperature. After the reaction was completed, the reactants were concentrated, and 40ml of ethanol and 50ml of 0.1N sodium hydroxide solution were added and stirred for 10 minutes at room temperature. Then, the reactants were concentrated, and 20ml of ethanol was added and stirred for 10 minutes, 5 times repeatedly. Afterwards, 50ml of ether was added to the resulting residue, and stirred for 1 hour at room temperature. The resulting white crystals were filtered through a filter paper, washed with 10ml of ether three times, and dried to give rosuvastatin sodium salt(yield: 89.7%).
1H NMR (CDCb, 200MHz) δ: 7.15(m, 4H); 6.62(d, IH, J=16Hz); 4.99(dd, IH, J=16Hz, 7Hz); 4.22(m, IH), 3.72(m, 2H); 3.36(s, 3H); 2.24(m, 2H); 2.13(s, 3H); 1.37(s, 3H); 1.34(s, 3H) [α]D = +29.0(C=1.0, distilled water).

Claims

What is claimed is:
1. A process for the production of the chiral compound of formula (I) comprising the steps of: (i) selectively hydro lyzing the compound of formula (II) with a microorganism to give the compound of formula (HI):
Figure imgf000022_0001
(π) (m)
(ii) reacting the compound of formula (III) with isobutylene under acidic catalyst to give the compound of formula (IN):
Figure imgf000022_0002
(HI) (TV)
(iii) protecting the hydroxy group of the compound of formula (IN) to give the compound of formula (N):
Figure imgf000022_0003
(TV) (N)
(iv) reacting the compound of formula (N) with the compound of formula (NI) to give the compound of formula (I):
Figure imgf000022_0004
(V) (NI) (I) wherein,
X is P(=O)(Rι)2 or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl; R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and
P is a hydroxy protecting group.
2. The process according to claim 1, wherein X is P(=O)(OMe)2, and P is t- butyldimethylsilyl group.
3. A chiral compound of formula (I):
Figure imgf000023_0001
(I) wherein, X is P(=O)(Rι)2 or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl; and
P is a hydroxy protecting group.
4. The chiral compound according to claim 3, wherein X is P(=O)(OMe)2, and
P is t-butyldimethylsilyl group.
5. A process for the production of the HMG-CoA reductase inhibitor of formula
(XI) comprising the steps of reacting the aldehyde compound of formula (NH) with the chiral compound of formula (I), deprotecting the hydroxy group of the trans compound of formula (NIII), reducing the ketone group of the compound of formula (IX), and cleaving the t-butyl group of the 1,3-dihydroxyester of formula (X):
Figure imgf000024_0001
(XI) wherein,
X is P(=O)(Rι)2 or S(O)Rι, wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl;
P is a hydroxy protecting group; and A is
Figure imgf000024_0002
6. The process according to claim 5, wherein the HMG-CoA reductase inhibitor is rosuvastatin.
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