WO2010027113A2

WO2010027113A2 - Process for preparing (s)-(-)-felodipine

Info

Publication number: WO2010027113A2
Application number: PCT/KR2008/005239
Authority: WO
Inventors: Jin Auh; Duk Kwon Won; Byung Hyun Moon; O Zoon Kwon; Chang Woo Jong; Kyung Yong Jin; Kyoung Ho Bae; Hee Yoon Lee; Jung Ah Shin
Original assignee: Ahn-Gook Pharmaceutical Co., Ltd; Korea Advanced Institute Of Science And Technology
Priority date: 2008-09-04
Filing date: 2008-09-04
Publication date: 2010-03-11
Also published as: WO2010027113A3; CN102143948A; CN102143948B

Abstract

The embodiment proposes a method for preparing (S)-(-)- ethyl methyl 4-(2,3-dichlorophenyl)- 1,4-dihydro-2,6-dimethyl-3,5-pyridine- dicarboxylate (hereinafter, referring to as "(S)-(-)-felodipine", and more particularly, a method for effectively preparing the (S)-(-)-felodipine through a selective transesterification of -hydroxy ester after synthesizing a felodipine derivate including a chiral separation compound and isolating (S)-isomers. The chiral separation compound is synthesized from (R)-glycidol or (S)-glycidol through reaction with various nucleophiles and epoxide.

Description

[DESCRIPTION] [Invention Title]

PROCESS FOR PREPARING (S)-(-)-FELODIPINE [Technical Field]

<i> The embodiment relates to a method for preparing (S)-(-)-felodipine using (R)-glycidol or (S)-glycidol as a starting material, and more particularly, to a method for effectively preparing (S)-(-)-felodipine through a selective transesterif ication from (S)-isomer isolated after preparing ester of 1-hydroxyethyl derivative as an intermediate.

[Background Art]

<2> Felodipine is a generic name of ethyl methyl 4-(2,3-dichlorophenyl)- l,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate as shown in following Formula 1, which is a calcium channel blocker acting for a long period of time and is well known for their effectiveness in the treatment of cardiovascular disease such as angina pectoris and hypertension. <3> [Formula 1]

<5> As shown in Formula 1, the felodipine is a chiral compound having asymmetric carbons. Generally, in therapeutic effects of chiral compounds used as drugs, pure isomer compounds are very superior to isomer mixtures. Further, the chiral compounds have different pharmacological characteristics according to steric configuration of the isomer compounds or salt forms thereof. As for the felodipine, S-(-)-isomers better on remedial result and pharmacokinetic characteristics than R-(+) isomers do (see, Eur. J. Clin. Pharm. , 1993, 44, 113, P.A. Soon et al.). There is, therefore, a need for development of technique to synthesize chiral compounds, i.e., the felodipine with optically pure isomers.

<6> A process for synthesizing a racemic felodipine is disclosed in Korean Patent No. 10-0488384 and so on. Meanwhile, as for stereoselective synthesis of S-(-)-felodipine, there are disclosed a synthesis method through isolation of diastereomer intermediates using chiral auxiliary groups (see Tetrahedon Lett., 1989, 30, 6423, B. Lamm et al.), a synthesis method through optical resolution of monocarboxylic acids as intermediates (see WO 88/07524), a stereoselective synthesis method through an asymmetric reduction reaction using chiral auxiliary groups from pyridine compounds (see Mo1ecules(ECHC), 1996, 16) or the like but it is known that they have the limitation to direct industrial application and there is not yet disclosed a method for optically purely obtaining S-(-)-felodipine or a synthesis method which is industrially applicable. And, although as for related derivative compounds, an optical resolution method using an enzyme (see Curr. Org. Chem. 1999, 3, 77, K. Achiwa et al.) is disclosed, the method is not used for synthesis of the S-(- )-felodipine.

<7> Among the above-mentioned methods, the synthesis method using the chiral auxiliary group is the most practical method so far and a practical synthesis process thereof is noted in detail, but an electron withdrawing group is needed to form a negative ion at a beta position of a chiral alcohol which forms an ester with the chiral auxiliary group. [Disclosure] [Technical Problem]

<8> The embodiment employs a selective transesterif ication using various chiral auxiliary groups as a central reaction in order to overcome limitation of a selective hydrolysis used in the conventional preparation method of (S)- (-)-felodipine.

<9> The embodiment relates to a method for preparing (S)-(-)-felodipine by using low-priced (R)-glycidol or (S)-glycidol as a starting material of the selective transesterif ication and a chiral auxiliary group, wherein a process of the method is simple and economical in comparison with the conventional synthesis methods and various intermediates can be secured, so that the method can be applied to asymmetric synthesis of a dihydropyridine compound in addition to the felodipine. [Technical Solution]

<io> The embodiment provides a method for preparing (S)-(-)-felodipine including steps of: synthesizing a chiral auxiliary group for optical resolution of the felodipine by using (R)-glycidol or (S)-glycidol as a starting material; synthesizing an intermediate of the felodipine from the chiral auxiliary group; isolating two diastereomers; and selectively transesterifying a β -hydroxy ester by direct sodium methoxide treatment.

<ii> The method can directly prepare the felodipine from the intermediate without a selective hydrolysis of ester and a synthesis process of methyl ester by using the photoactive intermediate. Accordingly, one step can be omitted in comparison with the conventional method and the chiral auxiliary group can be recovered and reused, which are advantages of the method.

<12> Hereinafter, the present invention will be described in detail.

<13> The present invention includes two steps of: synthesis of a chiral auxiliary group for distinguishing an optical isomer of the felodipine and synthesis of (S)-(-)-felodipine using the same.

<14> As shown in Reaction formula 1, a chiral auxiliary group is first prepared by adding various nucleophi les(Nu) to a compound obtained by reacting (R)-glycidol or (S)-glycidol with dihydropyran in the presence of an acid catalyst such as pyridinium p -toluenesulfonate (PPTs), p-toluene- sulfonic acid(TsOH), camphoresuIfonic acid. At this time, the nucleophi les(Nu) includes all necleophiles which can be reacted with epoxide, as well as RiSH, RiRoNH, RiOH, RR0R₃CH or the like and conjugate base thereof, i.e., things having forms obtained by separating a hydrogen ion and in the formulas, R and R3 represent H, Ri represents phenyl and Ro represents toluenesul fonate(Ts) . <15> [Reaction formula 1]

<17> As for synthesis of an intermediate of the felodipine using the chiral auxiliary group thus obtained, as shown in Reaction formula 2, the intermediate is prepared by reacting ketoester obtained by reacting the chiral auxiliary group with dichitin, with 2,3- dichlorobenzaldehyde and reacting the ketoester with ethyl 3-amino-2-butenoate.

<18> [Reaction formula 2]

Benzene, reflux, 4h

74% 78%

EtO

<20> As for preparation of (S)-(-)-felodipine, as shown in Reaction formula 3, a diastereomer mixture obtained in the reaction is first treated with acid such as p -toluene sulfonic acid, camphor sulfonic acid, pyridinium tosylate and acetic acid to form a hydroxy group and then isomers are isolated through recrystallization or chromatography using a silica gel. <21> When the isolated isomers are reacted with methoxy salt such as sodium methoxide (NaOMe) respectively, only β -hydroxy ester is selectively transesterif ied to directly prepare the (S)-(-)-felodipine.

<22> [Reaction formula 3]

Na (1.1eqVMeOH(0.4M)

Reflux, 5.5h

<24> At this time, the chiral auxiliary group recovered after preparing the (S)-(-)-felodipine can be reused through a selective reaction by a known method (see E. J. Org. Chem., 2005, 4891, A.T. Khan, et al.) as shown in Reaction formula 4.

<25> [Reaction formula 4]

OH OH

Bi(NO,)_}5H₂O

HO T Nu DHP THPO Nu CH₂CI₂

<26>

<27> Hereinafter, the present invention will be more fully illustrated referring to Examples. However, it should be understood that these Examples are suggested only for illustration and should not be construed to limit the scope of the present invention. It will be appreciated by those skilled in the art that numerous modifications could be made without departing from the scope and the spirit of the invention. [Advantageous Effects]

<28> The embodiments relate to a method for preparing (S)-(-)-felodipine through the selective transesterif ication using various chral auxiliary groups in order to overcome the limitation of selective hydrolysis used in the conventional method for preparing (S)-(-)-felodipine, wherein the process thereof is simple in comparison with the conventional synthesis methods, the method can reduce the cost because the low-priced (R)- or (S)- glycidol is used as the starting material, and various intermediates can be secured, so that the method can be applied to asymmetric synthesis of a dihydropyridine compound in addition to the felodipine.

[Best Mode]

<29> Example l : Nu=PhSH

<30> Procedure 1

70%

<31>

<32> After dissolving (R)-glycidol 6 g (80.99 mmol) into a solvent, methylene chloride(CH₂Cl₂) 70 ml (1.1 M), 3,4-dihydropyran (DHP) 11.3 ml (1.5 eq) and Pyridinium p -Toluene sulfonate(PPTs)I g (0.05 eq) are added. After reacting the resultant mixture at room temperature for 6 hours, 15 to 20 ml of water is added. The reaction mixture is neutralized using 20 to 30 ml of sodium bicarbonate (NaHCOs) and extracted with ether 100 ml approximately three times. After dehydrating the reaction mixture using anhydrous sodium sulfate (Na₂SO.!), the solvent is concentrated under reduced pressure to give a targeted product 8.8 g (55 mmol, yield: 69.1%). <33> Procedure 2

.. 96%

<34> <35> After dissolving sodium hydride (NaH) 2.65 g (1.2 eq) into Tetrahydrofuran (THF) 40 ml, benzenethiol 6.87 ml (1.2 eq) is gradually added to the solution at a temperature of 0^°C . After mixing the reaction mixture for 30 minutes, the product 8.8 g (55 mmol) prepared in the Procedure 1 is dissolved into tetrahydrofuran 20 ml and is added to pre-prepared benzenethiol sodium salt. The reaction mixture is reacted for 12 hours at room temperature. And then, the reaction mixture is added with 10 to 15 ml of water, neutralized using 30 to 40 ml of ammonium chloride (NH₄Cl), and extracted with ethyl acetate (EA) 80 ml three times. After dehydrating the reaction mixture with anhydrous sodium sulfate (Na2S04), the solvent is concentrated under reduced pressure to give a targeted product 14.23 g (53 mmol, yield: 96%). <36> Procedure 3

<37> ^74%

<38> After dissolving the product 1.77 g (6.59 mmol) prepared in the Procedure 2 into acetone 15 ml (0.44 M), the mixture solution is added with dichitin 606 μH (1.2 eq) and pyridine 107 μi (0.2 eq) and stirred under reflux for 4 hours. The solvent is concentrated under reduced pressure and the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ratio of 1:5 (EA:Hx) to give a targeted product 1.7 g (4.823 mmol, yield: 73.1%). <39> Procedure 4

<41> After dissolving the product 1.7 g (4.823 mmol) prepared in the Procedure 3 into benzene 12 ml (0.4 M), 2,3-dichlorobenzene aldehyde 1.02 g (1.2 eq), piperidine 96 μϋ (0.3 eq) and acetic acid 55 μi (0.3eq) are added. After stirring the mixture solution under reflux for 2 hours, the reaction mixture is added with water and extracted with ethyl acetate. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ratio of 1:5 (EA:Hx) to give a targeted product 1.9 g (3.737 mmol, yield: 77.4%).

<42> Procedure 5

EtO

<44> After adding pyridine 10 ml to the product 1.9 g (3.737 mmol) prepared in the Procedure 4, the resultant mixture is added with ethyl-S^¬ aminocrotonate 520 μi. (1.1 eq) and stirred under reflux for 4 hours. The temperature is cooled to room temperature and the pyridine is concentrated and removed. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ratio of 1:3 to give a targeted product 1.67 g (2.69 mmol, yield: 72%). <45> Procedure 6

A B

<46>

<47> After dissolving the product 644 mg( 1.038 mmol) prepared in the Procedure 5 into ethanol 4 ml (0.25 M), the resultant mixture is added with p -toluene-sulfonic acid(p -TsOH) 394 mg (2 eq) and reacted for 4 hours at room temperature. The reaction mixture is added with water and extracted with ethyl acetate. And the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ratio of 1:1 to give a targeted product 412 mg (0.768 mmol, yield: 74%).

<48> Procedure 7

<50> After dissolving sodium 5 mg (1.1 eq) into methanol 0.5 ml (0.4 M), the resultant solution is gradually added to the product 107 mg (0.1995 mmmol) prepared in the Procedure 6 and stirred under reflux for 5.5 hours at a temperature of 70^°C. After fully concentrating the solvent under reduced pressure, water, ammonium chloride(aq. ) and ethyl acetate for extraction are added. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:1 to give (S)-(-)-felodipine 61.3 mg (0.1596 mmol, yield: 80%) and chiral auxiliary groups 19 mg (yield: 51%) without protecting groups. As a result of

245 measuring specific rotation under [«]5S9 - = _-7. 13 C=I , methanol (TL paper 25 reference! ^⁵⁸⁹= -7.3 C=I, methanol), (S)-form of Enantiomeric excess is 97.6%.

<51> Example 2: Nu=PhOH <52> Procedure 1

<53> <54> The product 1 g(6.32 mmol) prepared in the Procedure 1 of the Example 1 and sodium hydroxide 320 mg (8.00 mmol) are dissolved into distilled water 6 ml (1 M) and reacted for 8 hours at a temperature of 100^°C. The reaction solution is neutralized using 1 N hydrochloric acid 8 ml and extracted with ethyl acetate 10 ml three times. And then, the reaction solution is dehydrated with anhydrous sodium sulfate and the solvent is concentrated under reduced pressure. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:3 to give a targeted product 1.35 g (5.35 mmol, yield: 84.7%).

<55> Procedure 2

<57> After dissolving the product 1.35 g (5.35 mmol) prepared in the Procedure 1 into acetone 10 ml (0.5 M), the resultant solution is added with dichitin 0.5 ml (1.2 eq) and pyridine 90 μJt (0.2 eq) and stirred under reflux for 4 hours. The reaction mixture is added with water and extracted with ethyl acetate 20 ml three times. The reaction mixture is dehydrated using anhydrous sodium sulfate and the solvent is concentrated under reduced pressure to give a targeted product 1.71 g (5.08 mmol, yield: 95.0%).

<58> Procedure 3

<60> After dissolving the product 1.71 g (5.08 mmol) prepared in the Procedure 2 into benzene 10 ml (0.5 M), 2,3-dichlorobenzaldehyde 1.07 g (1.2 eq), piper idine 150 μ$ (0.3 eq) and acetic acid 87 μJt (0.3 eq) are added to a resultant solution. The mixture is stirred under reflux for 2 hours, added with water, and extracted with ethyl acetate. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:5 to give a targeted product 1.88 g (3.81 mmol, yield: 75.0%).

<61> Procedure 4

<63> After adding pyridine 8 ml (0.5 M) to the product 1.88g (3.81 mmol) prepared in the Procedure 3, ethyl-3-aminocrotonate 0.6 ml (1.2 eq) is added to a resultant solution. The resultant solution is stirred under reflux for 4 hours and cooled to room temperature. And then, the pyridine is concentrated and removed. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:2 to give a targeted product 1.73 g (2.86 mmol, yield: 75.1%). <64> Procedure 5

<66> After dissolving the product 1.73 g (2.86 mmol) prepared in the Procedure 4 into ethanol 10 ml (0.29 M), a resultant solution is added with -toluene-sulfonic acid 1.1 g (2 eq) and reacted for 4 hours at room temperature. The reaction mixture is added with water and extracted with ethyl acetate. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:2 to give a targeted product 1.19 g (2.29 mmol, yield: 80%).

<67> Procedure 6

<69> After dissolving sodium 5.3 mg (1.2 eq) into methanol 1 ml (0.19 M), a resultant solution is gradually added to the product 100 mg (0.191 mmmol) prepared in the Procedure 5. The reaction mixture is stirred under reflux for 2 hours at a temperature of 70^°C. After fully concentrating the solvent under reduced pressure, water, ammonium chloride(aq. ) and ethyl acetate for extraction are added to the reaction mixture. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:1 to obtain (S)-(-)-felodipine 73.4 mg (0.153 mmol, yield: 80%). <70> Example 3: Nu=MeSO₂Ph

<7i> Procedure 1

<72>

<73> Methylphenyl sulfone 1.18 g (7.55 mmol) is dissolved into anhydrous tetrahydrofuran 80 ml and added with n-butyl lithium (n-BuLi) 12.1 ml (1.6 M) at a temperature of -78°C . After stirring the resultant solution for 30 minutes at the same temperature, tetrahydrofuran 5 ml is added to the product 1 g (6.32 mmol) prepared in the Procedure 1 of the Example 1 and the temperature is gradually adjusted to room temperature. The reaction mixture is reacted for 2 hours at the room temperature, neutralized using ammonium chloride 100 ml, and extracted with ethyl acetate 100 ml three times. The reaction mixture is dehydrated using anhydrous sodium sulfate and the solvent is concentrated under reduced pressure. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:3 to give a targeted product 1.85 mg (yield: 93%).

<74> Procedure 2

<76> After di ssolving the product 1.85 g (5.88 mmol ) prepared in the

Procedure 1 into acetone 10 ml (0.6 M) , dichi t in 0.54 ml ( 1.2 eq) and pyridine 97 μl (0.2 eq) are added to the resultant solution. The mixture is stirred under reflux for 4 hours, added with water 10 ml, and extracted with ethyl acetate 20 ml three times. The reaction mixture is dehydrated using anhydrous sodium sulfate and the solvent is concentrated under reduced pressure to give a targeted product 2.11 g (5.29 mmol, yield: 90.0%).

<77> Procedure 3

<79> After dissolving the product 2.11 g (5.29 mmol) prepared in the Procedure 2 into benzene 10 ml (0.5 M), 2,3-dichlorobenzene aldehyde 1.11 g (1.2 eq), piperidine 160 [Λ (0.3 eq) and acetic acid 90 ιά (0.3 eq) are added. The resultant mixture is stirred under reflux for 2 hours, added with water, and extracted with ethyl acetate. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:5 to give a targeted product 2.06 g (3.71 mmol, yield: 70.1%).

<80> Procedure 4

<81> <82> After pyridine 8 ml (0.5 M) and ethyl-3-aminocrotonate 0.6 ml (1.2 eq) are added to the product 2.06 g (3.71 mmmol) prepared in the Procedure 3, the resultant mixture is stirred under reflux for 4 hours. The temperature is cooled to room temperature and the pyridine is concentrated and removed. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:2 to give a targeted product 1.73 g (2.60 mmol, yield: 70.1%).

<83> Procedure 5

<84>

<85> After dissolving the product 1.73 g (2.60 mmol) prepared in the Procedure 4 into ethanol 10 ml (0.26 M), the resultant solution is added with p -toluene-sulfonic acid 1.0 g (2 eq) and reacted for 4 hours at room temperature. The reaction mixture is added with water and extracted with ethyl acetate. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:2 to give a targeted product 1.29 g (yield: 85%).

<86> Procedure 6

<87> 80% <88> After dissolving sodium 4.7 mg (1.2 eq) into methanol 1 ml (0.17 M), the resultant solution is gradually added to the product 100 mg (0.172 mmol) prepared in the Procedure 5. The reaction mixture is stirred under reflux for 2 hours at a temperature of 70^°C . After fully concentrating the solvent under reduced pressure, the reaction mixture is added with water and sodium chloride(aq. ) and extracted with ethyl acetate. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:1 to give (S)-(-)-felodipine 53 mg

(0.137 mmol, yield: 80%). <89> Example 4: Nu=PhNHTs <90> Procedure 1

78%

<91>

<92> After dissolving the product 1 g (6.32 mmol) prepared in the Procedure 1 of the Example 1 into 1,4-dioxane solvent 6 ml (1 M), potassium carbonate (K₂CO₃) 88 mg (0.1 eq), triethyl-benzyl-ammonium chloride(TEBA) 144 mg (0.1 eq), and p -toluenesulfonani lide 1.72 g (1.1 eq) are added. The mixture solution is reacted for 8 hours at a temperature of 120°C and added with water 3 to 4 ml. The reaction mixture is neutralized using ammonium chloride 4 to 5 ml and extracted with ethyl acetate 10 ml three times. Herein, the reaction mixture is dehydrated with anhydrous sodium sulfate and the solvent is concentrated under reduced pressure. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:3 to give a targeted product 2g (4.93 mmol, yield: 78%).

<93> Procedure 2

<94>

<95> After dissolving the product 1.23 g (3.03 mmol) prepared in the Procedure 1 into acetone 6 ml (0.5 M), the resultant solution is added with dichitin 280 ≠. (1.2 eq) and pyridine 50 μl (0.2 eq) and stirred under reflux for 4 hours. And then, the reaction mixture is added with 3 to 4 ml of water and extracted with ethyl acetate 10 ml three times. Herein, the reaction mixture is dehydrated with anhydrous sodium sulfate and the solvent is concentrated under reduced pressure to give a targeted product 1.46 g (2.982 mmol, yield: 98.4%).

<96> Procedure 3

<97> <98> After dissolving the product 1.46 g (2.982 mmol) prepared in the Procedure 2 into benzene 7.5 ml (0.4 M), 2,3-dichlorobenzene aldehyde 626 mg (1.2eq), piper idine 88 μi (0.3eq) and acetic acid 51 μJl (0.3eq) are added. After the reaction mixture is stirred under reflux for 2 hours, the reaction mixture is added with water and extracted with ethyl acetate. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:5 to give a targeted product 1.43g (2.212 mmol, yield: 74.2%).

<99> Procedure 4

<101> After adding pyridine 5 ml (0.44 M) to the product 1.43 g (2.212 mmol) prepared in the Procedure 3, the resultant solution is added with ethyl-S^¬ aminocrotonate 308 μJl (1.1 eq) and stirred under reflux for 4 hours. The temperature is cooled to room temperature and the pyridine is concentrated and removed. And then, the residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:2 to give a targeted product 1.34g (1.769 mmol, yield: 80%).

<102> Procedure 5

<103> <104> After dissolving the product 520 mg (0.686 mmol) prepared in the Procedure 4 into ethanol 2.5 ml (0.27 M), the resultant solution is added with p -toluene sulfonic acid 262 mg (2 eq) and reacted for 4 hours at room temperature. The reaction mixture is added with water and extracted with ethyl acetate. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:2 to give a targeted product 300 mg (yield: 65%).

<105> Procedure 6

<107> After dissolving sodium 3.8 mg (1.2 eq) into methanol 1 ml (0.13 M), the resultant solution is gradually added to the product 93 mg (0.138 mmmol) prepared in the Procedure 5 and stirred under reflux for 2 hours at a temperature of 70"C. After fully concentrating the solvent under reduced pressure, water, ammonium chloride(aq. ) and ethyl acetate for extraction are added. The residue is purified through a column using a developing solvent containing ethyl acetate and nucleic acid which are in the ration of 1:1 to give (S)-(-)-felodipine 44.5 mg (0.116 mmol , yield: 84%).

<108> Example 5: Preparation of felodipine using (S)-glycidol as a starting material

<109> Procedure 1

<111> Using (S)-glycidol 60 g (0.8 mol), the procedures as described in the Example 1 were carried out to obtain (R,S)-3-ethyl 5-((S)-l-hydroxy-3- (phenylthio)propane-2-i 1 )4-(2,3-dichlorophenyl )-2,6-dimethyl-l,4- dihydropyridine-3,5-dicarboxylate 5 g (9.3 mmol). The diastereomer mixture is added to a solvent 8 ml including benzene and ethyl acetate in the ratio of 2:1 and heated to give a solution. The solution is crystallized at room temperature and filtered to obtain pure (R)-3-ethyl 5-((S)-l-hydroxy-3- (phenylthio)propane-2-i 1 )4-(2,3-dichlorophenyl )-2,6-dimethyl-l,4- dihydropyridine-3,5-dicarboxylate 1.75 g (3.3 mmol).

<112> Procedure 2

<113> <114> The product prepared in the Procedure 1 is reacted with sodium methoxide as the Example 1 to obtain (S)-(-)-felodipine. As a result of measuring specific rotation under ^[otj589 = -7.25 C=I, methanol (TL paper reference; ^k"⁹ = -7.3 C=I, methanol), (S)-form of Enantiomeric excess is 99.3%.

Claims

[CLAIMS] [Claim 1]

A method for preparing (S)-(-)-felodipine, comprising the steps of:

(a) obtaining a compound of Formula 3 by reacting (R)- or (S)-glycidol of Formula 2 with dihydropyran (DHP) and adding nucleophiles (Nu);

[Formula 2]

[Formula 3]

(b) obtaining a compound of Formula 5 by reacting the compound of Formula 3 with dichitin of Formula 4;

[Formula 4]

[Formula 5]

(c) obtaining a compound of Formula 7 by reacting the compound of Formula 5 with 2,3-dichlorobenzaldehyde of Formula 6; [Formula 6]

[Formula 7]

(d) obtaining a felodipine intermediate of Formula 9 by reacting the compound of Formula 7 with 3-amino-2-butenoate of Formula 8; [Formula 8]

(e) isolating (S)-isomers by treating the felodipine intermediate of Formula 9 with acid; and

(f) obtaining (S)-(-)- felodipine of Formula 1 by selectively transesterifying the (S)-isomers with methoxy salt

[Formula 1]

[Claim 2]

The method for preparing (S)-(-)-felodipine according to claim 1, further comprising the step of: reacting a chiral auxiliary group recovered after preparing the (S)-(- )-felodipine with DHP to be converted into the compound of Formula 3. [Claim 3]

The method for preparing (S)-(-)-felodipine according to claim 1 or 2, wherein the nucleophiles (Nu) is any one selected from a group consisting of necleophiles which can be reacted with epoxide and include RiSH, RiR₂NH, RiOH,

RR₂R₃CH and conjugate base thereof (wherein, R and R₃ represent H, Ri represents phenyl, and R₂ represents tosylate(Ts)) .

[Claim 4]

The method for preparing (S)-(-)-felodipine according to claim 1 or 2, wherein the acid is one selected from a group consisting of -toluene- sulfonic acid, camphoresuIfonic acid, pyridinium tosylate, and acetic acid. [Claim 5]

The method for preparing (S)-(-)-felodipine according to claim 1 or 2, wherein the metholxy salt is sodium methoxide. [Claim 6]

The method for preparing (S)-(-)-felodipine according to claim 1 or 2, wherein in the step (c), the isomers are isolated through recrystallization or chromatography using a silica gel.