(19)
(11)EP 2 251 316 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
21.02.2018 Bulletin 2018/08

(21)Application number: 09719934.3

(22)Date of filing:  04.03.2009
(51)Int. Cl.: 
C07C 67/08  (2006.01)
C07C 57/30  (2006.01)
C07B 53/00  (2006.01)
C07C 59/68  (2006.01)
C07C 59/64  (2006.01)
C07C 69/65  (2006.01)
C07C 69/734  (2006.01)
C07C 51/493  (2006.01)
C07C 69/612  (2006.01)
C07C 53/00  (2006.01)
C07C 59/84  (2006.01)
C07C 69/736  (2006.01)
C07C 69/738  (2006.01)
C07C 69/616  (2006.01)
(86)International application number:
PCT/JP2009/054012
(87)International publication number:
WO 2009/113428 (17.09.2009 Gazette  2009/38)

(54)

METHOD FOR PRODUCING OPTICALLY ACTIVE ESTER AND METHOD FOR PRODUCING OPTICALLY ACTIVE CARBOXYLIC ACID

VERFAHREN ZUR HERSTELLUNG OPTISCH AKTIVEN ESTERS UND VERFAHREN ZUR HERSTELLUNG OPTISCH AKTIVER CARBOXYLSÄURE

PROCÉDÉ DE FABRICATION D'UN ESTER OPTIQUEMENT ACTIF ET PROCÉDÉ DE FABRICATION D'UN ACIDE CARBOXYLIQUE OPTIQUEMENT ACTIF


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

(30)Priority: 11.03.2008 JP 2008061512
28.03.2008 JP 2008087223
07.10.2008 JP 2008260902

(43)Date of publication of application:
17.11.2010 Bulletin 2010/46

(73)Proprietor: Tokyo University Of Science Educational Foundation Administrative Organization
Shinjuku-ku Tokyo 162-8601 (JP)

(72)Inventors:
  • SHIINA, Isamu
    Tokyo 162-8601 (JP)
  • NAKATA, Kenya
    Tokyo 162-8601 (JP)

(74)Representative: Ström & Gulliksson AB 
Studentgatan 1 P.O. Box 4188
203 13 Malmö
203 13 Malmö (SE)


(56)References cited: : 
WO-A1-2008/140074
  
  • ISAMU SHIINA ET AL: "Kinetic Resolution of Racemic Carboxylic Acids Using Achiral Alcohols by the Promotion of Benzoic Anhydrides and Tetramisole Derivatives: Production of Chiral Nonsteroidal Anti-Inflammatory Drugs and Their Esters", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 2008, no. 35, 1 December 2008 (2008-12-01), pages 5887-5890, XP002732443, ISSN: 1434-193X, DOI: 10.1002/EJOC.200800942 [retrieved on 2008-11-04]
  • 'Dai 94 Kai Symposium on Organic Synthesis, Japan, 30 October, 2008', 30 October 2008 deel KEN'YA TANAKA ET AL.: 'Chikan Ansoku Kosan Musuibutsuho o Mochiita Samazama na Racemi Dai 2 Kyu Benzyl Alcohol-rui no Sokudoronteki Kogaku Bunkatsu', pages 14 - 15, XP008167938
  • KEN'YA TANAKA ET AL.: 'Chikan Ansoku Kosan Musuibutsu o Dassui Shukugozai to suru Racemi Carboxylic Acid Oyobi Alcohol no Sokudoronteki Bunkatsu' DAI 93 KAI SYMPOSIUM ON ORGANIC SYNTHESIS, JAPAN, 30 MAY, 2008 08 May 2008, pages 1 - 4, XP008167939
  • SHIINA, I. ET AL.: 'The first asymmetric esterification of free carboxylic acids with racemic alcohols using benzoic anhydrides and tetramisole derivatives: an applicayion to the kinetic resolution of secondary benzylic alcohols' TETRAHEDRON LETTERS vol. 48, 2007, pages 8314 - 8317, XP022313021
  • BIRMAN, V.B. ET AL.: 'Kinetic Resolution of Propargylic Alcohols Catalyzed by Benzotetramisole' ORGANIC LETTERS vol. 8, no. 21, 2006, pages 4859 - 4861, XP008129981
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] The present invention relates to a method for producing an optically active ester and a method for producing an optically active carboxylic acid, and more specifically, it relates to a method for producing an optically active ester where one enantiomer of a racemic carboxylic acid is selectively esterified, and in addition, it relates to a method for producing an optically active carboxylic acid which is the other enantiomer.

BACKGROUND ART



[0002] Optically active esters and optically active carboxylic acids are used in various fields such as pharmaceutical products, intermediates of biologically active substances, intermediates of natural product synthesis, and the like.

[0003] In the background art, as a method for producing an optically active ester, a method of production from a racemic secondary benzyl alcohol in the presence of an acid anhydride, using tetramisole or benzotetramisole as a catalyst has been known (see Non-Patent Document 1). Further, a method for producing an optically active ester from a racemic propargylic alcohol in the presence of an acid anhydride using benzotetramisole as a catalyst has been known (see Non-Patent Document 2). However, these production methods have the problem that the structures of the acid anhydride are very limited, and the like, and the substrate generality is poor. Thus, the present inventors have previously proposed a method for producing an optically active ester by reacting a racemic secondary benzyl alcohol and a free carboxylic acid in the presence of a benzoic anhydride or its derivative, using tetramisole or benzotetramisole as a catalyst (see Non-Patent Document 3).

[0004] On the other hand, as a method for produing an optically active carboxylic acid, a method of crystallization separation of a diastereomer salt of a racemic carboxylic acid and a separation agent, using an optically active amine as a separation agent has been known (see Patent Document 1). However, this production method has the problems of high substrate specificity, and that the identification of an optically active amine suitable for the structure of the carboxylic acid, and the selection of the recrystallization solvent are difficult. Further, because the separation is repeated multiple times, the operation is complicated.

Non-Patent Document 1: Birman, V. B.; Li, X.; Org. Lett.; 2006, 7, pp. 1351-1354

Non-Patent Document 2: Birman, V. B.; Guo, L.; Org. Lett.; 2006, 21, pp. 4859-4861

Non-Patent Document 3: Shiina, I.; Nakata, K.; Tetrahedron Lett.; 2007, 48, pp. 8314-8317

Patent Document 1: Japanese Unexamined Patent Publication No. H9-143101


DISCLOSURE OF THE INVENTION


Problems to be Solved by the Invention



[0005] Incidentally, in the above described production methods of an optically active ester, because one of the enantiomers of the racemic alcohol is selectively esterified to become an optically active ester, the other enantiomer remains as an optically active alcohol. Accordingly, if a racemic carboxylic acid and an alcohol were reacted, and one of the enantiomers of the racemic carboxylic acid could be selectively esterified, it could be considered possible to produce an optically active carboxylic acid along with the production of an optically active ester, but such a method of production has not been carried out in the prior art.

[0006] The present invention, in consideration of the above problems, has the objective of providing a method for producing an optically active ester by highly selective esterification of one of the enantiomers of a racemic carboxylic acid, along with providing a method for producing an optically active carboxylic acid which is the other enantiomer.

Means for Solving the Problems



[0007] The present inventors carried out diligent research to solve the above problem. As a result, they achieved the completion of the present invention by discovering that the above problem can be solved by reacting a racemic carboxylic acid and a specified alcohol or phenol derivative under specified conditions. More specifically, the present invention is as follows.

[0008] The first aspect of the present invention is a method for producing an optically active ester comprising reacting a racemic carboxylic acid shown by the formula (g) below and an alcohol shown by the formula (a) below or a phenol derivative shown by the formula (b) below, in the presence of a benzoic anhydride or a derivative of benzoic anhydride obtained from benzoic acid where an alkyl group, alkoxy group, amino group or hydroxyl group is bonded to the phenyl group, and a catalyst shown by any of the formulae (c) to (f) below, and selectively esterifying one enantiomer of the racemic carboxylic acid

wherein, in the formula (a), Ra represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group;

in the formula (b), Rb represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group; n represents an integer of 1 to 5; and in the case that a plurality of Rb is present, they may be the same or different;

in the formulae (c) to (f), X represents any of the following substituent groups,



        -(CH2)2-S-CH3 -CH2-SR -(CH2)2-NHR -CH2CONHR -(CH2)2CONHR



and R represents a protecting group,

in the formula (g), Rg1 and Rg2 represent organic groups which differ from each other , and the organic groups are selected from the group consisting of alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, alkylaryl group, akylheteroaryl group, alkoxyaryl group, and alkoxyheteroaryl group, and may be optionally substituted by an alkyl group, alkoxy group, aryl group, heteroaryl group, acyl group or halogen atom.

[0009] In the preferred embodiment, one of the carbon atoms of Rg1 and Rg2 bonded to the asymmetric carbon is bonded to another atom by a multiple bond.

[0010] In the formula (b), Rb is preferably a naphthyl group, substituted at the 2,6 positions of the phenol.

[0011] The second aspect of the invention is a method for producing an optically active carboxylic acid comprising reacting a racemic carboxylic acid shown by the formula (g) below, an alcohol shown by the formula (a) below or a phenol derivative shown by the formula (b) below, in the presence of a benzoic anhydride or a derivative of benzoic anhydride obtained from benzoic acid where an alkyl group, alkoxy group, amino group or hydroxyl group is bonded to the phenyl group, and a catalyst shown by one of formulae (c) to (f) below, and selectively esterifying one enantiomer of the racemic carboxylic acid

wherein, in the formula (a), Ra represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group,

in the formula (b), Rb represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group; and n represents an integer of 1 to 5; in the case that a plurality of Rb is present, they may be the same or different;

in the formulae (c) to (f), X represents any of the following substituent groups,



        -(CH2)2-S-CH3) -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR



and R represents a protecting group,

in the formula (g), Rg1 and Rg2 represent organic groups which differ from each other, and the organic groups are selected from the group consisting of alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, alkylaryl group, akylheteroaryl group, alkoxyaryl group, and alkoxyheteroaryl group, and may be optionally substituted by an alkyl group, alkoxy group, aryl group, heteroaryl group, acyl group or halogen atom.

Effects of the Invention



[0012] According to the present invention, it is possible to produce an optically active ester by highly selective esterification of one of the enantiomers of a racemic carboxylic acid, along with the production of an optically active carboxylic acid of the other enantiomer.

PREFERRED MODE FOR CARRYING OUT THE INVENTION



[0013] The method for producing an optically active ester and the method for producing an optically active carboxylic acid of the present invention are characterized in reacting a racemic carboxylic acid and a specified alcohol or a phenol derivative, in the presence of a benzoic anhydride or its derivative, and a specified catalyst, and selectively esterifying one enantiomer of the racemic carboxylic acid.

[0014] The optically active ester and the optically active carboxylic acid obtained by the production method of the present invention respectively correspond to the different enantiomers of the racemic carboxylic acid. Accordingly, the method for producing the optically active ester and the method for producing the optically active carboxylic acid according to the present invention can be understood to be a method of optical resolution of a racemic carboxylic acid.

Racemic Carboxylic Acid



[0015] The racemic carboxylic acid used in the production method of the present invention is not particularly limited, but preferably has an asymmetric carbon at the α position of the carboxyl group as shown below in formula (g).



[0016] In the above formula (g), Rg1 and Rg2 represent organic groups which differ from each other. As the organic groups, alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, alkylaryl group, akylheteroaryl group, alkoxyaryl group, alkoxyheteroaryl group and the like can be mentioned. These organic groups may be optionally substituted by an alkyl group, alkoxy group, aryl group, heteroaryl group, acyl group, halogen atom and the like.

[0017] Further, for Rg1 and Rg2, it is preferable that one of the carbon atoms of Rg1 and Rg2 which bonds to the asymmetric carbon is bonded by a multiple bond to another atom, and that the other carbon atom is bonded by a single bond to another atom. In this way, it is possible to increase the enantiomer selectivity rate. Because the carbon atom bonded to the asymmetric carbon is bonded to another atom by a multiple bond, the asymmetric carbon may be bonded to an alkenyl group, alkynyl group, aryl group, heteroaryl group, or the like.

Alcohol



[0018] The alcohol used in the production method of the present invention is shown by formula (a) below.



[0019] In the above formula (a), Ra represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group which may have a substituent group. As the substituent group of Ra, an alkyl group, alkoxy group, aryl group, halogen atom and the like may be mentioned. In particular, as Ra, the 2-tolyl group, 1-naphthyl group, and 9-phenanthryl group are preferable. By using such an alcohol, it is possible to produce an optically active ester and optically active carboxylic acid with a high enantiomer selectivity rate.

Phenol Derivative



[0020] The phenol derivative used in the production method of the present invention is shown by the formula (b) below.



[0021] In the above formula (b), Rb represents preferably a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group. As the substituent group of Rb, an alkyl group, alkoxy group, aryl group, halogen atom and the like can be mentioned. Further, n represents an integer of 1 to 5, and n = 2 is preferable. In the case that a plurality of Rb are present, they may be the same or different. Among these phenol derivatives, one where the 2,6 positions of the phenol are substituted with naphthyl groups is preferable.

Benzoic Anhydride or its Derivative



[0022] The benzoic anhydride or its derivative used in the production method of the present invention functions as a dehydrating condensing agent. As the derivative of the benzoic anhydride, one obtained from benzoic acid where an electron-donating group such as an alkyl group, alkoxy group, amino group, hydroxyl group or the like is bonded to the phenyl group is preferable, and one obtained from a 1 to 3 substituted benzoic acid group with alkyl groups or alkoxy groups of 1 to 3 carbons bonded thereto is more preferable.

Catalyst



[0023] The catalyst used in the production method of the present invention is shown by the below formulae (c) to (f).



[0024] In the above formulae (c) to (f), X represents any of the substituent groups below. R represents a protecting group such as an alkyl group, acyl group, silyl group, or the like.



        -(CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR





[0025] Among the catalysts shown by formulae (c) to (f) above, the catalyst shown by the above formula (d), when X is a phenyl group, is known as tetramisole, and the catalyst shown by the above formula (e), when X is a phenol group, is known as benzotetramisole. These catalysts are commercially available, and can also be synthesized using an amino acid as the side chain of the substituent group shown by X.

Reaction Conditions and the Like



[0026] The production of the optically active ester and the optically active carboxylic acid is carried out by adding a racemic carboxylic acid, an alcohol or a phenol derivative, a benzoic anhydride or its derivative, and the catalyst to the solvent. As the solvent, dichloromethane, chlorobenzene or the like can be mentioned. Further, in order to neutralize the acid originating from the benzoic anhydride or its derivative generated as the reaction progresses, it is preferable to add a base into the reaction system. As this base, an organic base not having nucleophilicity (trimethylamine, triethylamine, diisopropylethylamine) is preferable.

[0027] The sequence of addition into the solvent is arbitrary, but it is preferable to add the base, catalyst, and alcohol or phenol derivative in order to the solution containing the racemic carboxylic acid and the benzoic anhydride or its derivative.

[0028] The respective addition amounts are not particularly limited, but are preferably, with respect to the racemic carboxylic acid, 0.5 to 1.0 equivalents of the alcohol or phenol derivative, 0.5 to 1.5 equivalents of the benzoic anhydride or its derivative, 1.0 to 3.0 equivalents of the base, and 0.1 to 10 mol% of the catalyst.

[0029] The reaction temperature is preferably -23 to 30°C, and the reaction time is preferably 10 min to 48 hr.

EXAMPLES



[0030] Hereinafter, the present invention is explained more detail by way of Examples.

Experimental Example 1: Production of Optically Active Ester and Optically Active Carboxylic Acid Using a Variety of Alcohols



[0031] 



[0032] As shown in the above reaction equation, by adding at room temperature in order, 2.4 eq of diisopropylethylamine to a dichloromethane solution including 1.2 eq of benzoic anhydride (Bz2O) and 1.0 eq racemic 2-phenylpropionic acid, and 5 mol% benzotetramisole (BTM) with respect to the carboxylic acid, and 0.75 eq of alcohol, after stirring the reaction mixture solution for a predetermined time at room temperature, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 3 or 4 times with diethylether or dichloromethane. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ester and a part of the unreacted optically active carboxylic acid. Then 1 M hydrochloric acid was added to the water layer, and after adjusting the pH to 2, extraction was carried out 4 times with diethyl ether or dichloromethane. After-treatment was carried out in the same way as above, and unreacted optically active carboxylic acid was further recovered, and added to the previously obtained optically active carboxylic acid. The results are shown in Table 1.

[0033] The enantiomeric excess ratio ee was measured by the HPLC analysis method with a chiral column. Further, the reaction rate ratio s was calculated as s = [ln(1-C)(1-ee of product))]/[ln(1-C)(1+ee of product)], according to the method of Kagan (Top. Stereochem., 1988, 18, pp. 249-330).
Table 1
No.R1R2TimeYield of 1a/% (1a/1c)Yield of 1b/%ee/% 1a/1bs
1 Ph H 12 h 40 (8/1) 60 33/23 2
2 c-Hex 3 d 39 (23/1) 31 0/3 1
3 Ph Ph 12 h 42 (99/1) 37 33/19 2
4 2-MeC6H4 2-MeC6H4 6 h 32 (85/1) 39 89/34 24
5 Bn Bn 16 h 12 (>99/1) 5 3/0.03 1
6 1-Nap 1-Nap 4 h 40 (46/1) 6 82/52 17
7 2-Nap 2-Nap 11 h 51 (>99/1) 1 26/37 2
8 9-Phe 9-Phe 40 m 31 (>99/1) 33 84/28 15


[0034] As can be understood from Table 1, when using as an alcohol 1,1-di(2-tolyl)methanol, 1,1-diphenylmethanol, 1,1-di(1-naphthyl)methanol, 1,1-di(2-napthyl)methanol, or 1,1-di(9-phenanthryl)methanol (Entries 3, 4, and 6 to 8), in particular 1,1-di(2-tolyl)methanol, 1,1-di(1-naphthyl)methanol, or 1,1-di(9-phenanthryl)methanol, it is possible to obtain the optically active esters and optically active carboxylic acids with a higher enantiomeric selectivity rates than for the case of using other alcohols (Entries 1,2, and 5).

Experimental Example 2: Production of Optically Active Ester and Optically Active Carboxylic Acid Using Various Phenol Derivatives



[0035] 



[0036] As shown in the above reaction equation, by adding at room temperature in order, 2.4 eq of diisopropylethylamine to a dichloromethane solution including 1.2 eq of benzoic anhydride (Bz2O) and 1.0 eq racemic 2-phenylpropionic acid, and 5 mol% benzotetramisole (BTM) with respect to the carboxylic acid, and 0.75 eq of phenol derivative, after stirring the reaction mixture solution for a predetermined time at room temperature, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with dichloromethane. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ester and a part of the unreacted optically active carboxylic acid. Then 1 M hydrochloric acid was added to the water layer, and after adjusting the pH to 2, extraction was carried out 4 times with dichloromethane. After-treatment was carried out in the same way as above, and unreacted optically active carboxylic acid was further recovered, and added to the previously obtained optically active carboxylic acid. The results are shown in Table 2.
Table 2
No.R3nTimeYield of 2a/% (2a/2c)Yield of 2b/%ee/% 2a/2bs
9 2-Me 9 h 48 (3.4/1) 11 15/11 2
10 2-MeO 9 d 60 (6.3/1) 9 16/17 2
11 2-(2'-C6H4OH) 13 h 17 (3.6/1) 21 41/19 3
12 2,6-Me2 12 h 12 (0.6/1) 5 45/9 3
13 2,6-Ph2 15 h 19 (0.8/1) 36 58/8 4
14 2,6-(1-Nap)2 8 h 14 (1.2/1) 31 77/15 9
15 2,6-(2-Nap)2 3 h 29 (0.7/1) 43 64/23 6


[0037] As can be understood from Table 2, when using as a phenol derivative 2,6-di(1-naphthyl)phenol or 2,6-di(2-naphthyl)phenol (Entries 14 and 15), it is possible to obtain the optically active esters and optically active carboxylic acids with a higher enantiomeric excess ratios ee and reaction rate ratios than for the case of using other phenol derivatives (Entries 9 to 13).

Experimental Example 3: Production of Optically Active Ester and Optically Active Carboxylic Acid Using 1,1-di(1-naphthyl)methanol



[0038] 



[0039] As shown in the above reaction equation, an optically active ester and optically active carboxylic acid were obtained by reacting 1,1-di(1-naphthyl)methanol and various racemic carboxylic acids. The results are shown in Table 3.
Table 3
No.R4R5Acid AnhydrideTimeYield of 3a/%Yield of 3b/%ee/% 3a/3bs
16 Me H PMBA 12 h 36 39 91/52 36
17 Me H Bz2O 6 h 45 29 89/48 27
18 Me Me PMBA 12 h 37 31 83/45 17
19 Me Me Bz2O 6 h 30 23 85/28 16
20 Me OMe PMBA 12 h 44 35 86/47 21
21 Me OMe Bz2O 6 h 49 29 84/65 22
22 Me Cl PMBA 12 h 48 33 83/46 17
23 Me Cl Bz2O 6 h 52 26 83/27 14
24 Et H PMBA 12 h 45 40 67/40 7.5
25 Et H Bz2O 6 h 46 29 39/30 3.0
26 CH2Ph H PMBA 12 h 55 37 58/41 5.5
27 CH2Ph H Bz2O 6 h 48 28 73/43 10


[0040] As can be understood from Table 3, when using 1,1-di(1-naphthyl)methanol as the alcohol, optically active esters and optically active carboxylic acids were obtained with high enantiomer excess ratios ee and reaction rate ratios s, and high enantiomer selectivity rates.

[0041] Below, the production method and identification results of optically active esters and optically active carboxylic acids of Table 3 are shown.

Entry 16



[0042] To a dichloromethane solution (1.5 mL) containing p-methoxybenzoic anhydride (PMBA) (103.0 mg, 0.360 mmol) and racemic 2-phenylpropionic acid (45.1 mg, 0.300 mmol); diisopropylethylamine (94.0 µL, 0.540 mmol), benzotetramisole (3.8 mg, 0.015 mmol), and 1,1-di(1-naphthyl)methanol (42.8 mg, 0.151 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 12 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with diethyl ether. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ester (45.0 mg, 36%, 91% ee) and a part of the unreacted optically active carboxylic acid. Then 1 M hydrochloric acid was added to the water layer, and after adjusting the pH to 2, extraction was carried out 4 times with diethyl ether. After-treatment was carried out in the same way as above, and unreacted optically active carboxylic acid was further recovered, and added to the previously obtained optically active carboxylic acid (17.5 mg, 39%, 52% ee).

di-(1-naphthyl)methyl (R)-2-phenylpropanoate



[0043] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 1.0 mL/min): tR = 13.8 min (4.4%), tR = 18.3 min (95.6%);
Mp: 128°C (i-PrOH/hexane);
IR (KBr): 3067, 1728, 1600, 1509, 776, 699 cm-1;
1H NMR (CDCl3) : δ8.29 (s, 1H, 1'-H), 7.99 - 7.94 (m, 1H, Ph), 7.84 - 7.79 (m, 1H, Ph), 7.74 (t, J = 7.0 Hz, 2H, Ph), 7.68 (d, J = 8.0 Hz, 1H, Ph), 7.63 (d, J = 8.5 Hz, 1H, Ph), 7.45 - 7.38 (m, 2H, Ph), 7.35 - 7.31 (m, 1H, Ph), 7.23 - 7.14 (m, 7H, Ph), 7.11 (t, J = 7.5 Hz, 1H, Ph), 7.06 (d, J = 7.5 Hz, 1H, Ph), 6.90 (d, J = 7.0 Hz, 1H, Ph), 3.77 (q, J = 7.0 Hz, 1H, 2-H), 1.45 (d, J = 7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.5, 140.0, 134.8, 134.6, 133.8, 133.7, 131.2, 130.8, 129.1, 128.9, 128.7, 128.64, 128.57, 127.8, 127.2, 126.7, 126.4, 126.3, 125.9, 125.6, 125.2, 125.0, 123.5, 123.3, 71.1, 45.6, 18.2;
HR MS: calculated for C30H24O2Na (M + Na+) = 439.1669; found 439.1668.

(S)-2-phenylpropionic acid



[0044] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05 flow rate = 0.5 mL/min): tR = 39.6 min (24.1%), tR = 43.4 min (75.9%);
1H NMR (CDCl3) : δ10.95 (br s, 1H, COOH), 7.30 - 7.16 (m, 5H, Ph), 3.67 (q, J = 7.2 Hz, 1H, 2-H), 1.45 (d, J = 7.2 Hz, 3H, 3-H).

Entry 18


di-(1-naphthyl)methyl (R)-2-(4-tolyl)propanoate



[0045] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min): tR = 9.5 min (7.6%), tR = 13.4 min (92.4%);
IR (neat): 3051, 1733, 1598, 1512, 801, 777, 732 cm-1;
1H NMR (CDCl3): δ8.27 (s, 1H, 1'-H), 7.98 - 7.91 (m, 1H, Ph), 7.83 - 7.76 (m, 1H, Ph), 7.72 (t, J = 8.2 Hz, 2H, Ph), 7.66 (d, J = 8.2 Hz, 1H, Ph), 7.62 (d, J = 8.6 Hz, 1H, Ph), 7.44 - 7.36 (m, 1H, Ph), 7.31 (t, J = 7.5 Hz, 1H, Ph), 7.22 - 7.14 (m, 2H, Ph), 7.13 - 7.01 (m, 4H, Ph), 6.97 (d, J = 7.9 Hz, 2H, Ph), 6.92 (d, J = 7.5 Hz, 1H, Ph), 3.72 (q, J = 7.0, 1H, 2-H), 2.25 (s, 3H, Me), 1.42 (d, J = 7.0, 3H, 3-H);
13C NMR (CDCl3): δ173.7, 137.0, 136.7, 134.9, 134.6, 133.8, 133.7, 131.2, 130.9, 129.2, 129.1, 128.8, 128.7, 128.6, 128.3, 127.6, 126.7, 126.3, 126.2, 125.8, 125.6, 125.3, 125.2, 125.0, 123.5, 123.3, 71.1, 45.2, 21.0, 18.2;
HR MS: calculated for C31H26O2 (M + Na+) = 453.1825; found 453.1816.

(S)-2-(4-tolyl)propionic acid



[0046] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.5 mL/min); tR = 43.2 min (23.0%), tR = 46.7 min (77.0%);
1H NMR (CDCl3) : δ10.63 (br s, 1H, COOH), 7.13 (d, J = 7.8, 2H, Ph), 7.07 (d, J = 7.8, 2H, Ph), 3.63 (q, J = 7.0 Hz, 1H, 2-H), 2.26 (s, 3H, Me), 1.42 (d, J = 7.0 Hz, 3H, 3-H).

Entry 20



[0047] di(1-naphthyl)methyl (R)-2-(4-methoxyphenyl)propanoate
HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/min); tR = 10.5 min (7.2%), tR = 12.8 min (85.6%);
IR (neat): 3059, 1733, 1608, 1512, 783, 733 cm-1;
1H NMR (CDCl3): δ8.26 (s, 1H, 1'-H), 7.97 - 7.89 (m, 1H, Ph), 7.85 - 7.58 (m, 5H, Ph), 7.46 - 7.04 (m, 8H, Ph), 6.93 (d, J = 6.9 Hz, 1H, Ph), 6.75 - 6.67 (m, 2H, Ph), 3.78 - 3.68 (m, 4H, 2-H, OMe), 1.42 (d, J = 6.9 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.7, 158.7, 134.8, 134.6, 133.8, 133.6, 132.1, 131.2, 130.9, 129.1, 128.83, 128.76, 128.7, 128.6, 128.3, 126.7, 126.3, 126.2, 125.8, 125.6, 125.3, 125.2, 125.0, 123.5, 123.3, 113.9, 71.0, 55.3, 44.8, 18.2;
HR MS: calculated for C31H26O2Na (M + Na+) = 469.1774; found 469.1754.

(S)-2-(4-methoxyphenyl)propionic acid



[0048] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min); tR = 34.7 min (17.5%), tR = 36.4 min (82.5%);
1H NMR (CDCl3) : δ10.99 (br s, 1H, COOH), 7.17 (d, J = 8.7 Hz, 2H, Ph), 6.79 (d, J = 8.7 Hz, 2H, Ph), 3.72 (s, 3H, OMe), 3.61 (q, J = 7.2 Hz, 1H, 2-H), 1.42 (d, J = 7.2 Hz, 3H, 3-H).

Entry 22


di(1-naphthyl)methyl (R)-2-(4-chlorophenyl)propanoate



[0049] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/min); tR = 17.1 min (8.4%), tR = 19.3 min (91.6%);
IR (neat): 3052, 1737, 1599, 1510, 837, 777 cm-1;
1H NMR (CDCl3): δ8.26 (d, J = 3.0 Hz, 1H, 1'-H), 7.90 (dd, J = 7.5, 3.0 Hz, 1H, Ph), 7.81 (d, J = 7.5 Hz, 1H, Ph), 7.75 (t, J = 8.5 Hz, 2H, Ph), 7.70 (d, J = 8.0 Hz, 1H, Ph), 7.62 (dd, J = 8.5, 3.0 Hz, 1H, Ph), 7.45 - 7.32 (m, 3H, Ph), 7.26 - 7.04 (m, 8H, Ph), 6.93 (dd, J = 7.0, 3.0 Hz, 1H, Ph), 3.73 (qd, J = 8.5, 1.5 Hz, 1H, 2-H), 1.45 - 1.41 (m, 3H, 3-H);
13C NMR (CDCl3): δ173.1, 138.4, 134.5, 134.4, 133.8, 133.7, 133.0, 131.1, 130.8, 129.2, 129.1, 128.9, 128.7, 128.6, 128.3, 126.7, 126.4, 126.1, 125.9, 125.7, 125.3, 125.2, 124.5, 123.3, 123.2, 71.4, 45.0, 18.0;
HR MS: calculated for C30H23O2ClNa (M + Na+) = 473.1279; found 473.1284.

(S)-2-(4-chlorophenyl)propionic acid



[0050] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min); tR = 31.7 min (21.4%), tR = 34.0 min (78.6%);
1H NMR (CDCl3) : δ9.15 (br s, 1H, COOH), 7.39 - 7.09 (m, 4H, Ph), 3.69 (q, J = 7.0 Hz, 1H, 2-H), 1.48 (d, J = 7.0 Hz, 3H, 3-H).

Entry 24


di(1-naphthyl)methyl (R)-2-phenylbutanoate



[0051] HPLC of 2-phenylbutan-1-ol derived from the title compound (CHIRALPAK AS-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min); tR = 16.0 min (16.4%), tR = 17.4 min (83.6%);
IR (neat): 3034, 1734, 1599, 1510, 779, 679 cm-1;
1H NMR (CDCl3) : δ8.28 (s, 1H, 1'-H), 7.94 (d, J = 7.6 Hz, 1H, Ph), 7.82 - 7.76 (m, 1H, Ph), 7.71 (dd, J = 8.3, 3.5 Hz, 2H, Ph), 7.64 (d, J = 8.3 Hz, 1H, Ph), 7.59 (d, J = 8.3 Hz, 1H, Ph), 7.43 - 7.34 (m, 2H, Ph), 7.33 - 7.26 (m, 1H, Ph), 7.20 - 7.11 (m, 7H, Ph), 7.10 - 7.02 (m, 2H, Ph), 6.88 (d, J = 6.5, 1H, Ph), 3.50 (t, J = 7.5 Hz, 1H, 2-H), 2.13 - 2.02 (m, 1H, 3-H), 1.78 - 1.67 (m, 1H, 3-H), 0.79 (t, J = 7.3 Hz, 3H, 4-H);
13C NMR(CDCl3): δ173.0, 138.5, 134.8, 134.5, 133.8, 133.6, 131.2, 130.8, 129.1, 128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 127.2, 126.7, 126.3, 126.2, 125.8, 125.6, 125.2, 125.0, 133.5, 123.3, 71.0, 53.5, 26.1, 12.2;
HR MS: calculated for C31H26O2Na (M + Na+) = 453.1825; found 453.1834.

(S)-2-phenylbutanoic acid



[0052] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min); tR = 20.0 min (30.0%), tR = 22.8 min (70.0%);
1H NMR (CDCl3) : δ10.28 (br s, 1H, COOH), 7.31 - 7.14 (m, 5H, Ph), 3.39 (t, J = 7.5 Hz, 1H, 2-H), 2.13 - 1.93(m, 1H, 3-H), 1.82 - 1.62 (m, 1H, 3-H), 0.83 (t, J = 7.5 Hz, 3H, 4-H).

Entry 26


di(1-naphthyl)methyl (R)-2,3-diphenylpropanoate



[0053] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min); tR = 12.3 min (13.5%), tR = 23.1 min (86.5%);
IR (neat): 3033, 1736, 1600, 1511, 780, 678 cm-1;
1H NMR (CDCl3): δ8.15 (s, 1H, 1'-H), 7.78 - 7.56 (m, 5H, Ph), 7.49 (t, J = 8.3Hz, 1H, Ph), 7.38 - 7.14 (m, 11H, Ph), 7.13 - 6.94 (m, 5H, Ph), 6.76 (dd, J=7.5 Hz, 1H, Ph), 7.06 (d , J = 10.5, 7.0Hz, 1H, Ph), 3.94 (dd, J = 10.0, 5.5 Hz, 1H, 2-H), 3.40 (dd, J = 13.7, 10.0 Hz, 1H, 3-H), 2.92 (dd, J = 13.7, 5.5 Hz, 1H, 3-H);
13C NMR(CDCl3): δ172.4, 139.0, 138.2, 134.35, 134.30, 133.7, 133.6, 131.0, 130.8, 129.0, 128.9, 128.68, 128.63, 128.57, 128.4, 128.3, 128.1, 127.5, 126.7, 126.33, 126.31, 126.0, 125.7, 125.6, 125.20, 124.97, 123.4, 123.3, 71.4, 53.6, 39.2;
HR MS: calculated for C36H28O2Na (M + Na+) = 515.1982, found 515.1963.

(S)-2,3-diphenylpropionic acid



[0054] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/10/0.01, flow rate = 0.75 mL/min); tR = 12.5 min (21.9%), tR = 15.5 min (78.1%);
1H NMR (CDCl3) : δ10.35 (br s, 1H, COOH), 7.28 - 6.98 (m, 10H, Ph), 3.78 (dd, J = 8.2, 7.0 Hz, 1H, 2-H), 3.33 (dd, J = 13.8, 8.2 Hz, 1H, 3-H), 2.96 (dd, J = 13.8, 7.0 Hz, 1H, 3-H).

Experimental Example 4: Production of Optically Active Ester and Optically Active Carboxylic Acid Using 1,1-di(9-phenanthryl)methanol



[0055] 



[0056] As shown in the above reaction equation, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(9-phenanthryl)methanol and various racemic carboxylic acids. The results are shown in Table 4.
Table 4
No.R6R7Acid AnhydrideTimeYield of 4a/%Yield of 4b/%ee/% 4a/4bs
28 Me H PMBA 12 h 42 42 91/52 37
29 Me H Bz2O 6 h 42 33 89/48 27
30 Me Me PMBA 12 h 41 44 85/44 19
31 Me Me Bz2O 6 h 42 19 87/54 24
32 Me OMe PMBA 12 h 39 42 82/49 16
33 Me OMe Bz2O 6 h 36 25 78/48 13
34 Me Cl PMBA 12 h 47 43 80/57 16
35 Me Cl Bz2O 6 h 53 24 80/54 15
36 Et H PMBA 12 h 25 63 76/16 8. 5
37 Et H Bz2O 6 h 28 27 87/15 17
38 CH2Ph H PMBA 12 h 40 52 86/42 21
39 CH2Ph H Bz2O 6 h 47 30 87/56 25


[0057] As can be understood from Table 4, when 1,1-di(9-phenanthryl)methanol is used as the alcohol, the enantiomer excess ratios ee and the reaction rate ratios s become high, and optically active esters and optically active carboxylic acids are obtained with a high enantiomer selectivity rate.

[0058] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 4 are shown.

Entry 28



[0059] To a dichloromethane solution (2.0 mL) containing p-methoxybenzoic anhydride (68.7 mg, 0.240 mmol) and racemic 2-phenylpropionic acid (30.0 mg, 0.200 mmol); diisopropylethylamine (62.7 µL, 0.360 mmol), benzotetramisole (2.5 mg, 0.010 mmol), and 1,1-di(9-phenanthryl)methanol (38.4 mg, 0.100 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 12 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with dichloromethane. After mixing the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ester (43.3 mg, 42%, 91% ee) and a part of the unreacted optically active carboxylic acid. Then 1 M hydrochloric acid was added to the water layer, and after adjusting the pH to 2, extraction was carried out 4 times with dichloromethane. After-treatment was carried out in the same way as above, and unreacted optically active carboxylic acid was further recovered, and added to the previously obtained optically active carboxylic acid (12.4 mg, 42%, 52% ee).

di-(9-phenanthryl)methyl (R)-2-phenylpropanoate



[0060] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.5 mL/mi): tR = 30.0 min (95.6%), tR = 34.2 min (4.4%);
IR (KBr): 3064, 1731, 1495, 1451, 1163, 749, 726 cm-1;
1H NMR (CDCl3) : δ8.82 - 8.59 (m, 4H, Ph), 8.42 (s, 1H, 1'-H), 8.20 - 8.11 (m, 1H, Ph), 7.84 - 7.25 (m, 18H, Ph), 3.91 (q, J = 7.2 Hz, 1H, 2-H), 1.56 (d, J = 7.2 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.5, 140.1, 132.9, 132.7, 131.1, 130.9, 130.7, 130.6, 130.5, 130.2, 129.8, 129.1, 128.8, 127.9, 127.4, 127.3, 127.2, 127.0, 126.9, 126.7, 126.5, 126.4, 126.2, 124.2, 123.9, 123.4, 123.1, 122.4, 122.4, 71.0, 45.7, 18.1.

Entry 30


di-(9-phenanthryl)methyl (R)-2-(4-tolyl)propanoate



[0061] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/mi): tR = 26.7 min (93.3%), tR = 40.4 min (6.7%);
IR (KBr): 3068, 1732, 1451, 1154, 750, 726 cm-1;
1H NMR (CDCl3) : δ8.81 - 8.53 (m, 4H, Ph), 8.42 (s, 1H, 1'-H), 8.25 - 8.10 (m, 1H, Ph), 7.83 - 7.05 (m, 17H, Ph), 3.85 (q, J = 6.9 Hz, 1H, 2-H), 2.40 (s, 3H, Me), 1.53 (d, J = 6.9 Hz, 3H, 3-H);
13C NMR (CDCl3) : δ173.6, 137.2, 137.0, 132.9, 132.7, 131.1, 131.1, 130.9, 130.7, 130.5, 130.2, 129.8, 129.5, 129.1, 129.1, 128.3, 128.0, 127.8, 127.3, 127.2, 127.0, 126.9, 126.6, 126.4, 126.4, 126.2, 124.3, 124.0, 123.4, 123.1, 122.4, 122.4, 70.8, 45.3, 21.1, 18.0.

Entry 32


di(9-phenanthryl)methyl (R)-2-(4-methoxyphenyl)propanoate



[0062] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 1.0 mL/mi): tR = 22.6 min (9.0%), tR = 26.3 min (91.0%);
IR (KBr): 3075, 1733, 1511, 1451, 1248, 1032, 750, 726 cm-1;
1H NMR (CDCl3): δ8.84 - 8.64 (m, 4H, Ph), 8.40 (s, 1H, 1'-H), 8.18 - 8.12 (m, 1H, Ph), 7.80 - 7.35 (m, 12H, Ph), 7.30 - 7.19 (m, 3H, Ph), 6.88 - 6. 82 (m, 2H, Ph), 3.86 (q, J = 7.2 Hz, 1H, 2-H), 3.84 (s, 3H, OMe), 1.54 (d, J = 7.2 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.0, 158.9,1 33.0, 132.8, 132.2, 131.1, 131.0, 130.7, 130.6, 130.5, 130.3, 129.9, 129.1, 129.1, 129.0, 127.9, 127.3, 127.2, 127.0, 126.9, 126.7, 126.5, 126.4, 126.3, 124.3, 124.0, 123.4, 123.1, 122.5, 122.4, 114.2, 70.9, 55.3, 44.9, 18.1.

Entry 34


di(9-phenanthryl)methyl (R)-2-(4-chlorophenyl)propanoate



[0063] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.5 mL/mi): tR = 37.4 min (10.1%), tR = 46.4 min (89.8%);
IR (KBr): 3067, 1735, 1493, 1451, 1151, 750, 726 cm-1;
1H NMR (CDCl3): δ8.87 - 8.63 (m, 4H, Ph), 8.40 (s, 1H, 1'-H), 8.17 - 8.09 (m, 1H, Ph), 7.80 - 7.20 (m, 17H, Ph), 3.89 (q, J = 7.2 Hz, 1H, 2-H), 1.55 (d, J = 7.2 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.0, 138.5, 133.3, 132.6, 132.5, 131.0, 130.9, 130.9, 130.6, 130.6, 130.4, 130.1, 129.7, 129.2, 129.1, 129.0, 128.3, 127.9, 127.3, 127.1, 126.9, 126.7, 126.5, 126.2, 124.1, 123.8, 123.4, 123.2, 122.4, 122.4, 71.1, 45.1, 17.9.

Entry 36


di(9-phenanthryl)methyl (R)-2-phenylbutanoate



[0064] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.5 mL/mi): tR = 23.4 min (93.5%), tR = 29.6 min (6.5%);
IR (KBr): 3057, 1727, 1450, 1359, 1154, 755, 727 cm-1;
1H NMR (CDCl3) : δ8.84 - 8.53 (m, 4H, Ph), 8.32 (s, 1H, 1'-H), 8.11 - 7.98 (m, 1H, Ph), 7.76 - 7.14 (m, 18H, Ph), 3.60 (dd, J = 7.7, 7.7 Hz, 1H, 2-H), 2.22 - 2.04 (m, 1H, 3-H), 1.84 - 1.63 (m, 1H, 3-H), 0.87 (t, J = 7.2 Hz, 3H, 4-H).

Entry 38


di(9-phenanthryl)methyl (R)-2,3-diphenylpropanoate



[0065] HPLC of 2,3-diphenylpropan-1-ol derived from the title compound (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/mi): tR = 14.7 min (93.4%), tR = 18.7 min (6.6%);
IR (KBr): 3064, 1723, 1495, 1451, 1145, 748, 726 cm-1;
1H NMR (CDCl3) : δ8.79 - 8.55 (m, 4H, Ph), 8.29 (s, 1H, 1'-H), 7.90 - 7.80 (m, 1H, Ph), 7.71 - 7.10 (m, 23H, Ph), 4.10 (dd, J = 10.0, 5.4 Hz, 1H, 2-H), 3.54 (dd, J = 13.9, 10.0 Hz, 1H, 3-H), 3.02 (dd, J = 13.9, 5.4 Hz, 1H, 3-H);
13C NMR (CDCl3): δ172.3, 139.1, 138.4, 132.6, 132.5, 131.0, 131.0, 130.8, 130.6, 130.6, 130.4, 130.1, 129.7, 129.2, 129.1, 129.0, 128.9, 128.4, 128.3, 128.3, 127.9, 127.6, 127.3, 127.2, 127.0, 126.9, 126.9, 126.6, 126.5, 126.4, 126.4, 126.1, 124.3, 123.9, 123.3, 123.1, 122.4, 122.3, 71.3, 53.7, 39.3.

Experimental Example 5: Production of Optically Active Ester and Optically Active Carboxylic Acid Using 2,6-di(1-naphthyl)phenol and 2,6-di(2-naphthyl)phenol



[0066] 



[0067] As shown by the above reaction equation, an optically active ester and optically active carboxylic acid are obtained by reacting 2,6-di(1-naphthyl)phenol and 2,6-di(2-naphthyl)phenol and racemic 2-phenolpropionic acid. The results are shown in Table 5.
Table 5
No.R8nAcid AnhydrideTimeYield of 5a/%Yield of 5b/%ee/% 5a/5bs
40 2,6-(1-Nap) 2 PMBA 4 h 21 58 86/18 16
41 2,6-(1-Nap) 2 Bz2O 8 h 14 31 77/15 9
42 2,6-(2-Nap) 2 PMBA 3 h 15 71 67/11 6
43 2,6-(2-Nap) 2 Bz2O 3 h 29 43 64/23 6


[0068] As can be understood from Table 5, when 2,6-di(1-naphthyl)phenol and 2,6-di(2-naphthyl)phenol are used as a phenol derivative, in particular when 2,6-di(1-naphthyl)phenol is used as the phenol derivative and and p-methoxybenzoic anhydride is used as the acid anhydride (Entry 40), the enantiomer excess ratios ee and the reaction rate ratios s become high, and an optically active ester and optically active carboxylic acid are obtained with a high enantiomer selectivity rate.

[0069] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 5 are shown.

Entry 40



[0070] To a dichloromethane solution (1.5 mL) containing p-methoxybenzoic anhydride (103.1 mg, 0.360 mmol) and racemic 2-phenylpropionic acid (45.0 mg, 0.300 mmol); diisopropylethylamine (130.0 µL, 0.720 mmol), benzotetramisole (3.8 mg, 0.015 mmol), and 2,6-di(1-naphthyl)phenol (77.9 mg, 0.225 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 4 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with dichloromethane. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ester (29.8 mg, 21%, 86% ee) and a part of the unreacted optically active carboxylic acid. Then 1 M hydrochloric acid was added to the water layer, and after adjusting the pH to about 2, extraction was carried out 4 times with dichloromethane. After-treatment was carried out in the same way as above, and unreacted optically active carboxylic acid was further recovered, and added to the previously obtained optically active carboxylic acid (26.2 mg, 58%, 18% ee).

2,6-di(1-naphthyl)phenyl (R)-2-phenylpropanoate



[0071] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.3 mL/min); tR = 29.6 min (93.0%), tR = 33.6 min (7.0%);
1H NMR (CDCl3) : δ7.92 - 7.65 (m, 6H, Ph), 7.55 - 7.29 (m, 11H, Ph), 7.02 - 6.69 (m, 3H, Ph), 6.27 - 6.10 (m, 2H, Ph), 2.75 (qd, J = 7.2, 6.9 Hz, 1H, 2-H), 0.39 (dq, J = 8.7, 7.2 Hz, 3H, 3-H).

Entry 42



[0072] To a dichloromethane solution (1.5 mL) containing p-methoxybenzoic anhydride (103.1 mg, 0.360 mmol) and racemic 2-phenylpropionic acid (45.0 mg, 0.300 mmol); diisopropylethylamine (130.0 µL, 0.720 mmol), benzotetramisole (3.8 mg, 0.015 mmol), and 2,6-di(2-naphthyl)phenol (77.9 mg, 0.225 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 3 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with dichloromethane. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ester (21.7 mg, 15%, 67% ee) and a part of the unreacted optically active carboxylic acid. Then 1 M hydrochloric acid was added to the water layer, and after adjusting the pH to about 2, extraction was carried out 4 times with dichloromethane. After-treatment was carried out in the same way as above, and unreacted optically active carboxylic acid was further recovered, and added to the previously obtained optically active carboxylic acid (31.5 mg, 71%, 11% ee).

2,6-di(2-naphthyl)phenyl (R)-2-phenylpropanoate



[0073] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 1.0 mL/min); tR = 21.3 min (16.3%), tR = 23.9 min (83.7%);
1H NMR (CDCl3) : δ7.93 - 7.65 (m, 8H, Ph), 7.56 - 7.39 (m, 8H, Ph), 7.25 (s, 1H, Ph), 6.95 - 6.85 (m, 1H, Ph), 6.79 - 6.70 (m, 2H, Ph), 6.67 - 6.58 (m, 2H, Ph), 3.35 (q, J = 7.2 Hz, 1H, 2-H), 0.95 (d, J = 7.2 Hz, 3H, 3-H).

Experimental Example 6: Production of Optically Active Ester and Optically Active Carboxylic Acid Using Ibuprofen (Optical Resolution of Ibuprofen)



[0074] 



[0075] As shown by the above reaction equation, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(1-naphthyl)methanol or 1,1-di(9-phenanthryl)methanol and racemic ibuprofen. The results are shown in Table 6.
Table 6
No.R9Acid AnhydrideTimeYield of 6a/%Yield of 6b/%ee/% 6a/6bs
44 1-Nap PMBA 12 h 39 33 92/36 34
45 1-Nap Bz2O 6 h 43 26 89/55 30
46 9-Phen PMBA 12 h 39 30 89/49 27
47 9-Phen Bz2O 6 h 36 33 90/42 27


[0076] As can be understood from Table 6, both when using 1,1-di(1-naphthyl)methanol and when using 1,1-di(9-phenanthryl)methanol as the alcohol, ibuprofen is optically resolved with a high enantiomer selectivity, and an optically active ester and optically active carboxylic acid are obtained.

[0077] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 6 are shown.

Entry 44



[0078] To a dichloromethane solution (1.0 mL) containing p-methoxybenzoic anhydride (68.9 mg, 0.241 mmol) and racemic ibuprofen (41.2 mg, 0.200 mmol); diisopropylethylamine (62.7 µL, 0.360 mmol), benzotetramisole (2.5 mg, 0.010 mmol), and 1,1-di(1-naphthyl)methanol (28.4 mg, 0.100 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 12 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with diethylether. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ibuprofen ester (36.9 mg, 39%, 92% ee) and the unreacted optically active ibuprofen (13.6 mg, 33%, 36% ee).

(R)-ibuprofen di(1-naphthyl)methylester



[0079] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/mi): tR = 6.1 min (4.1%), tR = 10.7 min (95.9%);
IR (neat): 3036, 1735, 1599, 1512, 782, 679 cm-1;
1H NMR (CDCl3): δ8.29 (s, 1H, 1"-H), 8.02 - 7.93 (m, 1H, Ph), 7.85 - 7.60 (m, 5H, Ph), 7.47 - 7.26 (m, 3H, Ph), 7.24 - 7.02 (m, 6H, Ph), 7.00 - 6.88 (m, 3H, Ph), 3.74 (q, J = 7.1 Hz, 1H, 2-H), 2.38 (d, J = 7.1 Hz, 2H, 1'-H), 1.78 (qq, J = 6.6, 6.6 Hz, 1H, 2'-H), 1.43 (d, J = 7.1 Hz, 3H, 3-H), 0.84 (d, J = 6.6Hz, 6H, 3'-H);
13C NMR (CDCl3): δ173.7, 140.6, 137.2, 134.9, 134.7, 133.8, 133.7, 131.2, 130.9, 129.3, 129.1, 128.8, 128.7, 128.6, 127.5, 126.7, 126.3, 125.8, 125.6, 125.2, 125.0, 123.5, 123.4, 70.9, 45.3, 45.0, 30.2, 22.4, 18.1;
HR MS: calculated for C34H32O2Na (M + Na+) = 495.2295; found 495.2276.

(S)-ibuprofen



[0080] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/100/0.1, flow rate = 1.0 mL/min); tR = 26.3 min (77.5%), tR = 28.5 min
(22.5%);
1H NMR (CDCl3) : δ10.30 (br s, 1H, COOH), 7.14 (d, J = 7.9 Hz, 2H, Ph), 7.02 (d, J = 7.9 Hz, 2H, Ph), 3.63 (q, J = 7.3 Hz, 1H, 2-H), 2.37 (q, J = 7.3 Hz, 2H, 1'-H), 1.77 (qq, J = 6.5, 6.5 Hz, 1H, 2'-H), 1.42 (d, J = 7.3 Hz, 2H, 3-H), 0.82 (d, J = 6.5 Hz, 6H, 3'-H).

Entry 46


(R)-ibuprofen di(9-phenanthryl)methylester



[0081] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.5 mL/mi): tR = 18;.4 min (5.6%), tR = 24.9 min (94.4%);
IR (KBr): 3068, 1732, 1451, 1155, 750, 726 cm-1;
1H NMR (CDCl3) : δ8.83 - 8.60 (m, 4H, Ph), 8.40 (s, 1H, 1"-H), 8.18 - 8.09 (m, 1H, Ph), 7.82 - 7.04 (m, 17H, Ph), 3.89 (q, J = 7.2 Hz, 1H, 2-H), 2.61 - 2.45 (m, 2H, 1'-H), 2.00 - 1.81 (m, 1H, 2'-H), 1.55 (d, J = 7.2 Hz, 3H, 3-H), 0.95 (d, J = 6.6 Hz, 6H, 3'-H);
13C NMR (CDCl3): δ173.7, 133.0, 132.7, 131.1, 131.0, 130.9, 130.6, 130.6, 130.4, 130.2, 129.8, 129.5, 129.1, 127.9, 127.5, 127.3, 127.2, 127.0, 126.9, 126.9, 126.6, 126.4, 126.2, 124.3, 123.9, 123.3, 123.1, 122.4, 122.4, 70.8, 45.3, 45.1, 30.2, 22.5, 22.4, 18.2.

Experimental Example 7: Production of Optically Active Ester and Optically Active Carboxylic Acid Using Ketoprofen (Optical Resolution of Ketoprofen)



[0082] 



[0083] As shown by the above formula, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(1-naphthyl)methanol or 1,1-di(9-phenanthryl)methanol and racemic ketoprofen. The results are shown in Table 7.
Table 7
No.R10Acid AnhydrideTimeYield of 7a/%Yield of 7b/%ee/% 7a/7bs
48 1-Nap PMBA 12 h 55 36 77/58 14
49 1-Nap Bz2O 6 h 55 27 80/50 15
50 9-Phen PMBA 12 h 53 43 72/60 11
51 9-Phen Bz2O 6 h 49 19 75/43 11


[0084] As can be understood from Table 7, both when using 1,1-di(1-naphthyl)methanol and when using 1,1-di(9-phenanthryl)methanol as the alcohol, ketoprofen is optically resolved with a high enantiomer selectivity, and an optically active ester and optically active carboxylic acid are obtained.

[0085] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 7 are shown.

Enrty 49



[0086] To a dichloromethane solution (2.0 mL) containing benzoic anhydride (54.2 mg, 0.240 mmol) and racemic ketoprofen (50.8 mg, 0.200 mmol); diisopropylethylamine (62.7 µL, 0.360 mmol), benzotetramisole (2.5 mg, 0.010 mmol), and 1,1-di(1-naphthyl)methanol (28.4 mg, 0.100 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 6 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with diethylether. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ketoprofen ester (56.8 mg, 55%, 80% ee) and the unreacted optically active ketoprofen (13.8 mg, 27%, 50% ee).

(R)-ketoprofen di(1-naphthyl)methylester



[0087] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/4, flow rate = 1.0 mL/mi): tR = 16.7 min (10.1%), tR = 46.3 min (89.9%);
IR (neat): 3035, 1735, 1660, 1599, 1511, 780, 680 cm-1;
1H NMR (CDCl3) : δ8.28 (s, 1H, 1'-H), 7.93 - 7.85 (m, 1H, Ph), 7.82 - 7.54 (m, 6H, Ph), 7.52 - 7.44 (m, 2H, Ph), 7.44 - 7.06 (m, 13H, Ph), 6.95 (d, J = 7.1 Hz, 1H, Ph), 3.81 (q, J = 7.1 Hz, 1H, 2-H), 1.46 (d, J = 7.1 Hz, 3H, 3-H);
13C NMR (CDCl3): δ196.3, 173.0, 140.1, 137.8, 137.3, 134.5, 134.4, 133.8, 133.7, 132.4, 131.6, 131.1, 130.8, 129.9, 129.5, 129.2, 128.93, 128.91, 128.86, 128.7, 128.6, 128.3, 128.2, 126.7, 126.4, 126.1, 125.9, 125.7, 125.4, 125.2, 125.0, 123.2, 71.4, 45.5, 17.9.
HR MS: calculated for C37H28O3Na (M + Na+) = 543.1931; found 543.1910.

(S)-ketoprofen



[0088] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/10/0.01, flow rate = 1.0 mL/min); tR = 15.0 min (20.0%), tR = 17.7 min (80%);
1H NMR (CDCl3) : δ10.67 (br s, 1H, COOH), 7.85 - 7.76 (m, 3H, Ph), 7.69 (dt, J = 7.5, 1.5 Hz, 1H, Ph), 7.63 - 7.54 (m, 2H, Ph), 7.52 - 7.42 (m, 3H, Ph), 3.83 (q, J = 7.0 Hz, 1H, 2-H),1.56 (d, J = 7.0 Hz, 3H, 3-H).

Entry 51


(R)-ketoprofen di(9-phenanthryl)methylester



[0089] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/mi): tR = 34.6 min (86.0%), tR = 45.7 min (14.0%);
IR (neat): 3060, 1733, 1658, 1159, 754, 721 cm-1;
1H NMR (CDCl3) : δ8.84 - 8.60 (m, 4H, Ph), 8.42 (s, 1H, 1'-H), 8.16 - 8.06 (m, 1H, Ph), 7.82 - 7.32 (m, 20H, Ph), 7.28 - 7.32 (m, 2H, Ph), 3.99 (q, J = 6.9 Hz, 1H, 2-H), 1.60 (d, J = 6.9 Hz, 3H, 3-H);
13C NMR (CDCl3): δ196.3, 173.1, 140.2, 138.0, 137.4, 134.6, 134.5, 133.9, 133.7, 132.4, 131.6, 131.2, 131.0, 130.0, 129.6, 129.2, 128.9, 128.7, 128.6, 128.3, 128.2, 126.7, 126.5, 126.1, 125.9, 125.8, 125.4, 125.2, 125.0, 123.3, 71.5, 45.6, 18.0.

Experimental Example 8: Production of Optically Active Ester and Optically Active Carboxylic Acid Using Naproxen (Optical Resolution of Naproxen)



[0090] 



[0091] As shown by the above reaction equation, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(1-naphthyl)methanol or 1,1-di(9-phenanthryl)methanol and racemic naproxen. The results are shown in Table 8.
Table 8
No.R11Acid AnhydrideTimeYield of 8a/%Yield of 8b/%ee/% 8a/8bs
52 1-Nap PMBA 12 h 53 37 77/62 15
53 1-Nap Bz2O 6 h 52 36 79/62 16
54 9-Phen PMBA 12 h 49 42 87/61 26
55 9-Phen Bz2O 6 h 50 27 88/61 30


[0092] As can be understood from Table 8, both when using 1,1-di(1-naphthyl)methanol and when using 1,1-di(9-phenanthryl)methanol as the alcohol, naproxen is optically resolved with a high enantiomer selectivity, and an optically active ester and optically active carboxylic acid are obtained.

[0093] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 8 are shown.

Entry 55



[0094] To a dichloromethane solution (2.0 mL) containing benzoic anhydride (54.3 mg, 0.240 mmol) and racemic naproxen (46.1 mg, 0.200 mmol); diisopropylethylamine (62.7 µL, 0.360 mmol), benzotetramisole (2.5 mg, 0.010 mmol), and 1,1-di(9-phenanthryl)methanol (38.4 mg, 0.100 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 6 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with dichloromethane. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active naproxen ester (59.7 mg, 50%, 88% ee) and the unreacted optically active naproxen (12.6 mg, 27%, 61% ee).

(R)-naproxen di(9-phenanthryl)methylester



[0095] HPLC (CHIRALCELL OD-H, i-PrOH/hexane = 1/4, flow rate = 0.75 mL/mi): tR = 23.7 min (94.1%), tR = 41.1 min (5.9%);
IR (KBr): 3063, 1731, 1605, 1265, 1028, 749, 727 cm-1;
1H NMR (CDCl3) : δ8.84 - 8.50 (m, 4H, Ph), 8.43 (s, 1H, 1'-H), 8.25 - 8.12 (m, 1H, Ph), 7.80 - 7.08 (m, 18H, Ph), 6.83 - 6.75 (m, 1H, Ph), 4.03 (q, J = 7.1 Hz, 1H, 2-H), 3.96 (s, 3H, OMe), 1.64 (d, J = 7.1 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.5, 157.9, 135.2, 134.0, 132.9, 132.6, 131.0, 130.9, 130.6, 130.6, 130.3, 130.2, 129.8, 129.5, 129.1, 129.0, 128.9, 128.3, 128.0, 127.4, 127.3, 127.2, 126.8, 126.6, 126.6, 126.5, 126.4, 126.3, 126.2, 124.2, 123.9, 123.4, 123.1, 122.4, 122.2, 119.0, 105.6, 71.0, 55.4, 45.7, 18.0.

(S)-naproxen



[0096] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/10/0.01, flow rate = 1.0 mL/min); tR = 13.8 min (18.9%), tR = 15.8 min (81.1%);
1H NMR (CDCl3) : δ9.42 (br s, 1H, COOH), 7.68 - 7.55 (m, 3H, Ph), 7.33 - 7.28 (m, 1H, Ph), 7.13 - 6.99 (m, 2H, Ph), 3.83 (s, 3H, OMe), 3.79 (q, J = 7.2 Hz, 1H, 2-H), 1.50 (d, J = 7.2 Hz, 3H, 3-H).

Entry 53


(R)-naproxen di(1-naphthyl)methylester



[0097] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 1.0 mL/mi): tR = 13.7 min (10.6%), tR = 17.4 min (89.4%);
IR (neat): 3034, 1733, 1604, 1508, 782, 679 cm-1;
1H NMR (CDCl3): δ8.29 (s, 1H, 1'-H), 8.00 - 7.90 (m, 1H, Ph), 7.82 - 6.96 (m, 17H, Ph), 6.95 - 6.81 (m, 2H, Ph), 3.86 (q, J = 7.0 Hz, 1H, 2-H), 3.79 (s, 3H, OMe), 1.49 (d, J = 7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.6, 157.6, 135.1, 134.7, 134.5, 133.8, 133.7, 133.6, 131.2, 130.8, 129.3, 129.1, 128.9, 128.8, 128.7, 128.6, 128.3, 127.1, 126.7, 126.5, 126.3, 126.2, 125.8, 125.6, 125.3, 125.2, 125.0, 123.4, 123.3, 118.9, 105.5, 71.2, 55.2, 45.5, 18.3;
HR MS: calculated for C35H28O3Na (M + Na+) = 519.1931; found 519.1932.

Experimental Example 9: Production of Optically Active Ester and Optically Active Carboxylic Acid Using Flurbiprofen (Optical Resolution of Flurbiprofen)



[0098] 



[0099] As shown by the above reaction equation, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(1-naphthyl)methanol or 1,1-di(9-phenanthryl)methanol and racemic flurbiprofen. The results are shown in Table 9.
Table 9
No.R12Acid AnhydrideTimeYield of 9a/%Yield of 9b/%ee/% 9a/9bs
56 1-Nap PMBA 12 h 53 34 83/37 15
57 1-Nap Bz2O 6 h 53 25 83/8 12
58 9-Phen PMBA 12 h 48 32 81/64 18
59 9-Phen Bz2O 6 h 41 28 88/44 23


[0100] As can be understood from Table 9, both when using 1,1-di(1-naphthyl)methanol and when using 1,1-di(9-phenanthryl)methanol as the alcohol, flurbiprofen is optically resolved with a high enantiomer selectivity, and an optically active ester and optically active carboxylic acid are obtained.

[0101] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 9 are shown.

Entry 59



[0102] To a dichloromethane solution (2.0 mL) containing benzoic anhydride (54.3 mg, 0.240 mmol) and racemic flurbiprofen (48.9 mg, 0.200 mmol); diisopropylethylamine (62.7 µL, 0.360 mmol), benzotetramisole (2.5 mg, 0.010 mmol), and 1,1-di(9-phenanthryl)methanol (38.4 mg, 0.100 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 6 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with dichloromethane. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active flurbiprofen ester (50.4 mg, 41%, 88% ee) and the unreacted optically active flurbiprofen (13.4 mg, 28%, 44% ee).

(R)-flurbiprofen di(9-phenanthryl)methylester



[0103] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/mi): tR = 14.9 min (6.3%), tR = 16.9 min (93.7%);
IR (KBr): 3062, 1736, 1450, 1416, 1166, 1146, 749, 726 cm-1;
1H NMR (CDCl3): δ8.84 - 8.62 (m, 4H, Ph), 8.42 (s, 1H, 1'-H), 8.17 - 8.08 (m, 1H, Ph), 7.80 - 7.32 (m, 19H, Ph), 7.20 - 7.11 (m, 2H, Ph), 3.95 (q, J = 7.0 Hz, 1H, 2-H), 1.60 (d, J = 7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ172.9, 160.7, 158.8, 141.4, 141.3, 135.5, 132.7, 132.6, 131.0, 131.0, 130.9, 130.7, 130.6, 130.5, 130.1, 129.8, 129.1, 129.0, 129.0, 128.5, 128.1, 128.0, 127.9, 127.8, 127.3, 127.1, 127.0, 126.7, 126.7, 126.7, 126.5, 126.4, 124.2, 123.9, 123.9, 123.9, 123.4, 123.2, 122.5, 122.4, 115.7, 115.5, 71.3, 45.2, 17.8.

(S)-flurbiprofen



[0104] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min); tR = 24.9 min (18.2%), tR = 35.0 min (81.8%);
1H NMR (CDCl3) : δ9.45 (br s, 1H, COOH), 7.57 - 7.49 (m, 2H, Ph), 7.48 - 7.33 (m, 4H, Ph), 7.22 - 7.11 (m, 2H, Ph), 3.80 (q, J = 7.2 Hz, 1H, 2-H), 1.56 (d, J = 7.2 Hz, 3H, 3-H).

Entry 57


(R)-flurbiprofen di(1-naphthyl)methylester



[0105] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/mi): tR = 9.8 min (8.3%), tR = 16.9 min (91.7%);
IR (neat): 3035, 1734, 1599, 1513, 783, 679 cm-1;
1H NMR (CDCl3): δ8.29 (s, 1H, 1'-H), 7.95 - 7.86 (m, 1H, Ph), 7.80 - 7.72 (m, 1H, Ph), 7.70 (d, J = 8.1 Hz, 2H, Ph), 7.64 (d, J = 8.1 Hz, 2H, Ph), 7.46 - 7.04 (m, 12H, Ph), 7.01 - 6.90 (m, 3H, Ph), 3.74 (q, J = 7.0 Hz, 1H, 2-H), 1.44 (t, J = 7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.5, 140.0, 134.8, 134.6, 133.8, 133.7, 131.2, 130.8, 129.1, 128.9, 128.7, 128.64 ,128.57 ,127.8, 127.2, 126.7, 126.4, 126.3, 125.9, 125.6, 125.2, 125.0, 123.5, 123.3, 71.1, 45.6, 18.2;
HR MS: calculated for C36H27O2FNa (M + Na+) = 533.1887; found 533.1865.

Experimental Example 10: Production of Optically Active Ester and Optically Active Carboxylic Acid Using Fenoprofen (Optical Resolution of Fenoprofen)



[0106] 



[0107] As shown by the above reaction equation, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(1-naphthyl)methanol or 1,1-di(9-phenanthryl)methanol and racemic fenoprofen. The results are shown in Table 10.
Table 10
No.R13Acid AnhydrideTimeYield of 10a/%Yield of 10b/%ee/% 10a/10bs
60 1-Nap PMBA 12 h 46 42 82/53 17
61 1-Nap Bz2O 6 h 46 34 84/40 16
62 9-Phen PMBA 12 h 47 39 78/60 15
63 9-Phen Bz2O 6 h 54 36 78/50 14


[0108] As can be understood from Table 10, both when using 1,1-di(1-naphthyl)methanol and when using 1,1-di(9-phenanthryl)methanol as the alcohol, fenoprofen is optically resolved with a high enantiomer selectivity, and an optically active ester and optically active carboxylic acid are obtained.

[0109] Below, the production method and identification results of optically active esters and optically active carboxylic acids in Table 10 are shown.

Entry 60



[0110] To a dichloromethane solution (1.0 mL) containing p-methoxybenzoic anhydride (68.7 mg, 0.240 mmol) and racemic fenoprofen (48.2 mg, 0.199 mmol), and 1,1-di(naphthyl)methanol (28.2 mg, 0.099 mmol); diisopropylethylamine (62.7 µL, 0.360 mmol) and benzotetramisole (2.5 mg, 0.010 mmol), were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 12 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with diethyl ether. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active fenoprofen ester (46.8 mg, 46%, 82% ee) and the unreacted optically active fenoprofen (20.2 mg, 42%, 53% ee).

(R)-fenoprofen di(1-naphthyl)methylester



[0111] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 1.0 mL/mi): tR = 20.4 min (8.9%), tR = 23.9 min (91.1%);
IR (neat): 3036, 1735, 1585, 1484, 781, 679 cm-1;
1H NMR (CDCl3): δ8.28 (s, 1H, 1'-H), 7.92 (d, J = 8.0 Hz, 1H, Ph), 7.82 - 7.62 (m, 5H, Ph), 7.43 - 7.30 (m, 3H, Ph), 7.27 - 7.09 (m, 7H, Ph), 6.98 - 6.91 (m, 3H, Ph), 6.86 - 6.83 (m, 1H, Ph), 6.82 - 6.73 (m, 3H, Ph), 3.72 (q, J = 7.0 Hz, 1H, 2-H), 1.42 (d, J = 7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.1, 157.3, 157.0, 141.9, 134.7, 134.6, 133.8, 133.7, 131.2, 130.9, 129.8, 129.7, 129.1, 128.9, 128.8, 128.7, 128.3, 126.7, 126.4, 126.1, 125.9, 125.7, 125.3, 125.2, 125.1, 123.4, 123.3, 123.1, 122.6, 118.7, 118.4, 117.6, 71.2, 45.5, 17.9;
HR MS: calculated for C36H28O3Na (M + Na+) = 531.1931; found 531.1948.

(S)-fenoprofen



[0112] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min); tR = 26.0 min (23.4%), tR = 30.9 min (76.6%);
1H NMR (CDCl3) : δ11.8 (br s, 1H, COOH), 7.24 - 7.10 (m, 3H, Ph), 7.00 - 6.85 (m, 5H, Ph), 6.76 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H, Ph), 3.58 (q, J = 7.2 Hz, 1H, 2-H), 1.37 (d, J = 7.2 Hz, 3H, 3-H).

Entry 62


(R)-fenoprofen di (1-phenanthryl)methylester



[0113] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.5 mL/mi) : tR = 17.9 min (88.9%), tR = 20.8 min (11.1%);
IR (KBr): 3070, 1736, 1584, 1486, 1232, 751, 726 cm-1;
1H NMR (CDCl3): δ8.85 - 8.60 (m, 4H, Ph), 8.40 (s, 1H, 1'-H), 8.20 - 8.05 (m, 1H, Ph), 7.82 - 6.72 (m, 22H, Ph), 7.20 - 7.11 (m, 2H, Ph), 3.88 (q, J = 7.2 Hz, 1H, 2-H), 1.55 (d, J = 7.2 Hz, 3H, 3-H);
13C NMR (CDCl3): δ173.1, 157.6, 156.8, 142.0, 132.8, 132.7, 131.1, 131.1, 130.9, 130.7, 130.7, 130.5, 130.2, 130.0, 129.8, 129.6, 129.1, 129.1, 127.8, 127.3, 127.1, 127.0, 126.7, 126.7, 126.7, 126.6, 126.5, 126.5, 124.2, 124.0, 123.4, 123.3, 123.2, 122.6, 122.5, 122.4, 118.9, 118.3, 117.5, 71.2, 45.6, 17.9;
HR MS: calculated for C44H32O3Na (M + Na+) = 631.2244; found 631.2254.


Claims

1. A method for producing an optically active ester comprising:

reacting a racemic carboxylic acid shown by the formula (g) below and an alcohol shown by the formula (a) below or a phenol derivative shown by the formula (b) below, in the presence of a benzoic anhydride or a derivative of benzoic anhydride obtained from benzoic acid where an alkyl group, alkoxy group, amino group or hydroxyl group is bonded to the phenyl group, and a catalyst shown by any of the formulae (c) to (f) below, and

selectively esterifying one enantiomer of the racemic carboxylic acid

wherein, in the formula (a), Ra represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group,

in the formula (b), Rb represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group; n represents an integer of 1 to 5; and in the case that a plurality of Rb is present, they may be the same or different,

in the formulae (c) to (f), X represents any of the following substituent groups,



        -(CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR



and R represents a protecting group,

in the formula (g), Rg1 and Rg2 represent organic groups which differ from each other, and the organic groups are selected from the group consisting of alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, alkylaryl group, akylheteroaryl group, alkoxyaryl group, and alkoxyheteroaryl group, and may be optionally substituted by an alkyl group, alkoxy group, aryl group, heteroaryl group, acyl group or halogen atom.


 
2. The method for producing an optically active ester according to claim 1, wherein in the formula (g), one of the carbon atoms of Rg1 and Rg2 bonded to the asymmetric carbon is bonded to another atom by a multiple bond.
 
3. The method for producing an optically active ester according to claim 1 or 2, wherein in the formula (b), Rb is a naphthyl group substituted at the 2,6 positions of the phenol.
 
4. A method for producing an optically active carboxylic acid comprising:

reacting a racemic carboxylic acid shown by the formula (g) below, an alcohol shown by the formula (a) below or a phenol derivative shown by the formula (b) below, in the presence of a benzoic anhydride or a derivative of benzoic anhydride obtained from benzoic acid where an alkyl group, alkoxy group, amino group or hydroxyl group is bonded to the phenyl group, and a catalyst shown by any of the formulae (c) to (f) below, and

selectively esterifying one enantiomer of the racemic carboxylic acid

wherein, in the formula (a), Ra represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group,

in the formula (b), Rb represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group, which may have a substituent group; n represents an integer of 1 to 5; in the case that a plurality of Rb is present, they may be the same or different,

in the formulae (c) to (f), X represents any of the following substituent groups,

- (CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR

and R represents a protecting group,

in the formula (g), Rg1 and Rg2 represent organic groups which differ from each other, and the organic groups are selected from the group consisting of alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, alkylaryl group, akylheteroaryl group, alkoxyaryl group, and alkoxyheteroaryl group, and may be optionally substituted by an alkyl group, alkoxy group, aryl group, heteroaryl group, acyl group or halogen atom.


 


Ansprüche

1. Ein Verfahren zum Herstellen eines optisch aktiven Esters, umfassend:

das Reagierenlassen einer racemischen Carbonsäure, wie durch die Formel (g) unten gezeigt, und eines Aklohols, wie durch die Formel (a) unten gezeigt, oder eines Phenolderivats, wie durch die Formel (b) unten gezeigt, in Gegenwart eines Benzoesäureanhydrids oder eines Derivats eine Benzoesäureanhydrids, erhalten aus einer Benzoesäure, bei der eine Alkylgruppe, Alkoxygruppe, Aminogruppe oder Hydroxylgruppe an die Phenylgruppe gebunden ist, und eines Katalystors, wie durch eine der Formeln (c) bis (f) unten gezeigt, und

selektives Verestern eines Enantiomers der racemischen Carbonsäure,

wobei in der Formal (a) Ra eine Phenylgruppe, eine Naphthylgruppe, eine Anthrylgruppe oder Phenanthrylgruppe darstellt, die eine Substituentengruppe aufweisen kann,

in der Formel (b) Rb eine Phenylgruppe, eine Naphthylgruppe, eine Anthrylgruppe oder eine Phenanthrylgruppe darstellt, die eine Substituentengruppe aufweisen kann, n eine ganze Zahl von 1 bis 5 darstellt; und im Fall, dass eine Vielzahl von Rb vorliegen, diese dieselben oder unterschiedlich sein können,

in den Formeln (c) bis (f) X eine der folgenden Substituentengruppen darstellt



        -(CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR



und R eine Schutzgruppe darstellt,

in der Formel (g) Rg1 und Rg2 organische Gruppen darstellen, die sich voneinander unterscheiden, und die organischen Gruppen ausgewählt sind aus der Gruppe bestehend aus Alkylgruppe, Alkenylgruppe, Alkinylgruppe, Arylgruppe, Heteroarylgruppe, Alkoxyalkylgruppe, Alkoxyalkenylgruppe, Alkoxyalkinylgruppe, Arylalkylgruppe, Arylalkenylgruppe, Arylalkinylgruppe, Heteroarylalkylgruppe, Heteroarylalkenylgruppe, Heteroarylalkinylgruppe, Alkylarylgruppe, Alkylheteroarylgruppe, Alkoxyarylgruppe und Alkoxyheteroarylgruppe und gegebenenfalls durch eine Alkylgruppe, Alkoxygruppe, Arylgruppe, Heteroarylgruppe, Acylgruppe oder ein Halogenatom substituiert sein können.


 
2. Das Verfahren zum Herstellen eines optisch aktiven Esters gemäß Anspruch 1, wobei in der Formel (g) eines der Kohlenstoffatome von Rg1 und Rg2, die an den asymmetrischen Kohlenstoff gebunden sind, über eine Mehrfachbindung an ein weiteres Atom gebunden ist.
 
3. Das Verfahren zum Herstellen eines optisch aktiven Esters gemäß Anspruch 1 oder 2, wobei in der Formel (b) Rb eine Naphthylgruppe ist, die an den 2,6-Positionen des Phenols substituiert ist.
 
4. Ein Verfahren zum Herstellen einer optisch aktiven Carbonsäure, umfassend:

Reagierenlassen einer racemischen Carbonsäure, wie in der Formel (g) unten gezeigt, eines Alkohols, wie in der Formel (a) unten gezeigt, oder eines Phenolderivats, wie in der Formel (b) unten gezeigt, in Gegenwart eines Benzoesäureanhydrids oder eines Derivats eines Benzoesäureanhydrids, erhalten aus Benzoesäure, bei der eine Alkylgruppe, Alkoxygruppe, Aminogruppe oder Hydroxylgruppe an die Phenylgruppe gebunden ist, und eines Katalysators, wie durch eine der Formeln (c) bis (f) unten gezeigt, und

selektives Verestern eines Enantiomers der racemischen Carbonsäure,

wobei in der Formel (a) Ra eine Phenylgruppe, eine Naphthylgruppe, eine Anthrylgruppe oder eine Phenanthrylgruppe darstellt, die eine Substituentengruppe aufweisen kann,

in der Formel (b) Rb eine Phenylgruppe, eine Naphthylgruppe, eine Anthrylgruppe oder eine Phenanthrylgruppe darstellt, die eine Substituentengruppe aufweisen kann, n eine ganze Zahl von 1 bis 5 darstellt, wobei im Fall, dass eine Vielzahl von Rb vorliegen, diese dieselben oder unterschiedlich sein können,

in den Formeln (c) bis (f) X eine der folgenden Substituentengruppen darstellt



        -(CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR



und R eine Schutzgruppe darstellt,

in der Formel (g) Rg1 und Rg2 organische Gruppen darstellen, die sich voneinander unterscheiden, und die organischen Gruppen ausgewählt sind aus der Gruppe bestehend aus Alkylgruppe, Alkenylgruppe, Alkinylgruppe, Arylgruppe, Heteroarylgruppe, Alkoxyalkylgruppe, Alkoxyalkenylgruppe, Alkoxyalkinylgruppe, Arylalkylgruppe, Arylalkenylgruppe, Arylalkinylgruppe, Heteroarylalkylgruppe, Heteroarylalkenylgruppe, Heteroarylalkinylgruppe, Alkylarylgruppe, Alkylheteroarylgruppe, Alkoxyarylgruppe und Alkoxyheteroarylgruppe und gegebenenfalls durch eine Alkylgruppe, Alkoxygruppe, Arylgruppe, Heteroarylgruppe, Acylgruppe oder ein Halogenatom substituiert sein können.


 


Revendications

1. Procédé de production d'un ester optiquement actif comprenant :

la réaction d'un acide carboxylique racémique représenté par la formule (g) ci-dessous et d'un alcool représenté par la formule (a) ci-dessous ou d'un dérivé de phénol représenté par la formule (b) ci-dessous, en présence d'un anhydride benzoïque ou d'un dérivé d'anhydride benzoïque obtenu à partir d'un acide benzoïque dans lequel un groupe alkyle, un groupe alcoxy, un groupe amino ou un groupe hydroxyle est lié au groupe phényle, et d'un catalyseur représenté par l'une quelconque des formules (c) à (f) ci-dessous, et

l'estérification sélective d'un énantiomère de l'acide carboxylique racémique

dans laquelle, dans la formule (a) , Ra représente un groupe phényle, un groupe naphtyle, un groupe anthryle, ou un groupe phénanthryle, qui peut avoir un groupe substituant,

dans la formule (b), Rb représente un groupe phényle, un groupe naphtyle, un groupe anthryle, ou un groupe phénanthryle, qui peut avoir un groupe substituant ; n représente un nombre entier allant de 1 à 5 ; et dans le cas où une pluralité de Rb est présente, ils peuvent être identiques ou différents,

dans les formules (c) à (f), X représente l'un quelconque des groupes substituants suivants,



        -(CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR



et R représente un groupe protecteur,

dans la formule (g) , Rg1 et Rg2 représentent des groupes organiques qui sont différents l'un de l'autre, et les groupes organiques sont sélectionnés dans le groupe constitué d'un groupe alkyle, d'un groupe alcényle, d'un groupe alcynyle, d'un groupe aryle, d'un groupe hétéroaryle, d'un groupe alcoxyalkyle, d'un groupe alcoxyalcényle, d'un groupe alcoxyalcynyle, d'un groupe arylalkyle, d'un groupe arylalcényle, d'un groupe arylalcynyle, d'un groupe hétéroarylalkyle, d'un groupe hétéroarylalcényle, d'un groupe hétéroarylalcynyle, d'un groupe alkylaryle, d'un groupe alkylhétéroaryle, d'un groupe alcoxyaryle, et d'un groupe alcoxyhétéroaryle, et peuvent être facultativement substitués avec un groupe alkyle, un groupe alcoxy, un groupe aryle, un groupe hétéroaryle, un groupe acyle ou un atome d'halogène.


 
2. Procédé de production d'un ester optiquement actif selon la revendication 1, dans lequel dans la formule (g) , un des atomes de carbone de Rg1 et Rg2 lié au carbone asymétrique est lié à un autre atome par une liaison multiple.
 
3. Procédé de production d'un ester optiquement actif selon la revendication 1 ou 2, dans lequel dans la formule (b), Rb est un groupe naphtyle substitué aux positions 2,6 du phénol.
 
4. Procédé de production d'un acide carboxylique optiquement actif comprenant :

la réaction d'un acide carboxylique racémique représenté par la formule (g) ci-dessous, d'un alcool représenté par la formule (a) ci-dessous ou d'un dérivé de phénol représenté par la formule (b) ci-dessous, en présence d'un anhydride benzoïque ou d'un dérivé d'anhydride benzoïque obtenu à partir d'un acide benzoïque dans lequel un groupe alkyle, un groupe alcoxy, un groupe amino ou un groupe hydroxyle est lié au groupe phényle, et d'un catalyseur représenté par l'une quelconque des formules (c) à (f) ci-dessous, et

l'estérification sélective d'un énantiomère de l'acide carboxylique racémique

dans laquelle, dans la formule (a), Ra représente un groupe phényle, un groupe naphtyle, un groupe anthryle, ou un groupe phénanthryle, qui peut avoir un groupe substituant,

dans la formule (b), Rb représente un groupe phényle, un groupe naphtyle, un groupe anthryle, ou un groupe phénanthryle, qui peut avoir un groupe substituant ; n représente un nombre entier allant de 1 à 5 ; dans le cas où une pluralité de Rb est présente, ils peuvent être identiques ou différents,

dans les formules (c) à (f), X représente l'un quelconque des groupes substituants suivants,



        -(CH2)2-S-CH3 -CH2-SR -(CH2)4-NHR -CH2CONHR -(CH2)2CONHR



et R représente un groupe protecteur,

dans la formule (g) , Rg1 et Rg2 représentent des groupes organiques qui sont différents l'un de l'autre, et les groupes organiques sont sélectionnés dans le groupe constitué d'un groupe alkyle, d'un groupe alcényle, d'un groupe alcynyle, d'un groupe aryle, d'un groupe hétéroaryle, d'un groupe alcoxyalkyle, d'un groupe alcoxyalcényle, d'un groupe alcoxyalcynyle, d'un groupe arylalkyle, d'un groupe arylalcényle, d'un groupe arylalcynyle, d'un groupe hétéroarylalkyle, d'un groupe hétéroarylalcényle, d'un groupe hétéroarylalcynyle, d'un groupe alkylaryle, d'un groupe alkylhétéroaryle, d'un groupe alcoxyaryle, et d'un groupe alcoxyhétéroaryle, et peuvent être facultativement substitués avec un groupe alkyle, un groupe alcoxy, un groupe aryle, un groupe hétéroaryle, un groupe acyle ou un atome d'halogène.


 




REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description




Non-patent literature cited in the description