JPH07109259A

JPH07109259A - Production of optically active 1,4-dihydropyridine compound

Info

Publication number: JPH07109259A
Application number: JP13157792A
Authority: JP
Inventors: Yoshihiko Hirose; 芳彦広瀬; Kinya Kariya; 金弥苅谷; Seiji Sasaki; 征治佐々木; Kazuo Achinami; 一雄阿知波
Original assignee: Amano Pharmaceutical Co Ltd
Current assignee: Amano Enzyme Inc
Priority date: 1992-04-24
Filing date: 1992-04-24
Publication date: 1995-04-25

Abstract

PURPOSE:To efficiently obtain the compound by subjecting a 1,4-dihydropyridine compound to asymmetric hydrolysis by utilizin an enzymatic catalyst to stereoselectively hydrolyze one party thereof alone. CONSTITUTION:Using an enzymatic catalyst (e.g. a lipase or esterase derived from Pseudomonas or Candida), a 1,4-dihydropyridine compound of formula I [X is of formula II (R1-R3 are each H, halogen, nitro, nitrile or CF3) or alkyl; R4-R5 are each lower alkyl; R7 is acyl; R8 is H, lower alkoxymethyl or lower acyloxymethyl] is subjected to asymmetric hydrolysis to obtain the objective optically active 1,4-dihydropyridine of formula III (* denotes optically active point; R9 is acyl or H). With this method, one party of the compound of the formula I can be stereoselectively hydrolyzed by the enzymatic catalyst. This method is excellent in both asymmetric yield and reaction rate. The compound of the formula III can be served for the medical area through developing 1,4- dihydropyridine-based medicines as optically active products.

Description

Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は酵素の立体選択性を利用
した医薬品の重要中間体である光学活性１，４−ジヒド
ロピリジン−２−ヒドロキシメチル化合物の製造方法に
関する。FIELD OF THE INVENTION The present invention relates to a method for producing an optically active 1,4-dihydropyridine-2-hydroxymethyl compound, which is an important intermediate for pharmaceuticals by utilizing the stereoselectivity of an enzyme.

【０００２】[0002]

【従来の技術】光学活性１，４−ジヒドロピリジン誘導
体の分割に関する方法は報告されている〔ケミカル・フ
ァーマシューティカル・ブリチン（Chem. Pharm. Bul
l.），37巻，2225頁（1989），及び同誌、39巻，108頁
（1991）並びにジャーナル・メディシナル・ケミストリ
ー（J. Med. Chem.），29巻，2504頁（1986）〕。2. Description of the Related Art A method for resolving an optically active 1,4-dihydropyridine derivative has been reported [Chem. Pharm. Bul.
l.), 37, 2225 (1989), and ibid, 39, 108 (1991) and Journal Medicinal Chemistry (J. Med. Chem.), 29, 2504 (1986)].

【０００３】２−ヒドロキシメチル誘導体に関する方法
は、ラセミ体の合成が報告されている〔ケミカル・ファ
ーマシューティカル・ブリチン，39巻，3189頁（199
1）〕。As a method for the 2-hydroxymethyl derivative, the synthesis of a racemate has been reported [Chemical Pharmaceutical Bulletin, Vol. 39, p. 3189 (199).
1)].

【０００４】また、ジアステレオ分割による方法は報告
されている〔ジャーナル・メディシナル・ケミストリ
ー，29巻，1696頁（1986）〕。Also, a method based on diastereo division has been reported [Journal Medicinal Chemistry, 29, 1696 (1986)].

【０００５】[0005]

【発明が解決しようとする課題】しかしながら、上記の
公知の方法においては、もう一つの光学活性なアルコー
ルを必要とし、更に、目的とする光学活性体とするには
エステル交換等の工程を必要とするため、工程が複雑で
あり工業的な方法とは言えない。However, the above-mentioned known method requires another optically active alcohol, and further requires a step such as transesterification to obtain the desired optically active substance. Therefore, the process is complicated and cannot be said to be an industrial method.

【０００６】２−ヒドロキシメチル−１，４−ジヒドロ
ピリジン骨格を有する医薬品は、ラセミ体として医療に
供されているのが現状であり、それぞれの光学活性体に
ついて薬理作用に大きな差があることが報告〔ジャーナ
ル・メディシナル・ケミストリー，29巻，1696頁（198
6）〕されており、速やかに解決することが望まれてい
た。[0006] At present, pharmaceuticals having a 2-hydroxymethyl-1,4-dihydropyridine skeleton are provided for medical use as racemates, and it is reported that each optically active substance has a large difference in pharmacological action. [Journal Medicinal Chemistry, 29, 1696 (198
6)] has been done, and it was desired to solve the problem promptly.

【０００７】本発明者は、酵素触媒による不斉加水分解
によって、効率よく２−ヒドロキシメチル−１，４−ジ
ヒドロピリジン骨格を合成できる不斉合成法を検討し、
ここに完成した。The present inventor has studied an asymmetric synthesis method capable of efficiently synthesizing a 2-hydroxymethyl-1,4-dihydropyridine skeleton by an asymmetric hydrolysis with an enzyme catalyst,
Completed here.

【０００８】[0008]

【課題を解決するための手段】加水分解酵素触媒による
不斉分割の基質として適する１，４−ジヒドロピリジン
化合物を鋭意検討したところ、一般式［Ｉ］MEANS FOR SOLVING THE PROBLEMS When the 1,4-dihydropyridine compound suitable as a substrate for the asymmetric resolution catalyzed by a hydrolase was studied earnestly, the compound of the general formula [I]

【０００９】[0009]

【化５】 [Chemical 5]

【００１０】〔式中、Ｘは下記の一般式［ＩＩ］[Wherein X is the following general formula [II]

【００１１】[0011]

【化６】 [Chemical 6]

【００１２】（式中、Ｒ₁、Ｒ₂、Ｒ₃は同一でも異なっ
ていてもよく、水素原子、ハロゲン原子、ニトロ基、ニ
トリル基又はトリフロロメチル基を表す。）或いは、ア
ルキル基を示し、Ｒ₄、Ｒ₅、Ｒ₆は低級アルキル基を表
し、Ｒ₇はアシル基を表し、Ｒ₈は水素原子、低級アルコ
キシメチル基又は低級アシルオキシメチル基を表す。〕
で表される１，４−ジヒドロピリジン化合物が酵素触媒
によって一方のみが立体選択的に加水分解されて一般式
［ＩＩＩ］(Wherein R ₁ , R ₂ and R ₃ may be the same or different and represent a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group) or an alkyl group. , R ₄ , R ₅ and R ₆ represent a lower alkyl group, R ₇ represents an acyl group, and R ₈ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group. ]
One of the 1,4-dihydropyridine compounds represented by the formula is hydrolyzed stereoselectively by an enzyme catalyst, and the compound represented by the general formula [III]

【００１３】[0013]

【化７】 [Chemical 7]

【００１４】〔式中、Ｘは下記の一般式［ＩＩ］[Wherein X is the following general formula [II]

【００１５】[0015]

【化８】 [Chemical 8]

【００１６】（式中、Ｒ₁、Ｒ₂、Ｒ₃は同一でも異なっ
ていてもよく、水素原子、ハロゲン原子、ニトロ基、ニ
トリル基又はトリフロロメチル基を表す。）或いは、ア
ルキル基を示し、Ｒ₄、Ｒ₅、Ｒ₆は低級アルキル基を表
し、Ｒ₈は水素原子、低級アルコキシメチル基又は低級
アシルオキシメチル基を表し、Ｒ₉はアシル基または水
素原子を表し、＊は光学活性点を表す。〕で表される
１，４−ジヒドロピリジン化合物を生成し、その不斉収
率、反応収率共に満足する結果を得ることができた。な
お、Ｒ₉がアシル基である光学活性な一般式［ＩＩＩ］
で表される化合物は通常の加水分解方法、例えばメタノ
ール中アンモニア水等により容易に加水分解され、もう
一方の光学活性体を得ることができる。(Wherein R ₁ , R ₂ and R ₃ may be the same or different and represent a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group) or an alkyl group. , R ₄ , R ₅ and R ₆ represent a lower alkyl group, R ₈ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group, R ₉ represents an acyl group or a hydrogen atom, and * represents an optically active site. Represents ] The 1,4-dihydropyridine compound represented by the following formula was produced, and the asymmetric yield and the reaction yield were both satisfactory. In addition, R ₉ is an acyl group, an optically active compound represented by the general formula [III]
The compound represented by can be easily hydrolyzed by an ordinary hydrolysis method, for example, aqueous ammonia in methanol or the like to obtain the other optically active substance.

【００１７】以下に、本発明を詳細に説明する。前記一
般式［Ｉ］および［ＩＩＩ］で表される化合物におい
て、Ｘはアルキル基〔例えばメチル基、ベンジル基、シ
クロヘキシル基等〕或いは一般式［ＩＩ］（式中、
Ｒ₁、Ｒ₂、Ｒ₃は、水素原子、ハロゲン原子、ニトロ
基、ニトリル基、トリフロロメチル基等であり、これら
は同一でも異なっていても良い。）を表し、Ｒ₄、Ｒ₅，
Ｒ₆はメチル基、エチル基、イソプロピル基等の低級ア
ルキル基や置換基のあるアルキル基〔例えば置換基とし
てはフッ素、塩素、低級アルコキシ基等〕を表す。Ｒ₇
はアセチル基、プロピオニル基、ブチロイル基、ベンゾ
イル基等のアシル基を示す。Ｒ₈は、低級アルコキシメ
チル基、又は低級アシルオキシメチル基、又は水素原子
を表す。Ｒ₉は、アセチル基、プロピオニル基、ブチロ
イル基、ベンゾイル基等のアシル基又は水素原子を表
す。The present invention will be described in detail below. In the compounds represented by the above general formulas [I] and [III], X is an alkyl group [for example, a methyl group, a benzyl group, a cyclohexyl group, etc.] or a general formula [II] (in the formula,
R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen atom, a nitro group, a nitrile group, a trifluoromethyl group or the like, and these may be the same or different. ), R ₄ , R ₅ ,
R ₆ represents a lower alkyl group such as a methyl group, an ethyl group, an isopropyl group or an alkyl group having a substituent [for example, the substituent is fluorine, chlorine, a lower alkoxy group, etc.]. R ₇
Represents an acyl group such as an acetyl group, a propionyl group, a butyroyl group and a benzoyl group. R ₈ represents a lower alkoxymethyl group, a lower acyloxymethyl group, or a hydrogen atom. R ₉ represents an acyl group such as an acetyl group, a propionyl group, a butyroyl group, a benzoyl group or a hydrogen atom.

【００１８】本発明に用いる酵素としては上記一般式
［Ｉ］で表されるラセミの１，４−ジヒドロピリジンか
ら上記一般式［ＩＩＩ］で表される光学活性１，４−ジ
ヒドロピリジンを生成させる活性を有する酵素なら、如
何なるものでもよいが具体的には、シュードモナス（Ps
eudomonas）属、キャンディダ（Candida）属に由来する
リパーゼやエステラーゼが挙げられる。The enzyme used in the present invention has an activity of producing optically active 1,4-dihydropyridine represented by the above general formula [III] from racemic 1,4-dihydropyridine represented by the above general formula [I]. Any enzyme may be used as long as it is a Pseudomonas (Ps
Examples include lipases and esterases derived from the genus eudomonas and the genus Candida.

【００１９】更に詳しくは、シュードモナス・セパシア
（Pseudomonas cepacia）、シュードモナス・エルギノ
ーサ（Pseudomonas aeruginosa）、シュードモナス・フ
ラギ（Pseudomonas fragi）、キャンディダ・ルゴサ
（Candida rugosa）等に由来するリパーゼやエステラ
ーゼが挙げられる。More specifically, lipases and esterases derived from Pseudomonas cepacia, Pseudomonas aeruginosa, Pseudomonas fragi, Candida rugosa and the like can be mentioned.

【００２０】例えば、これらのリパーゼ、エステラーゼ
は、リパーゼＰＳ（商品名：天野製薬社製）、リパーゼ
ＡＹ（商品名：天野製薬社製）、リパーゼＡＨ（商品
名：天野製薬社製）、コレステロールエステラーゼ「ア
マノ」ＩＩ（商品名：天野製薬社製）、リパーゼＢ（商
品名：サッポロビール社製）として市販されており、こ
れらを利用できる。For example, these lipases and esterases include lipase PS (trade name: Amano Pharmaceutical Co., Ltd.), lipase AY (trade name: Amano Pharmaceutical Co., Ltd.), lipase AH (trade name: Amano Pharmaceutical Co., Ltd.), cholesterol esterase. "Amano" II (trade name: manufactured by Amano Pharmaceutical Co., Ltd.) and lipase B (trade name: manufactured by Sapporo Breweries) are commercially available, and these can be used.

【００２１】これらの用いられる酵素は粗製品であって
も、精製されたものであってもよい。又、これらの酵素
を生産する菌体も利用できる。The enzyme used may be a crude product or a purified product. In addition, bacterial cells that produce these enzymes can also be used.

【００２２】本発明の反応は通常、０〜４０℃、１〜２
４０時間で行い、反応系を攪拌するように行うのが好ま
しい。又、このようなリパーゼやエステラーゼは、その
まま用いてもよいが、適当な担体に担持させて固定化リ
アクターとしてもよい。The reaction of the present invention is usually carried out at 0 to 40 ° C. for 1 to 2
It is preferable to carry out the reaction for 40 hours and to stir the reaction system. Further, such a lipase or esterase may be used as it is, but may be supported on an appropriate carrier to be used as an immobilized reactor.

【００２３】本発明の反応は緩衝液中で行うこともでき
るが、通常は水を含む有機溶媒中で行われる。使用する
有機溶媒としては、特に制限されたものではないが、例
えばジエチルエーテル、イソプロピルエーテル、エタノ
ール、メタノール、アセトン、ジメチルホルムアミド、
ベンゼン、クロロホルム等を挙げることができる。反応
終了後に酵素は、常法に従って、例えばろ紙を用いたろ
過等で簡単に除くことができる。反応生成物は、例えば
水を多く含む場合にはクロロホルム、ベンゼン、ジエチ
ルエーテル等で抽出、分離できる。更に反応生成物は例
えばシリカゲルカラムクロマトグラフィー等を用いて容
易に精製できる。Although the reaction of the present invention can be carried out in a buffer, it is usually carried out in an organic solvent containing water. The organic solvent used is not particularly limited, for example, diethyl ether, isopropyl ether, ethanol, methanol, acetone, dimethylformamide,
Examples thereof include benzene and chloroform. After completion of the reaction, the enzyme can be easily removed by a conventional method, for example, by filtration using filter paper. When a large amount of water is contained, the reaction product can be extracted and separated with chloroform, benzene, diethyl ether or the like. Furthermore, the reaction product can be easily purified by using, for example, silica gel column chromatography.

【００２４】以下、実施例により本発明をより具体的に
詳述するが、本発明はこれらに限定されたものではな
い。Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

【００２５】[0025]

【Example】

実施例１ジケテン（21g）の四塩化炭素溶液（50ml）に臭素の四
塩化炭素溶液（50ml）を氷冷下で１時間かけて滴下し
た。室温にて１時間攪拌後、反応液を氷冷下、アルコー
ル（120ml）に滴下した。更に室温にて１時間攪拌後、
反応液を減圧濃縮して得た残渣を蒸留し目的物を得た。エチル４−ブロムアセト酢酸エステル（59％、90-100
℃／10mmHg）イソプロピル４−ブロムアセト酢酸エステル（62％、
75-82℃／25mmHg）Example 1 To a carbon tetrachloride solution (50 ml) of diketene (21 g), a carbon tetrachloride solution of bromine (50 ml) was added dropwise under ice cooling over 1 hour. After stirring at room temperature for 1 hour, the reaction solution was added dropwise to alcohol (120 ml) under ice cooling. After stirring at room temperature for 1 hour,
The residue obtained by concentrating the reaction solution under reduced pressure was distilled to obtain the desired product. Ethyl 4-bromoacetoacetate (59%, 90-100
℃ / 10mmHg) Isopropyl 4-bromoacetate (62%,
75-82 ℃ / 25mmHg)

【００２６】実施例２上記で得られたエチル４−ブロムアセト酢酸エステル
或いは、イソプロピル４−ブロムアセト酢酸エステル
（100mmol）を酢酸ナトリウム（120mmol）の酢酸溶液
（100ml）に加え、90℃で18時間攪拌した。反応液を減
圧濃縮後、ジクロロメタンで希釈し、水、飽和食塩水で
洗い、硫酸マグネシウムで乾燥した。乾燥剤をろ去後、
ろ液を減圧濃縮して得た残渣を蒸留し、目的物を得た。エチル４−アセトキシアセト酢酸エステル（48％、11
5℃、５mmHg）イソプロピル４−アセトキシアセト酢酸エステル（48
％、115℃、５mmHg）Example 2 The ethyl 4-bromoacetoacetic acid ester or isopropyl 4-bromoacetoacetic acid ester (100 mmol) obtained above was added to an acetic acid solution (100 ml) of sodium acetate (120 mmol), and the mixture was stirred at 90 ° C. for 18 hours. . The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, washed with water and saturated brine, and dried over magnesium sulfate. After removing the desiccant,
The residue obtained by concentrating the filtrate under reduced pressure was distilled to obtain the desired product. Ethyl 4-acetoxyacetoacetate (48%, 11
5 ° C, 5 mmHg) Isopropyl 4-acetoxyacetoacetic acid ester (48
%, 115 ° C, 5 mmHg)

【００２７】実施例３上記で得られたエチル４−アセトキシアセト酢酸エス
テル（1.88g）とメチル３−アミノクロトン酸エステ
ル（1.15g）と２−クロロベンズアルデヒド（1.41g）を
イソプロパノール（10ml）に溶解し、18時間還流した。
反応液を減圧濃縮して得た残渣をシリカゲルカラムクロ
マトグラフィー（酢酸エチル／ヘキサン＝１／４）に付
し、黄色結晶（2.85g、70％）を得た。〔エチルメチル２−アセトキシメチル−４−（２−
クロロフェニル）−１，４−ジヒドロ−６−メチル−
３，５−ピリジンジカルボキシレート〕Example 3 The ethyl 4-acetoxyacetoacetic acid ester (1.88 g), methyl 3-aminocrotonic acid ester (1.15 g) and 2-chlorobenzaldehyde (1.41 g) obtained above were dissolved in isopropanol (10 ml). And refluxed for 18 hours.
The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/4) to give yellow crystals (2.85 g, 70%). [Ethyl methyl 2-acetoxymethyl-4- (2-
Chlorophenyl) -1,4-dihydro-6-methyl-
3,5-Pyridinedicarboxylate]

【００２８】生成物の融点及び各種スペクトルデータを
示す。 mp : 122-124℃ (AcOEt/n-Hexane) IR(nujol) : 3324, 1717, 1699, 1686cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.20(3H,t,J=7.0Hz,CH₃ CH₂), 2.1
9(3H,s,CH₃CO),2.33(3H,s,CH₃), 3.62(3H,s,OCH₃), 4.0
8, 4.10(2H,dq,J=7.0,10.7Hz,2×CH_AH_BCH₃), 5.27, 5.3
9(2H,d,J=15.0Hz,CH_AH_BOAC), 5.43(1H,s,>CH-), 6.58(1
H,s,NH), 7.00-7.25, 7.28-7.37(4H,m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.21, 19.62, 20.91, 37.36, 5
0.87, 60.26, 61,40,103.77, 104.91, 126.94, 127.59,
129.39, 131.41,132.48, 141.64, 143.67, 145.17, 16
6.73, 167.80,170.77The melting point and various spectral data of the product are shown. mp: 122-124 ℃ (AcOEt / n-Hexane) IR (nujol): 3324, 1717, 1699, 1686cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.20 (3H, t, J = 7.0Hz, CH ₃ CH ₂ ), 2.1
9 (3H, s, CH ₃ CO), 2.33 (3H, s, CH ₃ ), 3.62 (3H, s, OCH ₃ ), 4.0
8, 4.10 (2H, dq, J = 7.0,10.7Hz, 2 × CH _A H _B CH ₃ ), 5.27, 5.3
9 (2H, d, J = 15.0Hz, CH _A H _B OAC), 5.43 (1H, s,> CH-), 6.58 (1
H, s, NH), 7.00-7.25 , 7.28-7.37 (4H, m, C 6 H 4) 13 C-NMR (CDCl 3) ppm: 14.21, 19.62, 20.91, 37.36, 5
0.87, 60.26, 61,40, 103.77, 104.91, 126.94, 127.59,
129.39, 131.41, 132.48, 141.64, 143.67, 145.17, 16
6.73, 167.80,170.77

【００２９】実施例４実施例２で得られたイソプロピル２−アセトキシアセ
ト酢酸エステル（2.02g）とメチル３−アミノクロト
ン酸エステル（1.15g）と２，３−ジクロロベンズアル
デヒド（1.75g）から実施例３の方法に従い、黄色結晶
（1.90g，43％）を得た。〔イソプロピルメチル２−アセトキシメチル−４−
（２，３−ジクロロフェニル）−１，４−ジヒドロ−６
−メチル−３，５−ピリジンジカルボキシレート〕Example 4 Example from isopropyl 2-acetoxyacetoacetic acid ester (2.02 g), methyl 3-aminocrotonic acid ester (1.15 g) and 2,3-dichlorobenzaldehyde (1.75 g) obtained in Example 2. According to the method of 3, yellow crystals (1.90 g, 43%) were obtained. [Isopropyl methyl 2-acetoxymethyl-4-
(2,3-Dichlorophenyl) -1,4-dihydro-6
-Methyl-3,5-pyridinedicarboxylate]

【００３０】生成物の融点、及び各種スペクトルデータ
を示す。 mp : 66-69℃ (AcOEt/n-Hexane) IR(nujol) : 3362, 1747, 1724, 1689cm^-1 ¹ H-NMR(CDCl₃) ppm : 1.03, 1,26(6H,d,J=6.3Hz,OCH(CH
₃ )₂), 2.19(3H,s,CH₃CO), 2.32(3H,s,CH₃), 3.62(3H,s,
OCH₃),4.98(1H,m,OCH₃), 5.32(2H,ABq,J=15.1Hz,-CH
₂O),5.47(1H,s,>CH-), 6.59(1H,s,NH), 7.05-7.30(3H,
m,C₆H₃)¹³ C-NMR(CDCl₃) ppm: 19.68, 20.90, 21.47, 21.85, 3
8.66, 50.91, 61.44,67.77, 103.35, 104.91, 127.04,
128.34, 128.41,129.82, 132.89, 141.71, 143.81, 14
7.50, 166.06,167.68, 170.68The melting point of the product and various spectral data are shown. mp: 66-69 ° C (AcOEt / n-Hexane) IR (nujol): 3362, 1747, 1724, 1689cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.03, 1,26 (6H, d, J = 6.3 Hz, OCH ( CH
₃ ) ₂ ), 2.19 (3H, s, CH ₃ CO), 2.32 (3H, s, CH ₃ ), 3.62 (3H, s,
OCH ₃ ), 4.98 (1H, m, OCH ₃ ), 5.32 (2H, ABq, J = 15.1Hz, -CH
₂ O), 5.47 (1H, s,> CH-), 6.59 (1H, s, NH), 7.05-7.30 (3H,
m, C ₆ H ₃ ) ¹³ C-NMR (CDCl ₃ ) ppm: 19.68, 20.90, 21.47, 21.85, 3
8.66, 50.91, 61.44, 67.77, 103.35, 104.91, 127.04,
128.34, 128.41,129.82, 132.89, 141.71, 143.81, 14
7.50, 166.06, 167.68, 170.68

【００３１】実施例５実施例３の方法に従い、エチル２−アセトキシルアセ
ト酢酸エステル（1.88g）とメチル３−アミノクロト
ン酸エステル（1.15g）と置換アルデヒド（10mmol）を
イソプパノール（10ml）中、同様の反応を行い、次に示
す化合物を得た。〔エチルメチル２−アセトキシメ
チル−４−（２，３−ジクロロフェニル）−１，４−ジ
ヒドロ−６−メチル−３，５−ピリジンジカルボキシレ
ート〕Example 5 According to the method of Example 3, ethyl 2-acetoxyl acetoacetic acid ester (1.88 g), methyl 3-aminocrotonic acid ester (1.15 g) and substituted aldehyde (10 mmol) in isopanol (10 ml), The same reaction was performed to obtain the compound shown below. [Ethyl methyl 2-acetoxymethyl-4- (2,3-dichlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate]

【００３２】収率、融点及び各種スペクトルデータを示
す。収率 : 2.87g，65％ mp : 102-104℃ (AcOEt/n-Hexane) IR(Kbr) : 3310, 1718, 1700, 1690cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.18(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.1
8(3H,s,CH₃CO),2.32(3H,s,CH₃), 3.61(3H,s,OCH₃), 4.0
6(2H,q,J=7.0Hz,CH₂CH₃), 5.14, 5.42(2H,d,J=15.6Hz,C
H₂O),5.47(1H,s,>CH-), 6.62(1H,s,NH), 7.06-7.36(3H,
m,C₆H₃)¹³ C-NMR(CDCl₃)ppm : 14.25, 19.65, 20.90, 38.69, 5
0.96, 60.39, 61.42,103.58, 104.72, 127.16, 128.58,
129.72, 131.14,133.01, 141.94, 143.98, 147.62, 16
6.60, 167.68,170.75The yield, melting point and various spectral data are shown. Yield: 2.87g, 65% mp: 102-104 ℃ (AcOEt / n-Hexane) IR (Kbr): 3310, 1718, 1700, 1690cm -1 1 H-NMR (CDCl 3) ppm: 1.18 (3H, t , J = 7.0Hz, CH ₂ CH ₃ ), 2.1
8 (3H, s, CH ₃ CO), 2.32 (3H, s, CH ₃ ), 3.61 (3H, s, OCH ₃ ), 4.0
6 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 5.14, 5.42 (2H, d, J = 15.6Hz, C
H ₂ O), 5.47 (1H, s,> CH-), 6.62 (1H, s, NH), 7.06-7.36 (3H,
m, C ₆ H ₃ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.25, 19.65, 20.90, 38.69, 5
0.96, 60.39, 61.42, 103.58, 104.72, 127.16, 128.58,
129.72, 131.14,133.01, 141.94, 143.98, 147.62, 16
6.60, 167.68, 170.75

【００３３】実施例６実施例５に従って下記の化合物を得た。〔エチルメチル２−アセトキシメチル−１，４−ジ
ヒドロ−６−メチル−４−（３−ニトロフェニル）−
３，５−ピリジンジカルボキシレート〕Example 6 The following compound was obtained according to Example 5. [Ethyl methyl 2-acetoxymethyl-1,4-dihydro-6-methyl-4- (3-nitrophenyl)-
3,5-Pyridinedicarboxylate]

【００３４】収率、融点及び各種スペクトルデータを示
す。収率 : 2.42g，58％ mp : 91-93℃ (AcOEt/n-Hexane) IR(KBr) : 3305, 1719, 1702, 1689cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.22(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.1
8(3H,s,CH₃CO),2.37(3H,s,CH₃), 3.63(3H,s,CH₃), 4.10
(2H,q,CH₂ CH₃),5.09(1H,S,>CH-), 5.30(2H,s,CH₂O), 6.
70(1H,s,NH),7.26-7.70, 7.85-8,14(4H,m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.25, 19.88, 20.90, 39.82, 5
1.30, 60.56, 61.36,103.18, 104.20, 121.65, 122.96,
128.92, 134.32,142.39, 144.72, 148.47, 149.15, 16
6.20, 167.39,170.80The yield, melting point and various spectral data are shown. Yield: 2.42g, 58% mp: 91-93 ° C (AcOEt / n-Hexane) IR (KBr): 3305, 1719, 1702, 1689cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.22 (3H, t , J = 7.0Hz, CH ₂ CH ₃ ), 2.1
8 (3H, s, CH ₃ CO), 2.37 (3H, s, CH ₃ ), 3.63 (3H, s, CH ₃ ), 4.10
(2H, q, CH ₂ CH ₃ ), 5.09 (1H, S,> CH-), 5.30 (2H, s, CH ₂ O), 6.
70 (1H, s, NH) , 7.26-7.70, 7.85-8,14 (4H, m, C 6 H 4) 13 C-NMR (CDCl 3) ppm: 14.25, 19.88, 20.90, 39.82, 5
1.30, 60.56, 61.36, 103.18, 104.20, 121.65, 122.96,
128.92, 134.32, 142.39, 144.72, 148.47, 149.15, 16
6.20, 167.39, 170.80

【００３５】実施例７実施例５に従って下記の化合物を得た。〔エチルメチル２−アセトキシメチル−１，４−ジ
ヒドロ−６−メチル−４−（２−ニトロフェニル）−
３，５−ピリジンジカルボキシレート〕Example 7 The following compound was obtained according to Example 5. [Ethyl methyl 2-acetoxymethyl-1,4-dihydro-6-methyl-4- (2-nitrophenyl)-
3,5-Pyridinedicarboxylate]

【００３６】収率、融点及び各種スペクトルデータを示
す。収率 : 3.39g，81％ mp : 99-102℃ (AcOEt/n-Hexane) IR(KBr) : 3305, 1735, 1700, 1686cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.16(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.1
8(3H,s,CH₃CO),2.32(3H,s,CH₃), 3.56(3H,s,CH₃O), 4.0
3, 4.06(2H,dq,J=7.0Hz,J=2.4Hz,CH₂ CH₃), 5.32(2H,s,O
CH₂),5.78(1H,s,>CH-), 6.63(1H,s,NH), 7.10-7.76(4H,
m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.14, 19.77, 20.90, 30.96, 3
4.65, 51.13, 60.56,61.47, 103.75, 104.89, 124,09,
127.33, 131.25,132.96,141.77, 142.45, 144.55, 147.
90, 166.43,167.34, 170.75The yield, melting point and various spectral data are shown. Yield: 3.39 g, 81% mp: 99-102 ° C (AcOEt / n-Hexane) IR (KBr): 3305, 1735, 1700, 1686 cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.16 (3H, t , J = 7.0Hz, CH ₂ CH ₃ ), 2.1
8 (3H, s, CH ₃ CO), 2.32 (3H, s, CH ₃ ), 3.56 (3H, s, CH ₃ O), 4.0
3, 4.06 (2H, dq, J = 7.0Hz, J = 2.4Hz, CH ₂ CH ₃ ), 5.32 (2H, s, O
CH ₂ ), 5.78 (1H, s,> CH-), 6.63 (1H, s, NH), 7.10-7.76 (4H,
m, C ₆ H ₄ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.14, 19.77, 20.90, 30.96, 3
4.65, 51.13, 60.56, 61.47, 103.75, 104.89, 124,09,
127.33, 131.25,132.96,141.77, 142.45, 144.55, 147.
90, 166.43, 167.34, 170.75

【００３７】実施例８実施例５に従って下記の化合物を得た。〔エチルメチル２−アセトキシメチル−４−（２−
トリフルオロメチルフェニル）−１，４−ジヒドロ−６
−メチル−３，５−ピリジンジカルボキシレート〕Example 8 The following compound was obtained according to Example 5. [Ethyl methyl 2-acetoxymethyl-4- (2-
Trifluoromethylphenyl) -1,4-dihydro-6
-Methyl-3,5-pyridinedicarboxylate]

【００３８】収率、融点及び各種スペクトルデータを示
す。収率 : 2.86g，65％ mp : 116-118℃ (AcOEt/n-Hexane) IR(KBr) : 3400, 1742, 1700, 1685cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.14(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.1
6(3H,s,CH₃CO), 2.32(3H,s,CH₃), 3.56(3H,s,CH₃), 4.1
2(2H,dq,J=7.0Hz,2.4Hz), 5.27(2H,S,CH₂φ), 5.56(1H,
s,CH₃), 6.47(1H,s,NH), 7.10-7.60(4H,m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.03, 19.59, 20.90, 35.76, 5
0.90, 60.34, 61.53,105.00, 106.25, 116.08, 126.48,
126.76, 131.31,132.11, 134.38, 141.42, 143.47, 14
6.48, 166.71,167.73, 170.80The yield, melting point and various spectral data are shown. Yield: 2.86g, 65% mp: 116-118 ° C (AcOEt / n-Hexane) IR (KBr): 3400, 1742, 1700, 1685cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.14 (3H, t , J = 7.0Hz, CH ₂ CH ₃ ), 2.1
6 (3H, s, CH ₃ CO), 2.32 (3H, s, CH ₃ ), 3.56 (3H, s, CH ₃ ), 4.1
2 (2H, dq, J = 7.0Hz, 2.4Hz), 5.27 (2H, S, CH ₂ φ), 5.56 (1H,
s, CH ₃ ), 6.47 (1H, s, NH), 7.10-7.60 (4H, m, C ₆ H ₄ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.03, 19.59, 20.90, 35.76, 5
0.90, 60.34, 61.53,105.00, 106.25, 116.08, 126.48,
126.76, 131.31, 132.11, 134.38, 141.42, 143.47, 14
6.48, 166.71, 167.73, 170.80

【００３９】実施例９実施例５に従って下記の化合物を得た。〔エチルメチル２−アセトキシメチル−１，４−ジ
ヒドロ−６−メチル−４−フェニル−３，５−ピリジン
ジカルボキシレート〕Example 9 The following compound was obtained according to Example 5. [Ethyl methyl 2-acetoxymethyl-1,4-dihydro-6-methyl-4-phenyl-3,5-pyridinedicarboxylate]

【００４０】収率、融点及び各種スペクトルデータを示
す。収率 : 3.11g，83％ mp : 108-110℃ (AcOEt/n-Hexane) IR(KBr) : 3320, 1720, 1700, 1690cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.22(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.1
5(3H,s,CH₃CO), 2.33(3H,s,CH₃), 3.62(3H,s,CH₃), 4.0
7(2H,q,CH₂ CH₃),4.98(1H,s,>CH-), 5.13, 5.41(2H,d,J=
15.6Hz,OCH₂),6.61(1H,s,NH), 7.06-7.36(5H,m,C₆H₅)¹³ C-NMR(CDCl₃)ppm : 14.20, 19.65, 20.84, 39.54, 5
1.02, 60.22, 61.42,103.86, 105.17, 126.42, 127.84,
128.07, 141.48,143.92, 146.99, 166.71, 167.85, 17
0.75The yield, melting point and various spectral data are shown. Yield: 3.11g, 83% mp: 108-110 ℃ (AcOEt / n-Hexane) IR (KBr): 3320, 1720, 1700, 1690cm -1 1 H-NMR (CDCl 3) ppm: 1.22 (3H, t , J = 7.0Hz, CH ₂ CH ₃ ), 2.1
5 (3H, s, CH ₃ CO), 2.33 (3H, s, CH ₃ ), 3.62 (3H, s, CH ₃ ), 4.0
7 (2H, q, CH ₂ CH ₃ ), 4.98 (1H, s,> CH-), 5.13, 5.41 (2H, d, J =
15.6Hz, OCH ₂ ), 6.61 (1H, s, NH), 7.06-7.36 (5H, m, C ₆ H ₅ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.20, 19.65, 20.84, 39.54, 5
1.02, 60.22, 61.42, 103.86, 105.17, 126.42, 127.84,
128.07, 141.48, 143.92, 146.99, 166.71, 167.85, 17
0.75

【００４１】実施例１０実施例５に従って下記の化合物を得た。〔エチルメチル２−アセトキシメチル−１，４−ジ
ヒドロ−４，６−ジメチル−３，５−ピリジンジカルボ
キシレート〕Example 10 The following compound was obtained according to Example 5. [Ethyl methyl 2-acetoxymethyl-1,4-dihydro-4,6-dimethyl-3,5-pyridinedicarboxylate]

【００４２】収率及び各種スペクトルデータを示す。収率 : 2.47g，79％ IR(neat) : 3330, 1740, 1700, 1685cm^-1 ¹ H-NMR(CDCl₃)ppm : 0.96(3H,d,J=6.8Hz,CH₃), 1.30(3
H,t,J=7.0Hz,CH₃ CH₂), 2.16(3H,s,CH₃CO), 2.28(3H,s,C
H₃), 3.72(3H,s,CH₃), 3.83(1H,q,J=6.8Hz,>CH-), 4.19
(2H,q,J=7.0Hz,CH₂ CH₃), 5.24(2H,s,CH₂O), 6.51(1H,s,
NH)¹³ C-NMR(CDCl₃)ppm : 14.42, 19.54, 20.90, 22.15, 2
8.63, 51.07, 60.17,61.42, 104.32, 106.09, 141.82,
144.49, 166.88,168.07, 170.86The yield and various spectral data are shown. Yield: 2.47g, 79% IR (neat): 3330, 1740, 1700, 1685cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 0.96 (3H, d, J = 6.8Hz, CH ₃ ), 1.30 (3
H, t, J = 7.0Hz, CH ₃ CH ₂ ), 2.16 (3H, s, CH ₃ CO), 2.28 (3H, s, C
H ₃ ), 3.72 (3H, s, CH ₃ ), 3.83 (1H, q, J = 6.8Hz,> CH-), 4.19
(2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 5.24 (2H, s, CH ₂ O), 6.51 (1H, s,
NH) ¹³ C-NMR (CDCl ₃ ) ppm: 14.42, 19.54, 20.90, 22.15, 2
8.63, 51.07, 60.17, 61.42, 104.32, 106.09, 141.82,
144.49, 166.88, 168.07, 170.86

【００４３】実施例１１実施例５に従って下記の化合物を得た。〔エチルメチル２−アセトキシメチル−４−ベンジ
ル−１，４−ジヒドロ−６−メチル−３，５−ピリジン
ジカルボキシレート〕Example 11 The following compound was obtained according to Example 5. [Ethyl methyl 2-acetoxymethyl-4-benzyl-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate]

【００４４】収率及び各種スペクトルデータを示す。収率 : 2.19g，48％ IR(neat) : 3330, 1730, 1720, 1690cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.23(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.1
0(3H,s,CH₃CO), 2.20(3H,s,CH₃), 2.56(2H,d,J=5.4Hz,C
H₂), 3.58(3H,s,CH₃), 4.04(2H,q,J=7.0Hz,CH₂CH₃), 4.
17(1H,t,J=5.4Hz,>CH-), 5.17(2H,s,CH₂O), 6.23(1H,s,
NH),6.78-7.38(5H,m,C₆H₅)¹³ C-NMR(CDCl₃)ppm : 14.31, 19.31, 20.79, 35.56, 4
2.21, 50.90, 60.11,61.13, 101.65, 103.35, 125.80,
127.39, 130.12,138.75, 142.73, 145.40, 166.88, 16
7.96, 170.75The yield and various spectral data are shown. Yield: 2.19g, 48% IR (neat): 3330, 1730, 1720, 1690cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.23 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.1
0 (3H, s, CH ₃ CO), 2.20 (3H, s, CH ₃ ), 2.56 (2H, d, J = 5.4Hz, C
H ₂ ), 3.58 (3H, s, CH ₃ ), 4.04 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 4.
17 (1H, t, J = 5.4Hz,> CH-), 5.17 (2H, s, CH ₂ O), 6.23 (1H, s,
NH), 6.78-7.38 (5H, m , C 6 H 5) 13 C-NMR (CDCl 3) ppm: 14.31, 19.31, 20.79, 35.56, 4
2.21, 50.90, 60.11, 61.13, 101.65, 103.35, 125.80,
127.39, 130.12,138.75, 142.73, 145.40, 166.88, 16
7.96, 170.75

【００４５】実施例１２実施例３で得たエチルメチル２−アセトキシメチル
−４−（２−クロロフェニル）−１，４−ジヒドロ−６
−メチル−３，５−ピリジンジカルボキシレート（１
ｇ）を水飽和のイソプロピルエーテル（80ml）に懸濁
し、リパーゼＡＨ（500mg）を加え、室温にて攪拌し
た。原料と生成物が等量になった段階で酵素をろ過によ
り除き、ろ液を減圧濃縮して得た残渣をシリカゲルカラ
ムクロマトグラフィー（酢酸エチル／ヘキサン＝１／
４）に付し、目的物を得た。Example 12 Ethyl methyl 2-acetoxymethyl-4- (2-chlorophenyl) -1,4-dihydro-6 obtained in Example 3
-Methyl-3,5-pyridinedicarboxylate (1
g) was suspended in water-saturated isopropyl ether (80 ml), Lipase AH (500 mg) was added, and the mixture was stirred at room temperature. The enzyme was removed by filtration when the raw material and the product were in equal amounts, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (ethyl acetate / hexane = 1 /
Then, the product of interest was obtained.

【００４６】それぞれの収率、融点、比旋光度及び各種
スペクトルデータを示す。尚、光学純度はＨＰＬＣ分析
（カラム：キラルセルＡＳ）により決定した。〔（−）−エチルメチル２−アセトキシメチル−４
−（２−クロロフェニル）−１，４−ジヒドロ−６−メ
チル−３，５−ピリジンジカルボキシレート〕収率 : 50％光学純度 : 92%ee [α]_D : -30.9°(c=1.0, Acetone)The respective yields, melting points, specific optical rotations and various spectrum data are shown. The optical purity was determined by HPLC analysis (column: Chiralcel AS). [(-)-Ethylmethyl 2-acetoxymethyl-4
-(2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate] Yield: 50% Optical purity: 92% ee [α] _D : -30.9 ° (c = 1.0, Acetone)

【００４７】〔（＋）−エチルメチル４−（２−ク
ロロフェニル）−１，４−ジヒドロ−２−ヒドロキシメ
チル−６−メチル−３，５−ピリジンジカルボキシレー
ト〕収率 : 49％光学純度 : 90%ee [α]_D : +14.8°(c=1.0, Acetone) IR(neat) : 3382, 1694, 1680cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.18(3H,t,J=7.3Hz,CH₂ CH₃ ), 2.3
1(3H,s,CH₃), 3.62(3H,s,OCH₃), 4.05(2H,q,J=7.3Hz,CH
₂ CH₃), 4.73(2H,ABq,J=6.4Hz,CH₂O), 5.41(1H,s,>CH-),
7,00-7.39(5H,m,C₆He₄ and NH)¹³ C-NMR(CDCl₃)ppm : 14.23, 19.34, 37.16, 50.91, 6
0.07, 60.48, 101.29,104.13, 126.95, 127.45, 129.2
5, 131.41, 132.29,144.12, 145.77, 147.65, 167.83,
168.32[(+)-Ethylmethyl 4- (2-chlorophenyl) -1,4-dihydro-2-hydroxymethyl-6-methyl-3,5-pyridinedicarboxylate] Yield: 49% Optical purity: 90% ee [α] _D : + 14.8 ° (c = 1.0, Acetone) IR (neat): 3382, 1694, 1680cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.18 (3H, t, J = 7.3Hz , CH ₂ CH ₃ ), 2.3
1 (3H, s, CH ₃ ), 3.62 (3H, s, OCH ₃ ), 4.05 (2H, q, J = 7.3Hz, CH
₂ CH ₃ ), 4.73 (2H, ABq, J = 6.4Hz, CH ₂ O), 5.41 (1H, s,> CH-),
7,00-7.39 (5H, m, C ₆ He ₄ and NH) ¹³ C-NMR (CDCl ₃ ) ppm: 14.23, 19.34, 37.16, 50.91, 6
0.07, 60.48, 101.29, 104.13, 126.95, 127.45, 129.2
5, 131.41, 132.29, 144.12, 145.77, 147.65, 167.83,
168.32

【００４８】実施例１３実施例１２の方法に従い、リパーゼＰＳ又はコレステロ
ールエステラーゼについて同様に行った。結果を表１に
示す。Example 13 The same procedure as in Example 12 was carried out for lipase PS or cholesterol esterase. The results are shown in Table 1.

【００４９】[0049]

【表１】 [Table 1]

【００５０】実施例１４実施例４で得られたイソプロピルメチル２−アセトキ
シメチル−４−（２，３−ジクロロフェニル）−１，４
−ジヒドロ−６−メチル−３，５−ピリジンジカルボキ
シレート（１ｇ）にコレステロールエステラーゼ（３３
０ｍｇ）を用いて実施例１２と同様に行い、それぞれの
生成物を得た。Example 14 Isopropylmethyl 2-acetoxymethyl-4- (2,3-dichlorophenyl) -1,4 obtained in Example 4
-Dihydro-6-methyl-3,5-pyridinedicarboxylate (1 g) with cholesterol esterase (33
(0 mg) was used in the same manner as in Example 12 to obtain each product.

【００５１】収率、融点及び各種スペクトルデータを示
す。尚、光学純度は、ＨＰＬＣ分析（キラルセルＯＤ）
により決定した。〔（−）−イソプロピルメチル−２−アセトキシメチル
４−（２，３−ジクロロフェニル）−１，４−ジヒドロ
−６−メチル−３，５−ピリジンジカルボキシレート〕収率 : 50％光学純度 : 98%ee [α]_D : -37.6°(c=0.5, Acetone)The yield, melting point and various spectral data are shown. The optical purity was determined by HPLC analysis (chiralcel OD).
Determined by [(-)-Isopropylmethyl-2-acetoxymethyl 4- (2,3-dichlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate] Yield: 50% Optical purity: 98 % ee [α] _D : -37.6 ° (c = 0.5, Acetone)

【００５２】〔（＋）−イソプロピルメチル−４−
（２，３−ジクロロフェニル）−１，４−ジヒドロ−２
−ヒドロキシメチル−６−メチル−３，５−ピリジンジ
カルボキシレート〕収率 : 42％光学純度 : 92%ee [α]_D : +34.4°(c=0.5, Acetone) IR(neat) : 3500, 3380, 1700, 1686cm^-1 ¹ H-NMR(CDCl₃)ppm : 0.99, 1.25(6H,d,J=6.3Hz,CH₂(CH
₃)₂ ), 2.31(3H,s,CH₃), 3.62(3H,s,OCH₃), 4.74(2H,s,C
H₂O),4.93(1H,m,OCH), 5.45(1H,s,>CH-), 7,03-7.32(3
H,m,C₆H₃), 7.35(1H,s,NH)¹³ C-NMR(CDCl₃)ppm : 19.42, 21.50, 21.90, 38.51, 5
0.94, 60.51, 67.48,101.44, 103.69, 127.07, 128.26,
129.80, 130.87,132.74, 144.27, 147.62, 148.12, 16
7.15, 168.19[(+)-Isopropylmethyl-4-
(2,3-Dichlorophenyl) -1,4-dihydro-2
-Hydroxymethyl-6-methyl-3,5-pyridinedicarboxylate] Yield: 42% Optical purity: 92% ee [α] _D : + 34.4 ° (c = 0.5, Acetone) IR (neat): 3500, 3380, 1700, 1686cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 0.99, 1.25 (6H, d, J = 6.3Hz, CH ₂ ( CH
₃ ) ₂ ), 2.31 (3H, s, CH ₃ ), 3.62 (3H, s, OCH ₃ ), 4.74 (2H, s, C
H ₂ O), 4.93 (1H, m, OCH), 5.45 (1H, s,> CH-), 7,03-7.32 (3
H, m, C ₆ H ₃ ), 7.35 (1H, s, NH) ¹³ C-NMR (CDCl ₃ ) ppm: 19.42, 21.50, 21.90, 38.51, 5
0.94, 60.51, 67.48, 101.44, 103.69, 127.07, 128.26,
129.80, 130.87, 132.74, 144.27, 147.62, 148.12, 16
7.15, 168.19

【００５３】実施例１５実施例１４の方法に従って、リパーゼＡＨ、リパーゼＰ
Ｓについて同様に行った。結果を表２に示す。Example 15 Lipase AH, lipase P according to the method of Example 14
The same was done for S. The results are shown in Table 2.

【００５４】[0054]

【表２】 [Table 2]

【００５５】実施例１６実施例５で得られた２−アシロキシメチル体（各１ｇ）
にリパーゼＡＨ（０．５ｇ）を作用させ、実施例１２に
従い、生成物を得た。収率、融点及び各種スペクトルデ
ータを示す。Example 16 2-acyloxymethyl compound obtained in Example 5 (1 g each)
Lipase AH (0.5 g) was allowed to act on the above, and the product was obtained according to Example 12. The yield, melting point and various spectral data are shown.

【００５６】尚、光学純度は、ＨＰＬＣ分析（キラルセ
ルＯＤ）により決定した。〔（−）−エチルメチル２−アセトキシメチル−４
−（２，３−ジクロロフェニル）−１，４−ジヒドロ−
６−メチル−３，５−ピリジンジカルボキシレート〕収率 : 48％光学純度 : 99.5%ee [α]_D : -39.0°(c=1.0, Acetone)The optical purity was determined by HPLC analysis (chiralcel OD). [(-)-Ethylmethyl 2-acetoxymethyl-4
-(2,3-Dichlorophenyl) -1,4-dihydro-
6-Methyl-3,5-pyridinedicarboxylate] Yield: 48% Optical purity: 99.5% ee [α] _D : -39.0 ° (c = 1.0, Acetone)

【００５７】〔（＋）−エチルメチル４−（２，３
−ジクロロフェニル）−１，４−ジヒドロ−２−ヒドロ
キシメチル−６−メチル−３，５−ピリジンジカルボキ
シレート〕収率 : 45％光学純度 : 97.7%ee [α]_D : +26.8°(c=1.0, Acetone) IR(KBr) : 3440, 3320, 1700, 1675cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.16(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.3
1(3H,s,CH₃), 3.32(1H,t,J=4.8Hz,OH), 3.60(3H,s,C
H₃), 4.02(2H,q,J=7.0Hz,CH₂ CH₃), 4.72(2H,d,J=4.8Hz,
CH₂), 5.43(1H,s,>CH-), 6.91-7.36(3H,m,C₆H₃)¹³ C-NMR(CDCl₃)ppm : 14.25, 19.42, 38.46, 50.96, 6
0.11, 60.56, 101.19,103.98, 127.10, 128.35, 129.6
6, 130.91, 132.84,144.21, 147.56, 148.13, 167.51,
168.02[(+)-Ethylmethyl 4- (2,3
-Dichlorophenyl) -1,4-dihydro-2-hydroxymethyl-6-methyl-3,5-pyridinedicarboxylate] Yield: 45% Optical purity: 97.7% ee [α] _D : + 26.8 ° (c = 1.0, Acetone) IR (KBr): 3440, 3320, 1700, 1675cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.16 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.3
1 (3H, s, CH ₃ ), 3.32 (1H, t, J = 4.8Hz, OH), 3.60 (3H, s, C
H ₃ ), 4.02 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 4.72 (2H, d, J = 4.8Hz,
_{CH 2), 5.43 (1H,} s,> CH-), 6.91-7.36 (3H, m, C 6 H 3) 13 C-NMR (CDCl 3) ppm: 14.25, 19.42, 38.46, 50.96, 6
0.11, 60.56, 101.19, 103.98, 127.10, 128.35, 129.6
6, 130.91, 132.84, 144.21, 147.56, 148.13, 167.51,
168.02

【００５８】実施例１７実施例６で得られた２−アシロキシメチル体を用いて実
施例１６と同様に操作した。Example 17 The same operation as in Example 16 was carried out using the 2-acyloxymethyl derivative obtained in Example 6.

【００５９】〔（−）−エチルメチル２−アセトキ
シメチル−１，４−ジヒドロ−６−メチル−４−（３−
ニトロフェニル）−３，５−ピリジンジカルボキシレー
ト〕収率 : 45％光学純度 : 96.2%ee [α]_D : -36.9°(c=1.0, Acetone)[(-)-Ethylmethyl 2-acetoxymethyl-1,4-dihydro-6-methyl-4- (3-
Nitrophenyl) -3,5-pyridinedicarboxylate] Yield: 45% Optical purity: 96.2% ee [α] _D : -36.9 ° (c = 1.0, Acetone)

【００６０】〔（＋）−エチルメチル−１，４−ジヒ
ドロ−２−ヒドロキシメチル−６−メチル−４−（３−
ニトロフェニル）−３，５−ピリジンジカルボキシレー
ト〕収率 : 35％光学純度 : 93.6%ee [α]_D : +27.7°(c=1.0, Acetone) IR(KBr) : 3450, 3310, 1680cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.21(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.3
8(3H,s,CH₃), 3.13(1H,t,J=4.8Hz,OH), 3.62(3H,s,C
H₃), 4.06(2H,q,J=7.0Hz,CH₂ CH₃), 4.77(2H,d,J=4.8Hz,
CH₂), 5.06(1H,s,>CH-), 7.16-7.36, 7.40-7.70, 7.82-
8.12(4H,m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.31, 19.71, 39.88, 51.25, 6
0.22, 60.56, 100.63,103.53, 121.54, 122.96, 128.8
1, 134.38, 145.00,147.73, 148.36, 149.72, 167.05,
167.73[(+)-Ethylmethyl-1,4-dihydro-2-hydroxymethyl-6-methyl-4- (3-
Nitrophenyl) -3,5-pyridinedicarboxylate] Yield: 35% optical _{purity: 93.6% ee [α] D} : + 27.7 ° (c = 1.0, Acetone) IR (KBr): 3450, 3310, 1680cm - ¹ ¹ H-NMR (CDCl ₃ ) ppm: 1.21 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.3
8 (3H, s, CH ₃ ), 3.13 (1H, t, J = 4.8Hz, OH), 3.62 (3H, s, C
H ₃ ), 4.06 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 4.77 (2H, d, J = 4.8Hz,
CH ₂ ), 5.06 (1H, s,> CH-), 7.16-7.36, 7.40-7.70, 7.82-
8.12 (4H, m, C ₆ H ₄ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.31, 19.71, 39.88, 51.25, 6
0.22, 60.56, 100.63, 103.53, 121.54, 122.96, 128.8
1, 134.38, 145.00, 147.73, 148.36, 149.72, 167.05,
167.73

【００６１】実施例１８実施例７で得られた２−アシロキシメチル体を用いて実
施例１６と同様に操作した。Example 18 The same operation as in Example 16 was carried out using the 2-acyloxymethyl derivative obtained in Example 7.

【００６２】〔（＋）−エチルメチル２−アセトキ
シメチル−１，４−ジヒドロ−６−メチル−４−（２−
ニトロフェニル）−３，５−ピリジンジカルボキシレー
ト〕収率 : 33％光学純度 : 98.3%ee [α]_D : +47.0°(c=1.0, Acetone)[(+)-Ethylmethyl 2-acetoxymethyl-1,4-dihydro-6-methyl-4- (2-
Nitrophenyl) -3,5-pyridinedicarboxylate] Yield: 33% Optical purity: 98.3% ee [α] _D : + 47.0 ° (c = 1.0, Acetone)

【００６３】〔（−）−エチルメチル１，４−ジヒ
ドロ−２−ヒドロキシメチル−６−メチル−４−（２−
ニトロフェニル）−３，５−ピリジンジカルボキシレー
ト〕収率 : 43％光学純度 : 94.3%ee [α]_D : -27.0°(c=1.0, Acetone) IR(neat) : 3450, 3350, 1725, 1685cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.03(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.3
2(3H,s,CH₃), 3.55(3H,s,CH₃O), 3.98, 4.02,(2H,dq,J=
7.0Hz,J=2.4Hz,CH₂ CH₃), 4.74(2H,s,CH₂), 5.76(1H,s,>
CH-), 7.00-7.76(4H,m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.08, 19.54, 34.54, 51.07, 6
0.22, 60.56, 101.19,104.83, 123.98, 127.10, 131.3
1, 132.90, 142.28,144.78, 147.73, 148.07, 167.28,
167.73[(-)-Ethylmethyl 1,4-dihydro-2-hydroxymethyl-6-methyl-4- (2-
Nitrophenyl) -3,5-pyridinedicarboxylate] Yield: 43% Optical purity: 94.3% ee [α] _D : -27.0 ° (c = 1.0, Acetone) IR (neat): 3450, 3350, 1725, 1685cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.03 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.3
2 (3H, s, CH ₃ ), 3.55 (3H, s, CH ₃ O), 3.98, 4.02, (2H, dq, J =
7.0Hz, J = 2.4Hz, CH ₂ CH ₃ ), 4.74 (2H, s, CH ₂ ), 5.76 (1H, s,>
CH-), 7.00-7.76 (4H, m , C 6 H 4) 13 C-NMR (CDCl 3) ppm: 14.08, 19.54, 34.54, 51.07, 6
0.22, 60.56, 101.19, 104.83, 123.98, 127.10, 131.3
1, 132.90, 142.28, 144.78, 147.73, 148.07, 167.28,
167.73

【００６４】実施例１９実施例８で得られた２−アシロキシメチル体を用いて実
施例１６と同様に操作した。〔（−）−エチルメチル２−アセトキシメチル−４
−（２−トリフルオロメチルフェニル）−１，４−ジヒ
ドロ−６−メチル−３，５−ピリジンジカルボキシレー
ト〕収率 : 44％光学純度 : 89.9%ee [α]_D : -20.3°(c=1.0, Acetone)Example 19 The same operation as in Example 16 was carried out using the 2-acyloxymethyl derivative obtained in Example 8. [(-)-Ethylmethyl 2-acetoxymethyl-4
-(2-Trifluoromethylphenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate] Yield: 44% Optical purity: 89.9% ee [α] _D : -20.3 ° (c = 1.0, Acetone)

【００６５】〔（＋）−エチルメチル４−（２−ト
リフルオロメチルフェニル）−１，４−ジヒドロ−２−
ヒドロキシメチル−６−メチル−３，５−ピリジンジカ
ルボキシレート〕収率 : 44％光学純度 : 99.9%ee [α]_D : +5.5°(c=1.0, Acetone) IR(KBr) : 3430, 3350, 1717, 1691, 1670cm
^-1 ¹ H-NMR(CDCl₃)ppm : 1.12(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.3
0(3H,s,CH₃), 3.19(1H,t,J=3.6Hz), 3.56(3H,s,CH₃),
3.99(2H,dq,J=7.0Hz,J=2.4Hz,CH₂ CH₃), 4.72(2H,d,J=3.
6Hz,CH₂O),5.54(1H,s,>CH-), 7.08(1H,s,NH), 7.16-7.6
2(4H,m,C₆H₄)¹³ C-NMR(CDCl₃)ppm : 14.08, 19.42, 35.56, 50.90 ,6
0.11, 60.91, 102.67,105.51, 125.80, 126.14, 126.4
8, 126.65, 126.76,127.84, 131.37, 132.05, 143.53,
147.05, 147.28,167.68, 168.13[(+)-Ethylmethyl 4- (2-trifluoromethylphenyl) -1,4-dihydro-2-
Hydroxymethyl-6-methyl-3,5-pyridinedicarboxylate] Yield: 44% Optical purity: 99.9% ee [α] _D : + 5.5 ° (c = 1.0, Acetone) IR (KBr): 3430, 3350 , 1717, 1691, 1670cm
^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.12 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.3
0 (3H, s, CH ₃ ), 3.19 (1H, t, J = 3.6Hz), 3.56 (3H, s, CH ₃ ),
3.99 (2H, dq, J = 7.0Hz, J = 2.4Hz, CH ₂ CH ₃ ), 4.72 (2H, d, J = 3.
6Hz, CH ₂ O), 5.54 (1H, s,> CH-), 7.08 (1H, s, NH), 7.16-7.6
_{2 (4H, m, C 6} H 4) 13 C-NMR (CDCl 3) ppm: 14.08, 19.42, 35.56, 50.90, 6
0.11, 60.91, 102.67, 105.51, 125.80, 126.14, 126.4
8, 126.65, 126.76, 127.84, 131.37, 132.05, 143.53,
147.05, 147.28,167.68, 168.13

【００６６】実施例２０実施例９で得られた２−アシロキシメチル体を用いて実
施例１６と同様に操作した。〔（−）−エチルメチル２−アセトキシメチル−
１，４−ジヒドロ−６−メチル−４−フェニル−３，５
−ピリジンジカルボキシレート〕収率 : 43％光学純度 : 99.8%ee [α]_D : -35.9°(c=1.0, Acetone)Example 20 The procedure of Example 16 was repeated using the 2-acyloxymethyl derivative obtained in Example 9. [(-)-Ethylmethyl 2-acetoxymethyl-
1,4-dihydro-6-methyl-4-phenyl-3,5
-Pyridine dicarboxylate] Yield: 43% Optical purity: 99.8% ee [α] _D : -35.9 ° (c = 1.0, Acetone)

【００６７】〔（＋）−エチルメチル１，４−ジヒ
ドロ−２−ヒドロキシメチル−６−メチル−４−フェニ
ル−３，５−ピリジンジカルボキシレート〕収率 : 45％光学純度 : 95.6%ee [α]_D : +18.9°(c=1.0, Acetone) IR(KBr) : 3470, 3350, 1685, 1662cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.20(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.3
2(3H,s,CH₃), 3.32(1H,t,J=4.8Hz,OH), 3.60(3H,s,C
H₃), 4.03(2H,q,J=7.0Hz,CH₂ CH₃), 4.68(2H,d,J=4.8Hz,
CH₂), 4.93(1H,s,>CH-), 6.98-7.32(5H,m,C₆H₅)¹³ C-NMR(CDCl₃)ppm : 14.25, 19.54, 39.48, 51.02, 6
0.00, 60.68, 101.59,104.26, 126.31, 127.84, 128.0
1, 144.21, 147.11,147.50, 167.68, 168.25[(+)-Ethylmethyl 1,4-dihydro-2-hydroxymethyl-6-methyl-4-phenyl-3,5-pyridinedicarboxylate] Yield: 45% Optical purity: 95.6% ee [ α] _D : + 18.9 ° (c = 1.0, Acetone) IR (KBr): 3470, 3350, 1685, 1662cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.20 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.3
2 (3H, s, CH ₃ ), 3.32 (1H, t, J = 4.8Hz, OH), 3.60 (3H, s, C
H ₃ ), 4.03 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 4.68 (2H, d, J = 4.8Hz,
CH ₂ ), 4.93 (1H, s,> CH-), 6.98-7.32 (5H, m, C ₆ H ₅ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.25, 19.54, 39.48, 51.02, 6
0.00, 60.68, 101.59, 104.26, 126.31, 127.84, 128.0
1, 144.21, 147.11, 147.50, 167.68, 168.25

【００６８】実施例２１実施例１０で得られた２−アシロキシメチル体を用いて
実施例１６と同様に操作した。〔（−）−エチルメチル２−アセトキシメチル−
１，４−ジヒドロ−４，６−ジメチル−３，５−ピリジ
ンジカルボキシレート〕収率 : 40％光学純度 : 64.2%ee [α]_D : -18.2°(c=1.0, Acetone)Example 21 The same operation as in Example 16 was carried out using the 2-acyloxymethyl derivative obtained in Example 10. [(-)-Ethylmethyl 2-acetoxymethyl-
1,4-dihydro-4,6-dimethyl-3,5-pyridinedicarboxylate] Yield: 40% Optical purity: 64.2% ee [α] _D : -18.2 ° (c = 1.0, Acetone)

【００６９】〔（＋）−エチルメチル１，４−ジヒ
ドロ−２−ヒドロキシメチル−４，６−ジメチル−３，
５−ピリジンジカルボキシレート〕収率 : 32％光学純度 : 74.8%ee [α]_D : +5.5°(c=1.0, Acetone) IR(neat) : 3450, 3350, 1700, 1685, 1670cm
^-1 ¹ H-NMR(CDCl₃)ppm : 0.94(3H,d,J=6.8Hz,CH₃), 1.26(3
H,t,J=7.0Hz,CH₂ CH₃ ),2.26(3H,s,CH₃), 3.72(3H,s,C
H₃), 3.83(1H,q,J=6.8Hz,>CH-), 4.14(2H,q,J=7.0Hz,CH
₂ CH₃), 4.65(2H,s,CH₂),7.11(1H,s,NH)¹³ C-NMR(CDCl₃)ppm : 14.42, 19.37, 22.38, 28.40, 5
1.02, 59.83, 60.62,102.10, 104.66, 144.78, 147.68,
167.90, 168.47[(+)-Ethylmethyl 1,4-dihydro-2-hydroxymethyl-4,6-dimethyl-3,
5-Pyridinedicarboxylate] Yield: 32% Optical purity: 74.8% ee [α] _D : + 5.5 ° (c = 1.0, Acetone) IR (neat): 3450, 3350, 1700, 1685, 1670cm
^-1 ¹ H-NMR (CDCl ₃ ) ppm: 0.94 (3H, d, J = 6.8Hz, CH ₃ ), 1.26 (3
H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.26 (3H, s, CH ₃ ), 3.72 (3H, s, C
H ₃ ), 3.83 (1H, q, J = 6.8Hz,> CH-), 4.14 (2H, q, J = 7.0Hz, CH
₂ CH ₃ ), 4.65 (2H, s, CH ₂ ), 7.11 (1H, s, NH) ¹³ C-NMR (CDCl ₃ ) ppm: 14.42, 19.37, 22.38, 28.40, 5
1.02, 59.83, 60.62, 102.10, 104.66, 144.78, 147.68,
167.90, 168.47

【００７０】実施例２２実施例１１で得られた２−アシロキシメチル体を用いて
実施例１６と同様に操作した。〔（−）−エチルメチル２−アセトキシメチル−４
−ベンジル−１，４−ジヒドロ−６−メチル−３，５−
ピリジンジカルボキシレート〕収率 : 30％光学純度 : 96.5%ee [α]_D : -19.5°(c=1.0, Acetone)Example 22 The 2-acyloxymethyl derivative obtained in Example 11 was used and operated in the same manner as in Example 16. [(-)-Ethylmethyl 2-acetoxymethyl-4
-Benzyl-1,4-dihydro-6-methyl-3,5-
Pyridinedicarboxylate] Yield: 30% Optical purity: 96.5% ee [α] _D : -19.5 ° (c = 1.0, Acetone)

【００７１】〔（−）−エチルメチル４−ベンジル
−１，４−ジヒドロ−２−ヒドロキシメチル−６−メチ
ル−３，５−ピリジンジカルボキシレート〕収率 : 48％光学純度 : 71.4%ee [α]_D : -3.3°(c=1.0, Acetone) IR(neat) : 3450, 3360, 1690, 1680cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.19(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.2
0(3H,s,CH₃), 2.53(2H,d,J=5.4Hz,CH₂), 3.56(3H,s,C
H₃), 3.97(2H,q,J=7.0Hz,CH₂ CH₃), 4.12(1H,t,J=5.4Hz,
>CH-), 4.58(1H,s,NH), 6.76-7.24(5H,m,C₆H₅)¹³ C-NMR(CDCl₃)ppm : 14.31, 19.14, 35.39, 42.55, 5
0.96, 59.83, 60.56,99.55, 102.27, 125.74, 127.39,
130.06, 139.04,145.63, 148.64, 167.96, 168.42[(−)-Ethylmethyl 4-benzyl-1,4-dihydro-2-hydroxymethyl-6-methyl-3,5-pyridinedicarboxylate] Yield: 48% Optical purity: 71.4% ee [ α] _D : -3.3 ° (c = 1.0, Acetone) IR (neat): 3450, 3360, 1690, 1680cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.19 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.2
0 (3H, s, CH ₃ ), 2.53 (2H, d, J = 5.4Hz, CH ₂ ), 3.56 (3H, s, C
H ₃ ), 3.97 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 4.12 (1H, t, J = 5.4Hz,
> CH-), 4.58 (1H, s, NH), 6.76-7.24 (5H, m, C 6 H 5) 13 C-NMR (CDCl 3) ppm: 14.31, 19.14, 35.39, 42.55, 5
0.96, 59.83, 60.56,99.55, 102.27, 125.74, 127.39,
130.06, 139.04, 145.63, 148.64, 167.96, 168.42

【００７２】実施例２３実施例５で得られたエチルメチル２−アセトキシメ
チル−４−（２，３−ジクロロフェニル）−１，４−ジ
ヒドロ−６−メチル−３，５−ピリジンジカルボキシレ
ート（17.69g）をメタノール（300ml）に懸濁させ、そ
こへ濃アンモニウム水（10ml）を加え、室温で３時間攪
拌した。メタノールを濃縮し、残渣をジクロロメタンに
溶解させ、、水洗後、硫酸マグネシウムにて乾燥、ろ
去、ジクロロメタンを濃縮して得た残渣をメタノールで
結晶化させ、黄色結晶（11.5g，72％）を得た。〔エチルメチル４−（２，３−ジクロロフェニル）
−１，４−ジヒドロ−２−ヒドロキシメチル−６−メチ
ル−３，５−ピリジッッジカルボキシレート〕Example 23 Ethyl methyl 2-acetoxymethyl-4- (2,3-dichlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate obtained in Example 5 (17.69) g) was suspended in methanol (300 ml), concentrated ammonium water (10 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Methanol was concentrated, the residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate, filtered off, and the residue obtained by concentrating dichloromethane was crystallized with methanol to give yellow crystals (11.5 g, 72%). Obtained. [Ethyl methyl 4- (2,3-dichlorophenyl)
-1,4-Dihydro-2-hydroxymethyl-6-methyl-3,5-pyrididge carboxylate]

【００７３】実施例２４上記で得られた２−ヒドロキシメチル体（4.0g）をピリ
ジン（50ml）に溶解し、無水プロピオン酸（1.95g）を
加え、室温で18時間攪拌した。ピリジンを濃縮して得ら
れた残渣をジクロロメタンに溶解させ、希塩酸、水、飽
和食塩水で洗浄後、硫酸マグネシウムで乾燥した。ろ過
後、ジクロロメタンを留去して得られた残渣をエーテル
−ヘキサンで再結晶し、黄色結晶（3.0g，65％）を得
た。〔エチルメチル４−（２，３−ジクロロフェニル）
−１，４−ジヒドロ−６−メチル−２−プロピオニルオ
キシメチル−３，５−ピリジンジカルボキシレート〕Example 24 The 2-hydroxymethyl derivative (4.0 g) obtained above was dissolved in pyridine (50 ml), propionic anhydride (1.95 g) was added, and the mixture was stirred at room temperature for 18 hours. The residue obtained by concentrating pyridine was dissolved in dichloromethane, washed with diluted hydrochloric acid, water, and saturated saline, and then dried over magnesium sulfate. After filtration, dichloromethane was distilled off and the obtained residue was recrystallized from ether-hexane to obtain yellow crystals (3.0 g, 65%). [Ethyl methyl 4- (2,3-dichlorophenyl)
-1,4-Dihydro-6-methyl-2-propionyloxymethyl-3,5-pyridinedicarboxylate]

【００７４】融点及び各種スペクトルデータを示す。 mp : 109-112℃ IR(KBr) : 3330, 1735, 1700, 1680cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.17(3H,t,J=7.0Hz,CH₂ CH₃ ), 1.1
9(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.30(3H,s,CH₃), 2.42(2H,q,
J=7.0Hz,CH₂ CH₃), 3.60(3H,s,CH₃), 4.06(2H,q,J=7.0H
z,CH₂ CH₃), 5.06, 5.40(2H,d,J=15.6Hz,>CH-), 5.45(1
H,s,>CH-), 6.60(1H,s,NH), 6.92-7.38(3H,m,C₆H₃)¹³ C-NMR(CDCl₃)ppm : 9.08, 14.20, 19.59, 27.49, 38.
63, 50.90, 60.28,61.19, 103.52, 104.55, 127.10, 12
8.47, 129.66,131.03,132.96, 142.05, 143.92, 147.5
6, 166.54,167.62, 174.10The melting point and various spectral data are shown. mp: 109-112 ℃ IR (KBr): 3330, 1735, 1700, 1680cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.17 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 1.1
9 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.30 (3H, s, CH ₃ ), 2.42 (2H, q,
J = 7.0Hz, CH ₂ CH ₃ ), 3.60 (3H, s, CH ₃ ), 4.06 (2H, q, J = 7.0H
z, CH ₂ CH ₃ ), 5.06, 5.40 (2H, d, J = 15.6Hz,> CH-), 5.45 (1
H, s,> CH-), 6.60 (1H, s, NH), 6.92-7.38 (3H, m, C 6 H 3) 13 C-NMR (CDCl 3) ppm: 9.08, 14.20, 19.59, 27.49, 38 .
63, 50.90, 60.28, 61.19, 103.52, 104.55, 127.10, 12
8.47, 129.66, 131.03, 132.96, 142.05, 143.92, 147.5
6, 166.54, 167.62, 174.10

【００７５】実施例２５実施例２４に従い、無水酪酸を用い、２−ブチロイルオ
キシメチル体（65％）を得た。融点及び各種スペクトル
データを示す。〔エチルメチル２−ブチロイルオキシメチル−４−
（２，３−ジクロロフェニル）−１，４−ジヒドロ−６
−メチル−３，５−ピリジンジカルボキシレート〕 mp : 96-98℃ IR(KBr) : 3340, 1735, 1700, 1680cm^-1 ¹ H-NMR(CDCl₃)ppm : 0.97(3H,t,J=7.0Hz,CH₂CH₂ CH₃ ),
1.17(3H,t,J=7.0Hz,CH₂ CH₃ ), 1.69(2H,m,CH₂ CH₂ CH₃),
2.30(3H,s,CH₃),2.39(2H,t,J=7.0Hz,CH₂ CH₂CH₃), 3.59
(3H,s,CH₃),4.06(2H,q,J=7.0Hz,CH₂ CH₃), 5.14, 5.44(2
H,d,J=15.7Hz,CH₂O), 5.46(1H,s,>CH-), 6.60(1H,s,N
H),6.84-7.36(3H,m,C₆H₃)¹³ C-NMR(CDCl₃)ppm : 13.63, 14.20, 18.46, 19.59, 3
6.02, 38.63, 50.90,60.28, 61.08, 103.52, 104.60, 1
27.10, 128.47,129.66, 131.03, 132.96, 142.11, 143.
92, 147.56,166.54, 167.62, 173.36Example 25 According to Example 24, butyric anhydride was used to obtain a 2-butyroyloxymethyl compound (65%). The melting point and various spectral data are shown. [Ethyl methyl 2-butyroyloxymethyl-4-
(2,3-Dichlorophenyl) -1,4-dihydro-6
-Methyl-3,5-pyridinedicarboxylate] mp: 96-98 ° C IR (KBr): 3340, 1735, 1700, 1680cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 0.97 (3H, t, J = 7.0Hz, CH ₂ CH ₂ CH ₃ ),
1.17 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 1.69 (2H, m, CH ₂ CH ₂ CH ₃ ),
2.30 (3H, s, CH ₃ ), 2.39 (2H, t, J = 7.0Hz, CH ₂ CH ₂ CH ₃ ), 3.59
(3H, s, CH ₃ ), 4.06 (2H, q, J = 7.0Hz, CH ₂ CH ₃ ), 5.14, 5.44 (2
H, d, J = 15.7Hz, CH ₂ O), 5.46 (1H, s,> CH-), 6.60 (1H, s, N
H), 6.84-7.36 (3H, m, C ₆ H ₃ ) ¹³ C-NMR (CDCl ₃ ) ppm: 13.63, 14.20, 18.46, 19.59, 3
6.02, 38.63, 50.90, 60.28, 61.08, 103.52, 104.60, 1
27.10, 128.47,129.66, 131.03, 132.96, 142.11, 143.
92, 147.56, 166.54, 167.62, 173.36

【００７６】実施例２６実施例２４に従い、無水安息香酸を用い、２−ベンゾイ
ルオキシメチル体（78％）を得た。融点及び各種スペク
トルデータを示す。〔エチルメチル２−ベンゾイルオキシメチル−４−
（２，３−ジクロロフェニル）−１，４−ジヒドロ−６
−メチル−３，５−ピリジンジカルボキシレート〕 mp : 119-123℃ IR(KBr) : 3340, 1728, 1695, 1685cm^-1 ¹ H-NMR(CDCl₃)ppm : 1.20(3H,t,J=7.0Hz,CH₂ CH₃ ), 2.2
8(3H,s,CH₃), 3.59(3H,s,CH₃), 4.09(2H,q,J=7.0Hz,CH₂
CH₃), 5.36, 5.66(2H,d,J=15.7Hz,CH₂O), 5.52(1H,s,>C
H-), 6.74(1H,s,NH), 7.10-7.64, 7.90-8.16(8H,m,C₆H₅
and C₆H₃)¹³ C-NMR(CDCl₃)ppm : 14.25, 19.65, 38.69, 50.96, 6
0.39, 61.70, 103.47,105.11, 127.16, 128.53, 128.7
0, 129.15, 129.78,131.03, 132.96, 133.75, 142.11,
144.04, 147.62,166.60, 167.62(C×2)Example 26 According to Example 24, benzoyl anhydride was used to obtain a 2-benzoyloxymethyl compound (78%). The melting point and various spectral data are shown. [Ethyl methyl 2-benzoyloxymethyl-4-
(2,3-Dichlorophenyl) -1,4-dihydro-6
-Methyl-3,5-pyridinedicarboxylate] mp: 119-123 ° C IR (KBr): 3340, 1728, 1695, 1685 cm ^-1 ¹ H-NMR (CDCl ₃ ) ppm: 1.20 (3H, t, J = 7.0Hz, CH ₂ CH ₃ ), 2.2
8 (3H, s, CH ₃ ), 3.59 (3H, s, CH ₃ ), 4.09 (2H, q, J = 7.0Hz, CH ₂
CH ₃ ), 5.36, 5.66 (2H, d, J = 15.7Hz, CH ₂ O), 5.52 (1H, s,> C
H-), 6.74 (1H, s, NH), 7.10-7.64, 7.90-8.16 (8H, m, C ₆ H ₅
and C ₆ H ₃ ) ¹³ C-NMR (CDCl ₃ ) ppm: 14.25, 19.65, 38.69, 50.96, 6
0.39, 61.70, 103.47, 105.11, 127.16, 128.53, 128.7
0, 129.15, 129.78, 131.03, 132.96, 133.75, 142.11,
144.04, 147.62, 166.60, 167.62 (C x 2)

【００７７】実施例２７実施例２５で得られた２−アシロキシメチル体について
リパーゼＡＨを用い実施例１６の方法に従い、生成物を
得た。それぞれの光学純度と比旋光度を示す。〔（−）−エチルメチル２−プロピオニルオキシメ
チル体〕収率 : 46％光学純度 : 89.2%ee [α]_D : -40.2°(c=1.0, Acetone) 〔（＋）−エチルメチル２−ヒドロキシメチル体〕収率 : 40％光学純度 : 98.5%ee [α]_D : +23.0°(c=1.0, Acetone)Example 27 A product was obtained from the 2-acyloxymethyl derivative obtained in Example 25 by using Lipase AH according to the method of Example 16. The optical purity and the specific rotation of each are shown. [(−)-Ethylmethyl 2-propionyloxymethyl derivative] Yield: 46% Optical purity: 89.2% ee [α] _D : -40.2 ° (c = 1.0, Acetone) [(+)-Ethylmethyl 2-hydroxy Methyl form] Yield: 40% Optical purity: 98.5% ee [α] _D : + 23.0 ° (c = 1.0, Acetone)

【００７８】実施例２８実施例２６で得られた２−アシロキシメチル体について
リパーゼＡＨを用い実施例１６の方法に従い、生成物を
得た。それぞれの光学純度と比旋光度を示す。〔（−）−エチルメチル２−ブチロイルオキシメチ
ル体〕収率 : 38％光学純度 : 95.3%ee [α]_D : -40.6°(c=1.0, Acetone) 〔（＋）−エチルメチル２−ヒドロキシメチル体〕収率 : 44％光学純度 : 98.9%ee [α]_D : +22.4°(c=1.0, Acetone)Example 28 A product was obtained from the 2-acyloxymethyl derivative obtained in Example 26 by using Lipase AH according to the method of Example 16. The optical purity and the specific rotation of each are shown. [(−)-Ethylmethyl 2-butyroyloxymethyl derivative] Yield: 38% Optical purity: 95.3% ee [α] _D : -40.6 ° (c = 1.0, Acetone) [(+)-Ethylmethyl 2- Hydroxymethyl derivative] Yield: 44% Optical purity: 98.9% ee [α] _D : + 22.4 ° (c = 1.0, Acetone)

【００７９】実施例２９実施例２６で得られた２−ベンゾイルオキシメチル体に
ついてリパーゼＡＹを用い、実施例１６の方法に従い、
生成物を得た。それぞれの光学純度と比旋光度を示す。〔（−）−エチルメチル２−ベンゾイルオキシメチ
ル体〕収率 : 42％光学純度 : 36.5%ee [α]_D : -8.4°(c=1.0, Acetone) 〔（＋）−エチルメチル２−ヒドロキシメチル体〕収率 : 23％光学純度 : 37.8%ee [α]_D : +10.9°(c=1.0, Acetone)Example 29 According to the method of Example 16, using lipase AY for the 2-benzoyloxymethyl derivative obtained in Example 26,
The product was obtained. The optical purity and the specific rotation of each are shown. [(−)-Ethylmethyl 2-benzoyloxymethyl derivative] Yield: 42% Optical purity: 36.5% ee [α] _D : -8.4 ° (c = 1.0, Acetone) [(+)-Ethylmethyl 2-hydroxy Methyl form] Yield: 23% Optical purity: 37.8% ee [α] _D : + 10.9 ° (c = 1.0, Acetone)

【００８０】[0080]

【発明の効果】このように、本発明の前記式［Ｉ］で表
すラセミの１，４−ジヒドロピリジン化合物を酵素触媒
による加水分解で、前記式［ＩＩＩ］で表される光学活
性１，４−ジヒドロピリジン化合物を不斉収率、反応収
率共に優れた結果で得られた。本発明により、従来ラセ
ミ体として開発、医薬として医療に供されている多くの
１，４−ジヒドロピリジン系医薬品を光学活性体として
開発、医療に供する新規方法を見い出した。As described above, the racemic 1,4-dihydropyridine compound represented by the above formula [I] of the present invention is hydrolyzed by an enzyme catalyst to obtain the optically active 1,4-dihydropyridine compound represented by the above formula [III]. The dihydropyridine compound was obtained with excellent asymmetric yield and reaction yield. According to the present invention, a novel method has been found in which many 1,4-dihydropyridine drugs, which have been conventionally developed as racemates and used as medicines for medical treatment, are developed as optical active bodies and used for medical treatment.

───────────────────────────────────────────────────── フロントページの続き (72)発明者佐々木征治愛知県西春日井郡西春町大字九之坪西城屋敷51 天野製薬株式会社中央研究所内 (72)発明者阿知波一雄静岡県静岡市上沓谷町15−５ ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Seiji Sasaki Seiji Sasaki, Nishiharu Kasugai-gun, Aichi 51 Kunotsubo Saijo Yashiki 51, Amano Pharmaceutical Co., Ltd. Central Research Laboratory (72) Inventor Kazuo Achinami 15-5 Kamizaya, Shizuoka, Shizuoka Prefecture

Claims

[Claims]

1. A compound represented by the general formula [I]: [Wherein X is the following general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group.) Or an alkyl group, R ₄ , R ₅ and R ₆ represent a lower alkyl group, R ₇ represents an acyl group, and R ₈ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group. ] The enzyme is allowed to act on the 1,4-dihydropyridine compound represented by the general formula [III] [Wherein X is the following general formula [II] (In the formula, R ₁ , R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a nitrile group or a trifluoromethyl group.) Or an alkyl group, R ₄ , R ₅ and R ₆ represent a lower alkyl group, R ₈ represents a hydrogen atom, a lower alkoxymethyl group or a lower acyloxymethyl group, R ₉ represents an acyl group or a hydrogen atom, and * represents an optically active point. ] The manufacturing method of the 1, 4- dihydro pyridine compound represented by these.