JPH08333339A - Production of optically active piperidineacetic acid derivative - Google Patents

Production of optically active piperidineacetic acid derivative

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Publication number
JPH08333339A
JPH08333339A JP14144495A JP14144495A JPH08333339A JP H08333339 A JPH08333339 A JP H08333339A JP 14144495 A JP14144495 A JP 14144495A JP 14144495 A JP14144495 A JP 14144495A JP H08333339 A JPH08333339 A JP H08333339A
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JP
Japan
Prior art keywords
optically active
acid
ester
acetic acid
compound
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Pending
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JP14144495A
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Japanese (ja)
Inventor
Masayasu Fukagawa
Masaharu Ichihara
Ryoichi Kawakami
Hiroshi Yamazaki
廣志 山崎
良一 川上
正治 市原
雅保 深川
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Fujisawa Pharmaceut Co Ltd
藤沢薬品工業株式会社
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Application filed by Fujisawa Pharmaceut Co Ltd, 藤沢薬品工業株式会社 filed Critical Fujisawa Pharmaceut Co Ltd
Priority to JP14144495A priority Critical patent/JPH08333339A/en
Publication of JPH08333339A publication Critical patent/JPH08333339A/en
Application status is Pending legal-status Critical

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Abstract

PURPOSE: To obtain a compound useful as an intermediate for producing a compound which is an excellent adenosine antagonist, useful in the field of medicine industry and having extremely high optical purity in good yield.
CONSTITUTION: This optically active piperidineacetic acid derivative, e. g. (R)-2-(2-piperidyl)acetic acid benzyl ester.L-tartaric acid salt can be produced by leading a racemic modification of a piperidineacetic acid derivative such as 2-(2-piperidyl)acetic acid expressed by the formula (R is a protected carboxy group such as benzyloxycarbonyl group) to a diastereomer using an optically active acid such as L-tartaric acid, D-mandelic acid or D-10-camphorsulfonic acid, carrying out fractional crystallization of the diastereomer and as necessary further, decomposing the separated crystal to the resolving reagent and the original compound.
COPYRIGHT: (C)1996,JPO

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【産業上の利用分野】本発明は、優れたアデノシン拮抗剤であるピラゾロピリジン化合物を製造するための中間体として有用な光学活性なピペリジン酢酸誘導体の製造法に関するものであり、医薬品産業の分野において有用である。 BACKGROUND OF THE INVENTION This invention relates to the preparation of useful optically active piperidine acetic acid derivatives as intermediates for the preparation of pyrazolopyridine compound is an excellent adenosine antagonists, the field of pharmaceutical industry in useful.

【0002】 [0002]

【従来の技術】従来光学活性なピペリジン酢酸誘導体を製造するに当っては、ピペリジンエタノールの段階で光学分割し[例えば、ジャーナル・オブ・アメリカン・ケミカル・ソサイエティー(J.Am.Chem.So It is hitting the producing Conventionally optically active piperidine acetic acid derivatives, optical resolution in the stage of piperidineethanol [e.g., Journal of American Chemical Society (J.Am.Chem.So
c. c. )、第82巻、2613頁(1960年)]、得られた光学活性なピペリジンエタノールを酸化してピペリジン酢酸へと導く必要があった。 ), 82 vol., 2613, pp (1960)], it was necessary to oxidize the resulting optically active piperidine ethanol leads to piperidine acetate.

【0003】 [0003]

【発明が解決しようとする課題】上記の方法では、光学分割の段階での光学純度が低いという欠点があり、また、トータルでの収率が低いという問題があった。 In the above method [0006] There optical purity disadvantage that lower at the stage of optical resolution, also, the yield in total is low.

【0004】 [0004]

【課題を解決するための手段】本発明者らは、ピペリジン酢酸誘導体を直接光学分割することにより上記の課題を解決できることを見い出し、本発明を完成した。 The present inventors have SUMMARY OF THE INVENTION It finds that can solve the above problems by directly optically resolved piperidine acetic acid derivatives, and accomplished the present invention.

【0005】本発明の光学活性なピペリジン酢酸誘導体の製造法は、一般式(I): The preparation method of an optically active piperidine acetic acid derivatives of the present invention is the general formula (I):

【化2】 ## STR2 ## (式中、Rは保護されたカルボキシ基を意味する)で示されるピペリジン酢酸誘導体のラセミ体を、光学活性な酸を用いて光学分割して、一般式(I)で示される化合物の光学活性体を得ることからなる。 (Wherein, R refers to a protected carboxy group) Racemic piperidine acetic acid derivatives represented by, and optical resolution using an optically active acid, the general formula optically active compounds of formula (I) It consists of obtaining the body.

【0006】化合物(I)における好適な「保護されたカルボキシ基」としては、エステル化されたカルボキシ基が挙げられ、それらのエステル化されたカルボキシ基のエステル部分の具体例としては、例えばメチルエステル、エチルエステル、プロピルエステル、イソプロピルエステル、ブチルエステル、イソブチルエステル、第三級ブチルエステル、ペンチルエステル、ヘキシルエステル、1−シクロプロピルエチルエステル等の低級アルキルエステルが挙げられる。 [0006] Suitable "protected carboxy group" in the compound (I), include esterified carboxy group, specific examples of the ester moiety thereof esterified carboxy group, for example methyl ester , ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, include lower alkyl esters such as 1-cyclopropylethyl ester. これらの低級アルキルエステルは適当な置換基を有していてもよく、その例として、 Lower alkyl esters may have a suitable substituent, and examples thereof,
例えばアセトキシメチルエステル、プロピオニルオキシメチルエステル、ブチリルオキシメチルエステル、バレリルオキシメチルエステル、ピバロイルオキシメチルエステル、1−アセトキシエチルエステル、1−プロピオニルオキシエチルエステル、2−プロピオニルオキシエチルエステル、ヘキサノイルオキシメチルエステル等の低級アルカノイルオキシ(低級)アルキルエステル、例えば2−メシルエチルエステル等の低級アルカンスルホニル(低級)アルキルエステルまたは例えば2−ヨードエチルエステル、2,2,2−トリクロロエチルエステル等のモノ(またはジまたはトリ)−ハロ(低級)アルキルエステルが挙げられる。 For example acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryl oxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxy-ethyl ester, 2-propionyloxy-ethyl ester, hexa lower alkanoyloxy, such as pivaloyloxymethyl ester (lower) alkyl esters, such as 2-lower alkanesulfonyl (lower) alkyl esters or such as 2-iodoethyl ester, such as mesyl ethyl ester, such as 2,2,2-trichloroethyl ester mono (or di or tri) - include halo (lower) alkyl esters. ;さらに、エステル部分としては、例えばビニルエステル、アリルエステル等の低級アルケニルエステル;例えばエチニルエステル、プロピニルエステル等の低級アルキニルエステル;例えばベンジルエステル、4−メトキシベンジルエステル、4− ; Furthermore, the ester moiety, such as vinyl esters, lower alkenyl esters such as allyl esters; such as ethynyl ester, lower alkynyl esters such as propynyl ester; e.g. benzyl ester, 4-methoxybenzyl ester, 4-
ニトロベンジルエステル、フェネチルエステル、トリチルエステル、ベンズヒドリルエステル、ビス(メトキシフェニル)メチルエステル、3,4−ジメトキシベンジルエステル、4−ヒドロキシ−3,5−ジ第三級ブチルベンジルエステル等の適当な置換基を有していてもよいアル(低級)アルキルエステル;例えばフェニルエステル、4−クロロフェニルエステル、トリルエステル、4 Nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, suitable substituents such as 4-hydroxy-3,5-di-tert-butyl-benzyl ester which may have a group ar (lower) alkyl esters; e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, 4
−第三級ブチルフェニルエステル、キシリルエステル、 - tert-butylphenyl ester, xylyl ester,
メシチルエステル、クメニルエステル等の適当な置換基を有していてもよいアリールエステル等のようなものが挙げられる。 Mesityl ester include those such as aryl ester which may have suitable substituent such as click Mesnil ester.

【0007】上述の「保護されたカルボキシ基」の中で、好ましいものとしては、適当な置換基を有していてもよいアル(低級)アルコキシカルボニル基、より好ましいものとしては、低級アルコキシ、低級アルキル、ヒドロキシまたはニトロを置換基として有していてもよいフェニル(低級)アルコキシカルボニル基、さらに好ましいものとしては、ベンジルオキシカルボニル基が挙げられる。 [0007] Among the "protected carboxy group" described above, in which preferable appropriate optionally substituted ar (lower) alkoxycarbonyl groups, as more preferable, lower alkoxy, lower alkyl, hydroxy or nitro which may have as a substituent a phenyl (lower) alkoxycarbonyl group is more preferably a is benzyloxycarbonyl group.

【0008】本発明の製造法で用いられる光学活性な酸としては、例えば、L−酒石酸、D−マンデル酸、D− [0008] As an optically active acid used in the production method of the present invention, for example, L- tartaric acid, D- mandelic acid, D-
10−カンファースルホン酸等が挙げられるが、これらは、化合物(I)における「保護されたカルボキシ基」 10 Although camphorsulfonic acid and the like, they are "protected carboxy group" in the compound (I)
の種類に応じて適宜選択される。 It is appropriately selected depending on the type. 例えば、化合物(I) For example, Compound (I)
における「保護されたカルボキシ基」が「ベンジルオキシカルボニル基」である場合には、DまたはL−酒石酸が最も望ましい。 If "protected carboxy group" is a "benzyloxycarbonyl group" is, D or L- tartaric acid is most preferable.

【0009】本発明における光学分割は常法に従って行うことができる。 [0009] optical resolution in the present invention can be carried out according to a conventional method. 即ち、ピペリジン酢酸誘導体(I)のラセミ体を分割試薬たる光学活性な酸と反応させてジアステレオマーへと導き、分別結晶を行ない、必要によりさらに分離した結晶を分割試薬ともとの化合物に分解することにより行うことができる。 That is, decomposition of racemic piperidine acetic acid derivatives (I) is reacted with a resolving agent serving optically active acids lead to diastereomers performs fractional crystallization, the crystals divided reagent and the original compounds were further separated if necessary it can be carried out by.

【0010】 [0010]

【発明の効果】本発明によれば、極めて光学純度の高いピペリジン酢酸誘導体の光学活性体を得ることができる。 According to the present invention, it is possible to obtain a very optically active compound of high optical purity piperidine acetic acid derivatives.

【0011】 [0011]

【実施例】以下、実施例により、本発明を具体的に説明する。 EXAMPLES The following examples illustrate the present invention in detail.

【0012】実施例1 2−(2−ピペリジル)酢酸(ラセミ体)(50.0 [0012] Example 1 2- (2-piperidyl) acetate (racemate) (50.0
g)をトルエン(275ml)に溶解する。 The g) is dissolved in toluene (275 ml). 室温下、ベンジルアルコール(75.6g)、p−トルエンスルホン酸一水和物(73.2g)を加え、撹拌する。 At room temperature, benzyl alcohol (75.6 g), p-toluenesulfonic acid monohydrate (73.2 g) was added and stirred. 溶液を加温し、還流下100〜115℃にて4時間反応する。 The solution was warmed to react 4 hours at the reflux under 100 to 115 ° C..
反応終了後、濃縮し、トルエンを留去して、2−(2− After completion of the reaction, concentrated, toluene was distilled off, 2- (2-
ピペリジル)酢酸ベンジルエステルを得る。 Obtaining a piperidyl) benzyl acetate ester. 20±5℃ 20 ± 5 ℃
にて酢酸エチル(500ml)、水(250ml)を加え、撹拌下20%炭酸ナトリウム水溶液を用いてpHを9〜10に調整する。 With ethyl acetate (500 ml), water (250 ml) was added to adjust the pH to 9-10 with stirring 20% ​​aqueous sodium carbonate. 分離した酢酸エチル層を濃縮し、 Concentration of the separated ethyl acetate layer,
L−酒石酸(52.5g)をエチルアルコール(150 Ethyl L- tartaric acid (52.5g) alcohol (150
ml)に溶解した溶液を加え、撹拌する。 Solution in ml) is added and stirred. 溶液中に種結晶を加え、20〜25℃にて結晶を析出させる。 A seed crystal was added to the solution, to precipitate crystals at 20-25 ° C.. 0℃まで冷却した後、析出した結晶を濾取し、乾燥して、 After cooling to 0 ° C., the precipitated crystals were collected by filtration and dried to give
(R)−2−(2−ピペリジル)酢酸ベンジルエステル・L−酒石酸塩(45.5g)を得る。 Obtain (R) -2- (2- piperidyl) acetate benzyl ester · L-tartrate (45.5 g). 光学純度を高速液体クロマトグラフィー[HPLC:カラム;CHIR The optical purity by high performance liquid chromatography [HPLC: Column; CHIR
ALCEL OD−R(ダイセル化学工業社製),移動層;20%アセトニトリル含水,流速;1ml/mi ALCEL OD-R (manufactured by Daicel Chemical Industries, Ltd.), mobile phase; 20% acetonitrile water, flow rate; 1 ml / mi
n,検出;UV220nm]で測定すると、光学純度は99.1%eeであった。 n, detection; as measured by UV 220 nm], the optical purity was ee 99.1%. 融点 127−128℃ MASS 234 (分子イオンピーク) 尚、出発物質である2−(2−ピペリジル)酢酸(ラセミ体)は、2−(2−ピペリジル)エタノール(ラセミ体)を常法により酸化して得ることができる。 Mp 127-128 ° C. MASS 234 (molecular ion peak) Incidentally, The starting material 2- (2-piperidyl) acetate (racemate) of 2- (2-piperidyl) ethanol (racemic) was oxidized by a conventional method it can be obtained.

【0013】参考例 上記で得られた(R)−2−(2−ピペリジル)酢酸ベンジルエステル・L−酒石酸塩は、以下に示される反応工程により、アデノシン拮抗剤として有用な(2R)− [0013] obtained in Reference Example above (R) -2- (2- piperidyl) acetate benzyl ester · L-tartrate, the reaction steps shown below, useful as adenosine antagonists (2R) -
1−[3−(2−フェニルピラゾロ[1,5−a]ピリジン−3−イル)アクリロイル]−2−(カルボキシメチル)ピペリジン(トランス異性体)(特開平5−11 1- [3- (2-phenyl-pyrazolo [1,5-a] pyridin-3-yl) acryloyl] -2- (carboxymethyl) piperidine (trans isomer) (JP-A-5-11
2566号公報に実施例3として記載)へと導くことができる。 In 2566 JP can be guided to the described) as Example 3.

【化3】 [Formula 3] 上記反応は、特開平5−112566号公報に記載の方法と同様にして行うことができる。 The above reaction can be carried out analogously to the method described in JP-A-5-112566.

Claims (2)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】 一般式(I): 【化1】 1. A general formula (I): ## STR1 ## (式中、Rは保護されたカルボキシ基を意味する)で示されるピペリジン酢酸誘導体のラセミ体を光学活性な酸を用いて光学分割して、一般式(I)で示される化合物の光学活性体を得ることを特徴とする光学活性なピペリジン酢酸誘導体の製造法。 (Wherein, R refers to a protected carboxy group) Racemic piperidine acetic acid derivatives represented by by optical resolution using an optically active acid, an optically active form of a compound represented by the general formula (I) process for producing an optically active piperidine acetic acid derivatives, characterized in that to obtain.
  2. 【請求項2】 一般式(I)におけるRがベンジルオキシカルボニル基であり、用いられる光学活性な酸が光学活性な酒石酸である請求項1に記載の光学活性なピペリジン酢酸誘導体の製造法。 Wherein R in the general formula (I) is a benzyloxycarbonyl group, the preparation of optically active piperidine acetic acid derivatives of claim 1 optically active acid is optically active tartaric acid used.
JP14144495A 1995-06-08 1995-06-08 Production of optically active piperidineacetic acid derivative Pending JPH08333339A (en)

Priority Applications (1)

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Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
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Publications (1)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007145852A (en) * 1996-12-26 2007-06-14 Tanabe Seiyaku Co Ltd Acid adduct salt of optically active piperidine derivative and method for producing the same
JP2012211174A (en) * 2004-11-05 2012-11-01 Boehringer Ingelheim Internatl Gmbh Method for production of chiral 8-(3-amino-piperidin-1-yl)-xanthine
US9603851B2 (en) 2010-05-05 2017-03-28 Boehringer Ingelheim International Gmbh Combination therapy
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US9815837B2 (en) 2006-05-04 2017-11-14 Boehringer Ingelheim International Gmbh Polymorphs
US10034877B2 (en) 2008-08-06 2018-07-31 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US10080754B2 (en) 2006-05-04 2018-09-25 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US10092571B2 (en) 2009-11-27 2018-10-09 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US10195203B2 (en) 2012-05-14 2019-02-05 Boehringr Ingelheim International GmbH Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007145852A (en) * 1996-12-26 2007-06-14 Tanabe Seiyaku Co Ltd Acid adduct salt of optically active piperidine derivative and method for producing the same
JP2011063619A (en) * 1996-12-26 2011-03-31 Mitsubishi Tanabe Pharma Corp Acid addition salt of optically active piperidine derivative and process for producing the same
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
JP2012211174A (en) * 2004-11-05 2012-11-01 Boehringer Ingelheim Internatl Gmbh Method for production of chiral 8-(3-amino-piperidin-1-yl)-xanthine
US9751855B2 (en) 2004-11-05 2017-09-05 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US10080754B2 (en) 2006-05-04 2018-09-25 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US9815837B2 (en) 2006-05-04 2017-11-14 Boehringer Ingelheim International Gmbh Polymorphs
US10301313B2 (en) 2006-05-04 2019-05-28 Boehringer Ingelheim International Gmbh Polymorphs
US10034877B2 (en) 2008-08-06 2018-07-31 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US10092571B2 (en) 2009-11-27 2018-10-09 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US9603851B2 (en) 2010-05-05 2017-03-28 Boehringer Ingelheim International Gmbh Combination therapy
US10004747B2 (en) 2010-05-05 2018-06-26 Boehringer Ingelheim International Gmbh Combination therapy
US10195203B2 (en) 2012-05-14 2019-02-05 Boehringr Ingelheim International GmbH Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition

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