JP2974181B2 - A new method for producing cyclobutanol - Google Patents
A new method for producing cyclobutanolInfo
- Publication number
- JP2974181B2 JP2974181B2 JP28938291A JP28938291A JP2974181B2 JP 2974181 B2 JP2974181 B2 JP 2974181B2 JP 28938291 A JP28938291 A JP 28938291A JP 28938291 A JP28938291 A JP 28938291A JP 2974181 B2 JP2974181 B2 JP 2974181B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- cyclobutanol
- compound
- producing
- yeast
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
【0001】[0001]
【産業上の利用分野】本発明は、例えば抗ウイルス薬等
の医薬品の中間体として期待されるシクロブタノールの
製造法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing cyclobutanol, which is expected to be used as an intermediate for pharmaceuticals such as antivirals.
【0002】[0002]
【従来の技術】下記式(6)で表される核酸誘導体は抗
ウイルス薬等の医薬品として期待されている。この化合
物は、例えば、以下に示す反応式(1)に従って製造さ
れる(J.Chem.Soc.Chem.Commun.,1919(1989);Tetrahedro
n Lett.,30,6453(1989))。2. Description of the Related Art A nucleic acid derivative represented by the following formula (6) is expected as a drug such as an antiviral drug. This compound is produced, for example, according to the following reaction formula (1) (J. Chem. Soc. Chem. Commun., 1919 (1989); Tetrahedro)
n Lett., 30,6453 (1989)).
【0003】[0003]
【化3】 Embedded image
【0004】[式中、R’はベンゾイル基またはt−ブ
チルジフェニルシリル基を、Xはp−トルエンスルホニ
ルオキシ基またはメタンスルホニルオキシ基を、Yはベ
ンジルオキシ基または2−メトキシエトキシ基を示す][In the formula, R ′ represents a benzoyl group or a t-butyldiphenylsilyl group, X represents a p-toluenesulfonyloxy group or a methanesulfonyloxy group, and Y represents a benzyloxy group or a 2-methoxyethoxy group.]
【0005】[0005]
【発明が解決しようとする課題】上記反応式において、
一般式(1’)で表わされる化合物から一般式(2’)
で表わされる化合物への還元反応は、一般式(3’)で
表わされる化合物の副生を極力抑えるために、高価な還
元試薬(例えば、LS-Selectride)を用い、超低温(例え
ば、-78 ℃)で反応を行なわなければならないという問
題がある。In the above reaction formula,
From the compound represented by the general formula (1 ′), the compound represented by the general formula (2 ′)
In the reduction reaction to the compound represented by the formula, an expensive reducing reagent (for example, LS-Selectride) is used at an extremely low temperature (for example, −78 ° C.) in order to minimize the by-product of the compound represented by the general formula (3 ′). ) Has to be performed.
【0006】[0006]
【課題を解決するための手段】本発明は、一般式(1)According to the present invention, there is provided a compound represented by the general formula (1):
【0007】[0007]
【化4】 Embedded image
【0008】[式中Rは保護基を示す]で表わされる化
合物に、酵母を作用させることを特徴とする、一般式
(2)A compound represented by the general formula (2), wherein yeast is allowed to act on a compound represented by the formula: wherein R represents a protecting group.
【0009】[0009]
【化5】 Embedded image
【0010】[式中Rは保護基を示す]で表わされるシ
クロブタノールの製造法に関する。The present invention relates to a process for producing cyclobutanol represented by the formula: wherein R represents a protecting group.
【0011】一般式(1)及び(2)で表わされる化合
物の保護基としては、一般に保護基として使用されるも
のなら特に制限なく、エステル型保護基例えば、アセチ
ル基、ベンゾイル基等のアシル基、ジメチルカルバモイ
ル基、ジフェニルカルバモイル基等のカルバモイル基、
または、エーテル型保護基例えば、t−ブチルジメチル
シリル基、t−ブチルジフェニルシリル基等のシリル基
または、メトキシメチル基等の(C1 −C4 アルコキ
シ)C1 −C4 アルキル基、テトラヒドロピラニル基、
ベンジル基、4−メトキシベンジル基、トリチル基等の
1つ以上の置換または無置換フェニル基で置換されたメ
チル基が挙げられる。The protecting group for the compounds represented by the general formulas (1) and (2) is not particularly limited as long as it is generally used as a protecting group, and an ester-type protecting group, for example, an acyl group such as an acetyl group or a benzoyl group. A carbamoyl group such as a dimethylcarbamoyl group and a diphenylcarbamoyl group;
Or an ether type protecting groups such as, t- butyl dimethyl silyl group, or a silyl group such as t-butyl diphenyl silyl group, such as methoxymethyl group (C 1 -C 4 alkoxy) C 1 -C 4 alkyl group, tetrahydropyranyl Group,
Examples include a methyl group substituted with one or more substituted or unsubstituted phenyl groups such as a benzyl group, a 4-methoxybenzyl group, and a trityl group.
【0012】本発明で使用する酵母はビール酵母、清酒
酵母、パン酵母等、特に制限なく、例えば市販品のオリ
エンタル酵母社製ドライイーストや生酵母等が挙げられ
る。また、酵母は生きているものでも、死んでいるもの
でもよく、さらに種々の処理を施したものでもよい。処
理としては、例えば加熱処理、アセトン処理、固定化等
が挙げられる。生きた酵母を使用する場合には栄養源と
してグルコース等を添加して反応を行なうことができ
る。死んでいるものや、種々の処理を施したものを使用
する場合には補酵素或いは補酵素再生系を添加して反応
を行なうことができる。補酵素としては、例えばNADPH
が挙げられ、NADPH 再生系としては、例えばグルコース
脱水素酵素等が挙げられる。The yeast used in the present invention is not particularly limited, such as brewer's yeast, sake yeast, baker's yeast and the like, and examples include commercially available dry yeast and live yeast manufactured by Oriental Yeast. The yeast may be alive or dead, or may be subjected to various treatments. Examples of the treatment include a heat treatment, an acetone treatment, and immobilization. When using live yeast, the reaction can be carried out by adding glucose or the like as a nutrient source. In the case of using a dead product or a product subjected to various treatments, the reaction can be carried out by adding a coenzyme or a coenzyme regeneration system. As a coenzyme, for example, NADPH
And the NADPH regeneration system includes, for example, glucose dehydrogenase.
【0013】反応は、水或いは緩衝水溶液中、或いはこ
れに非親水性の有機溶媒を添加した二層系の溶媒中で行
なうことが望ましい。緩衝液としては、例えば0.1Mリン
酸緩衝液(pH7) 等が挙げられ、有機溶媒としては、例え
ば酢酸ブチル等が挙げられる。また、反応温度は、20℃
から35℃くらいが好ましい。The reaction is desirably carried out in water or an aqueous buffer solution, or in a two-layered solvent to which a non-hydrophilic organic solvent is added. Examples of the buffer include 0.1 M phosphate buffer (pH 7), and examples of the organic solvent include butyl acetate. The reaction temperature is 20 ° C
To about 35 ° C.
【0014】[0014]
【実施例】次に、実施例を挙げて本発明の製造法につい
て具体的に説明する。 実施例1. (1S,2S,3S)−2,3−ビス(ベンゾイルオキ
シメチル)シクロブタノール(化合物2a)の製造 5l のジャーファメンター(Mituwa KMJ-5B)中、蒸留水
(2.5l)、リン酸水素二ナトリウム・12水(59.63g)、リ
ン酸二水素カリウム(11.38g)にて作成したリン酸緩衝液
(約0.1M、pH=7.06)に、D−グルコース(333g,1.85mol)
及びプロナールST-1(0.25ml)を加え、30.0℃、300rpmに
て撹拌した。これに、ドライイースト(233g)を加え、さ
らに30分撹拌後、(2S,3S)−2,3−ビス(ベン
ゾイルオキシメチル)シクロブタノン(化合物1a)
(8.33g,24.6mmol)を加え、さらに2日間撹拌した。この
間、反応液表面付近に二酸化炭素が滞留するのを防ぐた
めに、空気を吹き込み続けた(2l/min)。また、化合物
(1a)の結晶が一部反応液表面付近の容器壁面に付着
するため、5 時間後及び13時間後に、蒸留水(0.2l)を加
え液面を上げた。反応終了後、反応混合物を遠心分離機
(3000rpm,10min)にて水層を分離した後、固形物をメタ
ノール(400ml+500ml) 、酢酸エチル(200mlx3) を用いて
抽出した。有機層を合わせて減圧濃縮した後、残渣にト
ルエンを加え、これを蒸留水、飽和重曹水、飽和食塩水
にて順次洗浄した。有機層を無水硫酸ナトリウムにより
乾燥した後減圧濃縮し、粗製の化合物(2a)(11g) を
得た。これをシリカゲルカラムクロマトグラフィー(8.3
3g, トルエン→トルエン:酢酸エチル=5:1) により精製
した後、得られた粗結晶体(9.5g)をヘキサンにより洗浄
し、白色結晶の(1S,2S,3S)−2,3−ビス
(ベンゾイルオキシメチル)シクロブタノール(化合物
2a)(6.71g,80%) を得た。この結晶中の(1R,2
S,3S)体(化合物3a)の含量は1%以下であっ
た。Next, the production method of the present invention will be specifically described with reference to examples. Embodiment 1 FIG. Preparation of (1S, 2S, 3S) -2,3-bis (benzoyloxymethyl) cyclobutanol (Compound 2a) In 5 l of jar fermenter (Mituwa KMJ-5B), distilled water (2.5 l), hydrogen hydrogen phosphate D-glucose (333 g, 1.85 mol) was added to a phosphate buffer (about 0.1 M, pH = 7.06) prepared with sodium 12 water (59.63 g) and potassium dihydrogen phosphate (11.38 g).
And Pronal ST-1 (0.25 ml) were added, and the mixture was stirred at 30.0 ° C. and 300 rpm. To this, dry yeast (233 g) was added, and after further stirring for 30 minutes, (2S, 3S) -2,3-bis (benzoyloxymethyl) cyclobutanone (compound 1a)
(8.33 g, 24.6 mmol) was added, and the mixture was further stirred for 2 days. During this time, air was continuously blown (2 l / min) to prevent carbon dioxide from staying near the surface of the reaction solution. Further, since the crystals of the compound (1a) partially adhered to the vessel wall near the surface of the reaction solution, distilled water (0.2 l) was added after 5 hours and 13 hours to raise the liquid level. After the reaction is completed, the reaction mixture is centrifuged.
After separating the aqueous layer at (3000 rpm, 10 min), the solid was extracted using methanol (400 ml + 500 ml) and ethyl acetate (200 ml × 3). After the organic layers were combined and concentrated under reduced pressure, toluene was added to the residue, which was washed successively with distilled water, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound (2a) (11 g). This was subjected to silica gel column chromatography (8.3
After purification by 3 g, toluene → toluene: ethyl acetate = 5: 1), the obtained crude crystals (9.5 g) were washed with hexane, and white crystals of (1S, 2S, 3S) -2,3-bis (Benzoyloxymethyl) cyclobutanol (compound 2a) (6.71 g, 80%) was obtained. (1R, 2
The content of the (S, 3S) form (compound 3a) was 1% or less.
【0015】 mp 76-77℃ 1H-NMR(200MHz FT,CDCl3 ) δ: 2.07−2.29(2H,m), 2.60−2.86(2H,m), 3.21(1H,d,J=3.4Hz), 4.27(1H,dd,J=4.5Hz,11.5H
z), 4.32−4.41(2H,m), 4.43−4.53(1H,m), 4.84(1H,dd,J=8.6Hz,11.5H
z), 7.38−7.62(6H,m), 8.00−8.07(4H,m). IR(KBr,disk)cm-1: 3280,1715. [α]D =−13.86゜ (c=0.967,CHC
l3 )Mp 76-77 ° C. 1H-NMR (200 MHz FT, CDCl 3 ) δ: 2.07-2.29 (2H, m), 2.60-2.86 (2H, m), 3.21 ( 1H, d, J = 3.4 Hz), 4.27 (1H, dd, J = 4.5 Hz, 11.5 H)
z), 4.32-4.41 (2H, m), 4.43-4.53 (1H, m), 4.84 (1H, dd, J = 8.6 Hz, 11.5H)
z), 7.38-7.62 (6H, m), 8.00-8.07 (4H, m). IR (KBr, disk) cm -1 : 3280, 1715. [Α] D = -13.86 ゜ (c = 0.968, CHC
l 3 )
【0016】[0016]
【効果】本発明によると、安価な試薬、例えばドライイ
ーストを用い、30℃前後という温和な条件で、しかも水
系溶媒で反応が進行し、化合物(2)が高選択的に高収
率で得られる。従って、本発明は例えば化合物(6)等
のシクロブタン骨格を有し、強い抗ウイルス作用を示す
核酸誘導体の製造に有用である。According to the present invention, the reaction proceeds with an aqueous solvent under mild conditions of about 30 ° C. using an inexpensive reagent, for example, dry yeast, and the compound (2) is obtained with high selectivity and high yield. Can be Therefore, the present invention is useful for producing a nucleic acid derivative having a cyclobutane skeleton such as compound (6) and exhibiting strong antiviral action.
Claims (1)
を作用させることを特徴とする、一般式(2) 【化2】 [式中Rは保護基を示す]で表わされるシクロブタノー
ルの製造法。1. A compound of the general formula (1) Wherein a compound represented by the formula (2) is obtained by reacting yeast with a compound represented by the general formula (2): A method for producing cyclobutanol represented by the formula: wherein R represents a protecting group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP28938291A JP2974181B2 (en) | 1991-10-09 | 1991-10-09 | A new method for producing cyclobutanol |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP28938291A JP2974181B2 (en) | 1991-10-09 | 1991-10-09 | A new method for producing cyclobutanol |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH05103679A JPH05103679A (en) | 1993-04-27 |
JP2974181B2 true JP2974181B2 (en) | 1999-11-08 |
Family
ID=17742498
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP28938291A Expired - Lifetime JP2974181B2 (en) | 1991-10-09 | 1991-10-09 | A new method for producing cyclobutanol |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2974181B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL117574A0 (en) * | 1995-04-03 | 1996-07-23 | Bristol Myers Squibb Co | Processes for the preparation of cyclobutanone derivatives |
-
1991
- 1991-10-09 JP JP28938291A patent/JP2974181B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH05103679A (en) | 1993-04-27 |
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