JP2974181B2 - A new method for producing cyclobutanol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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]

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]

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[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]

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]

According to the present invention, there is provided a compound represented by the general formula (1):

[0007]

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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]

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The present invention relates to a process for producing cyclobutanol represented by the formula: wherein R represents a protecting group.

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.

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.

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]

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.

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]

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)

(57) [Claims] 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.