JP2640519B2 - Organic germanium compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Prior Art] With respect to germanium Ge, which is a homologue of carbon, in recent years, research on organic compounds and publication of the results have been actively carried out, Attention has been drawn to the field, especially from the fields of medicine and pharmacy.

For example, carboxyethylgermanium sesquioxide (Japanese Patent Publication No. 46-2498), which is an organic germanium compound in which a propionic acid derivative of germanium and an oxygen atom are bonded at a ratio of 2: 3, has a hypotensive effect on spontaneously hypertensive rats. It has been reported to exhibit not only an amyloid change-reducing effect, but also an activation of macrophages, an interferon-inducing effect, an antitumor effect, and the like, and has been clinically used.

The carboxyethylgermanium sesquioxide is a compound represented by the chemical formula (Ge—CH ₂ —CH ₂ —COOH) ₂ O ₃ , and the conventionally developed organic germanium compound is of this type. Not only those of the formula A cyclic compound represented by the following formula has also been synthesized (see JP-A-61-267591).

Thus, as is apparent from the structural formula, the cyclic compound incorporates a germanium atom in the ring, so that it has a compound of another structure, for example, a germanium atom as a substituent for the ring. If such a compound can be synthesized, the organic germanium compound is expected to exhibit new utility.

[Problems to be Solved by the Invention] However, none of the conventionally known organic germanium compounds having a cyclic structure and containing a germanium atom in the substituent for the ring does not exist. Was expected.

[Means for Solving the Problems] The present invention has been made for the purpose of solving the above-mentioned disadvantages of the prior art, and the first organic germanium compound of the present invention has the formula Wherein the second organogermanium compound of the present invention is represented by the formula: (Wherein, R _{1 to} R ₃ each represent a lower alkyl group).

On the other hand, the method for producing an organogermanium compound of the present invention is represented by the formula (Wherein, R _{1 to} R ₃ represent a lower alkyl group.) The second organic germanium compound represented by the formula Or the first organic germanium compound represented by the formula: (Wherein, R _{1 to} R ₃ represent a lower alkyl group). Germanium trihalide HGeX ₃ (4) (wherein X represents a halogen atom) is added to the compound represented by the formula: Later, by reducing, the formula (Wherein, R _{1 to} R ₃ represent a lower alkyl group.) The organic germanium compound according to claim 2, which is represented by the following formula:

 Hereinafter, the present invention will be described in detail.

First, the first organogermanium compound of the present invention comprises 3-trihydrogermyl-4 represented by the above formula (1).
-Hydroxymethyl-γ-butyrolactone, that is, having the common name γ-butyrolactone as a basic skeleton,
A trihydrogermyl group —GeH ₃ is bonded to the position, and a hydroxymethyl group —CH ₂ OH is bonded to the γ position.

As apparent from the above structural formula, since the carbons at the β and γ positions of compound (1) are asymmetric, (βR, γR), (βS, γR), (βR , γS), (βS,
There are a total of four optical isomers of γS).

The above-mentioned organogermanium compound (1) of the present invention has a structure which has not existed conventionally.
It is fully expected to show new utility.

Therefore, the following experiment was conducted to confirm the usefulness of the above compound.

That is, it is known that some of the organic germanium compounds exhibit antibacterial properties (Japanese Patent Application Laid-Open No. 62-92), and the above compounds were also examined. It showed antibacterial activity against atypical mycobacterium, which was known to be absent.

On the other hand, as shown in the above formula (2), the second organogermanium compound of the present invention has a trihydroxygermyl group -GeH3 at the _3- position and a hydroxyl group at the 4- and 5-positions.
The OH-bonded pentanoic acid and the alcohol R ₁ OH form an ester bond, and the 4- and 5-position hydroxyl groups and the ketone
It is a compound that has formed an O-alkylidene structure with R ₂ COR ₃ .

Here, since R ₁ , R ₂ and R ₃ each represent a lower alkyl group, examples of the second organogermanium compound of the present invention include the following.

As apparent from the above structural formula, the carbons at the 3- and 4-positions of the compound (2) are asymmetric, so that the compound (2) also has (3R, 4R), (3S, 4R), (3R , 4S) and (3S, 4S).

The compound (2) is useful as an intermediate for synthesizing the compound (1).

On the other hand, the above-described organogermanium compound of the present invention can be produced by the production method of the present invention as described below.

That is, first, the equation The first compound of the present invention represented by the formula: (In the formula, R _{1 to} R ₃ represent a lower alkyl group.) The second organic germanium compound of the present invention represented by the following formula may be lactonized.

The above reaction proceeds in an appropriate solvent in the presence of an acidic catalyst.

In the above reaction, it has been found that γ-butyrolactone is preferentially produced and δ-valerolactone is not produced.

And the formula (Wherein R _{1 to} R ₃ represent a lower alkyl group.) The second organogermanium compound of the present invention represented by the formula:
formula (Wherein, R _{1 to} R ₃ represent a lower alkyl group). Germanium trihalide HGeX ₃ (4) (wherein X represents a halogen atom) is added to the compound represented by the formula: Later, it is sufficient to reduce.

The addition reaction of compound (4) to compound (3) is carried out, for example, by dissolving compound (3) in an appropriate solvent and adding compound (4) to this solution. Is carried out by adding an appropriate reducing agent to the solution of the adduct.

In the above reaction, it is not always necessary to isolate the adduct, and the reaction solution may be neutralized when the addition reaction is completed, and then the reducing agent may be added.

Further, since the compound has a double bond, there is a cis-trans geometric isomer, and since the carbon at the γ-position is asymmetric, each of the geometric isomers has an optical isomer, When germanium trihalide is added to any of them, the yield and the like of the obtained addition pair may change, but do not have a decisive effect on the addition reaction itself.

The method for producing the compound (3) as a starting material for the above reaction is disclosed in a known document (JACS, 104 , 1109 (1982)).

[Example] Next, an example of the present invention will be described.

Example 1 Synthesis of Compound (3) In a solution of 17.5 g (50 mmol) of (carboethoxymethylene) -triphenylphosphorane dissolved in 30 ml of benzene, D-acetone glyceroaldehyde (synthesized from D-mannitol) dissolved in 30 ml of benzene. ) 5.93g (45.6mmo)
l) was added, and the mixture was stirred at room temperature for 24 hours under an argon atmosphere. After completion of the reaction, the mixture was concentrated under reduced pressure, and the product was extracted with hexane. The obtained product was purified by silica gel column chromatography, and (3S) -1-ethoxycarbonyl-3,4-O-isopropylidene-1-butene-3,4-diol (R ₁ in compound (3)) ＝ C ₂ H ₅ , R ₂ ＝
5.39 g (59%) of the cis-form and 1.73 g (19%) of the trans-form of R ₃ = CH ₃ were obtained.

Cis-isomer ^{IR ν KBr / max cm -1:} 1720 (C = 0) 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, CH 2 -C H 3) 1.41,1.44 (3H, s, C ( _{C H 3) 2) 3.70 (} 1H, dd, H-4) 4.20 (2H, q, C H 2 -CH 3) 4.40 (1H, t, H-4 ') 5.50 (1H, bq, H-3) 5.81 (1H, dd, H-1) 6.34 (1H, dd, H-2) Trans form IR ν KBr / max cm ^-1 : 1720 (C = 0) ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H _{, t, CH 2 -C H 3} ) 1.45,1.42 (3H, s, C (C H 3) 2) 3.56 (1H, dd, H-4) 4.30 (2H, q, C H 2 -CH 3) 4.65 (1H, bq, H-3) 6.07 (1H, dd, H-1) 6.87 (1H, dd, H-2) L-acetone glyceroaldehyde synthesized from L-mannitol can be used under the same conditions. Was obtained.

5.37 g (26.8 mmol) of the cis unsaturated ester described in the above synthesis example was dissolved in 30 ml of ethyl ether and cooled with ice, and 8.17 g of trichlorogermane was added to this solution.
(45.4 mmol) and stirred at this temperature for 2 hours. After completion of the reaction, 15.8 g (0.14 mol) of potassium-t-butoxide dissolved in 20 ml of ethanol was added under ice cooling to make the reaction solution neutral.

Next, 7.0 g of potassium borohydride was added to this solution to reduce germanium. After completion of the reaction, the solution was filtered, concentrated under reduced pressure and washed with water, and the obtained product was purified by silica gel column chromatography.
Ethyl 3-trihydrogermyl-4,5-O-isopropylidene-4,5-dihydroxypentanoate (compound (2) in which R ₁ = C ₂ H ₅ , R ₂ = R ₃ = CH ₃ ) 1.87 g (25%) of the threo form and 1.93 g (26%) of the erythro form were obtained.

Threo body _{(2S, 3R) [α]} D = -1.4 ° _{(C = 1.22, CH 3 OH} ) 1 H-NMR (CDCl 3) δ: 0.937 (3H, t, O-CH 2 C H 3) 1.370, _{1.224 (6H, s, C (} C H 3)) 2 1.948 (1H, m, H-3) 2.314 (1H, dd, H-2) 2.456 (1H, dd, H-2 ') 3.366 (1H, dd , H-5) 3.744 (1H , dd, H-5 ') 3.745 (3H, d, Ge-H) 3.913 (2H, dg, O-C H 2 CH 3) 4.050 (1H, dt, H-4) erythro-form _{(2R, 3R) [α]} D = -4.1 ° _{(C = 1.29, CH 3 OH} ) 1 H-NMR (CDCl 3) δ: 0.932 (3H, t, O-CH 2 C H 3) 1.354, 1.258 (6 H, s, C (C H 3)) 2 2.470 (1H, dd, H-2) 2.674 (1H, dd, H-2 ') 3.362 (1H, t, H-5) 3.639 (3H, d, Ge-H) 3.797 ( 1H, dd, H-5 ') 3.911 (2H, dq, O-C H 2 CH 3) 4.045 (1H, ddd, H-4) in addition, a similar reaction of trans- As a result of using a saturated ester, the overall yield was 20%, and the ratio between the threo form and the erythro form was 2: 1.

Example 2 Synthesis of Compound (1) 2.68 g (10.2 mmol) of the above threo compound was added to dioxane: water =
Dissolve in a 4: 1 solution (25 ml) and add 1 g of Amberlyst 15
(Trade name) was added and stirred for 2 hours. After the completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The obtained product was purified by column chromatography on silica gel to give 3-
Trihydrogelmil-4-hydroxymethyl-γ-
0.89 g (1) of the threo form of butyrolactone (compound (1))
8%).

Similarly, from 1 g of the erythro form, 0.36 g (54%) of erythro form of 3-trihydrogermyl-4-hydroxymethyl-γ-butyrolactone (compound (1)) was obtained.

Threo form (2S, 3R) mp: 75.5-76 ° C [α] _D = +32.1 ゜ (C = 1.12, CH ₃ OH) Anal.Calcd .: C, 31.49; H, 5.59 Found: C, 31.47; H ^{, 5.34 1 H-NMR (C} 6 D 6 (D 2 O)) δ: 1.439 (1H, m, H-3) 2.052 (1H, dd, H-2) 2.264 (1H, dd, H-2 ') 3.173 (1H, dd, H-5) 3.390 (1H, dd, H-5 ') 3.486 (3H, d, Ge-H) 3.940 (1H, dt, H-4) Erythro form (2R, 3R) mp: _{59.0-61.5 ℃ [α] D = +} 59.4 ° _{(C = 1.10, CH 3 OH} ) Anal.Calcd .: C, 31,49; H, 5.29 Found: C, 31.33; H, 5.25 1 H-NMR ( C ₆ D ₆ (D ₂ O)) δ: 1.904 (1 H , m, H-3) 2.088 (1H, dd, H-2) 2.472 (1H, dd, H-2 ′) 3.499 (3H, d, Ge-H) 3.544 (1H, dd, H-5) 3.802 (1H, dd, H-5 ') 4.224 (1H, ddd, H-4) The optical purity of the above threo body and erythro body is respectively Was introduced into MTPA ester and analyzed by high performance liquid chromatography. As a result, it was confirmed that they were 99% _ee and 98% _ee respectively.

Experimental Example Antibacterial effect of compound (1) The following experiment confirmed that the usefulness of these compounds was in the antibacterial property against atypical mycobacterium.

Although the definition of atypical mycobacterium is currently inconsistent among researchers, the definition of mycobacteria other than mycobacterium tuberculosis and bovine bacteria has recently become widely used. (Amer. Rev. Tuberc., 71, 74, 195
5) A so-called fungal group consisting of various strains containing various bacterial species.

This atypical mycobacterium is present in the lungs, lymphocytes, skin ulcers, or bone marrow of infected humans, but the lungs are most commonly affected, and not only clinically but also histopathologically. It presents findings that are difficult to distinguish from pulmonary tuberculosis.On the other hand, it is not pathogenic to animals in general, but is highly pathogenic to mice. It induces lesions that are difficult to distinguish from pulmonary tuberculosis in histopathology.

There is no cure for this bacterial infection at this time, since no specific drug has been found at this time, except for excision of lesions such as lungs. When the organogermanium compound (1) of the present invention is acted on, These compounds significantly inhibited their growth.

 The results are shown in the following table.

As described above, the present invention is extremely excellent as an organic germanium compound and a method for producing the same.

Claims (4)

(57) [Claims] (1) Expression An organic germanium compound represented by the formula: (2) (Wherein, R _{1 to} R ₃ each represent a lower alkyl group). An organic germanium compound represented by the formula: (3) (Wherein, R _{1 to} R ₃ each represent a lower alkyl group). A method for producing an organic germanium compound, characterized in that the compound is represented by the formula: (4) (Wherein, R _{1 to} R ₃ represent a lower alkyl group). Germanium trihalide HGeX ₃ (4) (wherein X represents a halogen atom) is added to the compound represented by the formula: Later, by reducing, the formula (Wherein, R _{1 to} R ₃ represent a lower alkyl group.) A method for producing an organogermanium compound according to claim 2, which is represented by the following formula: