JPS5921957B2 - Method for producing α-methylene-γ-butyrolactones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION 5 The present invention relates to a novel method for producing α-methylene-γ-butyrolactones.

α-Methylene-γ-butyrolactones are biologically active natural products, such as anticancer drugs and antibiotics, and have been described in various literature. It is a compound that is described as C and is expected to be developed in the pharmaceutical field.

Conventionally, methods for producing such α-methylene-γ-butyrolactones include a method of carbonylating β,γ-acetylene alcohol, a ring element dehydration method of α-formyl lactone, a method of ring expansion of substituted cycloprobanes, A method of reacting γ-lactonylidenedriphenylphosphorane with formalin is known (for example, "Synt
hesis” 67 (1975), P. A. GriecO
reference).

However, all of these methods have various problems such as low yields, complicated operations, and expensive or difficult to obtain raw materials, making them impractical. No, no. The present inventors have conducted various studies to solve the drawbacks of such conventional methods. show.

Note that R1 and R2 or R1 and R3 may be combined to form a 5- to 7-membered ring. R4 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a cyclohexyl group) α-carboxy-α-thio substituted monomethyl-γ-butyrolactones dissolved in an aqueous layer and an electrolyte solution and an organic When the electrolytic solution is brought into contact with the organic layer at the interface thereof and subjected to an organic electrolytic synthesis reaction, the desired α
- Methylene-r-butyrolactones selectively transfer to the organic layer, preventing secondary electrolytic reactions, resulting in the surprising and remarkable effect that the desired product can be obtained in high yield. After discovering this fact, we have completed the present invention.

The α-carboxy-α-thio-substituted-methyl-γ-butyrolactones represented by the general formula (4) which serve as starting materials in the present invention are readily available compounds;
) Specific examples of γ-butyrolactones include:
For example, α-carboxy-α-methylmercaptomethyl-γ-butyrolactone α-carboxy-α-propylmercapto-methyl-γ-butyrolactone, α-carboxy-α-thiophenoxymethyl-r-butyrolactone, R,γ-tetramethylene -α-carboxy-α-methylmercaptomethyl-γ-butyrolactone, γ,r-pentamethylene-α-carboxy-α-methylmercaptomethyl-r-butyrolactone, γ,γ-tetramethylene-α-carboxy-α- Butylmercaptomethyl-γ-
Butyrolactone, γ,γ-hexamethylene α-carboxy-α-ethylmercaptomethyl-γ-butyrolactone, α-carboxy-α-methylmercaptomethyl-r
-Methyl-γ-butyrolactone, α-carboxy-α-ethylmercabutomethyl-γ-butyl-r-butyrolactone, α-carboxy-α-propylmercaptomethyl-γ-octyl-γ-butyrolactone, α-carboxy-α- Butylmercabutomethyl-β-methyl-γ-methyl-γ-butyrolactone, α-carboxy-α-methylmercabutomethyl-β-butyl-γ-ethyl-γ-butyrolactone, β,r-tetramethylene-α-carboxy -α-methylmercabutomethyl-γ-butyrolactone,
Examples include β,γ-hexamethylene-α-carboxy-α-1ethylmercaptomethyl-r-butyrolactone, β,γ-pentamethylene-α-carboxy-α-propylmercaptomethyl-γ-butyrolactone, and the like.

Examples of the supporting electrolyte used in the organic electrolytic synthesis reaction of the present invention include lithium perchlorate, magnesium perchlorate, quaternary alkyl ammonium perchlorate, quaternary ammonium perchlorate, quaternary alkylammonium boron tetrafluoride, Boron tetrafluoride quaternary ammonium, halogenated quaternary alkyl ammonium, halogenated quaternary ammonium,
Examples include alkali metal chloride, quaternary alkylammonium nitrate, quaternary alkylammonium paratoluenesulfonate, etc.

In illustrating such supporting electrolytes, alkyl refers to methyl, ethyl or propyl, alkali metal refers to lithium, sodium or potassium, and rogene refers to chlorine, bromine, iodine. say. Such supporting electrolyte is 0.1 to 10 w/v%, preferably 1 to 5 w/v%.
/v% concentration, and the solution has a concentration of 1 to 10 t1, preferably 2 to
It is used in a range of 5 t to constitute the aqueous layer of the electrolytic solution.

The Vc of the present invention has the general formula (4) used as a starting material.
The reaction is carried out in a state in which α-carboxy-γ-butyrolactones represented by ) are dissolved in the aqueous layer of an electrolytic solution as a salt of a corresponding alkali metal, alkali metal 10 group metal, ammonia, amine, or the like. In the present invention, examples of the organic layer constituting the organic layer include aromatic hydrocarbons such as benzene and toluene, aliphatic ethers such as ethyl ether and propyl ether, halogenated aliphatic hydrocarbons such as dichloromethane and dichloroethane, n-hexane, n
- Aliphatic hydrocarbons such as heptane, lower aliphatic carboxylic acid esters such as ethyl acetate and butyl acetate, and the like are used alone or in combination of two or more. The amount of such an organic solvent to be used is not particularly limited as long as it can sufficiently extract the reaction product α-methylene-γ-butyrolactone represented by the general formula 8, but it is usually used for the reaction product represented by the general formula ( The amount is in the range of 0.5 to 5 t per mole of the α-carboxy-r-butyrolactone represented by 4). According to the present invention, the reaction temperature is in the range of 0 to 100°C, more preferably in the range of 30 to 50°C.

Although the reaction time cannot be limited in relation to the current density, a range of 5 to 18 hours is usually adopted.

The electrodes used in the present invention are commercially available electrodes made of platinum, carbon, stainless steel, iron, etc. for electrolysis, or special electrodes made of conductive metal oxides such as carbon or titanium oxide in the form of a mesh. There are also electrodes that have been processed into shaped electrodes, and electrodes whose surfaces have been vapor-deposited and plated with other metals that form an oxide film.

The organic electrolytic synthesis reaction of the Vc of the present invention can be carried out at a constant voltage, but it can also be carried out by the generally used methods of current density regulation and potential regulation.

In order to simplify the electrolysis apparatus and operation, the organic electrolytic synthesis reaction is carried out by simply keeping the terminal voltage constant in the range of 1 to 10, preferably 1.5 to 3, although the electrode potential varies slightly. Even in the present invention, the target substance can be obtained in good yield. The organic electrolytic synthesis reaction is carried out within the above-mentioned voltage range VC and current density range of 1 to 10 A/Dm2. After the organic electrolytic synthesis reaction is completed, the organic layer is separated, the aqueous layer is extracted with ether, benzene, etc., the extract and organic layer are collected, washed with water, dried with anhydrous sodium sulfate, etc., and after separation, the furnace liquid is extracted. By concentrating under reduced pressure, a crude product of α-methylene-r-butyrolactones represented by the general formula rainbow can be obtained.

By purifying the crude product by a distillation method, a recrystallization method, a column method, etc., pure α-methylene-γ-butyrolactones represented by the general formula (2) can be obtained. Specific examples of α-methylene-γ-butyrolactones represented by the general formula 8 obtained by the method of the present invention as described above include α-methylene-γ-butyrolactone,
α-methylene-γ-methyl-γ-butyrolactone, α-
Methylene-β,γ-dimethyl-γ-butyrolactone, α-
Methylene-γ-butyl-γ-butyrolactone, α-methylene-γ-octyl-r-butyrolactone, α-methylene-β-butyl-γ-ethyl-γ-butyrolactone, α
-methylene-β-octyl-γ-butyl-r-butyrolactone, α-methylene-β, γ-tetramethylene-γ-
Butyrolactone, α-methylene-β, r-pentamethylene-r-butyrolactone, α-methylene-β, γ-hexamethylene-γ-butyrolactone, α-methylene-R,
γ-tetramethylene-γ-butyrolactone, α-methylene-γ, γ-pentamethylene-γ-butyrolactone, α
-methylene-γ,γ-hexamethylene-γ-butyrolactone, α-methylene-β-methyl-γ,γ-tetramethylene-γ-butyrolactone, α-methylene-β-octyl-γ,γ-hexamethylene-r- Examples include butyrolactone. Next, the method of the present invention will be explained with reference to Examples. Example 1 α-carboxy-α-thiophenoxymethyl-γ-butyrolactone 46%, 10(!) lithium perchlorate aqueous solution 15%, triethylamine 0.25%
m2 and 5 units of benzene were added to form a heterogeneous bilayer solution.

Two platinum electrode plates (1.5 rule x 2
csn2) was soaked, and an organic electrolytic synthesis reaction was carried out at a reaction temperature of 30 to 40° C., a constant voltage of 3 V, and a current density of 2 to 5 A/Drn2 for 12 hours. After electrolysis, the organic layer was separated and the aqueous layer was extracted with ether. The extract and organic layer were collected, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to thin layer chromatography to obtain almost pure α-methylene-γ-butyrolactone. The boiling point of the obtained α-methylene-γ-butyrolactone was 50-53°C/0.45 mmHf.

The yield is 17.6η, which is 9% of the theoretical yield.
It was 5%. Elemental analysis value: IR spectrum: 4●νv~U▲BreathXU-Hibiki▲▲Muno~ Q●Jll\l
~ Bll Example 2α-carboxy-α-thiophenoxymethyl-β,γ-tetramethylene-γ-butyrolactone 57η, 10% lithium perchlorate aqueous solution 15m2
, ethyl ether 5me1 caustic soda 7.577? ! 7
was added to form a heterogeneous bilayer solution.

Two platinum electrode plates (1.5 (1)
]×2csr1), 3V at a reaction temperature of 30-40℃
The organic electrolytic synthesis reaction was carried out for 12 hours at a constant voltage of 2 to 5 A/Dm2 and a current density of 2 to 5 A/Dm2. After electrolysis, the organic layer was separated and the aqueous layer was extracted with ether. The extract and organic layer were collected, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under regional pressure. The resulting residue was subjected to thin layer chromatography to obtain almost pure α-methylene-β, γ.
-tetramethylene-γ-butyrolactone was obtained. The melting point of the obtained α-methylene-β,γ-tetramethylene-γ-butyrolactone was 38 to 40°C.

The final yield was 26 mIi, which is 92% of the theoretical yield.
It was hot. Elemental analysis value: \V υノ1 υ● νuμ \−ν112ノExample 3α-carboxy-α-thiophenoxymethyl-γ-
68 mf of n-octyl-γ-butyrolactone and 0.25 m2 of triethylamine were added, and 15 mf of water and 200 mf of lithium perchlorate were added thereto, followed by 3 wt 1 of ether and 2 m2 of benzene to form a heterogeneous two-layer solution.

Two platinum electrode plates (1.5 cw1
X2 width 2) was soaked, and an organic electrolytic synthesis reaction was carried out at a reaction temperature of 20 to 30°C, a constant voltage of 3, and a current density of 2 to 5 A/Dm2 for 12 hours. After electrolysis, the organic layer was separated and the aqueous layer was extracted with an ether-benzene mixture (volume ratio 1:1). The organic layer and extract were collected, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography.
-methylene-rn-octyl-γ-butyrolactone 3
I got 8η. The yield was 92% of the theoretical yield. Example 4 α-carboxy-α-thiophenoxymethyl-γ,γ-
75 η of pentamethylene-γ-butyrolactone, 0.25 m 2 of triethylamine, 15 m 2 of water, and 200 η of lithium perchlorate were added, and 3~3 ether of ether and 2 pieces of benzene were added to obtain a heterogeneous two-layer solution.

Platinum electrode plate (1.5cn) x 2c is added to the aqueous layer of this two-layer solution.
mI), and electrolysis was carried out at a reaction temperature of 40 to 50°C, a constant voltage of 4, and a current density of 2 to 3 A/Dm2 for 5 hours. After electrolysis, the organic layer was separated and the aqueous layer was extracted with benzene. The organic layer and extract were collected, washed with water, dried over anhydrous sodium sulfate, filtered, and the aqueous solution was concentrated under reduced pressure. The obtained residue was purified with a silica gel column and further distilled under reduced pressure to obtain α-methylene-γ,γ-pentamethylene-γ-butyrolactone 3077V. Yield is 78% of theoretical yield
It was hot. The boiling point of the obtained α-methylene-γ, γ-pentamethylene-γ-butyrolactone is 73°C/0.008
It was mmHg.

Elemental analysis value: Theoretical value (%): C72.26 H8.49 Actual value (%)
:C72.21 H8.44IR spectrum.

1H-NMR: 13C-NMR:

Claims (1)

[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
_1, R_2 and R_3 each represent hydrogen or an alkyl group having 1 to 8 carbon atoms. Note that R_1 and R_2 or R_1 and R_3 may be combined to form a 5- to 7-membered ring. R_4 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a cyclohexyl group) An electrolytic solution prepared by dissolving α-carboxy-α-thio-substituted-methyl-γ-butyrolactone in an aqueous layer and an organic By creating a heterogeneous structure with layers and subjecting the electrolytic solution to an organic electrolytic synthesis reaction while contacting the organic layer at its interface, general formula (II) ▲Mathematical formula, chemical formula, table, etc.▼( II) (wherein, R_
1, R_2 and R_3 are the same as above). 2 The α-methylene-γ-butyrolactones represented by the general formula (II) are α-methylene-γ-butyrolactone, α-
Methylene-β,γ-tetramethylene-γ-butyrolactone, α-methylene-γ-n-octyl-γ-butyrolactone and α-methylene-γ,γ-pentamethylene-γ
- at least one selected from the group consisting of butyrolactone
The method according to claim 1, which is a species. 3. α-Carboxy-α-thio-substituted-methyl-γ-butyrolactones represented by general formula (I) are dissolved in the aqueous layer of the electrolytic solution as the corresponding alkali metal, alkaline earth metal, ammonia or amine salt. 2. The method according to claim 1, wherein the reaction is carried out in a state in which the reaction is carried out. 4 α-carboxy- whose aqueous layer is represented by the general formula (I)
The method according to claim 1, wherein the amount is 1 to 10 liters per mole of the α-thio substituted-methyl-γ-butyrolactone. 5. Claim 1, wherein the organic layer is constituted in a ratio of 0.5 to 5 liters per mole of α-carboxy-α-thio-substituted-methyl-γ-butyrolactone represented by general formula (I). Method described.