JPS6245231B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for synthesizing 2,2-dimethyl-5-hydroxythiazolidine derivatives, particularly β-
The present invention relates to an improved method for producing the above-mentioned 5-hydroxythiazolidine, which is useful as an important intermediate in the synthesis of cephalosporin, a lactam antibiotic.

Cephalosporin is a useful drug that is currently widely used along with penicillin. Regarding the synthesis of cephalosporin, see, for example, J.Am.Chem.
Reference is made to the total synthesis method for cephalosporin C of Woodward et al., described in Soc, 88, 852. In the synthesis of cephalosporin C or penicillin, a β-lactam compound (H), which is an important intermediate compound represented by the following formula, is used as a basic structural element.

The manufacturing process of this β-lactam compound (H) is summarized from the description in the above-mentioned literature as shown in the following table.

In the above β-lactam production process, the present inventors have specifically identified (E) from the above compound (C) via (D).
We investigated the process leading to the 2,2-dimethyl-5-hydroxythiazolidine compound and found that the essential requirements, hydrazodiesterification using dimethylazodicarboxylate and hydroxylation using highly toxic lead tetraacetate, are industrially viable. Focusing on this lack of practicality, we discovered a method for easily obtaining 5-hydroxy derivatives in one step, as opposed to the two steps of the prior art, and proposed it as Japanese Patent Application No. 1987-48769.

According to the prior invention, the 5-hydroxythiazolidine derivative of compound (E) can be produced in one step by oxygen-oxidizing the compound (C) in the presence of a photosensitizer. In this invention, the 2,2-dimethylthiazolidine derivative of compound (C) is dissolved in a polar solvent such as methanol, ethanol, or acetonitrile, and dimethylsulfamide (DMSO) is added in an amount approximately 10 times the molar amount of the starting compound. Sensitized oxygen oxidation proceeds smoothly, and 5-hydroxythiazolidine derivatives can be obtained in a yield of 60 to 70%.

As a result of various studies to develop this photosensitized oxygen oxidation method, the inventors of the present invention further conducted the above reaction in an aprotic solvent at a low temperature to produce an intermediate with the general formula 2,2-dimethyl- (in the formula, R ¹ is a lower alkyl group and R ² is an amino protecting group)
It has been found that 5-hydroperoxythiazolidine derivatives are produced almost quantitatively.

This 5-hydroperoxide () is quantitatively converted into 5-hydroperoxide by the action of an appropriate reducing agent such as dimethyl sulfide or triphenylphosphine according to the following formula.
It can be induced into the hydroxy form ().

Therefore, the present invention involves dissolving a 2,2-dimethylthiazolidine derivative represented by the formula () in an aprotic solvent, performing a photosensitized oxygen oxidation reaction at a low temperature, and then reducing the resulting compound of the formula (). It is characterized by Since the conversion rates in the first and second stages based on the above reaction formula are almost quantitative, the 5-hydroxylation reaction yield is 90 to 95%.
Or even better. This method can be said to be a much improved method compared to the 60-70% yield in the prior invention.

Conventionally known photosensitizers are used, and usually,
Methylene blue, thionine, chlorophyll, tetraphenylporphine, rose bengal supported in a polymer, etc. can be used.

An aprotic organic solvent must always be used as the reaction medium. Generally, benzene,
Aprotic organic solvents such as aromatic hydrocarbons such as toluene, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, and ethers such as tetrahydrofuran and dioxane are used. In the method of the present invention, when a protic solvent such as methanol or ethanol is used, the 5-hydroxyperoxide of formula () is present in a few percent.
only generated.

5 of formula () produced in the first stage reaction of the present invention
-Hydroperoxide itself is a new compound that has not been described in any literature. The compound can be isolated, but the reaction must be carried out at low temperatures to prevent decomposition. It is generally preferred to carry out the reaction at a temperature of -20°C to 0°C. Since the same solvent can be used for the subsequent reduction reaction as in the previous reaction, the reduction process can be carried out without isolating the intermediate, thereby improving the overall yield. It's convenient.

The invention can generally be practiced as follows. First, the 2,2-dimethylthiazolidine derivative is dissolved in 20 to 30 times the volume of the above-mentioned aprotic organic solvent, and 0.5 to 5% by weight of the 2,2-dimethylthiazolidine derivative is photosensitized based on the weight of the 2,2-dimethylthiazolidine derivative in the solution. After adding the agent, light irradiation is carried out at as low a temperature as possible, preferably -20° to 0°C, while blowing oxygen through a thin tube. The reaction is completed in 1.5 to 3 hours using the general-purpose light irradiation lamp described above. Completion of the reaction can be confirmed by the disappearance of the raw material compound by thin layer chromatography analysis of the collected sample. Since the resulting 5-hydroperoxy-2,2-dimethylthiazolidine derivative is unstable and gradually decomposes at room temperature, approximately an equivalent amount of reducing agent is added to the reaction mixture to achieve the object of the present invention. It is better to perform direct reduction treatment. This reduction reaction proceeds easily at room temperature and is usually completed after stirring for about 1 hour. When purification is performed by column chromatography,
A highly purified 5-hydroxy compound is obtained.

As the light irradiation lamp, general lamps such as high-pressure mercury lamps, halogen lamps, tungsten lamps, and sodium lamps are used.

The present invention will be explained below with reference to Examples.

Example 1 Production of 5-hydroperoxy-5-methoxycarbonyl-2,2-dimethylthiazolidine 3-benzoyl-4-methoxycarbonyl-
0.279 g of 2,2-dimethylthiazolidine was dissolved in 5 ml of tetrahydrofuran, and 15 ml of tetraphenylporphyrin was added as a photosensitizer. Light irradiation was performed for 3 hours using a 500W halogen lamp while blowing oxygen into the reaction solution from a thin tube while keeping the reaction solution at 0°C. Rf was determined by thin layer chromatography (silica gel, benzene: ethyl acetate: methanol = 10:4:1) analysis of the collected sample.
The raw material compound with Rf = 0.68 disappeared and the presence of a product with Rf = 0.58 was confirmed. The solvent tetrahydrofuran was distilled off at a low temperature under reduced pressure, and low-temperature column chromatography (0°C silica gel, benzene:ethyl acetate =
Separation of the Rf=0.58 product by 3:2) gave 0.296 g of 3-benzoyl-5-hydroperoxy-4-methoxycarbonyl-2,2-dimethylthiazolidine as a colorless oil. Yield 95% (gradual decomposition at room temperature).

NMR (benzene- _d6 ): δ2.10 (S, 3H) 2.20 (S, 3H) 3.15 (S, 3H) 5.60 (S, 1H) 5.75 (S, 1H) 7.20-7.80 (m, 5H) IR: 3230, 1740, 1620 cm ^-1 Example 2 Production of 5-hydroxy compound (E) from 5-hydroperoxide compound (C) 3-benzoyl-5-hydroperoxy-4-methoxycarbonyl-2 obtained in Example 1・2
-Dissolve 0.296 g of dimethylthiazolidine in tetrahydrofuran, add 0.262 g of triphenylphosphine as a reducing agent, and stir for 1 hour at room temperature. -5
-Hydroxy-4-methoxycarbonyl-2.2
-0.253 g of dimethylthiazolidine was obtained. Yield 90
%.

Melting point: 170-171℃ (decomposition) NMR (CDCl ₃ ): δ2.00 (S, 3H) 2.15 (S,
3H) 3.20 (d, 1H) 3.70 (S, 3H) 5.00 (S, 1H) 5.60 (d, 1H) 7.50 (S, 5H) IR: 3230, 1740, 1620 cm ^-1 Example 3 3-acetyl-4- Methoxycarbonyl-2.
2-dimethylthiazolidine 0.217g to toluene 5
10mg of methylene blue as photosensitizer dissolved in ml
was added, and the reaction solution was irradiated for 90 minutes with a high-pressure mercury lamp while blowing oxygen through a capillary while keeping the reaction solution at 0°C. The raw material compound disappeared by thin layer chromatography (silica gel, benzene: ethyl acetate: methanol = 10:4:1), and a 5-hydroperoxy compound was confirmed. Next, 0.262 g of triphenylphosphine was added to the reaction mixture, and after stirring at room temperature for 1 hour, 3-acetyl-5-hydroxy-4-methoxy was purified by column chromatography (silica gel, benzene: ethyl acetate = 3:2). Carbonyl-
0.222 g of 2,2-dimethylthiazolidine was obtained.
Yield 95%.

NMR (CDCl ₃ ): δ1.90 (S, 3H) 2.06 (S,
3H) 2.10 (S, 3H) 3.20 (broad 1H) 3.85 (S, 3H) 4.99 (S, 1H) 5.76 (S, 1H) IR: 3200, 1740, 1615 cm ^-1 Comparative example This comparative example is polar as a proton solvent. A case using methanol as a solvent will be explained. In addition to dissolving 0.279 g of 3-benzoyl-4-methoxycarbonyl-2,2-dimethylthiazolidine in 5 ml of methanol, light irradiation was carried out for 10 hours under exactly the same conditions as described in Example 1. However, by column chromatography, 3-benzoyl-5-hydroperoxy-4-methoxycarbonyl-2.
The yield of 2-dimethylthiazolidine is only 0.022
g, yield was only 7%.

Claims (1)

[Claims] 1. General formula (However, R ¹ in the formula is hydrogen or a lower alkyl group, and R ² is an amino protecting group) is dissolved in an aprotic solvent and photosensitized at low temperature. carry out the reaction,
Then generate the general formula (However, R ¹ and R ² in the formula have the above-mentioned meanings.) - A method for producing a dimethyl-5-hydroxythiazolidine derivative.