JPS59175478A - Preparation of 2,2-dimethyl-5-hydroxythiazolidine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for synthesizing caphalosporin, beta-lactam antibiotic, by one process simply and easily, by oxidizng a 2,2-dimethylthiazolidine derivative as a raw material with oxygen in the presence of a photosensitizer. CONSTITUTION:A 2,2-dimethylthiazolidine derivative shown by the formula I (R<1> is H, or lower alkyl; R<2> is amino-protecting group) is oxidized with oxygen in the presence of a photosensitizer in a polar solvent such as methanol, ethanol, acetonitrile, etc. to give a compound shown by the formula II. Preferably Rose Bengale, or methylene blue having good solubility in the polar solvent used in the above-mentioned reaction is used as the photosensitizer. Halogen-, tungsten-, sodium-lamp or mercury vapor lamp is used as a light irradiation lamp. An amount of the photosensitizer added is about 0.5-1wt% based on the raw material compound. The reaction is advanced smoothly by adding DMSO to it.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for the synthesis of 2,2-dimethyl-5-hydroxythiazolidine derivatives.

2.2-dimethyl-5-hydroxythiazolidine is β-
It is a compound useful as an intermediate in the synthesis of cephalosporins, which are lactam antibiotics.

Cephalosporins are useful drugs that are currently widely used along with penicillin, and are generally produced by a combination of fermentation and chemical synthesis methods.

On the other hand, a method for synthesizing cephalosporins by pure chemical synthesis has also been reported.

For example, J, Am, Chem, Soc, 88
, p. 852 describes the total synthesis of cephalosporin C by Wood-W3rd et al., in which cephalosporin C. It is produced via the important intermediate β-lactam compound (6) shown by the following formula.

Usually, this β-lactam compound is produced by first condensing a cysteine prisoner with acetone to form a thiazolidine ring.
Dimethylthiacylidine-4-carboxylic acid (Bl), amino group replaced with lower acyl group, benzoyl group.

It is protected with an amine protecting group such as a benzyloxycarbonyl group or t-butyloxycarbonyl group, and optionally used as a lower alkyl ester (C) in a subsequent step.

This can be summarized from the description in the above literature as follows.

false) (B) (C)eOO
C (D) (E) Notes (al Formation of thiazolidine ring by condensation with acetone.

(b) Amino group 4ft' by t-butyloxycarbonyl chloride! = and methyl esterification with diazomethane.

(c) Hydrazodiesterification using dimethyl azodicarboxylate.

(d) Hydroxyesterification with lead tetraacetate.

(eJ Azide esterification with aqueous sodium azide.

(f) Reduction with aluminum amalgam.

In the above β-lactam production process, the present inventors particularly (
5-Hydroxy derivatives that carry out step C) and step (1) (in the production of odors, this step oxidizes azodicarboxylic acid ester and acts on this ester with highly toxic lead tetraacetate, etc.) J, Am, Chem.

Bal in Soc, 97, 5957M (1975)
Dwin et al. teach a method of converting benzoyl peroxide into benzoate and hydrolyzing it, but this reaction also has a low yield and is therefore not practical.

Another object of the present invention is to provide a method for producing 5-hydroxy derivatives in a single step, which can be carried out extremely simply and easily in contrast to conventional techniques, and in a good yield.

According to the present invention, a 2゜2-dimethylthiazolidine compound represented by the general formula (wherein R1 is hydrogen or a lower alkyl group, and R2 is an amine protecting group) is treated in the presence of a photosensitizer. This is a method for producing a 2,2-dimethyl-5-hydroxy-thiacyridine derivative represented by the general formula (in which R1 and R2 have the above meanings) by oxygen oxidation.

Compounds of formula (II), which are the starting compounds of the present invention, are prepared by condensation of cysteine and acetone according to the teachings in the table above. According to the teachings of Mr. Woodw3rd, mentioned above, free cysteine 12 is refluxed in 250 CC of acetone for 125 hours. Make a complete solution, and after cooling, remove trace amounts of insoluble matter. P'/r! i, is concentrated to the saturation point, filtered and left to stand to obtain the desired 2,2-dimethylthiazolidine-4-carboxylic acid in a yield of 63 to 71X. It dissolves easily in water and has a melting point of 134-134.5°C.

As the amino protecting group of 2.2-dimethylthiazolidine-4-carboxylic acid, any appropriate carbonyl derivative group mentioned above may be selected, but the above-mentioned 2.2-dimethyl group is not taught in the above-mentioned literature. Thiazolidine-4-
The carboxylic acid is obtained by treatment with t-butyloxycarbonyl chloride generated in situ in methylene chloride from t-butyl alcohol, phosgene and pyridine.

The corresponding 3-1-butyloxycarbonyl-2,2-dimethylthiazolidine-4-carboxylic acid has a melting point of 114-1
14.5°C, [α]2J-85°.

The photosensitizers that can be used in the method of the present invention are those commonly used in known photosensitization oxidation reactions, such as rose bengal, methylene blue, and tetraphenylporphyrin. methanol for the reaction.

Polar solvents such as ethanol and acetonitrile are preferably used. Additionally, by adding DMSO, the reaction can proceed smoothly.

Therefore, these polar solvents KFl can be used as photosensitizers.
It is preferable to use rose bengal and methylene blue, which have good properties. The light irradiation lamp is halogen.

Tungsten, sodium and mercury lamps are used.

Specifically, the present invention will be carried out in the following manner.

2.2-dimethylthiazolidine derivative (TI) from 10 to
Good results can be obtained by dissolving the compound in 20 times the volume of methanol, ethanol, or (haacetonyl) and further adding DMSO in an amount of about IO times the mole of the starting compound (T). The amount of photosensitizer added is about 0.5 to 1% by weight based on the raw material compound. This reaction solution is irradiated with light while introducing oxygen through a #I tube. Although there are no strict regulations regarding reaction temperature and time, the reaction is completed in 2 to 3 hours at 20 to 30°C. After the reaction, the solvent is distilled off under reduced pressure and the product is subjected to silica gel column chromatography to obtain the desired 2,2-dimethyl-5-hydroxythiazolidine derivative (I) in a yield of 60 to 70%. I can do it. The reaction consumes only a small amount of photosensitizer, oxygen, and light source, and is a single step with a high yield compared to prior art methods that use toxic reagents or produce low yields. Since it makes it possible to produce the target compound, it can be said to have very high industrial utility value.

Incidentally, the method itself of irradiating a thioether compound with light in the presence of a photosensitizer and oxygen is known.

For example, Angew, CC11e, 74.510
(1962) teaches that dialkyl- and alkyl-arylthioethers give quantitative amounts of the corresponding sulfoxides under these conditions. On the other hand, in the case of the uninvention, the expected formation of sulfoxide by applying this reaction system to the thiazolidine derivative (II) is minimal, and due to the specificity of the substrate, a completely new type of sulfoxide is produced. 2,2-dimethyl-5, which is the reaction product of
-Hydroxythiazolidine could be produced at a high IJS14 rate. This fact is a completely unexpected result based on the teachings of the prior art and suggests the possibility of application of this photosensitized oxygen oxidation reaction system not only to the starting compounds of the present invention but also to the hydroxylation of other homologous compounds. It is something.

The specific implementation of the present invention will be explained below with reference examples and examples.

Reference Example 2. To a solution of 2-dimethyl-4-carboxythiazolidine hydrochloride (20 mmol) in pyridine, an equivalent amount of benzoyl chloride is added dropwise, and the mixture is stirred at room temperature for 8 hours.

The pyridine distillation residue is dissolved in dichloromethane and the solution is washed with water. The formed P layer was dried with anhydrous sulfuric acid), the solvent was evaporated to obtain a semi-crystalline mass, and 3-benzoyl-2,2-
Dimethyl-4-carboxythiasiridine is recovered. Yield 74%.

Melting point: 180-182°C. [α]D−+ 54°(CO
, 83, CHC4).

3-benzoyl-2,2-dimethyl-4-carboxythiasiridine (4 m m, ot) in methanol (20 m
e) A slight excess of diazomethane in ether was added to the solution at 0°C, stirred for 12 hours and the solvent was removed to give a white crystalline product. When recrystallized with ether/hexane,
White columnar crystals of 3-benzoyl-4-methoxycarbonyl-2,2-dimethylthiazolidine are obtained in a yield of 83%. Melting point: 105-106.5°C. [αt,,'-
180° (CO, 92, cHcz3).

3-benzoyl-4-methoxycarbonyl-2,2-dimethylthiazolidine 20P prepared in Example Reference Example (2) was dissolved in 40 dK of a7tonitrile, and DMSO5,
Add Or. Furthermore, 20η of methylene blue was added, and original irradiation was performed for 15 hours at room temperature using a 300W halogen lamp while introducing oxygen through a thin tube. After the solvent was distilled off under reduced pressure, the main product was separated by chromatography on silica gel (benzene:ethyl acetate=4:1). Recrystallization from chloroform/hexane gives a melting point of 170-17
Crystals 1.,3r (yield: 62%) were obtained at 1°C (decomposition).From the results of elemental analysis, NMR spectrum, and infrared absorption spectrum (attached drawing), this crystal was 3-benzoyl-5-hydroxy. -4-methoxycarbonyl-
It was confirmed that it was 2,2-dimethylthiazolidine.

Elemental analysis value C: 56.92 H: 5.80
N: 4.69 Calculated value C: 56.93) (:5
．． 80 N: 4°74 (q4 HI? No<) [α]D-75.3° (C1,26, CHC/!, )

[Brief explanation of the drawing]

FIG. 1 shows the NMR spectrum in deuterated chloroform of 3-benzoyl-5-hydroxy-4-methoxycarbonyl-2,2-dimethylthiorisolidine obtained in the example, and FIG. 2 shows the infrared absorption spectrum. Patent Applicant 2 Nippon Rikagaku Yakuhin Co., Ltd. Agent: Patent Attorney Yasuzo Umitsu

Claims (1)

[Scope of Claims] A 2゜2-dimethylthiazolidine derivative represented by the general formula (in which R1 is hydrogen or a lower alkyl group, and R2 is an amino protecting group) is treated with oxygen in the presence of a photosensitizer. A method for producing a 2,2-dimethyl-5-hydroxythiazolidine derivative represented by the general formula (wherein R1 and R2 have the above-mentioned meanings), which is characterized by being oxidized.