JPS603076B2 - Method for producing 5-carboxy 2-acetylthiophene - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (wherein R represents a hydrogen atom or a normal carboxyl group protecting group such as lower alkyl or phenyl group*, and x represents a normal carbonyl group) represents a protecting group.

The present invention relates to a method for producing 5-carboxy 2-acetylthiophene, which comprises oxidizing a thenyl acetate derivative represented by the following formula with a sub-box halide salt, and then removing the protective group of the carponyl group.

In the above general formula, x is a normal carbonyl group protecting group, so long as it does not interfere with the oxidation reaction by the hypohalite and can be removed after the reaction is completed, any normal protecting group may be used, such as ketal, hemithioketal,
Examples include dithioketal, thiazolidine, imidazolidine, and oxazolidine.

The usual protecting group for carboxyl group in R may be any usual protecting group that does not interfere with the oxidation reaction by hypohalite, such as a lower alkyl group, a phenyl group, and the like.

The 5-carboxyl 2-acetylthiophene of the present invention is one of the following compounds (Japanese Unexamined Patent Application Publication No. 1975-1973), which is one of the chenylthiazolylthioamide/alcohol derivatives that have a therapeutic effect on arrhythmia, various heart floaters, and hypertension. 25562, 1976-76069), and is also important as a synthetic intermediate for pharmaceuticals such as antibiotics, agricultural chemicals, and thiazole rubber drugs.

A method for synthesizing this 5-carboxy 2-acetylthiophene is a method by hydrolysis of '1' 5-cyano 2-acetylthiophene. Linstead, Noble
, and W [i or t; J. Chem. S.M. ,193
7,911, Dunn: Ber. ,B76.419(1
Based on 3)) Method by oxidation of 2,5-diacetylthiophene (Ha9ough and Kosak: J.A.
mer. Chem. S.M. '69, 1012 (1947
)) '31 Method by acylation of 2-thenoyl ester (K. Schoe and N. Pelonse)
k; Ann. , 1 (1962)) [41 2-methyl
A method of carboxylization of 2'-thienyl 1,3-dioxolane (acetylthiophene ketal) using n-butyllithium (Thames, McCIe
sKy:J. He to r ratio yclicChem. ,3'1
}, 104 (1966)), but it is difficult to produce the raw materials for industrial production, or ['1}, '2
}], the reagent used is industrially inappropriate ['1]
, '4)], are accompanied by dangers [{4)], and have low yields [[31], and are extremely difficult in all cases.

The present invention provides a particularly advantageous manufacturing method for easily industrially manufacturing 5-carboxy 2-acetylthiophene.

To explain in more detail, to carry out this reaction, compound (1) is added to a 3 mol or more alkaline hypohalite solution in water, alcohol, dioxane, etc., or a water-organic solvent such as water-alcohol, water-dioxane, etc. 5-carboxy 2-acetylthiophene can be obtained in high yield by carrying out the reaction at a temperature of 0° C. to 60 qo and then removing the protective group of the carbonyl group by a conventional method.

In this case, it is completely unpredictable whether oxidation by the hypohalite occurs first on the acetylmethyl group or on the methylene group adjacent to the thiophene ring and ester group. The oxidation by the secondary halide described in this invention occurs selectively on the methylene group, but in compounds where the ketone is not protected, such as shown in formula (0), this type of oxidation occurs on the acetyl group. A carboxylic acid derivative derived from a methyl group and represented by the formula (m) (R is a hydrogen atom, a lower alkyl group, or a phenyl group) is provided as the main product.

One of the features of the present invention is that when hypohalite is used under alkaline conditions, hydrolysis, oxidation to keto acids, and oxidative decarboxylation are thought to occur in terms of the reaction mechanism. The objective is to provide the desired 5-carboxy 2-acetylthiophene in high yield even when it has a ester group that is difficult to hydrolyze.

On the other hand, as a method for removing the protective group of the carbonyl group, a review is given by Mco Hada E, rPmtectivegrou.
psinOrganicChemisPy''(Pien
umPress London and New York), for example, ketals, hemithioketals (C.D. Sagi Rassl, F. Bakes. J.
Romo and G. Rose rudder: J. Am.
Chem. S ratio, 74, 3634 (1952)), oxazolidine (gandH, R, in E.P.Cbld,
NaCe; J, Am, Chem, S ratio, 77,359
(1955)), imidazolidine (Japanese. W. Wanzl
ickandW. Shio cell: Chem. Ber.
86, 1463 (1953)), etc., by treatment with dilute acids;
677,160 (19 I), E, J. Corey an
dR. B. Mitra: J. Am. Chem. Soc.
．． , 84, 29 (1962)) give ketones by treatment with mercury salts.

Although the product obtained in the practice of the present invention is sufficiently purified in the form of crystals obtained by acid-fractionating the reaction solution, it can be purified by recrystallization from a solvent such as water if necessary. Formula (1), which is the raw material of the present invention, has a wide range of applications, and is obtained by esterifying chenyl acetic acid, which has already been produced industrially, and then acylating it with acetic anhydride in the presence of phosphoric acid or zinc chloride. 5-acetyl obtained by
How to use 2-chainyl acetate (authored by McOME; rProtective Gmups ln0 "Hoko n
It can be easily synthesized by protecting the carbonyl* homogeneous group using icChemist (see p. 323).

In order to provide a more specific explanation, the following examples will be used, but these examples do not have a limiting meaning.

Reference Example I Synthesis of Z5-acetyl 2-thenyl methyl acetate 1.41 g (0.01 mol) of methyl 2-thenyl acetate and acetic anhydride 4
．． 2 females (0.04 mol) were mixed and allowed to overflow to 70 to 8 mol.

While keeping the reaction solution at the same temperature, add 0.0% to the bottom of the fly. Add Shigeru's 85% phosphoric acid dropwise. There is a slight temperature rise during this time, but there is no need for cooling. The reaction mixture is heated at 70-80°C for 3 hours. After cooling, the reaction solution was poured into water and extracted with ether.
The ether layer is washed with water and then dried over anhydrous magnesium sulfate to remove the ether. The obtained residue was recrystallized from petroleum ether-benzene to obtain 1.3-linked (76.5%) methyl 5-acetyl 2-chenylacetate (melting point: 43-4°C).
get. Reference Example 2 Synthesis of methyl ethylene acetal of 5-acetyl 2-thenyl acetate 0.977 g of ethylene glycol & 1.307 g of ethyl orthoformate and a catalytic amount of p-toluenesulfonic acid were dissolved in 10 w of benzene, and 0.57 g of ethylene glycol was dissolved in 10 w of benzene.
Add methyl 2-acetyl 5-chenyl acetate and stir at room temperature for 3 hours.

After the reaction, the reaction solution was placed in ice water and the organic layer was separated. The aqueous layer is further extracted with benzene (50% x 2), combined with the organic layer, washed with water, and dried over anhydrous magnesium sulfate. Benzene was removed under reduced pressure to obtain 0.28 (91%) yellow oil. This material showed that the absorption derived from acetyl carbonyl in 167 urine-1 disappeared in IR, and at the same time, it showed 64.00 in NMR (CDC 3).
Since a methylene signal originating from the dioxolane ring appears in (day, s), it is confirmed that it is the desired ketal. Example 1 6.9% bleached chloric acid aqueous solution containing an excess amount of caustic soda in advance (prepared from 2.5 parts of caustic soda to one part of chlorine)5. Take a spot and drop a fly on it with 0.20 5-
Acetyl 2-thenyl acetate methyl ethylene acetal was added dropwise to 5-helical ethanol.

As the temperature of the reaction liquid begins to rise as it is added dropwise, the reaction liquid is cooled so as not to rise above 40°C. After the addition, the reaction solution was heated at room temperature for 30 minutes. After the reaction, freshly reacted sodium sulfite is added to decompose excess subboxal chloric acid, then concentrated hydrochloric acid is added until the reaction solution reaches pHI, and the mixture is further stirred at room temperature for 30 minutes. The reaction solution was diluted with 30' of water and extracted with ether. The ether layer is washed with water, dried over anhydrous magnesium sulfate, and the ether is distilled off. The residue is recrystallized from water to obtain 0.1 crab (78.2%) of 5-carpoxy 2-acetylthiophene. The products in this reaction were identified from the separately synthesized primary product by IR, NM old, behavior on thin layer chromatography, and concentration test.

Example 2 Take the above 69% hypochlorous acid aqueous solution 25% and add 1 to it.
．． Dissolve 0 cough of 5-acetyl 2-chenyl acetate methyl ethylene acetal in 10 volumes of methanol and add dropwise while keeping the reaction solution below 4 pi.

After the dropwise addition, the reaction solution was allowed to stand at room temperature for 1 hour, and after decomposing excess submerged chloric acid with sodium sulfite, the mixture was adjusted to pHI with concentrated hydrochloric acid and left to stand for another 1 hour. After methanol is distilled off under reduced pressure, the resulting crystals are collected, washed with water, and then dried. Yield 0.
74 chicks (81%) The product in this reaction was identified as that obtained in Example 1 by IR, NMR, behavior on thin layer chromatography, and a mixed test.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom or a normal carboxyl group protecting group, and X represents a normal carbonyl group protecting group) 1. A method for producing 5-carboxy-2-acetylthiophene, which comprises oxidizing a thienyl acetate derivative represented by the formula with a hypohalite salt, and then removing the protective group of the carbonyl group. 2. The manufacturing method according to claim 1, wherein R is a hydrogen atom or a lower alkyl group.