FI90540C - Method for preparing 3-substituted thiophene - Google Patents

Description

90540

Process for the preparation of 3-substituted thiophene For the preparation of 3-position substituted thiophene 5

The invention relates to a process for the preparation of a 3-substituted thiophene of the formula (I) 10. rf wherein R1 is alkyl.

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Thiophene derivatives are important raw materials in the manufacture of various plastic products.

Thiophene is used as an intermediate in the manufacture of drugs, especially antihistamines, which contain a thiophene moiety. It is also an intermediate product in veterinary medicine. pesticides, dyes, etc.

In the laboratory, thiophene is preferably prepared by heating powdered anhydrous sodium succinate with phosphorus trisulfide to high temperatures in a stream of carbon dioxide. The crude thiophene from the effluent gas stream is condensed, steam distilled and dried. Alternatively, succinic anhydride is treated with phosphorus trisulfide or pentasulfide. The previously known Sokony vacuum process (Mobil Oil Corporation) was based on a non-catalytic continuous reaction of butane and sulfur at high temperature.

30: Newer processes for the preparation of thiophene and its derivatives are continuous: steam evaporation processes utilizing C4 feedstocks and sulfur sources, 2,90540 with special metal oxide catalysts to improve reaction rates and yields, and thiophene formation. U.S. Patent 3,197,483 discloses such a method. In this process, the vapor step reaction of furan and hydrogen sulfide is performed with a heteropolyacid-containing metal oxide catalyst to give thiophene and water at a relatively low temperature (300-400 ° C). The process can also be used to prepare 2-methylthiophene from 2-methylfuran and tetrahydrothiophene from tetrahydrofuran.

In another process, exemplified by U.S. Patent 3,822,289, C4-10 feedstocks such as 1-butene, butadiene, n-butyl alcohol, or crotonaldehyde are continuously reacted with carbon disulfide using an alkali-containing metal oxide catalyst at high temperatures (500 ° C). In general, carbon disulfide acts as a source of sulfur, which apparently converts to methane or carbon dioxide. This method can also be used to prepare 2- and 3-alkyl substituted thiophenes.

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In a third process, exemplified by U.S. Patent 3,939,179, a continuous high temperature reaction (500-600 ° C) between butane and sulfur occurs using a stirred metal oxide catalyst that dehydrates the butane. The hydrogen formed reacts rapidly with sulfur to produce hydrogen sulfide in a highly exothermic reaction. Hydrogen sulfide reacts with the butane residue to form thiophene in good yields. By this method 2- and 3-alkyl substituted thiophenes can be prepared from the highest hydrocarbons.

The preparation of some thiophene derivatives is known from Carpenter, A.J.

25 Chadwick, D.j. Org. Chem 1985, 50, 4362, from which the following reaction is known:

rC - pC z. ^ pC

^ S ^ CO-NH'Bu ^ CO-NLi'Bu ^ CO-NH'Bu 12 3 2 n-BuLi / - 10 * C / DME, E- * · = «electrophiles; l.

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Another method for preparing the aforementioned same material is known from Tetrahedron Letters, Vol. 14, pp. 1777-1780, 1985, in which thiophenecarboxylic acid is directly lithiated at the 3-position. However, this reaction is not as area-selective as the reaction with carboxamide, and in addition it must be carried out at a temperature of 5 to 78 ° C.

Japanese Patent Application 50154238 prepares thiophene by heating alkali salts of succinic or alkyl succinic acids at 280-340 ° C with phosphorus sulfide (1%) with a high boiling point hydrocarbon.

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In Japanese Patent Application 51006157, thiophenes are prepared by the reaction of succinic acid alkyl succinic acid and their derivatives with polysulfides in the presence of phosphorus.

The present invention relates to a new process for the preparation of a 3-substituted thiophene, utilizing the said Carpenter A.J., Chadwick D.J .; The reaction used in the Journal of the Organic Chemistry.

The invention for the preparation of said compound of formula I is thus characterized in that the N-alkyl-3-alkyl-2-thiophenamide of formula (II) (N, ... NT NT JIHR2 in which R1 and R2 are alkyl) is treated with a strong with an acid to remove the amide group and to give a compound of formula (I).

4,90540 The preparation of the 3-substituted thiophene from the amide of 2-thiophenecarboxylic acid takes place according to the following formula: 5 '26UU - * O ^ v, · - - 032 »

In the process, a reaction known from said article is first performed as a first step, after which the reaction is continued with a strong acid to obtain the desired compound. The advantages of the invention are that the amino group is removed from the product by taking advantage of the one-step reaction and in that the reaction can be carried out with a preferred acid without the need for a high temperature. Only carbon monoxide and amine hydroxide are obtained as by-products, from which the amide is recovered. In addition, the starting materials are readily available compounds.

The invention will now be described with reference to an embodiment, from which the method according to the invention will be explained in detail.

·. 25 EXAMPLE

N-t-butyl-2-thiophenamide 1.8 g (0.01 mol) were dissolved in 40 ml of tetrahydrofuran and cooled to -60 ° C. Nitrogen was used as a shielding gas in the reaction. 0.02 mol of butyllithium in hexane solution was added and stirring was continued in the same temperature for 30 minutes. Heptyl bromide 1.8 g (0.01 mol) was dissolved in tetrahydrofuran and added to a cold mixture which was allowed to slowly warm to room temperature.

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The shielding gas was removed and 40 ml of water was added to the mixture. The organic portion was extracted with ether (3 x 60 mL). The combined ether solutions were dried (Na 2 SO 4) and the solvent evaporated. By dissolving the product in petroleum ether and crystallizing in the cold, most of the impurities were removed by filtration. The reaction gave 5 g of N-t-butyl-3-heptyl-2-thiophenamide, representing a 72% yield. When the reaction lamp temperature was -10 ° C, undesired side reactions also occurred.

When dimethoxyethane is used as the solvent, the reaction already takes place at -10 ° C, yielding 80% yield.

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The resulting N-t-butyl-3-heptyl-2-thiophenamide was heated in 20% hydrochloric acid solution for about 65 h to remove the amide group. The organic compound was extracted from the cooled solution with ether, the solution was dried and the ether was evaporated. The isolated compound was 3-hepylthiophene with a boiling point of 247 ° C. In a 50 mmol batch, 50% yield was obtained.

The identification of the compound is shown in Figures 1-5.

Figure 1 shows the NMR spectrum of 3-heptylthiophene.

. · / 20

Figure 2 shows the IR spectrum of 3-heptylthiophene.

Figure 3 shows the mass spectrum of 3-heptylthiophene.

Figure 4 shows the NMR spectrum of N-t-butyl-3-heptyl-2-thiophenamide.

Figure 5 shows the IR spectrum of N-t-butyl-3-heptyl-2-thiophenamide.

Claims (4)

6 90540 A process for the preparation of a 3-substituted thiophene of the following formula (I) wherein R 1 is alkyl, characterized in that the N-alkyl-3-alkyl-2-thiophenamide of formula (II) rC ' Wherein R 1 and R 2 are alkyl, are treated with a strong acid to remove the amide group and thereby obtain a compound of formula (I). Process according to Claim 1, characterized in that R 1 is heptyl and R 2 is t-butyl. Process according to Claim 1 or 2, characterized in that the strong acid is preferably HCl and has a concentration in the range from 1 to 40%, preferably 20%. 30 I; 7 90540 Process according to one of Claims 1 to 3, characterized in that the reaction is carried out at a low temperature, preferably 30 to 150 ° C. 8 90540 Patentkraven