KR900008813B1 - Preparation for furan derivatives - Google Patents

Abstract

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Description

Method for producing furan derivative

The present invention relates to a novel process for preparing furan derivatives of the following structural formula (I) and acid addition salts thereof.

The compound of the above structural formula is known as ranitidine, and is widely used as an effective therapeutic agent for gastric ulcer and peptic ulcer. Methods for preparing the compound of formula (I) are known from Korean Patent Publication Nos. 81-355, 81-356, 86-63, 87-165 and the like. A drawback of these known methods is the release of a large amount of methyl mercaptankas, a low boiling point and toxic thiol compound. This methyl mercaptan is a highly flammable gas that is not only highly dangerous to fire when it is generated in a large amount at the production site, but also toxic and expensive to prevent it. Thus, manufacturing processes are disclosed in patent publications 86-63, 87-165, aiming at reducing the release of such gaseous thiols. However, these methods are not a method that can prevent the occurrence of methyl mercaptan inherently, there are still industrial problems. Moreover, these methods use expensive catalysts or react at higher temperatures, making the methyl mercaptan compound having a boiling point of 5.95 ° C. more difficult, as well as difficult to protect the operator. In addition, there are various industrial and economic drawbacks, such as causing large amounts of by-products to be blown into the air, causing pollution or disposing of them at high cost.

The present invention provides a novel method of preparation which is technically extremely advanced as a method of remedying various disadvantages of the known methods for preparing the compound of formula (I).

The raw materials used in the method of the present invention are represented by the following structural formulas (II), (III) and (IV).

To react the compound of formula (II) with the compound of formula (III) and formula (IV) in turn in one reactor to prepare the ranitidine of formula (I).

The compound of formula (II) is a known compound, but there have been no known examples of the use of the compound of formula (II) in the preparation of ranitidine. In addition, examples of substituting two different amine compounds in the compound of formula (II) have not been heard other than the present invention. In addition, there has never been an example in which a compound of formula (I) has been made by substituting two different amine compounds sequentially from a compound of formula (V), which is similar to formula (II).

The reaction of substituting two different amine compounds into cyclic dithio-2-nitromethylene compounds in turn is the first method of the present invention.

As such, the method of the present invention is a novel method and provides several advantages as described below. This will be described in detail as follows.

In the conventional method, a methyl group introduced into an intermediate raw material using a toxic or expensive raw material such as methyl iodine or dimethyl sulfate is finally separated into a methyl mercaptanicose form, thereby causing pollution or generating highly flammable gas. Not only does it endanger the site, but a separate facility has to be set up and disposed of at a high cost.

By using the method of the present invention, there is no occurrence of toxic and highly flammable methyl mercaptan cutlet, so that not only the above embankment problem is caused, but also the byproducts of the by-product have high boiling point and are safe in the industrial field. It is obtained as an expensive dithiol compound which is very useful and widely used, thus making the method of the present invention more valuable by eliminating waste of resources.

In the present invention, it is another feature that the whole process of the reaction is performed at room temperature. Since there is no heating or cooling, it is very important in the production process as a method of greatly saving energy, but the method of the present invention can obtain a great advantage in terms of energy saving. In the present invention, there is also an advantage that the reaction can be carried out very easily as a one-port reaction. The method of the present invention, which is an industrially significant advantage, is described in more detail as follows.

The compound of formula (II) is mixed together in the organic solvent with the compound of formula (III) and stirred at room temperature. At this time, the solvent may be methylene chloride, dichloroethane, chloroform, carbon tetrachloride, acetonitrile, THF, acetone, and the like, and methanol, ethanol, isopropanol, n-butanol, 2-butanol, t-butanol, and the like. You may mix and use together an appropriate amount.

Upon completion of this reaction, methylamine is added and stirring at room temperature yields the compound of formula (I) in high yield. Separation in the following conventional manner affords compounds of formula (I) in the form of useful salts. The invention is better illustrated by the following examples.

Example 1

Into a mixed solvent of 50 ml of dichloroethane and 30 ml of t-butanol, 12 g of 2-nitromethylene-1,3-dithiane and 10 g of 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethylamine After stirring for 24 hours at room temperature under nitrogen atmosphere, 6 ml of 40% aqueous methylamine solution was added thereto, and further stirred at the same temperature for 5 hours, and then the excess methylamine was removed under reduced pressure, 200 ml of dichloroethane was further added, and washed three times with 100 ml of water. And the solvent layer is dried with a forget-me-not. 4 g of c-HCI is added to the solvent layer so that the water layer has a pH of 4.5. The water layer was separated, and 100 ml of isoprophyl alcohol was added dropwise, and the seed of crystal was added and stirred to obtain 11.5 g of ranitidine hydrochloride.

m.p. = 139-140 ° C. (decomposition)

TLC = silica gel plate / dioxane: methanol: DMF = 6: 3: 2

Rf = 0.5

Example 2

Dissolve 60 g of 2-nitromethylene-1,3-dithiane in 250 ml of 1,2-dichloroethane and give 2-[[[[5- (dimethylamino) methyl-2-furanyl] methyl] at 25 ° C under nitrogen atmosphere. 50 g of thio] ethylamine was slowly added dropwise over about 10 hours, followed by further stirring for 10 hours, and then 30 ml of 20% methylamine metallol solution was further stirred at the same temperature for 6 hours, and then the remaining methylamine was removed under reduced pressure. 600 ml of ethane is further added, washed three times with 300 ml of water and the solvent layer is dried over forget-me-not. 5 ml of water was added to the organic solvent layer, c-HCI was added so that the water layer was pH = 4.5, and the water layer was separated and treated as in Example 1 to obtain 59 g of ranitidine hydrochloride.

Example 3

To 0.5 ml of methylene chloride, 0.2 g of 2-nitromethylene-1,3-dithiane and 0.14 g of 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethylamine were added, followed by nitrogen atmosphere. After stirring at 25 ° C. for 20 hours, 0.2 ml of 40% aqueous methylamine solution was added thereto, 5 ml of water including salt was added thereto, washed three times, and 1 ml of water was added to the methylene chloride layer, and then pH = 4.5 with d-HCI. TLC was isolated to give ranitidine.

Example 4

In 0.8 ml of 1,2-dichloroethane, 0.4 g of 2-nitromethylene-1,3-dithiane and 0.32 g of 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethylamine were added. After stirring at room temperature under nitrogen atmosphere for 24 hours, 0.7 ml of 40% aqueous methylamine solution and 2 ml of methanol were added thereto, and the mixture was stirred at room temperature for 6 hours, and then treated in the same manner as in Example 3 to TLC for acidic aqueous solution to obtain ranitidine.

Example 5

To 1 ml of methylene chloride, 0.2 g of 2-nitromethylene-1,3-dithiane and 0.15 g of 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethylamine were mixed and 25 ° C. After 22 hours of stirring at 0.2 ml of 40% aqueous methylamine solution and 0.5 ml of methanol were added thereto, and the mixture was stirred at 25 ° C. for 5 hours, followed by treatment as in Example 3, followed by TLC to obtain ranitidine.

Claims (1)

A method for preparing the compound of formula (I) or acid addition salt thereof by reacting a compound of formula (III) or an acid addition salt thereof with a compound of formula (II) and then reacting a compound of formula (IV).