DE2065698A1 - PROCESS FOR THE PREPARATION OF 2ISOPROPYL-6-METHYL-4 (3H) -PYRIMIDONE - Google Patents

Description

25 75o /

CHISSO CORPORATION, Osaka / Japan

Process for the preparation of 2-isopropyl-6-methyl-

-pyrimidone

The invention relates to a process for the preparation of 2-isopropyl-6-methyl-4 (j5H) -pyrimidone and in particular to a process for the preparation of 2-isopropyl-6-methyl-4 (5H) -pyrimidone by reacting ß-aminocrotonamide with an ester of an organic acid.

It is a process for the preparation of pyrimidone derivatives is known, in which ß-aminocrotonamide (I) with an organic Acid anhydride or an organic acid halide is reacted to produce a β-acylamino compound (II), with which a ring closure is then carried out by heating or by an alkali treatment Prepare pyrimidone derivative (III). (Tetsuzo Kato et al, Journal of the Pharmaceutical Society of Japan, Volume 87, page 955 (1967) and Volume 89, page 46o (1969)).

This procedure can be represented as follows:

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HHO "GH-O" O (RCO) _n O. CE ^ ^ O ^^ CE ^ ^ J ^

WH ₃ BH ₈ + odor -> I Γ ->} 'J

ι »MH ₂ .ir m

RCOCl ^ C = O ^ a ^

(D. (II) (III)

Herein R is alkyl or aryl.

However, this method has the following disadvantages: The acid anhydrides or acid halides used as starting materials need to be used are quite expensive; the process itself is laborious because it comprises two stages and the overall yield is low. Since a solvent must be used, the separation and Recovery of the solvent and an acid formed as a by-product after the separation of the reaction product necessary.

The process and the yield of the process mentioned (Kato et al) will be explained in more detail. The acylation of β-aminocrotonamide is carried out in chloroform using isobutyric anhydride as the aylating agent for 1 hour while heating under reflux. The yield of the ß-isobutyric acid amine compound is 62 wt .- ^. After isolation, the acyl compound is heated with a solution of sodium methylate methanol and the ring closure is carried out to give the 2-isopropylpyrimidone derivative, which is obtained in a yield of 75% by weight. The total yield of pyrimidone is thus 46% by weight .

The implementation of primary or secondary amines with carboxylic acid esters is known as an acylating agent, see Weygand-

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Hilgetag, Organic-Chemical Experimental Art, 3rd edition, Leipzig I964, pages 556 to 558. However, it is over can be seen in the literature (see G. Stork et al, J.Am.Chem. Soc. 85, 207-222 and Kato et al, Chem.Pharm.Bull. 17 (9) * I889-1895, 1969) that from ß-aminocrotonamide using conventional acylating agents do not contain β-N-acyl compounds can be produced.

In the case of the D.J. Braun, "The Pyrimidines", 1962, Interscience Publishers, p. 87 described the ring closure reaction in an alkaline medium to form a pyrimidine core a ring closure reaction with an isolated ß-acyl compound.

The aim of the invention is to create an improved process for the preparation of 2-isopropyl-6-methyl-4 (5H) -pyrimidone, in which an inexpensive raw material is used, a useful product can be obtained in one step the use of a solvent is unnecessary and a high yield is achieved.

The invention relates to a process for the preparation of 2-isopropyl-6-methyl-4 (^ i) -pyrimidone by acylation of ß-aminocrotonamide and subsequent ring closure with elimination of water, which is characterized in that ß-aminocrotonamide with at least 3 mol Isobutyrate is heated in the presence of 2 to 4 mol of sodium isobutylate for at least three hours to a temperature between 60 ^° C. and the boiling point of the reaction mixture.

The process according to the invention can be represented by the following formula:

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Ou ₃ -O «CH-σ« ο Η «W- Wf-U

RGOj ₁ R '

αϊ.

Ii

SIi NIl ₈

T ⁰ (II)

GH,

^V "'J

• Ν '· WK

where R and R 'are the isopropyl and isobutyl groups, respectively.

However, the above reaction does not proceed if the acid anhydride or in the above-mentioned known method the acid halide can only be replaced by an ester of an organic acid. It got surprising, however found that in the reaction of ß-aminocrotonamide with the isobutyric acid isobutyl ester in the presence of 2 to 4 moles of sodium isobutylate the condensation reaction and the Ring closure reaction take place simultaneously and very smoothly in one stage.

It is not clear via which reaction mechanism the alkali metal alcoholate causes the reaction to take place, since a Ester / amide exchange reaction of this type is not yet known. However, it is assumed that a so-called N-acylation process, which forms the first half of the present reaction, as an exchange reaction between the alcohol part of the ester and the amino part of the ß-aminocrotonamide runs and the effect of sodium isobutylate in the present reaction of the action of an alkali catalyst

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in an ester interchange reaction, so the real reagent in both cases is believed to be an alkali metal alcoholate is.

It is believed that an active interconnection such as.

Ii

IiMiJa O

exists and that an alkali metal alcoholate or an alkali metal contributes to the formation of the connection. It should be noted, however, that the present invention by The above assumptions about the reaction mechanism are not limited shall be.

The method according to the invention will now be described in more detail below explained.

The isobutyric acid isobutyester is used in the present process.

For the preparation of the sodium isobutylate used according to the invention Isobutyl alcohol and sodium isobutylate are used not noticeably hydrolyzed and which can be prepared anhydrous. The isobutyl alcohol is used in a sufficient amount used so that all of the sodium metal is converted to the sodium isobutylate. It is possible for this Purpose an excess amount of isobutyl alcohol as an inert one To use solvents, as described below, but too large an excess is undesirable because this

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is reduced by the yield.

Using sodium isobutylate as an alkali reagent:

To get the ß-aminocrotonamide in good yield with the isobutyrate isobutyl ester implement, at least 3 moles of isobutyl isobutyrate and 2 to 4 moles according to the invention Moles of sodium isobutylate used per mole of ß-aminocrotonamide.

When carrying out the process, sodium isobutylate is dissolved in the isobutyl isobutyl ester or it becomes metallic Sodium mixed with anhydrous isobutyl alcohol, to produce sodium isobutylate, followed by the addition of isobutyl isobutyrate. One can also use anhydrous Add isobutyl alcohol to the isobutyl isobutyrate and then add the sodium metal. You get in this way the sodium isobutylate dissolved in the isobutyl isobutyl ester. The ß-aminoorotonamide is then added to this. The addition is carried out with cooling because of the exothermic reaction. This will be the response Continued for 3 hours or more, during which time the reaction system was kept at a temperature of 6o C to the boiling point will.

In the reaction described above, an inert solvent such as benzene, toluene, carbon tetrachloride, a lower alcohol, etc. may be added.

After the completion of the reaction, the product can be recovered by an ordinary method. For example, you can the sodium present in the reaction mixture with an inorganic acid such as hydrochloric acid, sulfuric acid or the like, neutralize, filter off the precipitated salt,

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concentrate the resulting mother liquor under a reduced pressure to produce crude crystals and remove the crude crystals from a suitable solvent, such as acetone, chloroform, methanol, ethanol or the like, recrystallize.

The invention is illustrated in more detail by means of the following examples.

Example 1;

Preparation of 2-isopropyl-6-methyl-4 (j5H) -pyrimidone.

.1.3 g of metallic sodium in 40 ml of anhydrous Ethanol dissolved to make an ethanol solution of sodium ethylate to manufacture. 5gβ-aminocrotonamide and 6 g ethyl isobutyrate were then added. The resulting mixture was then stirred and refluxed for 5 hours.

After the completion of the reaction, the reaction mixture was treated in the same manner as in Example 4. In this way, 2.5 g of 2-isopropyl-6-methyl-4 (3H) -pyrimidone (colorless needle-shaped crystals) was obtained with a melting point of I70 to 17I ⁰ C (literature value I72 to 173 ° C). (Yield 33 *).

Example 2;

Preparation of 2-isopropyl-6-methyl-4 (3H) -pyrimidone

20 g of metallic sodium were anhydrous in 150 ml Isobutanol dissolved to make an isobutanol solution of sodium isobutylate to manufacture. 40 g of β-aminocrotonamide and 300 g of isobutyl isobutyrate were then added. The resulting The mixture was then refluxed for 5 hours with stirring.

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heats. After the completion of the reaction, the resultant became Reactiohsgemlsoh in the same way as in Example 4 treated.

In this way, 51 * 8 S 2-isopropyl-6-methyl-4 (3H) -pyrimidone (colorless, needle-shaped crystals) were obtained. (Yield 85.5 %) .
Mp 170 to 171 ^° C

Elemental analysis (chemical composition CgH ₁ pONp) theoretical {%) C: 63.13 », H: 7.95, N: 18.41 found {%) Ci 63.15, H: 8.00, N: 18, 50

- claim -

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Claims (1)

Claim Process for the preparation of 2-isopropyl-6-methyl-4 (j5H) -pyrimidone by acylation of ß-aminocrotonamide and subsequent ring closure with elimination of water, thereby gekennzei chnet that one ß-aminocrotonamide with at least 3 moles of isobutyl isobutyl ester in the presence from 2 to 4 moles of sodium isobutoxide for at least three hours heated to a temperature between 6o ° C and the boiling point of the reaction mixture. 409850/1095