JP2000154173A - Production of alkylated cyanoacetylurea - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an alkylated cyanoacetylurea by using a readily available raw material. SOLUTION: Industrially available cyanoacetylurea is reacted with a carbonyl compound in a polar solvent under reducing conditions to produce an alkylated cyanoacetylure represented by the general formula (R1 and R2 are each same or different and denote each hydrogen, a 1-12C alkyl group, a 3-8C cycloalkyl group, an aromatic ring or an aralkyl group). The production of isopropylated cyanoacetylurea by reacting the cyanoacetylurea with acetone is cited as a concrete example of the method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an alkylated cyanoacetylamino compound, and an anti-HI
The present invention relates to a method for producing an alkylated cyanoacetylurea, which is a useful raw material for 5-alkyl-substituted uracils, which are important intermediates for producing pharmaceuticals such as drug V.
More specifically, the present invention relates to a method for alkylating cyanoacetylurea by reacting cyanoacetylurea with a carbonyl compound in a polar solvent under reducing conditions. More specifically, the present invention relates to a production method for reacting cyanoacetylurea with acetone under reducing conditions to isopropylate the acetyl group of cyanoacetylurea.

[0002]

BACKGROUND OF THE INVENTION The product of the present invention, an alkylated cyanoacetylurea, is used for producing pharmaceuticals such as anti-HIV drugs and antiviral drugs, and photographic drugs such as silver halide stabilizers. Is a useful raw material for 5-alkyl-substituted uracils, which are important intermediates.

[0003] As a conventional technique for producing an alkylated cyanoacetylurea, there is known a method in which a cyanoalkylacetic acid, urea and acetic anhydride are heated and condensed (J).
ownnal of the American Ph
armaceuticalAssociation, 4
4 , 545 (1955)). The starting material cyanoalkylacetic acids can be obtained by reacting an ester compound of cyanoacetic acid with an alkyl halide, but the reaction must use a dangerous reagent such as sodium hydride in an anhydrous solvent, and Isolation of the product required hydrolysis of the ester followed by neutralization with acid. Inorganic salts such as sodium sulfate generated at this stage will contaminate equipment and the like in the reaction process, which is disadvantageous for production on a factory scale.

[0004] Further, in the production method of directly alkylating cyanoacetylurea, an alkylated cyanoacetylurea could not be obtained in good yield. Thus, a simple and industrially applicable method for producing an alkylated cyanoacetylurea using easily available raw materials has been desired.

[0005]

Accordingly, an object of the present invention is to provide an alkylated cyanoacetylurea useful as a raw material for synthesizing 5-alkyl-substituted uracils using a readily available raw material. To provide a simple and industrially applicable method. Another object of the present invention is to provide a simple and industrially applicable method for producing an alkylated cyanoacetylamino compound.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above-mentioned object, and as a result, an industrially available cyanoacetylamino compound and a carbonyl compound were reduced in a polar solvent under reducing conditions. By reacting with
It has been found that cyanoacetylamino compounds can be alkylated. By reacting cyanoacetylurea with a carbonyl compound in a polar solvent under reducing conditions,
It has been found that cyanoacetylurea can be alkylated. Further, by reacting with cyanoacetylurea using acetone as a solvent and a reagent under reducing conditions,
They have found that the acetyl group of cyanoacetylurea can be isopropylated, and have completed the present invention.

That is, the present invention relates to (1) a compound represented by the formula

[0008]

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Wherein a cyanoacetylamino compound having a group represented by the formula is reacted with a carbonyl compound.

[0010]

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A method for producing a compound in which the acetyl group of a cyanoacetylamino compound having a group represented by the formula (1) is alkylated with an alkyl which may be substituted, (2) performing the reaction in the presence of a reduction catalyst The method according to (1), wherein (3) the method according to (1) or (2), wherein the cyanoacetylamino compound is cyanoacetylurea, (4) in a polar solvent under reducing conditions, Equation (a)

[0012]

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The cyanoacetyl urea of the formula (b)

[0014]

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(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aromatic ring or an aralkyl group) A) a carbonyl compound of the formula (c)

[0016]

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Wherein R ¹ and R ² have the same meanings as defined above, and (5) under the reducing conditions, the formula (a)

[0018]

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Wherein N- (2-cyano-3) is reacted with acetone.
-Methylbutanoyl) urea, and (6) the method of (5), wherein the reaction is carried out in the presence of a reduction catalyst.

[0020]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, each definition used in the present specification will be described.

The alkyl group having 1 to 12 carbon atoms in R ¹ and R ² may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl , Heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
1 to 1 carbon atoms such as tert-butyl, pentyl, hexyl, etc.
6 are mentioned.

The cyclic alkyl group having 3 to 8 carbon atoms for R ¹ and R ² is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably cyclohexyl.

The aromatic ring in R ¹ and R ² is, for example, a phenyl group, a pyridyl group and the like, preferably a phenyl group.

The aralkyl group in R ¹ and R ² is
The alkyl portion has 1 or 2 carbon atoms, such as a benzyl group and a phenylethyl group.

In the present invention, the optionally substituted alkyl means a cyclic alkyl group having 3 to 8 carbon atoms, an aromatic ring,
It refers to an alkyl having 1 to 25, preferably 1 to 3 carbon atoms optionally having 1 to 3 substituents selected from aralkyl groups. Here, the cyclic alkyl group, aromatic ring, and aralkyl group having 3 to 8 carbon atoms are the same as defined in R ¹ and R ² .

Specific examples of the carbonyl compound include formaldehyde, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, cyclopropyl methyl ketone, acetophenone, acetaldehyde, propionaldehyde, cyclohexane carbaldehyde, benzaldehyde, 3-pyridine carbaldehyde, phenylacetaldehyde and the like. Is mentioned.

The carbonyl compound as a raw material may be a commercially available one or, for example, Organic Rea.
ctions, Vol. VI, 207, Journal
of Organic Chemistry, 52 ,
2559 (1987).

The production method using a polar solvent in the present invention will be described below by taking alkylation of cyanoacetylurea as an example, but other compounds can be produced according to this.

[0029]

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Wherein R ¹ and R ² have the same meanings as described above. The cyanoacetyl urea of the formula (a) is suspended or dissolved in a polar solvent, and the carbonyl compound of the formula (b), acetic acid, ammonium acetate Is added, and the mixture is reacted under reducing conditions to obtain a cyanoacetyl urea alkylated with an optionally substituted alkyl group represented by the formula (c). Preferably, the reaction is performed in the presence of a reduction catalyst. The end of the reaction
Confirm by disappearance or reduction of raw materials by high performance liquid chromatography. The method for isolating the target product after the reaction is not particularly limited, but the target product can be isolated by adding water to the filtrate from which the catalyst has been removed by filtration or by cooling to precipitate the target product.

By reacting a compound having a cyanoacetylamino group with a carbonyl compound in the same manner as described above, the acetyl group of the compound having a cyanoacetylamino group is alkylated with an optionally substituted alkyl group. The obtained compound can be obtained.

Although the reaction time depends on the amount of the catalyst, it is usually 3 hours.
To 12 hours, and the reaction temperature may be in the range of 0 to 50 ° C, preferably 20 to 30 ° C. The hydrogen pressure is between normal pressure and 30 kg / cm ² ,
/ Cm ² is preferred.

The carbonyl compound as a raw material is added in an amount of 1.0 to 2.0 times, preferably 1.1 to 1.5 times based on 1 mol of cyanoacetylurea.

The acetic acid is added in an amount of 0.1 to 1.0 times, preferably 0.2 to 0.4 times, per 1 mol of cyanoacetylurea.

The ammonium acetate is used in an amount of 0.05 to 0.5 times, preferably 1 time, per mole of cyanoacetylurea.
Add 0.1-0.2 times.

As the reduction catalyst, those usually used for reductive alkylation are used, and preferred are palladium carbon, platinum carbon and the like. The amount of the reduction catalyst used is, for example, 10% palladium carbon (50%
When a wet product is used, the content is 0.5 to 30% by weight, preferably 1 to 10% by weight.

The polar solvent used in the reaction has a relative dielectric constant of 10
These are the above solvents.

Examples of the reaction solvent include lower alcohols having 1 to 4 carbon atoms which may be linear or branched (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol), N, N-dimethylformamide , N, N-dimethylacetamide,
Polar organic solvents such as dimethyl sulfoxide, glycols such as ethylene glycol, ethylene glycol monomethyl ether (registered trademark: methyl cellosolve), water,
Alternatively, a mixed solvent thereof is used. Preferably, isopropanol and N, N-dimethylformamide are used. When the carbonyl compound used as a reaction reagent is a substance that can be used as a polar solvent, the carbonyl compound may be used as a reaction solvent. The reaction solvent is preferably used at 1 to 10 times the weight of cyanoacetylurea.

The acetylation of the acetyl group of cyanoacetylurea can be carried out by the above-mentioned production method. The reaction can also be carried out using acetone (R ¹ and R ² in the formula (b) are methyl) used as a reaction reagent also as a reaction solvent.

The production method when acetone is used as the reaction solvent is almost the same as the above production method. Cyanoacetylurea is suspended or dissolved in acetone, and acetic acid and ammonium acetate are added thereto. This is a method for obtaining N- (2-cyano-3-methylbutanoyl) urea by reacting under the following conditions. Preferably, the reaction is performed in the presence of a reduction catalyst. The termination of the reaction and the isolation of the desired product after the reaction can be carried out in the same manner as in the above-mentioned production method.

The reaction time depends on the amount of the catalyst, but is 3 to 1
Two hours are preferred, and the reaction temperature is 0 to 50 ° C, preferably 30 to 40 ° C. Also, the hydrogen pressure is 3
It is between 0 kg / cm ² and preferably between normal pressure and 10 kg / cm ² .

A method using acetone as a reaction solvent is as follows.
Acetone serves as both a solvent and a reaction reagent, and the amount of acetone used as a reaction reagent is 1.0 to 2.0 times mol, preferably 1.1 to 1.5 times, per mol of cyanoacetylurea. mol, and the amount of the solvent used is 1 to 20 times, preferably 5 to 10 times the weight of cyanoacetylurea.

The amount of acetic acid used in the method using acetone as a reaction solvent is 0.1 to 1.0 times mol, preferably 0.2 to 0.1 times mol of 1 mol of cyanoacetylurea.
It is 4 times mol.

The amount of ammonium acetate used in the method using acetone as the reaction solvent is 0.05 to 0.5 times mol, preferably 0.1 to 0.2 times mol, per mol of cyanoacetylurea.

As the reduction catalyst, those usually used for reductive alkylation are used, and preferred are palladium carbon, platinum carbon and the like. For example, when 5% palladium carbon (50% wet product) is used, the reduction catalyst is used in an amount of 0.5 to 30% by weight, preferably 1 to 10% by weight, based on cyanoacetyl urea.

[0046]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. Example 1 38.7 g of cyanoacetyl urea was suspended in 77.4 ml of N, N-dimethylformamide, and 24.6 ml of acetone was suspended.
1, 3.43 ml of acetic acid and 2.31 g of ammonium acetate were added. This suspension was subjected to catalytic hydrogenation at 30 ° C. for 9 hours at normal pressure in the presence of 0.78 g of 10% palladium carbon (50% wet product). The reaction mixture was warmed to 70 ° C. and the catalyst was filtered off. 150 ml of water was added to the filtrate to precipitate crystals, and the crystals were collected by filtration to obtain 40.1 g of N- (2-cyano-3-methylbutanoyl) urea. Melting point: 173-174 ° C IR (Nujol): 3336, 2256, 1690,
^{1106cm -1 1 H-NMR (270MHz} , DMSO-d 6) δ 0.
97 (3H, d), 1.00 (3H, d), 2.15
2.35 (1H, m), 3.85 (1H, d), 7.4
4 (2H, br), 10.49 (1H, br)

Example 2 116.1 g of cyanoacetylurea were suspended in 219.3 ml of N, N-dimethylformamide, and 73.1 of acetone was suspended.
ml, acetic acid 10.8 ml, ammonium acetate 6.93 g
Was added. This suspension is treated with 10% palladium on carbon (50%
Wet product) Hydrogen pressure 10kg / c in the presence of 2.33g
The catalytic hydrogenation was performed at 25 ° C. for 4 hours at m ² . The reaction mixture was warmed to 70 ° C. and the catalyst was filtered off. Water 74 in the filtrate
5 ml was added to precipitate crystals, and the crystals were collected by filtration to obtain crystals of N- (2-cyano-3-methylbutanoyl) urea in a yield of 134.5 g. The data of the obtained compound were the same as in Example 1.

Example 3 38.7 g of cyanoacetyl urea was added to isopropanol 7
Suspended in 7.4 ml, acetone 24.6 ml, acetic acid 3.
43 ml and 2.31 g of ammonium acetate were added. This suspension is 10% palladium carbon (50% wet product)
In the presence of 0.78 g, catalytic hydrogenation at normal pressure and 30 ° C.
Time went. The reaction mixture was heated at 80 ° C. for 1 hour, and the catalyst was removed by filtration. 150 ml of water was added to the filtrate to precipitate crystals, and the crystals were collected by filtration to give N- (2-cyano-
Crystals of 3-methylbutanoyl) urea were obtained in a yield of 21.7 g. The data of the obtained compound were the same as in Example 1.

Example 4 38.7 g of cyanoacetylurea was suspended in 77.4 ml of N, N-dimethylformamide, and acetaldehyde 1
8.8 ml, 3.43 ml of acetic acid, ammonium acetate 2.
31 g were added. This suspension was subjected to catalytic hydrogenation at 30 ° C. for 5 hours under normal pressure in the presence of 0.78 g of 10% palladium carbon (50% wet product). The catalyst was removed by filtration, 350 ml of water was added to the filtrate to precipitate crystals, and the crystals were collected by filtration to obtain N- (2-cyanobutanoyl) urea crystals in a yield of 24.2 g. ¹ H-NMR (270 MHz, DMSO-d ₆ ) δ 0.
99 (3H, t), 1.75-1.95 (2H, m),
3.86 (1H, t), 7.42 (2H, br), 1
0.50 (1H, br)

Example 5 78.6 g of cyanoacetylurea were suspended in 154.9 ml of N, N-dimethylformamide, and 48.8 of acetone was suspended.
g, 7.2 g of acetic acid, and 4.6 g of ammonium acetate. This suspension was subjected to catalytic hydrogenation in the presence of 3.1 g of 10% palladium carbon (50% wet product) at a hydrogen pressure of 10 kg / cm ² at 25 ° C. for 4 hours. The reaction mixture is
After heating to ℃ to dissolve insolubles, the catalyst was removed by filtration.
390 ml of water was added to the obtained filtrate to precipitate crystals,
The crystals were collected by filtration to obtain N- (2-cyano-3-methylbutanoyl) urea crystals in a yield of 89.7 g.
The data of the obtained compound were the same as in Example 1.

Example 6 51.6 g of cyanoacetyl urea was suspended in 516 ml of acetone, and 4.8 g of acetic acid and 3.2 g of ammonium acetate were added. The suspension was subjected to catalytic hydrogenation at normal pressure in the presence of 4.1 g of 5% palladium on carbon (50% wet product).
C. for 5 hours. The reaction mixture was heated to reflux to dissolve insolubles, and then the catalyst was removed by filtration. The obtained filtrate was concentrated to half the volume, 258 ml of water was added to precipitate crystals, and the crystals were collected by filtration to obtain crystals of N- (2-cyano-3-methylbutanoyl) urea in a yield of 62.5 g. Obtained. Melting point: 173-174 ° C IR (Nujol): 3336,2256,1690,
^{1106cm -1 1 H-NMR (270MHz} , DMSO-d 6) δ 0.
96 (3H, d), 1.00 (3H, d), 2.15
2.35 (1H, m), 3.85 (1H, d), 7.4
4 (2H, br), 10.49 (1H, br)

Example 7 25.8 g of cyanoacetyl urea was suspended in 258 ml of acetone, and 2.4 g of acetic acid and 1.5 g of ammonium acetate were added. This suspension was subjected to catalytic hydrogenation at 40 ° C. for 1 hour at a hydrogen pressure of 10 kg / cm ^{2 in} the presence of 2.1 g of 5% palladium carbon (50% wet product). The reaction mixture was heated to reflux to dissolve insolubles, and then the catalyst was removed by filtration. The obtained filtrate was concentrated to half the volume, 130 ml of water was added to precipitate crystals, and the crystals were collected by filtration to obtain N- (2-cyano-3-methylbutanoyl) urea crystals in a yield of 30.
Obtained in 7 g. The data of the obtained compound were the same as those in Example 6.

[0053]

Industrial Applicability According to the present invention, commercially available cyanoacetylurea can be alkylated by a simple and industrially available method, and it can be used as a medicament such as an anti-HIV drug or an antiviral drug, or a silver halide. Useful raw materials for 5-alkyl-substituted uracils, which are important intermediates for producing photographic drugs such as stabilizers, can be provided. Further, according to the present invention, an acetyl group portion of a compound having a cyanoacetylamino group can be alkylated easily and industrially.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Reo Matsuda 3-1-1, Utashima, Nishiyodogawa-ku, Osaka City Within Sumika Finechem Co., Ltd. (72) Inventor Katsuyuki Imamiya 3-1-1, Utashima, Nishiyodogawa-ku, Osaka-shi No. 21 Sumika Fine Chem Co., Ltd.

Claims (6)

[Claims] 1. A compound of the formula ## STR1 ## in a polar solvent under reducing conditions. Wherein a cyanoacetylamino compound having a group represented by the formula is reacted with a carbonyl compound. A method for producing a compound in which an acetyl group portion of a cyanoacetylamino compound having a group represented by the formula is alkylated with an optionally substituted alkyl. 2. The method according to claim 1, wherein the reaction is carried out in the presence of a reduction catalyst. 3. The method according to claim 1, wherein the cyanoacetylamino compound is cyanoacetylurea. 4. A compound of formula (a) under reducing conditions in a polar solvent. With a cyanoacetyl urea of formula (b) (Wherein R ¹ and R ² may be the same or different,
A hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cyclic alkyl group having 3 to 8 carbon atoms, an aromatic ring or an aralkyl group), and a carbonyl compound represented by the formula (c): ] (Wherein, R ¹ and R ² have the same meanings as described above). 5. A compound of the formula (a) under reducing conditions A method for producing N- (2-cyano-3-methylbutanoyl) urea, characterized by reacting cyanoacetylurea represented by the formula (1) with acetone. 6. The production method according to claim 5, wherein the reaction is performed in the presence of a reduction catalyst.