JPS6183168A - 2-mercapto-4-amino-5-formylpyrimidine and preparation thereof - Google Patents

Abstract

NEW MATERIAL:2-Mercapto-4-amino-5-formylpyrimidine expressed by formula I. USE:A raw material for synthesis of medicines, agricultural chemicals, etc. PREPARATION:(A) Propanenitriles expressed by formulae II or III (R<1>-R<5> each represent lower alkyl or both R<1> and R<2> and both R<3> and R<4> each represent lower alkylene and may be bonded with each other to form a ring) is reacted with a thiourea in the presence of a base, and the resultant 2-mercapto-4- amino-5-dialkoxymethylpyrimidine is hydrolyzed in the presence of an acid. Alternatively, (B) an alkali metal salt of a 2-hydroxymethylene-3,3-dialkoxypro panenitrile is reacted with thiourea in a solvent in the presence of a base to obtain the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a new compound, 2-mercapto-4-amino-5-formylpyrimidine, and a method for producing the same. 2-Mercapto-4-amino-5-formylpyrimidine and compounds obtained by variously converting the mercapto group at the 2-position, the amine group at the 4-position, the formyl group at the 5-position, etc. with other functional groups can be used, for example, in pharmaceuticals, It is a compound useful as a synthetic intermediate for agricultural chemicals, etc.

[Conventional technology]

No literature has been found so far that describes the 2-mercapto-4-amino-5-formyl bi-IJ midine of the present invention and its production method.

[Problem that the invention seeks to solve]

The present invention provides 2-mercapto-4-amino-5-formylpyrimidine and an industrially advantageous method for producing the same.

[Failure to solve the problem]

The present invention is.

2-mercapto-4-amino-5-formylpyrimidine, and general formula (1) or ■) [However, in formulas (I) and (II) + R'+
R2+ R3+ R' and R5 are the same or different lower alkyl groups; R1 and R2+ and R3 and R4 are lower alkylene groups and can be bonded to each other to form a ring. The propane nitriles represented by the above formula are reacted with thiourea in the presence of a base to obtain the general formula (2) [However, in the formula (2), R1 and R3 are the same as above. ] 2-mercapto-4-amino-5
- 2-mercapto-4-amino- characterized by hydrolyzing dialcoquine methylpyrimidine in the presence of an acid
Method for producing 5-formylpyrimidine and general formula (g) HOM [However, in 2〇, R1 and R2 are the same as above, and 1M represents an alkali metal. ] 2-
2-Mercapto-4, which is characterized by reacting an alkali metal salt of hydroxy/methyleae 1,3-dialcoquinopropanonitrile with thiourea in a solvent in the presence of a base.
-A method for producing amino-5-formylpyrimidine.

Next, the present invention will be explained in detail.

The first method for producing the compound of the present invention, 2-mercapto-4-amino-5-formylpyrimidine, is as follows.

2- represented by the general formula (I) which is the raw material of the present invention
R'+ R2, R3, R' and R5f in dialkoxy7methyl-6,3-dialkokinepropanenitrile and 2-alcoquinmethylene-6,5-dialkokinepropanenitrile represented by the above general formula (II)
d/'f l Examples include lower alkyl groups having 1 to 4 carbon atoms such as ethyl, propyl, and butyl.

R1 and u2t or R3 and R4 are lower alkylene groups having 1 to 4 carbon atoms, such as methylene, ethylene/, propylene/, etc., and can also be bonded to each other to form a ring.

These R'r R2+ R3+ R' and R5
may be all the same groups or may be partially the same groups.

Furthermore, they can all be different groups.

The propa/nitriles of these raw materials are 2, for example, 3-alkoxy-2-propenenitrile or 6,6-dialkoxypropanenitrile, in the presence of an alkali metal alcoholade, as a formic acid ester.

- React with a formylating agent such as carbon oxide at a temperature of 0 to 100'
An alkali metal salt of hydroxymethylene-3,3-dialkoxypropanenitrile is obtained. The salt is then reacted with an alkylating agent such as dialkyl sulfuric acid or an alkyl halide, or with a neutralizing equivalent or more of a mineral acid in alcohol. It can be easily obtained by

In the present invention, these general formulas (I) or (It
The raw material propanenitrile represented by ) may be used alone or in the form of a mixture.

Also, what is the amount of thiourea used, which is one of the raw materials?

The general formula (1) is represented by (II). It is preferably 0.5 to io mol, particularly 1 to 3 mol, per mol of propanenitrile.

Furthermore, alkali metal alcoholades and hydroxides are useful as bases used in this reaction. Examples of the alkali metal alcoholade include sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylade, potassium propylade, sodium butylade, and potassium butylade. Incidentally, an alkali metal alcoholade is usually prepared by dissolving an alkali metal in alcohol, or by mixing an alkali metal hydroxide with alcohol and then dehydrating the mixture. In the present invention, it is possible to use a pure alkali metal alcoholade, but it is also possible to directly use the alcohol solution containing the alkali metal alcoholade prepared as described above. Specific examples of alkali metal hydroxides include potassium hydroxide and sodium hydroxide.

°The amount of the base used in the present invention is preferably 0.7 to 1.5 mol per 1 mol of thiourea.

The reaction may be carried out without a solvent or in a solvent inert to the reaction. Most preferred such solvents are aliphatic alcohols such as methanol, ethanol, gropanol, and butanol. It is preferable to use 90.3 to 30 parts by weight of these solvents per 1 part by weight (1 total part by weight in the case of a mixture) of the compound represented by the general formula (1) or (II).

The reaction is carried out at a temperature of 0 to 1°C at normal pressure or under pressure.
It is carried out for 5 to 24 hours.

The general formula ('I) or (II) produced by the reaction of propane nitriles represented by the general formula ('I) or (II) with thiourea
goods). 2-Mercapto-4-amino-5-
Dialkoxymethylpyrimidino (the compound represented by 2) is also a compound not described in any literature.) is produced as a water-soluble alkali metal salt. The compound represented by 2■ is 1
Although the compound represented by the formula (I) may be isolated from the reaction solution by methods such as neutralization, filtration, extraction, and recrystallization and used in the next hydrolysis reaction, it is possible to isolate the compound represented by formula (I) from the reaction solution. It is more preferable to add a predetermined amount of acid and water to a reaction solution containing an alkali metal salt for hydrolysis because the operation can be simplified and there is no loss of reaction products due to isolation operations.

Examples of acids used in the present invention include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, p-toluenesulfonic acid, and cation exchange resins. These acids are preferably used in an amount of 0.5 to 5 mol per mol of propanenitrile. The amount of water used for hydrolysis is not particularly limited, but is usually 2 parts by weight of the compound represented by the formula (I) which is an intermediate reaction product.

Preferably 2 to 100 parts by weight are used.

The conditions for hydrolysis are appropriately selected depending on the concentration of the raw material, the amount of acid, etc. 1 Usually at a temperature of room temperature to 100 ° C and 0.1 to 2
By conducting for 4 hours, the target product 2-mercapto-
4-Amino-5-formylpyrimidine can be obtained in the form of an acid addition salt.

The second method for producing the compound of the present invention, 2-mercapto-4-amino-5-formylpyrimidine, is illustrated as follows.

Second method NH2CNH2 [Phase] (7) R1 and R2 in the alkali metal of 2-hydroxymethylene, 3-dialkoxypropanenitrile represented by the general formula (IID), which is the raw material of the present invention, are represented by the general formula (I) Or the same as those in ■, and a specific example of the alkali metal M is potassium.

Examples include sodium.

2-hydroxymethylene-3 represented by the general formula [phase]
, 6-Dialkoxypropanenitrile when an alkali metal salt and thiourea are reacted in a solvent in the presence of a base,
The base, type of solvent, amount used, reaction time, reaction temperature, etc. can be carried out under the same conditions as in the first method. After completion of the reaction, 2-mercapto-4-amine-5-formylpyrimidine is obtained as a water-soluble alkali metal salt.

As described above, they were produced by the first method and the second method. 2
-Mercapto-4-amino-5-formylpyrimidine can be easily isolated and purified from the reaction mixture by appropriately employing operations such as neutralization, extraction, concentration, filtration, and recrystallization.

〔Example〕

Next, examples of the present invention will be described. The yield is based on propanenitrile. Example 1 Thiourea 0.91? (12 mmol) +28wt%
2.12r of methanol solution of sodium methylate, (
11 mmol) and 2-methquine methylene/-L3-
1.60 P (10 mmol) of dimethoxypropane nitrile was mixed at room temperature and then heated under reflux for 6 hours. After the reaction is complete, add 10 mA of water to the residue after concentrating to remove methanol.
! was added to make a homogeneous solution.

Adjust the pH to 7 with 1N hydrochloric acid, collect the precipitated crystals, wash with water, and vacuum dry at about 50°C to obtain white crystals of 1.835F.
I got it. The elemental analysis values of this crystal are shown below.

CHN Elemental analysis Calculated value @) 41.78 5.47
20.90 (07HIIN3802) Actual value (support)) 42.28 5.44 21.30 Others, M
This product was confirmed to be 2-mercapto-4-amino-5-dimethoxymethylpyrimidine from S, NM, R, and IR.

(Yield 91%) Obtained white crystal product 1.51 F(7,5;
17 mol) was dissolved in 10 rrtl of 1N hydrochloric acid, and stirred for 2 hours while keeping the liquid temperature at 70"C. After the reaction was completed, the solution was stirred for 1 hour under cooling.
Adjust the pH to 7 with an aqueous N-caustic soda solution.

The number of precipitated crystals was counted. After further washing with water and methanol, the product was vacuum dried at about 50°C to obtain 1.10P of white crystals.

The elemental analysis values of this crystal are shown below.

HN elemental analysis calculated value @) 68.71 B, 2ro
27.10 (0, H5N3So) Actual value (%)
38313.29 27.22 Others, MS, NMR
, Engineering R confirmed that this product was 2-mercapto-4-amino-5-formylpyrimidine (yield: 9
5%) Example 2 2N-sodium ethylate in ethanol solution 30g,
Thiourea 456p (60 mmol) and 2-ethoxymethylene/-3,3-dimethoxypropanenitrile 8.5
5 r (50 mmol) were mixed at room temperature and then heated under reflux for 3 hours. Thereafter, 2N-H2BO470 ral t- was added to the residue from which most of the ethanol had been removed by concentration, and stirring was continued for 5 hours while keeping the liquid temperature at 60°C. After the reaction was completed, the pH was adjusted to 7 with a 1N caustic soda aqueous solution, and the precipitated crystals were collected.

After washing with water and cold methanol, it was vacuum dried at about 50"C to obtain white crystals of 7.01. The elemental analysis values of these crystals are shown below.

CHN Elemental analysis Calculated value @) 38.71 3.23
27.10 (05H5N3So) Actual value ←) 85 and 412 were confirmed to be 2-mercapto-4-amino-5-formylpyrimidine by MS, NMR, and Engineering R. (Yield: 90 cm) Example 5 28 wt% sodium methylate methanol solution 1
0.2F (53 mmol), thiourea 4.18f (55
2-di-n-butoxymethyl-3.3-di-butoxypropanenitrile 17.8r (so mmol) and n-butanol 4 (1 mA!) were mixed at room temperature and then at 80 °C for 2 h. After stirring, a solution of 12++t/(140mmol) of concentrated hydrochloric acid dissolved in 100g of water was added, and stirring was continued for 2 hours at 80'C.After cooling, the aqueous layer was separated and a 10wt% caustic soda aqueous solution was added. Add it little by little, adjust the pH to 7, and count the precipitated crystals. After washing with water and cold methanol, drying in vacuum at about 50°C yielded white crystals with a weight of 6.89. The elemental analysis values of these crystals are shown below. Shown: HN elemental analysis Calculated value @) 38.71 3.23
27.10 (as H5N5SO) Actual value (%)
38.96 3.01 26.80 This one is M
2-mercapto 4-amino-5- from S, NMR, Engineering R
It was confirmed to be formylpyrimidine. (Yield: 88 cm) Example 4 Thiourea 0.91 F (12 mmol), 28 wt%
2.12 p of a methanol solution of sodium methylate (1
1 mmol), sodium salt of 2-hydroxymethylene-6,3-dimethoxypropanenitrile (purity 90%)
1.83r (10 mmol) and 10 mmol of methanol were mixed at room temperature and then heated under reflux for 4 hours. After the reaction is complete,
After concentrating and removing methanol, 10 ytl of water was added to the residue to make a homogeneous solution.

The pH was adjusted to 7 with IN-HCl, and the precipitated crystals were separated, washed with water and cold methanol, and then dried under vacuum at about 50℃ to obtain 1.44 f of white crystals. The elemental analysis values of this crystal are shown below.

HN elemental analysis calculated value @) 38.71 B, 23
27.10 (05H5N3So) Actual value (!%)
39.03 3.11 27.41 This thing is
MS, NMR, 2-mercapto 4-amino-5
- Confirmed to be formylpyrimidine. (Yield: 93) Example 5 In Example 4, 2-hydroxymethylene/-6,3-
Sodium salt of 2-hydroxydimethylene-3,3-di-n-butoxypropanenitrile (91% purity) instead of sodium salt of dimethoxypropanenitrile 2.
The same procedure as in Example 4 was carried out except that 74 f (10 mmol) was used to obtain 1.407 white crystals. The elemental analysis values of this crystal are shown below.

HN elemental analysis Calculated value (%) 38.71 3. ! 3
27.10 (C5H5N3SO) Actual value (%)
38.44 3.52 27.29 This one is M
S, NMR, 2-mercapto 4-amino-5-
It was confirmed to be formylpyrimidine. (Yield 9o%)

Claims (3)

[Claims] (1) 2-mercapto-4-amino-5-formylpyrimidine. (2) General formula (I) or (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(II) [However, In formulas (I) and (II), R^1, R^2
, R^3, R^4 and R^5 are the same or different lower alkyl groups, and R^1 and R^2 and R^3 and R^4 are lower alkylene groups that are bonded to each other. It is also possible to form a ring. ] Propane nitriles represented by thiourea are reacted in the presence of a base, and the resulting general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(IV) [However, , in formula (IV), R^1 and R^2 are the same as above. 2-mercapto-4-, which is characterized by hydrolyzing 2-mercapto-4-amino-5-dialkoxymethylpyrimidine represented by ] in the presence of an acid.
Method for producing amino-5-formylpyrimidine. (3) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(III) [However, in formula (III), R^1 and R^2 are the same or different lower alkyl groups. Both are lower alkylene groups and can be bonded to each other to form a ring, and M represents an alkali metal. 2-mercapto-4-, which is characterized by reacting an alkali metal salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile represented by ] with thiourea in a solvent in the presence of a base.
Method for producing amino-5-formylpyrimidine.