JPH02221261A - Production of 2,4-diamino-6-substituted-pyrimidine-3-oxide - Google Patents

Abstract

PURPOSE:To easily produce the subject compound on an industrial scale by reacting a 2,4-diamino-6-substituted-pyrimidine with hydrogen peroxide in the presence of a catalyst consisting of a compound containing an atom of the group Vb, VIb, VIIb or VIII element of the periodic table. CONSTITUTION:The objective compound of formula II useful as a raw material for hair-tonic or remedy for hypertension, etc., is produced by reacting (A) a compound of formula I (X is Cl, Br, aryl or sulfonyloxy) with (B) hydrogen peroxide in the presence of (C) a catalyst consisting of one or more compounds selected from the compounds containing an atom of the group Vb, VIb, VIIb or VIII element of the periodic table, preferably tungsten or molybdenum, especially tungstic acid, its salt, heteropolyacid of tungstic acid, its salt, tungsten oxide and tungsten halide. The oxidizing agent used in the above process is industrially available in large quantity at a low cost and the process is advantageous because the steps such as the separation, disposal and reutilization of carboxylic acid and the separation of the product can be eliminated or simplified.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) This invention relates to 2,4-diamino-
The present invention relates to a method for producing 6-substituted-pyrimidine-3-oxide.

2.4-Diamino-6-substituted-pyrimidine-3-oxide is a compound useful as a raw material for hair growth agents, antihypertensive drugs, and the like. In particular, 2,4-diamino-6-(1-piperidinyl) has a hair growth stimulating effect and a blood pressure lowering effect.
-pyrimidine-3-oxide [minoxidil (MIN
OXIDIL)] Ya2.6-J7 Mi/-4-(1-
Piperidinyl)-1-(sulfoxy)-pyrimidinium hydroxide (minoxidil sulfate), methyl 5-(3,6-cyhydro-1(2H)
)-pyridyl-2,oxo.

2H-[1,2,4]oxadiazolo[2,3-alpyrimidine-7°carbamate (CARPRAZADIL
) is useful as an intermediate for

2,4-diamino-6-substituted-pyrimidine-3-oxide represented by formula (II) may be expressed as a tautomer represented by formula (III), but the same compound is substantially the same compound. It is. This patent uses the notation of formula (II).

(In the formula, X represents a group selected from the group consisting of a chlorine atom, a bromine atom, or an arylsulfonyloxy group.) (Prior art) 2.4-Diamino-6-substituted-pyrimidine-3-oxide is It can be produced by oxidizing a 6-substituted-pyrimidine to 2,4-diami.

The oxidizing agents used in this oxidation reaction include (1) aromatic percarboxylic acids such as m-chloro-perbenzoic acid (e.g., Japanese Patent Publication No. 55-1259), (2) peracetic acid (e.g., Japanese Patent Publication No. 60-24794). , He1v, Chim, Act
a, 65.1445 (1982)), (3) hydrogen peroxide and trifluoroacetic acid (e.g. J, Heteroc.
ycl. Chem, 9.73 (1972)), (
4) Hydrogen peroxide and acetic acid (e.g., JP-A-63-2387
1) etc. are known. Among these, trifluoroperacetic acid in (3) and peracetic acid in (4) are generated in the system, and these percarboxylic acids are considered to be the actual reactive species.

Alternatively, acylated 2,4-diamino-6-substituted-pyrimidine-3 can be obtained by reacting 2,4-diamino-6-substituted-pyrimidine with an acid anhydride in the presence of water and hydrogen peroxide.
-Methods for synthesizing oxides (for example, JP-A-63-2
3871) is also known. In this case as well, it is believed that the oxidation reaction progresses due to peracetic acid produced within the system.

(Problems to be Solved by the Invention) However, each of these conventional methods has the following problems.

A common problem when percarboxylic acids such as aromatic percarboxylic acids, peracetic acid, and trifluoroperacetic acid are used as oxidizing agents is that the corresponding carboxylic acid is produced by the reaction. Therefore, when manufacturing on an industrial scale,
A step is required to separate the corresponding carboxylic acid, and a step is also required to discard or reuse the separated corresponding carboxylic acid. This makes the manufacturing process complicated.

Furthermore, a salt of the corresponding carboxylic acid and 2,4-diamino-6-substituted-pyrimidine-3-oxide is formed, and the solubility increases due to the carboxylic acid, and 2,4-diamino-6
All or most of the -substituted-pyrimidine-3-oxide is dissolved. Therefore, 2,4-diamino-6-
For isolation of substituted-pyrimidine-3-oxide, 2,4-diamino-6-substituted-pyrimidine-3-
It is necessary to crystallize the oxide, which poses problems such as the process being complicated and the use of highly flammable solvents.

Furthermore, aromatic percarboxylic acids and trifluoroperacetic acids are expensive and difficult to obtain in large quantities. Furthermore, the yield is not fully satisfactory, as it is 44.7% when chloro-perbenzoic acid is used (Japanese Patent Publication No. 55-1259).

Also, a method of reacting 2,4-diamino-6-substituted-pyrimidine with an acid anhydride in the presence of water and hydrogen peroxide (
JP-A-63-23871) discloses acylated 2,4-diamino, 6. The problem is that a subsequent deacylation step is required to obtain substituted-pyrimidine-3-oxides.

The present inventor solves these problems 2, 4. We have intensively investigated methods for producing diamino-6-substituted, pyrimidine, and 3-oxides. As a result, 2,4-diamino-
We have discovered a method of reacting 6-substituted pyrimidine with hydrogen peroxide in the presence of a catalyst.

(Means for Solving the Problems) That is, the present invention provides a 2,4-diamino-6-substituted-pyrimidine compound represented by formula (I) (wherein X is a chlorine atom, a bromine atom, or an arylsulfonyloxy group). represents a group selected from the group consisting of ) in the periodic table, using one or more compounds selected from the group consisting of compounds containing atoms of group Vb, vib, ■b or ■ as a catalyst, This is a method for producing 2,4-diamino-6-substituted-pyrimidine-3-oxide represented by formula (II), which comprises reacting with hydrogen peroxide.

↑ (In the formula, X represents a group selected from the group consisting of a chlorine atom, a bromine atom, or an arylsulfonyloxy group.) Examples of the arylsulfonyloxy group include a benzenesulfonyloxy group, a p-)luenesulfonyloxy group, a p-chlorobenzenesulfonyloxy group, a p-bromobenzenesulfonyloxy group, and a p-methoxybenzenesulfonyloxy group. , 1,3-dimethylbenzenesulfonyloxy group, 1,3-dichlorobenzenesulfonyloxy group, and the like.

Examples of the 2,4-diamino-6-substituted-pyrimidine represented by formula (I) include 2,4-diamino-6-chloropyrimidine, 2,4-diamino-6-promopyrimidine, 2,4-diamino-6-chloropyrimidine,
, 4-diamino-6-benzenesulfonyloxypyrimidine, 2,4-diamino-6-(p-toluene sulfonyloxy)pyrimidine, 2,4-diamino-6-(p
-chlorobenzenesulfonyloxy)pyrimidine, 2,
4-Diazi/-6-(p-bromobenzenesulfonyloxy)pyrimidine, 2,4-diamino-6-(p-methoxybenzenesulfonyloxy)pyrimidine, 2,4-
Diamino-6-(1,3-dimethylbenzenesulfonyloxy)pyrimidine, 2,4-diamino-6-(1,3
-dichlorobenzenesulfonyloxy)pyrimidine, etc.

The 6-substituted 2,4-diami-pyrimidine represented by formula (I) is produced by a known method.

For example, 2,4-diamino-6-chloropyrimidine can be found in, for example, J, Am, Chem, Soc, ? 2
．． 1914 (1950); Chem.

2,4-diamino-6-(p-)luenesulfonyloxy)pyrimidine, which can be produced by the method described in Ber, 94, 12 (1961), is disclosed in JP-A-55-59.
It can be produced by the method described in No. 172.

There is no particular limit to the concentration of hydrogen peroxide, but it is usually 5.
Hydrogen peroxide at a concentration of ~90%, preferably 10~
Hydrogen peroxide at a concentration of 65% is used. Hydrogen peroxide is usually used in the form of an aqueous solution.

There is no particular limit to the amount of hydrogen peroxide, but it is usually 2,4
-diamino-6-substituted-pyrimidine 0.5-2
A 0 molar amount is used, preferably a 0.8 to 5.0 molar amount.

As the catalyst, one or more compounds selected from the group consisting of compounds containing atoms of groups Vblvxb, ■b, or ■ in the periodic table are used. vb, ■b on the periodic table
Examples of atoms of the 1■b1■ group include tungsten, -molybdenum, chromium, vanadium, iron, and osmium. In particular, compounds containing tungsten and compounds containing molybdenum are effective.

Examples of compounds containing tungsten include tungstic acid,
salts of tungstic acid, heteropolyacids of tungstic acid,
Examples include salts, oxides, halides, and sulfides of tungstic acid heteropolyacids. To give more detailed examples, the salts of tungstic acid include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, etc.
As the heteroatom of the heteropolyacid of tungstic acid,
Salts of heteropolyacids such as tungstic acid such as phosphorus and silicon include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, and ammonium salts. Examples of halides include chlorides and bromides.

Examples of compounds containing molybdenum include molybdic acid,
Salts of molybdic acid, heteropolyacids of molybdic acid, salts of heteropolyacids of molybdic acid, oxides, halides,
Examples include sulfides. To give more detailed examples, salts of molybdic acid include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, etc., and heteroatoms of heteropolyacids of molybdic acid. Examples of the salts of heteropolyacids such as molybdic acid include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, and ammonium salts.

Examples of halides include chlorides and bromides.

The amount of the catalyst is not particularly limited, but it is usually based on vb in the periodic table for 2,4-diamino-6-substituted-pyrimidine.
, (b), (b) or (b) group atoms in an amount of 0.1 to 10 mol %, preferably 0.5 to 5.0 mol %.

The reaction solvent is not particularly limited as long as it is inert to the reaction, but it usually includes water or water-miscible organic solvents,
For example, alcohols having 1 to 3 carbon atoms, dioxane, tetrahydrofuran, dimethylformamide, etc. may be used alone or in combination with water to the extent that a homogeneous phase is maintained. Water, methanol, and a mixture of water and methanol are particularly preferred from the viewpoint of yield, operability, and the like.

The amount of reaction solvent is not particularly limited, but usually 1 to 20 of 2,4-diamino-6-substituted-pyrimidine-3-oxide.
About 0 times the weight, preferably 2 to 20 times the weight is used.

The reaction temperature is usually 10 to 150°C, preferably 30°C.
~100°C is adopted. The 2,4-diamino-6-substituted pyrimidine-3-oxide represented by formula (II) is produced by the method described above. 2,4-diamino-6-substituted-pyrimidine-3 of formula (II)
Examples of -oxides include 2,4-diamino/-5-chloropyrimidine-3° oxide, 2,4-diamino-
6, Bromopyrimidine-3-oxide, 2,4-diamino-6-benzenesulfonyloxypyrimidine-3-
oxide, 2,4-diamino-(6-p-toluenesulfonyloxy)pyrimidine-3-oxide, 2,4
-Diamino-6-(p-chlorobenzenesulfonyloxy)pyrimidine-3-oxide, 2,4-diami/-
6-(p-':?' lomobenzenesulfonyloxy)pyrimidine-3-oxide, 2,4-diamino-6-(
p-methoxybenzenesulfonyloxy)pyrimidine-
3-oxide, 2,4-diamino-6-(1,3-dimethylbenzenesulfonyloxy)pyrimidine-3-oxide, 2,4-diamino-6-(1,3-dichlorobenzenesulfonyloxy)pyrimidine-3- Examples include oxide.

(Function) The reason why the process was simplified in the present invention is thought to be because when percarboxylic acid is used, the corresponding carboxylic acid is produced in the reaction, whereas when hydrogen peroxide is used, water is produced in the reaction. It will be done. Therefore, the step of separating the corresponding carboxylic acid is no longer necessary, and the step of discarding or reusing the separated corresponding carboxylic acid is also no longer necessary. In addition, the generated carboxylic acid is 2,4-diamino-6-
Substituted-pyrimidine-3, produces oxide and salt,
It is believed that the solubility increased and the 6-substituted pyrimidine-3-oxide was not completely or mostly dissolved in 2,4-diami, simplifying the isolation process.

(Effects of the Invention) In the present invention, in the production of 2,4-diamino-6-substituted-pyrimidine and 3-oxide, compared to when percarboxylic acid is used, it is possible to separate and dispose of the carboxylic acid produced by the reaction.
Processes such as reuse could be omitted.

Furthermore, the isolation process could also be simplified.

Furthermore, since hydrogen peroxide is used as the oxidizing agent, the oxidizing agent is inexpensive and can be obtained in large quantities on an industrial scale.

Therefore, on an industrial scale, 2,4-diamino-6-substituted
The production of pyrimidine-3-oxide has become easier. This patent will be explained in more detail using examples.

(Example) Example 1 7.23 g of 2.4-diamino-6-chloropyrimidine (
50 mmol), Na2WO4-2H200,3g (0
, 9 mmol) and stirred. 8.45 g (75 mmol) of 30% H2O2 was added and reacted under reflux for 6.5 hours. After cooling to room temperature, it was filtered and washed with 15 g of methanol. The obtained crystals were dried and 2,4-diamino-6-chloropyrimidine-3-
Oxide 6.46g (purity 289%, yield near 1%)
I got it.

NMR (DMSO-d6): δ6.1 (s, IH)
; δ7.5 (bs, 4H) purity was determined by high performance liquid chromatography [column (length 150 mm, diameter 6 mm);
Filler: Asahipak ODP-50 (Mukasei Kogyo Co., Ltd.); Eluent: 25mM (KH2PO4.

Na2HPO, a) /acetonitrile = 9/1; detector: UV.

260 nm).

Example 2 1.44 g of 2.4-diamino-6-chloropyrimidine (
10 mmol), Na2WO4-2H200,062g
(0.19 mmol) was added with 10 ml of methanol and stirred. 60% H2O20.84g (15mmo
1) was added and reacted under reflux for 6.5 hours. After cooling to room temperature, it was filtered and washed with methanol. The obtained crystals were dried and 2,4-diamino-6-chloropyrimidine-
1.24 g of 3-oxide (purity = 91%.

Yield near 0%) was obtained.

Example 3 1.44 g of 6-chloropyrimidine (1
0 mmol), Na2WO40,047g (0,1
9 mmol) was added with 10 ml of methanol and stirred. 1.69 g (15 mmol) of 30% H2O2 was added and reacted under reflux for 6.5 hours. After cooling to room temperature, it was filtered and washed with methanol. The obtained crystals were dried and
, 1.13 g of 4-diamino-6-chloropyrimidine-3-oxide (purity: 288%).

Yield: 62%) was obtained.

Examples 4 to 6 Under the same conditions as Example 3, the catalyst was converted to Na2WO4.2H20.
I reacted by replacing it with the following. The results are shown below.

Example 7 1.44 g (1.44 g) of 6-chloropyrimidine to 2,4-diami
0 mmol), Na2WO4-2H200,061g
(0.19 mmol) was added with 10 ml of pure water and stirred. 1.69 g (15 mmol) of 30% H2O2 was added and reacted at 63-67°C for 6.5 hours. After cooling to room temperature, it was filtered and washed with pure water. The obtained crystals were dried to obtain 1.03 g of 2;4-diamino-6-chloropyrimidine-3-oxide (purity = 51%, yield: 33%).

Procedural amendment (voluntary) April i, 1989 Director General of the Patent Office Yoshi 1) Tsuyoshi Moon 2. Name of the invention 2. Process for producing 4-cyacyno 6-substituted-pyrimidine-3-oxai 3. Person making the amendment Relationship to the case Address of patent applicant: 1 Teppocho, Sakai City, Osaka Prefecture Patent applicant: Daicel Chemical Industries, Ltd. 4, Subject of amendment: -1'・Detailed explanation of the invention in the specification column 5, Contents of amendment (1) "Pyrimidicin" on page 7, line 6 of the specification of the present application [
pyrimidine].

(1) “Pyrimidicine” on page 7, line 8 of the same book
1) Page 100, line 1 of the same book: “Ru2, 4-J [ru.2
, 4-Correct to J.

(1) Line 1 on page 111 of the same book [For example, Tanges J is
For example, correct to "Tanges".

(1) r Na2WO4J on page 16, line 20 of the same book
Correct to H2WO4J.

(1) r Na2WO on page 177, lines 8 to 9 of the same book
4-2H20J is corrected by rH2WO4J.

Claims (1)

[Claims] 1. 2,4-diamino-6-substituted-pyrimidine represented by formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (wherein, X is a chlorine atom, a bromine atom , or an arylsulfonyloxy group. ) represents one or more compounds selected from the group consisting of compounds containing atoms of group Vb, VIb, VIIb or VIII in the periodic table. 2,4-diamino- represented by formula (II), characterized in that the reaction is carried out with hydrogen peroxide using
A method for producing 6-substituted-pyrimidine-3-oxide. ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (II) (In the formula, X represents a group selected from the group consisting of a chlorine atom, a bromine atom, or an arylsulfonyloxy group.) 2. Contains tungsten as a catalyst One or two selected from the group consisting of a compound and a compound containing molybdenum
2. The manufacturing method according to item 1, using more than one type of compound. 3. Tungstic acid, tungstic acid salt as a catalyst,
2. The manufacturing method according to item 1, which uses one or more compounds selected from the group consisting of a heteropolyacid of tungstic acid, a salt of a heteropolyacid of tungstic acid, tungsten oxide, and tungsten halide.