JPS62123177A - Novel 6-(2-hydroxyphenyl)pyrimidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:6-(2-Hydroxyphenyl)pyrimidine derivative of formula I (R1 is lower alkyl, phenyl, methylthio, amino; R2 is nitro, amino) and its acid adduct in case of R2=amino. EXAMPLE:6-(2-Hydroxyphenyl)-2,4-dimethyl-5-nitropyrimidine. USE:It has an analgesic action and is used as a medicine. PREPARATION:The reaction of 2-methyl-3-nitrochromone of formula II with an amidine of formula III is carried out, preferably at a molar ratio of 1/(2-5), in a solvent such as methanol to give a compound of formula I where R2 is NO2. Subsequently, the product is reduced to convert the group R2 into NH2.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a novel 6-(2-hydroxyphenyl)pyrimidine derivative represented by the following general formula (I>), and furthermore, when R2 is an amino group, This invention relates to acid addition salts and methods for their production, and these compounds are useful as pharmaceuticals, particularly analgesics, as described below.

[Traditional technique'+! i ] The 6-(2-hydroxyphenyl)pyrimidine derivative represented by the general formula (1) is a compound that has not been described in any literature. Therefore, its useful physiological activity is also unknown. !
l! The method of making it is also unknown.

[Problems to be Solved by the Invention] The present invention solves the problem of the above-mentioned -1) 6-(2-
Created hydroxyphenyl)pyrimidine derivatives,
We aim to make its useful physiological effects clinically applicable, and to make it easy to produce with good yield.

[Means to Solve the Problem] The present scholars have studied the reactivity of chromone derivatives to nucleophiles, especially amines, and have found that this r! Based on the Jt research, the present invention was completed by creating a 6-(2-hydroxyphenyl)pyrimidine derivative represented by the above general formula (I>).

Naturally, the present defense is directed to the 6-(2-hydroxyphenyl)pyrimidine derivative represented by the general formula (I), its acid addition salt when R2 is an amino group, and its production (FA method). It costs something.

Specific examples of the 6-(2-hydroxyphenyl)pyrimidine derivative represented by the general formula (I) include the following compounds.

No, 1 6-(2-hydroxyphenyl)-2,
4-dimethyl-5-ditropyrimidine No. 2 2-ethyl-6-(2-hydroxyphenyl)-4-methyl-5-di]~pyrimidine No. 3
6-(2-hydroxyphenyl)-4-methyl-
5-nitro-2-(II-propyl)pyrimidine No. 4 6-(2-hydroxyphenyl)-4-
Methyl-5-nitro-2-phenylpyrimidine No. 5 2-(4-aminophenyl) -f3-(
2-hydroxyphenyl)-4-methyl-5-21
~Pyrimidine No., f3 6-(2-hydroxyphenyl)-4
-Methyl-2-methylthio-5-21~rovirimidine N
o, 7 2-amino°-G-(2-hydroxyphenyl)-4-methyl-5-21-ropyrimidine,
8 5-Amino-6-(2-hydroxyphenyl)
-2,4-dimethylpyrimidine No, 9 5-amino-2-ethyl-6-(2-hydroxyphenyl)-4-methylpyrimidine 1io, 105-amino-6-(2-hydroxyphenyl)-4- Methyl-2-(II-propyl)pyrimidine 140.115-amino-6-(2-hydroxyphenyl)-4-methyl-2-phenylpyrimidine 14o, 125-amino-2-(4-aminophenyl)-6 -(2-hydroxyphenyl)-4-methylpyrimidine No., 135-amino-6-(2-hydroxyphenyl)-4-methyl-2-methyldiopyrimidine No.
142.5-Diamino-6-(2-hydroxyphenyl)-4-methylpyrimidine The manufacturing method thereof will be explained below.

The 2-substituted-6-(2-hydroxyphenyl)-4-methyl-5-2-ropyrimidine derivative represented by the general formula (Ia) of the present invention is the 2-methyl-3-ropyrimidine derivative represented by the formula (II). -Produced by reacting ditrochromone with amidines represented by general formula (1).

In the reaction, for 1 mole of chromone derivative) 9 of formula (If),
Excess ■ of amidines of general formula (1), preferably 2 to 5
The reaction is carried out by air temperature stirring or heating under reflux using methanol, ethanol, isopropanol, dimethylformamide, water, or a mixture of the above-mentioned alcohols and water as a reaction solvent. Depending on the type of amidine used in the reaction, the reaction can also be promoted in the coexistence of an alkali such as sodium alcohol-1 or 1-ethylamine. After the reaction is completed, the solvent is distilled off from the reaction solution under reduced pressure, water is added to the residue, and diluted J=W is added to the aqueous solution to make it acidic. The resulting crystalline precipitate is then washed with water, dried, and then recrystallized from methanol, ethanol, alcohol, or a mixed solution of the above alcohols and water.
can do.

The general formula (Ia>[
2-substituted-6-(2-hydroxyphenyl)-4- represented by the formula, R1 has the same meaning as above.
The methyl-5-21-ropyrimidine derivative is dissolved in methanol or ethanol, and catalytically reduced by passing hydrogen through 5% palladium-carbon as a catalyst at air temperature and normal pressure to obtain the general formula (Ib). [In the formula, R1 represents the same meaning as above] can be easily converted into 2-substituted-5-amino-6-(2-hydroxyphenyl)-4-methylpyrimidine derivatives shown in Table 4. can. After the catalytic reduction, the catalyst is removed from the reaction mixture, and the solution is concentrated under reduced pressure to give J/r of the product. This is purified by recrystallization from methanol, ethanol, benbin, or a mixed solution of water and the above-mentioned alcohols.

The 2-substituted-5-amino-6-(2-hydroxyphenyl)-4-methylpyrimidine derivative obtained by the above procedure is 1q in the form of a free base, so this can be It can be converted into an acid addition salt by acid treatment according to a conventional method.The most typical acid addition salt is the hydrochloride.

[Function] The above general formula (I>
6-(2-hydroxyphenyl)-4 represented by
- Examples of tests regarding analgesic effects conducted on methylpyrimidine derivatives will be explained.

The analgesic effect was measured using acetic acid rising (ACetiCaCi).
(I Writing) method was used. Zunawara, mice (body weight around 25!J) were given 100 mg/I of the test compound.
(The body weight was measured after subcutaneous (S, C,) administration.Aspirin 200 mg/kg body weight was used as a positive control.

The results are shown in Table 1.

Table 1 As is clear from Table 1, a strong analgesic effect was observed in compound No. 4.8.11 at half the dose of the control. or,
No, 14. A weak analgesic effect was observed in this compound.

In particular, compound N018 showed a strong analgesic effect, with 50% efficacy 1 (ED=o) of 13.31 nU in subcutaneous administration.
/K (1 body weight.) In oral administration of compound No. 8, the analgesic effect was E D 50 = 31.61.
I weighed 1,197 pounds. Therefore, it was found that compound No. 8 exhibited strong analgesic activity upon subcutaneous and oral administration.

[Example] The present invention will be explained in more detail with reference to Examples below, but the invention is not limited to Suikomei.

Example 16-(2-hydroxyphenyl)-2゜4
-Dimethyl-5-nitropyrimidine (compound No. 1) Storium Ediler 1 to solution (Konkushiru 1-Lium 0.
7g1. ! ace1-amidine salt EI in jl [water ethanol 60d]! 2 Add 2.9 (J (30 mmol) of salt,
After stirring at air temperature, 2-methyl-3-21~rok[1
Add Mon 2.19 (10 mmol). After heating this mixture under reflux for 30 minutes, ethanol was distilled off from the reaction mixture under reduced pressure, and water was added to the residue. Dilute hydrochloric acid was added to the resulting solution, and the precipitate was collected by acidic washing. , Recrystallized from a water-ethanol mixture to obtain 1.5 g (yield: 61%) of the title compound. Its physical and chemical properties are as follows.

Properties: Yellow flaky crystals Melting point: 159-160°C Elemental analysis: 0121-1++ N303 Theory 11[:
Q 58.77 Fl 4.52 N
17.13 Experimental value: C58,77H4,51N 1
7.19 trade m analysis spectrum: m/e 245 (H”), 19901+ -1402>
Infrared absorption spectrum (KBr): cm-'1535
, 1355 (NO2'') Example 22-edyru-6-(2-hydroxyphenyl)-4-methyl-5-21-pyrimidine (compound N
o, 2) Soluton, lium, edilate solution (1 to 0.0% metal dust)
7 (3.3 g (30 mmol) of propioamidine hydrochloride and 20.1 g (10 mmol) of 2-methyl-3-2-dihydrochromone) were added to 7,1jj% water-ethanol [30++f>, and the same as in step 1 was added. to be processed. The obtained crude product was recrystallized from a mixture of lime water and ethanol to obtain m2 compound 2, og
(yield 77%). Its physical and chemical properties are as follows.

Properties: Yellow 1-shaped crystal Melting point: 121-122°C Elemental analysis: C131-113N303 Kawamei product 1 shift: C
60,231-15,05N 1 (i, 21 experimental value;
C60, IG +-15,08N 16.48 trade m Analysis spectrum: m/e 259 (14"), 213 () I" -80
2) Infrared absorption spectrum/L<(KBr:Cl1l-1
1530, 1% 0 (NO2) Example 36-(2-hydroxyphenyl)-4-methyl-5-nitro-2-(II-70L"/shinpyrimidine (compound NO, 3) Thorium ethylate solution' rIl (metal nari 1~umo, 7g, 1!11 water engineering') / -ru 60ali2
) Nitropimidine hydrochloride Jm3.71j (30
2.1 g (10 mmol) of 2-methyl-3-di: j ~ Rocromon was added, and the mixture was stirred in the same manner as in Example 1 for 98 hours. The resulting crude product was recrystallized from a water/ethanol mixture to obtain 9 g of m2 compound (yield: γ0 pieces). Its physicochemical properties are as follows.

Properties: Yellow scale crystal Melting point: 100-100.5°C Elemental analysis: C14t-1+st1303 theory: c
f31.53 1-15.53 N 15.38
Experimental value; C61,78 to I 5.61 N 1
5.29 Trade■ Analysis spectrum: nl/e 273(H+], 227(H”-NOz
>Infrared absorption spectrum (KBI'): C11"15
30, 13130 (802') Example 46-(2-
Hydroxyphenyl)-4-methyl-5-nitro-2-phenylpyrimidine (compound No. 4) Soluble in sodium ethylate) 1 night (1 to 0 metal dust)
．． ? C1, 60 Uf of absolute ethanol and benzamidine hydrochloric acid at 4. γq (30 mmol), 2-methyl-3-
Nitrochromone 2. Add ig, (io mmol) and as in Example 1! 2! ! Therefore, m2 compound 2.81J (
A yield of 91%) was obtained. Its physicochemical properties are as follows.

Properties: Yellow acicular crystals Melting point: 172-173°C Elemental analysis: C+y N13 N303 theoretical clay; C66
, 441-14, 26N 13. G7 Experiment I Direct; C6
B, 30 H4,27N 13.70 trade analysis spectrum: m/e 30? (H”n, 261()l+ −Na2
) Infrared absorption spectrum (Bl'): cm-115
20, 1360 (NO2) Example 5 2-(4-aminophenyl)-(3-(2
-hydro=1;diphenyl)-4-methyl-5-nitropyrimidine (compound No. 5) p-amino chloride solution (metal concentration 1 to 1.2 mm, absolute ethanol 60 n&) Benzamijinni Jj'f
fl & salt 5.4 g (213 mmol), 2-methyl-
Add 2.1 g (10 mmol) of 3-nitrochromone,
After heating under reflux for 1 hour, ethanol was distilled off from the reaction solution J under reduced pressure, water was added to the residue, and the precipitate was collected.
After washing with water, m2 compound 2. is recrystallized from an ethanol-water mixture. Ig (yield 65%) was obtained. Its physical and chemical properties are as follows.

Properties: Yellow fine crystals Melting point: 212-214°C Elemental analysis: C1y l-114Na 03% theory 1st shift:
C63,35Fl 4.38 N 17
．． 38 Jitsuha sword revision; C63, 32Fl 4.41
N 17.34fflFi analysis spectrum: m/e
322 (H”) infrared absorption spectrum (KBr):
cm-13460, 3380 (Nllz), 1
520. 1350(802) Example 6-(2-hydroxyphenyl)-4-methyl-2-methylthio-
5-nitropyrimidine (compound 11o, 6) 2-methyl-3-2-21-mouthochromone 2.10 (10 mmol), and S-medylysodiourea sulfate 2.89 (
10 mmol) was suspended in a mixture of 20,211f water and 60 ml of ethanol, heated to 60°C, and then mixed with 3 g (30 mmol) of ethanol and 3 ml of ethanol.
After the reaction, ethanol was distilled off under reduced pressure, the precipitate was collected monthly, and after washing with water,
Recrystallized from ethanol-water mixture to give m2 compound 2.50
(yield 90%) is 14. Its physicochemical properties are as follows.

Shape 11: Yellow flaky crystal Melting point: 159-160°C Elemental analysis: C12l-1o N303 SJ Satoshige Shigenao; C51,98 To1 4,00 N 15.1
5 Experimental value: C51,91I-13,99N 15.2
0 trade mother analysis spec 1 hell: +++/e 277 (toke), 231 (!I+ -NOz
) Infrared absorption subek1her (KBr): cm-115
28, 1353 (NO2) ``j\an Example 7 2-Amino-6-(2-hydroxyphenyl)-4-methyl-5-21-ropyrimidine (compound No. 1-lium ethylate solution) 1 ( 2.1 g (10 mmol) of 2-methyl-3-nitrochromone was added to 0.7 g of metal dust and 60 mmol of absolute ethanol, and 2.9 g (10 mmol) of guanidine salt was added. The obtained crystals were recrystallized from a water-ethanol mixture to obtain m2 compound 1,750 (yield 71%).
). Its physicochemical properties are as follows.

Properties: Yellow acicular crystals Melting point: 224-225°C Elemental analysis: Co I-1+o H403 Kawakumei 1st shift:
C53, CiG l-14,09N 22.7
G experimental value: C53,54Fl 4.07 N
22.79 trader analysis spectrum: m/e 246 (H"), 200 (H+ -NO2) infrared absorption spectrum (KBr): cm-13500,
3400 (N112), 1550. 1355
(802) Example 85-Amino-6-(2-hydroxyphenyl)-2,4-dimethylpyrimidine (Compound No. 8) 6-(2-hydroxyphenyl)-2,4-dimethyl-5- Nitropyrimidine (compound NO, 1 > 1,0
(1 (4 mmol) dissolved in methanol 140π1,
Catalytic reduction was performed by adding 5% palladium on carbon 4001+1 (l) and passing hydrogen under normal pressure at air temperature.Then, the reaction mixture was filtered to remove the catalyst, and the solution was concentrated under reduced pressure to obtain the The residue was recrystallized from a water-ethanol mixture.
0.46 g (yield 53%) of 2 compounds was obtained.

Its physicochemical properties are as follows.

Properties: Pale yellow prismatic crystal Melting point: 123-124°C Elemental analysis: C121-113N 301 Rishige Shigenao; C
6G, 9 [) To 1 6.09 N 1
9.52 Experimental value: C136,95to1 6.07
N 19.41 Trade History Analysis Subek 1-Rule: nl/e
215(H+) infrared absorption spectrum (KBr):
cm-13360 (+4112), 1G32 The free base obtained in the above reaction procedure was treated with hydrogen chloride in ethanol overnight in accordance with a conventional method to remove the J warm acid salt in the form of pale yellow needle-like crystals.

Melting point: 230-233°C Examples 9-14 21-ropyrimidine derivative (compound 'l'IIJH0,2
, 3, 4, 5°6 and 7) were treated in the same manner as in Example 8 to perform catalytic reduction to obtain 19-1 of each aminopyrimidine derivative shown in Table 2.

[Effects of the Invention] As mentioned above, the 6-(2-hydroxyphenyl)pyrimidine derivative represented by the general formula (1) of the present invention is a new substance, has an excellent analgesic effect, and can be used as a pharmaceutical. Useful.

In addition, if the general formula (I) of the present invention is used in your method,
The pyrimidine derivative represented by can be produced under mild conditions with a good yield, and is also an excellent industrial production method.

Claims (1)

[Claims] 1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) [In the formula, R_1 is a lower alkyl group, phenyl group, substituted phenyl group, methylthio group, or amino group, R_2 represents a nitro group or an amino group] A 6-(2-hydroxyphenyl)pyrimidine derivative, and when R_2 is an amino group, an acid addition salt thereof. 2) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) 2-methyl-3-nitrochromone represented by the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ... (III) [In the formula, R_1 represents a lower alkyl group, a phenyl group, a substituted phenyl group, a methylthio group, or an amino group] General formula (I a) characterized by reacting with an amidine represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (Ia) [In the formula, R_1 represents a lower alkyl group, phenyl group, substituted phenyl group, methylthio group, or amino group] 2-substituted-6 represented by A method for producing a -(2-hydroxyphenyl)-4-methyl-5-nitropyrimidine derivative. 3) General formula (Ia) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (Ia) [In the formula, R_1 represents a lower alkyl group, phenyl group, substituted phenyl group, methylthio group, or amino group] General formula (I b) characterized by reducing the 2-substituted-6-(2-hydroxyphenyl)-4-methyl-5-nitropyrimidine derivative represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ...(I b) [In the formula, R_1 represents a lower alkyl group, phenyl group, substituted phenyl group, methylthio group or amino group] 2-substituted-5-amino-6-(2-hydroxy A method for producing a (phenyl)-4-methylpyrimidine derivative and an acid addition salt thereof.