KR970008318B1 - Novel 1, 6-diaminopyrimidin-4-thione derivatives and process for preparing them - Google Patents

Abstract

Title derivatives(I), useful for treating disease owing to the bacteria having a penicillin antibiotic-resistance and for treating patient who oversensitive to penicillin, were prepared by the reaction of compound(III) and O-aryl(or alkyl) sulfonyl hydroxyl amine to synthesize the intermediate compound(II), which was substituted to compound(I) by using alkaline metal hydrothioxide(M-SH). In formula, R is H or C1-4 alkyl, R' is C1-4 alkyl, substitutable aryl and M is Li, Na or K.

Description

Novel 1,6-diamino pyrimidine-4-thione derivatives and preparation method thereof

The present invention relates to novel 1,6-diamino pyrimidine-4-thione derivatives of the general formula (I) below which are useful as intermediates of cephalosporin-based antibiotics and methods for their preparation.

Wherein R is hydrogen or a C _1-4 alkyl group (preferably methyl group).

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, and are particularly useful for the treatment of diseases caused by bacteria that are resistant to other antibiotics such as penicillin compounds and for the treatment of penicillin-sensitive patients. In many cases, it is desirable to use antibiotics that are active against both positive and gram-negative microorganisms, and it is well known that the antimicrobial activity of these cephalosporin antibiotics is greatly affected by the substituents at the 3 or 7 position of the cefe ring. It is a known fact.

Therefore, 7-β acyl has been shown to have high antibacterial activity against a wide range of Gram-negative and Gram-negative bacteria and to be very stable against β-lactamase produced by various Gram-negative bacteria as well as very stable in vivo. Research has been done on various substituents that can be introduced at the C-3 position of the amido group and the cefem ring.

In this regard, many studies have been conducted on cephalosporin antibiotics having stronger antimicrobial activity and broader antimicrobial spectrum, and a positively charged structure is introduced at the C-3 position of the cefe ring, which is a substituent capable of exerting broad antimicrobial activity. 4,6-diamino-1,5-substituted pyrimidine-2-thione derivatives represented by the following structural formulas (A) have been developed (see, for example, Korean Patent Nos. 47528, 47754, 47755 and 47756, etc.). ).

Wherein R ² is C _1-4 alkyl, C _3-4 alkenyl, C _3-4 cycloalkyl group, substituted or unsubstituted amino group or substituted or unsubstituted phenyl group, R ³ is hydrogen or C ₁ The alkyl group of _-4 is shown.

However, the compound of the general formula (I) according to the present invention is a compound which is structurally completely distinct from the compound described in the above-mentioned known patent specification, and the compound of the present invention is a substituent at the C-3 position of the cephalosporin compound. When introduced into, it exhibits very strong antibacterial activity against a wide range of pathogens, including gram positive and gram negative bacteria. Thus, the manufacturing method regarding the novel cefem compound of the following general formula (B) is demonstrated concretely as a reference example later.

Wherein R and R 'are the same as described above; R ¹ is C _1-4 alkyl, C _3-4 alkenyl, C _3-4 alkynyl group or C (R ^a ) (R ^b ) -COOH, wherein R ^a , R ^b are the same or different Each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b each represent ^a C _3-7 cycloalkyl group together with the carbon atom to which they are attached, and R ^a and R ^b are different; The carbon atoms to which they are attached become asymmetric centers, and these compounds are diastereo isomers and Q is CH or N.

The novel 1,6-diamino pyrimidine-4-thione derivatives represented by the general formula (I) according to the present invention are O-aryl (or alkyl) sulfonyl hydrides in the compounds of the general formula (III) It is prepared by synthesizing a compound of formula (II) by reacting a hydroxyl amine and then substituting it with an alkali metal hydrothioxide (M-SH).

In which R is the same as described above; R 'is a C _1-4 alkyl group (preferably methyl group) or a substituted aryl group (preferably 2,4,6-trimethylphenyl group, 4-methylphenyl group); M is an alkali metal atom, in particular lithium, sodium or potassium.

In the above scheme, O-aryl (or alkyl) sulfonylhydroxylamine, which can be preferably used when preparing an compound of formula (II) by introducing an amino group from the compound of formula (III), is O-methyleneylene. Phenylhydroxyl amines are preferred. At this time, the reaction temperature is preferably about -50 to 50 ℃, more preferably -30 to 20 ℃.

As the alkali metal hydrothioxide used for the substitution reaction, sodium hydrosulfide, potassium hydrosulfide or lithium hydrosulfide is particularly preferable, and the reaction temperature is appropriately in the range of 0 to 80 ° C.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

Synthesis of 1,6-diamino-4-thione

A) Synthesis of 4-amino-6-hydroxypyrimidine

To the solution in which 4-amino-6-hydroxy-2-mercaptopyrimidine (14.3 g) was suspended in distilled water (200 ml) was added nickel nickel (30 g) and heated to reflux for 6 to 10 hours. After cooling the reaction solution to 50 to 60 ℃ the filtered filtrate of the Ranikel is concentrated under reduced pressure and left for 1 hour at 0 to 5 ℃. The resulting solid was filtered, washed with distilled water (10 ml) and dried under reduced pressure to give the title compound (10.3 g) as a white solid.

NMR (δ, DMSO-d ₆ ): 4.98 (s, 1H), 6.42 (s, 2H), 7.78 (s, 1H), 11.41 (s, 1H)

B) Synthesis of 4-amino-6-chloropyrimidine

Solid (10.1 g) obtained in A) was added to a mixture solution of phosphorus oxychloride (50 ml) and N, N-dimethyl aniline (10 ml), heated to reflux for 3 hours, and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, added to cold ice water (100 ml), and the aqueous layer from which the separated N, N-dimethyl aniline was removed was neutralized with ammonia water and extracted with ethyl acetate (200 ml). The organic layer was dried over anhydrous forget-me-not and the organic solvent was removed under reduced pressure to obtain the title compound (6.3 g) as a yellow solid.

NMR (δ, DMSO-d ₆ ): 6.42 (s, 1H), 7.21 (s, 2H), 8.21 (s, 1H)

C) Synthesis of 1,6-diamino-3-methylpyrimidine-4-thione

O-mesitylene sulfonyl hydroxyl amine (15 g) dissolved in dichloromethane (30 ml) of a solution obtained by suspending solid (6.1 g) obtained in B) in dichloromethane (100 ml) after cooling to -30 to -20 deg. Add dropwise for 10 minutes. The temperature of the reaction solution was raised to room temperature and stirred for 20 minutes. The resulting solid was filtered, washed with ethyl ether (30 ml) and dried. The dried solid was suspended in ethyl alcohol (50 ml), and the reaction solution added with 70% sodium hydrosulfide (3 g) was stirred at room temperature for 30 minutes, and then the resulting solid was filtered, distilled water (20 ml) and acetone (20 ml). Washed with dryness to give the title compound (4.1 g) as a white solid.

m.p: Decomposition above 205 ℃

NMR (δ, DMSO-d ₆ ): 5.98 (s, 2H), 6.39 (s, 1H), 7.23 (s, 2H), 7.85 (s, 1H)

Example 2

Synthesis of 1,6-diamino-3-methylpyrimidine-4-thione

A) Synthesis of 4,6-dihydroxy-2-methylpyrimidine

Metal sodium (6.9 g) was added to ethyl alcohol (100 ml) and heated to reflux until a clear solution was added. Diethyl malonate (16 g) and acet amidine hydrochloride (7.95 g) were further heated to reflux for 10 hours. After cooling to room temperature, the resulting solid is filtered. The filtered solid was dissolved in distilled water (50 ml) and neutralized with concentrated hydrochloric acid. The resulting solid was filtered, washed with acetone (20 ml) and dried under reduced pressure to obtain the title compound (10.5 g) as a white solid.

NMR (δ, DMSO-d ₆ ): 2.18 (s, 3H), 11.35 (s, 1H), 11.92 (s, 1H)

B) Synthesis of 4-amino-6-methylpyridine

The solution obtained by suspending solid (10 g) obtained in A) in phosphorus oxychloride (50 ml) was heated to reflux for 3 hours, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated residue was added to cold ice water (100 ml) and the solution neutralized with ammonia water was extracted with ethyl acetate (200 ml). The organic layer is dried over anhydrous forget-me-not and the organic solvent is removed under reduced pressure to give a yellow solid. The solid obtained was added to a mixed solution of ethyl alcohol (100 ml) and aqueous ammonia (100 ml) and heated to reflux for 15 hours. The reaction solution was cooled to room temperature, ethyl alcohol was removed under reduced pressure, and the resulting solid was filtered, washed with ethyl ether (20 ml) and dried under reduced pressure to obtain the title compound (7.8 g) as a white solid.

NMR (δ, DMSO-d ₆ ): 2.29 (s, 3H), 6.28 (s, 1H), 7.11 (s, 2H)

C) Synthesis of 1,6-diamino-2,3-dimethylpyrimidine-4-thione

The solution obtained by suspending solid (7.5 g) obtained in B) in dichloromethane (100 ml) was cooled to −30 to −20 ° C., followed by dissolving mesitylene sulfonyl hydroxyl amine (15 g) dissolved in dichloromethane (30 ml). Add dropwise for minutes. The temperature of the reaction solution was raised to room temperature and stirred for 20 minutes. The resulting solid was filtered, washed with ethyl ether (30 ml) and dried. The dried solid was suspended in ethyl alcohol (50 ml), and the reaction solution added with 70% sodium hydrosulfide (3 g) was stirred at room temperature for 30 minutes, and then the resulting solid was filtered, distilled water (20 ml) and acetone (20 ml). Washed with dryness to give the title compound (4.8 g) as a white solid.

m.p: Decomposition above 210 ℃

NMR (δ, DMSO-d ₆ ): 2.41 (s, 3H), 5.82 (s, 2H), 6.31 (s, 1H), 7.23 (s, 2H)

Reference Example 1

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3- (1,6-diamino Synthesis of -3-methylpyrimidium-4-yl) thiomethyl-3-cepem-4-carboxylate

Paramethoxybenzyl 3-chloromethyl-7-{(Z) -2- (tert-butoxycarbonylprop-2-oxyimino) -2- [2- (triphenylmethyl) aminothiazole 4-yl] acetamido} -3-cepem-4-carboxylate (1 g) was dissolved in dimethyl sulfoxide (10 ml) and 1,6-diamino-3-methylpyrimidine-4 obtained in Preparation Example 1 Thion (200 mg) was added and stirred at room temperature for 2 hours. Diethyl ether (50 mg) was added to the reaction solution, followed by vigorous stirring. Dichloromethane (15 ml) was added to the residue from which diethyl ether was removed, and then ethyl ether (100 ml) was slowly added dropwise. The resulting solid was filtered, washed with ethyl ether (50 ml) and dried. The dried solid was added to a mixed solution of trifluoro acetic acid (6 ml) and anisole (3 ml) cooled to -30 ° C, the reaction solution was heated to room temperature, stirred for 1 hour, and the reaction solution was then heated to -50 ° C. Cool and add ethyl ether (50 ml) dropwise for 10 minutes. The resulting solid was filtered, washed with ethyl ether (20 ml) and dried, separated and purified using preparative liquid chromatography (μ-Bondapak C18 steel column: 19mn × 30cm) with 10% methanol solution as eluent. The title compound (250 mg) was obtained as a solid.

M.S (FAB, M + 1): 610

NMR (δ, D ₂ O-NaHCO ₃ ): 1.48 (d, 6H), 3.61 (ABq, 2H), 4.32 (ABq, 2H), 5.19 (d, 1H), 5.78 (d, 1H), 6.92 (s , 1H), 6.98 (s, 1H), 8.52 (s, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1700, 1660, 1590

Reference Example 2

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3- (6-amino-2- Synthesis of Methylpyrimidinium-4-yl) thiomethyl-3-cepem-4-carboxylate

Paramethoxybenzyl 3-chloromethyl-7-{(Z) -2- (tert-butoxycarbonylprop-2-oxyimino) -2- [2- (triphenylmethyl) aminothiazole 4-yl] acetamido} -3-cepem-4-carboxylate (1 g) was dissolved in dimethyl sulfoxide (10 ml) and 1,6-diamino-3-methylpyrimidine-4 obtained in Preparation Example 2 Thion (200 mg) was added and stirred at room temperature for 2 hours. Diethyl ether (50 mg) was added to the reaction solution, followed by vigorous stirring. Dichloromethane (15 ml) was added to the residue from which diethyl ether was removed, and then ethyl ether (100 ml) was slowly added dropwise. The resulting solid was filtered, washed with ethyl ether (50 ml) and dried. The dried solid was added to a mixed solution of trifluoro acetic acid (6 ml) and anisole (3 ml) cooled to -30 ° C, the reaction solution was heated to room temperature, stirred for 1 hour, and the reaction solution was then heated to -50 ° C. Cool and add ethyl ether (50 ml) dropwise for 10 minutes. The resulting solid was filtered, washed with ethyl ether (20 ml) and dried, separated and purified using preparative liquid chromatography (μ-Bondapak C18 steel column: 19mn × 30cm) with 10% methanol solution as eluent. The title compound (290 mg) was obtained as a solid.

M.S (FAB, M + 1): 624

NMR (δ, D ₂ O + NaHCO ₃ ): 1.49 (d, 6H), 2.62 (s, 3H), 3.65 (ABq, 2H), 4.27 (ABq, 2H), 5.17 (d, 1H), 5.81 (d, 1H ), 6.82 (s, 1H), 6.93 (s, 1H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1680, 1630, 1570

Claims (6)

A novel 1,6-diamino pyrimidine-4-thione derivative represented by the following general formula (I). Wherein R is hydrogen or a C _1-4 alkyl group. The compound of formula (I) according to claim 1, wherein R is hydrogen or a methyl group. After reacting a compound of the general formula (III) with O-aryl (or alkyl) sulfonylhydroxyl amine of the following general formula (A) to synthesize a compound of the general formula (II), it is an alkali metal hydroxythioxide A process for the preparation of novel 1,6-diamino pyrimidine-4-thione derivatives of the general formula (I) below characterized by substitution reaction using (M-SH). Wherein R is hydrogen or a C _1-4 alkyl group; R 'is a C _1-4 alkyl group or a substituted aryl group; M is lithium, sodium or potassium. 4. A method according to claim 3, wherein R is hydrogen or a methyl group and R 'is a methyl group, 2,4,6-trimethylphenyl group or 4-methylphenyl group. 4. The process of claim 3 wherein the O-aryl (or alkyl) sulfonylhydroxyl amine is O-mesitylenesulfonylhydroxyl amine. The method of claim 3, wherein the introduction of the amino group is carried out at a temperature of -30 to 20 ℃, the substitution reaction is carried out at a temperature of 0 to 80 ℃.