KR0126664B1 - Novel pyrimidine thione compound and process for its preparation - Google Patents

Abstract

This invention relates to 2-amino-1-substituted-cycloalka prymidine-4-thione derivative represented by the general formula where R is substituted or unsubstituted amino, C1-C4 alkyl or C3-C7 cycloalkyl, and n denotes from 2 to 7. This compound is synthesized from initial substance (IV) according to the following reactions: halogenation, akylation, substitution with an alkali metal hydrosulfide. This compound is useful as an intermediate of cephalosporin antibiotics.

Description

Novel pyrimidine thion compounds and preparation method thereof

The present invention provides novel pyrimidine thione compounds useful as intermediates of cephalosporinge antibiotics, more specifically 2-amino-1-substituted-cycloalcapyrimidine-4-thione derivatives represented by the following general formula (I) and It relates to a manufacturing method thereof.

Wherein R represents a substituted or unsubstituted amino group (preferably amino group), C _1-4 alkyl group (preferably methyl group) or C _3-7 cyclo alkyl group; n is 2 to 7, preferably 3 or 4.

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

Therefore, it has been shown to have high antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, and is also very stable against B-lactamase produced by various Gram-negative bacteria and has been tried to find very stable antibiotics in the body. Various substituents that can be introduced at the C-3 position of the B acyl amido group and the cefe ring have been studied.

In this regard, many studies have been conducted on cephalosporin antibiotics that have stronger antimicrobial activity and broader antimicrobial spectrum. 4,6-diamino-1,5-substituted pyrimidine-2-thione derivatives represented by the following structural formulas (A) have been developed (Korean Patent Nos. 47282, 47754, 47755 and 47756, etc.). Reference).

Wherein R ¹ 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 ² is hydrogen or C ₁ The alkyl group of _-4 is shown.

However, the compounds of the general formula (I) according to the present invention are structurally completely distinct from the compounds described in the above-mentioned known patent specification.

In addition, European Patent Application No. 150,507 discloses a cefem compound of the following general formula (B), which broadly defines a heterocyclo group as a substituent R which may be substituted for C-3 attachment of this compound.

However, the heterocyclo group defined in the European patent only broadly represents an optionally substituted triazolo pyrimidyl group or a thiazolopyrimidyl group and the like, and is a cycloalkyl fused 2-amino-1 substituted cycloal which is the core of the present invention. There is no mention or suggestion that caprimidine groups may be included.

Thus, the inventors of the present invention, as a result of repeated studies on the C-3 position substituents that can give a wide range of antimicrobial spectrum and stronger antimicrobial activity to the cephalosporin compound, the compound of formula (I) is a cephalosporin compound When introduced as a substituent at the C-3 position of the present invention was found to be able to exert a very strong antimicrobial activity against a wide range of pathogens, including Gram-positive bacteria and Gram-negative bacteria to complete the present invention.

Wherein R and n have the meanings given above.

The compound of general formula (I) according to the present invention can be usefully used to synthesize a novel cephalosporin-based antibiotic represented by the following general formula (C), examples of which will be described in detail later as examples. will be.

Wherein R is the same as described above; R ′ represents hydrogen, a C _1-4 alkyl group, or a C _2-4 alkenyl group, a C _2-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, wherein R ^a and 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 from each other. The carbon atoms to which they are attached become asymmetric centers, and in these compounds, R has n as described above.

The compound of general formula (I) according to the present invention can be usefully used to synthesize a novel cephalosporin-based antibiotic represented by the following general formula (C), examples of which will be described in detail later as examples. will be.

Wherein R is the same as described above; R ′ represents hydrogen, a C _1-4 alkyl group, or a C _2-4 alkenyl group, a C _2-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, wherein R ^a and 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 from each other. The carbon atoms to which they are attached become asymmetric centers, and these compounds are diastereo isomers; n is 2 to 7, preferably 3 to 4.

The novel 4-amino-1-substituted cyclo alcappyrimidine-4-thione derivatives of the general formula (I) according to the present invention are reacted with a halogenating agent by the compound of the general formula (IV) according to the following scheme After synthesizing the compound of (III), a substituent R is introduced into the compound to prepare a compound of the general formula (II), followed by substitution reaction with an alkali metal hydrosulfide (M-SH).

Wherein R and n are the same as described above; X represents an acid residue such as a halogen atom or sulfate; M is an alkali metal atom, in particular ritum, sodium or potassium. Preferred examples of the halogenating agent used in the reaction scheme are phosphorus oxychloride, phosphorus pentachloride or phosphorus trichloride, and the like, and in particular, when using phosphorus oxychloride, the reaction is preferably performed at its reflux temperature for 2 to 4 hours. .

In the reaction for preparing a compound of formula (II) by introducing a substituent R to a compound of formula (III), when R is an alkyl or cycloalkyl group, C _1-4 alkyl halide or C _3-7 cycloalkyl as an alkylating agent Halides are preferred and particularly preferably methyl iodide or ethyl iodide, when R is an amino group 0-alkyl (or aryl) sulfonylhydroxylamine, particularly preferably 0-mesitylenesulfonyl hydroxyl amine Is used to introduce the amino group.

In addition, as the alkali metal hydrothioxide used for the substitution reaction, sodium hydrosulfide and potassium hydrosulfide are particularly preferable. The reaction is carried out by using an alcohol such as methanol or ethanol as a solvent for 30 minutes to 1 hour at a solvent reflux temperature. Is complete.

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

Example 1 Synthesis of 1: 1,2-Diamino-1,5,6,7-tetrahydro-cyclopentapyrimidine-4-thione

A) Synthesis of 2-amino-6,7-dihydro-5H-cyclopentapyrimidin-4-ol

50 g of ethyl and 2-oxocyclopentanecarboxylate were dissolved in 200 ml of ethanol, 90 g of guanidine carbonate was added, and refluxed for 5 hours. The mixture was heated and refluxed under reduced pressure to remove ethanol, and the remaining residue was washed with distilled water and acetone and dried to give a white powder. 60 g was obtained.

NMR (DMSO-d ₆ ): 2.16 (m, 2H), 2.78 (m, 4H), 6.69 (s, 2H), 8.18 (s, 1H)

B) Synthesis of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine

To 20 g of 2-amino-6,7-dihydro-5H-cycloropenta pyrimidin-4-ol obtained in Example 1), 100 ml of phosphorus oxchloride was added and heated to reflux for 3 hours, followed by a portion of phosphorus oxy. The concentrated reaction solution removed by distillation of the chloride under reduced pressure was poured into 500 ml of ice water and neutralized with 20% ammonia water. 300 ml of ethyl acetate was added thereto, followed by extraction. The separated organic layer was dried over anhydrous magnesium sulfonate, distilled under reduced pressure, and the solvent was removed to obtain 10 g of a white solid compound.

NMR (DMSO-d ₆ ): 2.02 (m, 2H), 2.81 (m, 4H), 6.87 (s, 2H)

C) Synthesis of 1,2-diamino-1,5,6,7-tetrahydro-cyclopentapyrimidine-4-thione

5 g of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine obtained in Example 1) was dissolved in 100 ml of dichloromethane, and then 10 g of mesitylene sulfonyl hydroxylamine was dichloromethane at room temperature. After dissolving in 20ml of methane, 10g of mesitylenesulfonylhydroxyl amine in 20ml of dichloromethane was slowly added dropwise at room temperature for 10 minutes. The temperature of the reaction solution was raised to room temperature, followed by further stirring for 10 minutes. The resulting solid was filtered, washed with diethyl ether and dried to dissolve the solid obtained in 100 ml of methanol. 2.5 g of sodium hydrosulfide was added thereto, stirred at room temperature for 30 minutes, and the resulting solid was filtered, washed with distilled water and acetone, and dried to obtain 3.1 g of the title compound as a white powder.

NMR (DMSO-d ₆ ): 1.93 (m, 2H), 2.64 (t, 4H), 2.95 (t, 2H), 5.89 (s, 2H), 7.27 (s, 2H)

Melting Point: Decomposes above 195 ℃

Example 2 Synthesis of 2-amino-1-methyl-1,5,6,7-tetrahydro-cyclopentapyrimidine-4-thione

5 g of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine obtained in Example 1) was dissolved in 100 ml of tetrahydrofuran, and 10 g of methyl iodide was added thereto, followed by heating under reflux for 7 hours. I was. The reaction solution was cooled to room temperature, the resulting replacement was filtered, washed with diethyl ether and dried to dissolve the solid obtained in 100 ml of ethanol, 2.7 g of sodium hydrosulfide was added and stirred at room temperature for 30 minutes, and then the solid produced by the reaction. Filtration and washing with distilled water and acetone gave 3.1 g of the title compound as a white powder.

NMR (DMSO-d ₆ ): 1.89 (m, 2H), 2.51 (m, 4H), 3.22 (2, 3H), 6.34 (s, 2H)

Melting Point: Decomposes above 205 ℃

Example 3: Synthesis of 1,2-diamino-5,6,7,8-tetrahydro-1H-quinazolin-4-thione

A) Synthesis of 2-amino-5,6,7,8-tetrahydro-quinazolin-4-ol

30 g of ethyl 2-cyclohexanone carboxylate was dissolved in 150 ml of ethanol, 50 g of guanidine carbonate was added thereto, and the mixture was heated to reflux for 5 hours, and then distilled under reduced pressure to remove ethanol. The remaining residue was washed with distilled water and acetone, and dried to give a title of white powder. 40 g of compound was obtained.

NMR (DMSO-d ₆ ): 1.92 (m, 2H), 2.24 (t, 3H), 2.52 (t, 3H), 7.04 (s, 2H)

B) Synthesis of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine

To 20 g of 20 amino-5,6,7,8-tetrahydro-quinazolin-4-ol obtained in Example 3 A), 100 ml of phosphorus oxychloride was added and heated under reflux for 3 hours, followed by distillation under reduced pressure to obtain a portion of phosphorus. The oxychloride was removed and the concentrated reaction solution was poured into 50 ml of ice water and neutralized with 28% ammonia water. 300 ml of ethyl acetate was added thereto, and the organic layer was extracted, dried over anhydrous magnesium sulfate, distilled under reduced pressure, the catalyst was removed, and dried to obtain 12 g of the title compound as a white solid.

NMR (DMSO-d ₆ ): 1.88 (m, 2H), 2.30 (t, 3H), 2.64 (t, 3H), 5.18 (s, 2H)

C) Synthesis of 1,2-diamino-5,6,7,8-tetrahydro-1H-quinazolin-4-thione

5 g of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-alamine obtained in Example 3) was dissolved in 100 ml of dichloromethane, and the reaction solution was cooled to -50 ° C and mesityl. 11 g of rensulfonyl hydroxylamine dissolved in 20 ml of dichloromethane was slowly added dropwise for 10 minutes. After raising the temperature of the reaction solution to room temperature and stirring for 10 minutes, the resulting solid was filtered, washed with diethyl ether and dried to dissolve the solid obtained in 100 ml of methanol. 2.5 g of sodium hydrosulfite was added thereto, stirred at room temperature for 30 minutes, and the resulting solid was filtered, washed with acetone in distilled water, and dried to obtain 3.2 g of the title compound as a white powder.

NMR (DMSO-d ₆ ): 1.63 (m, 2H), 2.17 (t, 2H), 2.60 (t, 2H), 5.55 (s, 2H), 7.20 (s, 2H)

Melting Point: Decomposes above 210 ℃

Example 4 Synthesis of 2-amino-1-methyl-5,6,7,8-tetrahydro-1H-quinazolin-4-thione

5 g of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine obtained in Example 3) was dissolved in 100 ml of tetrahydrofuran, and 12 g of methyl iodide was added thereto, followed by heating for 9 hours. It was refluxed. The reaction solution was cooled to room temperature, the resulting solid was filtered, washed with diethyl ether and dried to dissolve the solid obtained with 100 ml of ethanol, and then 2.5 g of 70% -sodium hydrosulfide was added and stirred at room temperature for 30 minutes. The resulting solid was filtered, washed with distilled water and acetone and dried to obtain 3.0 g of the title compound as a white powder.

NMR (DMSO-d ₆ ): 1.61 (m, 4H), 2.04 (t, 2H), 2.42 (t, 2H), 3.31 (s, 2H), 6.53 (s, 2H)

Melting Point: Decomposes above 205 ℃

Reference Example 1 7- [Z] -2- (2-Aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3- (1,2 Synthesis of -diamino-1,5,6,7-tetrahydro-cyclopentapyridin-4-yl) thiomethyl-3-cepem-4-carboxylate

Paramethoxybenzyl 3-chloromethyl-7-{(Z) -2- (tert-butoxycarbonylprop-2-oxyimino) -2- [2- (triphenylmethyl) aminothiazole 1,2-diamino-1,5,6,7-tetra synthesized in Example 1 by dissolving 2.0 g of -4-yl] acetamido} -3-cefe-4-carboxylate in 30 ml of dimethyl sulfoxide. 350 mg of hydro-cyclopyrimidine-4-thione was added, followed by stirring at room temperature for 3 hours. 100 ml of diethyl ether was added to the reaction solution, followed by vigorous stirring. 20 ml of dichloromethane was dissolved in the residue from which the diethyl ether layer was removed, and then 100 ml of diethyl ether was slowly added dropwise to crystallize. The resulting solid was filtered, washed with 100 ml of diethyl ether, dried and dissolved in 6 ml of anisol. The solution was cooled to −20 ° C. and slowly added dropwise to 12 ml of trifluoroacetic acid. The reaction solution was then heated to room temperature and stirred for 3 hours. The reaction solution was cooled to −20 ° C., 100 ml of diethyl ether was slowly added dropwise to crystallize, filtered, washed with 200 ml of diethyl ether, and dried to obtain 1.4 g of a white solid. The obtained solid was purified by preparative liquid chromatography (μ-Bondapak C Steel Column, 19mm × 30cm) using 7% aqueous methanol solution as eluent to obtain 700 mg of the title compound as a white solid. M.S (FAB, M + 1): 682

NMR (δ, D ₂ O + NaHCO ₃ ): 1.53 (d, 6H), 2.22 (m, 2H), 2.78 (t, 2H), 3.13 (5, 2H), 3.13 (5, 2H), 3.59 (ABq , 2H), 4.32 (ABq, 2H), 5.15 (d, 1H), 5.78 (d, 1H), 6.96 (s, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1670, 1625, 1550

[Reference Example]

2: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (2-amino-1 Synthesis of -methyl-1,5,6,7-tetrahydro-cyclopentapyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

2-amino-3-methyl-3,5 synthesized in Example 2 instead of 1,2-diamino-1,5,6,7-tetrahydro-cyclopentapyrimidine-4-thione used in Example 1 680 mg of the title compound as a white powder was obtained in the same manner as Example 1 using, 6,7-tetrahydro-cyclopentapyrimidine-4-thione.

M.S (FAB, M + 1): 681

NMR (δ, D ₂ O + NaHCO ₃ ): 1.50 (d, 2H), 2.10 (m, 2H), 2.76 (t, 2H), 3.08 (5, 2H), 3.58 (ABq, 2H), 3.62 (s , 3H), 4.25 (ABq, 2H), 5.16 (d, 1H), 5.78 (d, 1H), 6.92 (s, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1670, 1610, 1540

[Reference Example]

3: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- (1,2-diamino- Synthesis of 5,6,7,8-tetrahydro-1H-quinazolinium-4-yl) thiomethyl-3-cepem-4-carboxylate

2,3-diamino-5,6 synthesized in Example 3 instead of 1,2-diamino-1,5,6,7-tetrahydro-cyclopentapyrimidine-4-thione used in Example 1, 350 mg of 7,8-tetrahydro-3H-quinazolin-4-thione was used in the same manner as in Example 1 to obtain 650 mg of the title compound as a white powder.

M.S (FAB, M + 1): 696

NMR (δ, D 2 O + NaHCO 3): 1.51 (d, 6H), 1.60 (m, 4H), 1.91 (t, 2H), 2.40 (t, 2H), 3.53 (ABq, 2H), 4.41 (ABq, 2H) , 5.16 (d, 1H), 5.76 (d, 1H), 6.94 (s, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1670, 1640, 1580

[Reference Example]

4: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-2 (2-amino- Synthesis of 1-methyl-5,6,7,8-tetrahydro-1H-quinazolinium-4-yl) thiomethyl-3-cepem-4-carboxylate

2-amino-1-methyl-5,6 synthesized in Example 4 instead of 1,2-diamino-1,5,6,7-tetrahydro-cyclopentapyrimidine-4-thione used in Example 1 670 mg of the title compound as a white powder was obtained in the same manner as in Example 1 using 360 mg of 7,7,8-tetrahydr-3-3H-quinazolin-4-thione.

M.S (FAB, M + 1): 695

NMR (δ, D ₂ O + NaHCO ₃ ): 1.54 (d, 6H), 1.59 (m, 4H), 1.86 (t, 2H), 2.20 (t, 2H), 3.53 (ABq, 2H), 3.59 (s , 3H), 4.27 (ABq, 2H), 5.15 (d, 1H), 5.75 (d, 1H), 6.97 (s, 1H)

IR (KBr, cm ^-1 ): 1760 (β-lactam), 1750, 1650, 1590

Claims (7)

The novel 2-amino-1-substituted-cycloalcapyrimidine-4-thione derivative represented by the following general formula (I). Wherein R represents an amino group, a C _1-4 alkyl group or a C _3-7 cycloalkyl group, and n is 2 to 7. The compound of formula (I) according to claim 1, wherein R is an amino group or a methyl group, and n is 3 or 4. After reacting a compound of the general formula (IV) with a halogenating agent to synthesize a compound of the general formula (III), a substituent R is introduced to the compound (III) to prepare a compound of the general formula (II) A method for producing a 2-amino-1-substituted-cycloalkapyrimidine-4-thione derivative of the general formula (I) below, characterized by a substitution reaction with an alkali metal hydrosulfide (M-SH). Wherein R represents an amino group, a C _1-4 alkyl group or a C _3-7 cycloalkyl group; n is 2 to 7; X represents an acid residue such as a halogen atom or sulfate; M is lithium, sodium or potassium. 4. The method of claim 3 wherein the halogenating agent is phosphorus oxychloride, phosphorus pentachloride or phosphorus chloride. 4. The process of claim 3 wherein the alkylating agent used to introduce the substituent R is methyl iodide or ethyl iodide. 4. The method according to claim 3, wherein when R is an amino group, the reagent used for introduction of the amino group is O-mesityline hydroxylamine. 4. The method of claim 3 wherein the alkali metal hydrosulfide is sodium hydrosulfide or potassium hydrosulfide.