KR930007816B1 - Process for preparing cephem compound - Google Patents

Abstract

3-Pyridinium methyl-7-thiazolyl acetamido cephalosporin cpds. of formula (I) and their physiologically acceptable acid addition salts are prepd. by reacting 3-substd. methyl cephalosporin cpds. of formula (II) with pyridine bases in the presence of trialkylsilyl trihalomethane sulfonate of formula (III). This process gives (I) in good yield. In formula (I) (syn isomer), R1=H, CH3 or -CRaRbCOOH (Ra,Rb=H,CH3); Q= pyridinium, 2,3-cyclopenteno-1-pyridinium or 2,3-cyclohexeno-1-pyridinium.

Description

New Preparation Method of Cefem Compound

The present invention relates to a new process for the preparation of β-lactam derivatives having the general formula (I) useful as an antimicrobial agent.

Wherein R ¹ is hydrogen, methyl, or (R _a and R _b each represent a hydrogen or methyl group, which may be the same or different), and Q represents a pyridinium group, a 2,3-cyclopenteno-1-pyridinium group or a 2,3-cyclohex. Seno-1-pyridinium group, meaning that the R ¹⁰ group is in the syn position.

The present invention relates to a new and advanced method for preparing cephalosporan acid derivatives, more particularly cephalosporonic acid of general formula (I) having a broad and powerful antimicrobial effect against Gram-positive bacteria and Gram-negative bacteria It relates to a new process for the preparation of derivatives.

Various methods have been published in the literature and patents to prepare a compound of formula (I) by nucleophilic substitution reaction of a pyridine derivative at the R ² position of the compound of formula (II).

In the formula, R ¹ is as described above, and R ² represents an acetoxy group or propionyl oxy group.

Japanese Patent Application Laid-Open No. 57-192, 394 discloses a compound of formula (II) corresponding to Q in a neutral aqueous solution containing iodide or thiocyanate ion when R ² is an acetoxy or carbamoyloxy group. Although a method of preparing a compound of formula (I) by performing a substitution reaction with a base is described, the yield of the compound of formula (I) has a disadvantage of low 38-49%.

U.S. Patent No. 4,336,253 describes a method of silylating a compound of formula (II) wherein R ² is an acetoxy group, converting it to a 3-iodine methyl compound using trimethyliodinesilane (TMSI) and reacting with a pyridine derivative However, the final yield of the compound of the general formula (I) was extremely low as less than 10%.

In Japanese Laid-Open Patent Publication No. 60-34973, a compound of the general formula (I) is prepared by substituting a compound of the general formula (II) with an excess of Q corresponding to Q in the presence of tri C ₁ to C ₄ alkyl iodinesilane. The process is described, but there is a disadvantage that the yield of the final product is relatively low, 15 to 68%.

MEANS TO SOLVE THE PROBLEM The present inventors reacted with the compound of general formula (II), and pyridine derivative corresponding to Q to produce the compound of general formula (I), The trialkyl silyl trihalomethane sulfonate compound represented by following General formula (III) The present invention has been completed by discovering a new fact that the use of the method can solve the disadvantages of the air methods and obtain the desired compound of general formula (I) in high yield.

In the formula, R ³ represents a C _1-4 -straight or branched alkyl group, and X represents a halogen such as fluoro, chloro, bromo, iodine or the like.

Hereinafter, the present invention will be described in detail.

In the present invention, a pyridine derivative corresponding to Q and a compound of formula (II) are substituted with an aprotic solvent in the presence of a compound of formula (III), and the physiologically acceptable compounds thereof A new method for producing acid addition salts and solvates thereof in high yield.

Wherein R ¹ , R ² , R ³ , Q and X are as described above.

Hereinafter, the present invention will be described in more detail.

Compounds of formula (II) used as starting materials in the present invention can be prepared using known methods (Korean Patent Publication Nos. 87-1332 and 87-1333), and trialkyl of formula (III) The silyltrihalo methanesulfonate compound is a compound which has not been used for 3-position substitution in cephalospropine chemistry so far and can be prepared by a known method (Synthesis, 1-26, 1980).

In the present invention, the method for preparing the compound of formula (I) is carried out by suspending the compound of formula (II), the compound of formula (III) and the pyridine derivative corresponding to Q in an appropriate solvent, or A silylating agent such as bistrimethylsilylacetamide (BSA), bistrimethylsilyltrifluoroacetamide (BSTFA), or bistrimethylsilylurea is added to the compound of formula (II) in a suitable solvent, followed by reaction. It can be carried out by adding the compound (III) and the pyridine derivative corresponding to Q.

Methylene chloride, chloroform, 1, 2-dichloroethane, etc. are included as a solvent used for manufacture of a compound of general formula (I), A bimetalene chloride is the most preferable. The reaction is carried out at a temperature of 5 ℃ to 80 ℃, most preferably at 40 ℃ to 45 ℃. It is preferable to use the same amount to 8 times the compound of the general formula (III) and the pyridine derivative corresponding to Q with respect to the compound of the general formula (II) as the starting material, and the silylating agent is preferably the same to 6 times the amount. Do.

The reaction may be overnight but typically completes in 1 to 3 hours.

The compound of general formula (I) can be obtained by distilling and concentrating the reaction solution, crystallizing by adding a solvent in a conventional manner, or by dissolving in water or an aqueous organic solution and purifying by chromatography to freeze-drying.

The acid addition salt of the general formula (I) is an organic solvent mixed with water after adding a dilute acid to an aqueous solution of the compound of the general formula (I) or an aqueous solution of the reaction solution purified by conventional physical and chemical methods, for example, methanol, It can be obtained by adding ethanol, isopropyl alcohol, or acetone or a mixed solvent thereof. The compound of general formula (I) can also be obtained as a solvate with a hydrate or a common solvent such as isopropyl alcohol, tetrahydrofuran, N, N-dimethylacetamide, etc. after completion of the reaction.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited thereto.

Example 1

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyimino-acetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate

Method A

5.4 ml (27.7 mmol) of trimethylsilyltrifluoromethanesulfonate (TMSOT _f ), 3.6 ml (30.7 mmol) of 2,3-cyclopentenopyridine and 7- [2- (2-aminothiazole) in 400 ml of methylene chloride -4-yl) -2-cin-methoxyiminoacetamido] cephalosporanic acid 1.8 g (3.95 mmol) was added. The mixture was heated to reflux for 1.5 hours, the solvent was distilled under reduced pressure, and the residue was dissolved in 20 ml of acetonitrile (1: 4) solution, and then the residue was filtered off. The filtrate was column chromatographed on silica gel using a water-acetonitrile (1: 4) mixed solvent to freeze-dry the product fractions to obtain 1.87 g (92%) of the title compound as a pure white powder.

IR (KBr, cm ^-1 ): 1780 (β-lactam carbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 1.95-2.38 (m, 2H, cyclopentene-2H), 2.80-3.46 (m, 6H, cyclopentene-4H, -SCH _2- ), 3.82 (s, 3H, -OCH ₃ ), 5.00-5.78 (m, 4H, -CH _2- , lactam-2H), 6.74 ((s, 1H, thiazole-H), 7.70-8.70 (m, 3H, Pyridine ring-H).

Method B

1.8 g (3.95 mmol) of 7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] cephalosporanic acid and 4.01 g (19.71 bistrimethylsilylacetamide) Mmol) was suspended in 12 ml of chloroform and stirred at 40 ° C for 1 hour. After the reaction solution was cooled to 10 ° C., 1.76 g (7.91 mmol) of trimethylsilyltrifluoromethanesulfonate was added dropwise, followed by 0.71 g (5.95 mmol) of 2,3-cyclopentenopyridine in 4 ml of chloroform at room temperature. Added dropwise.

The mixture was heated to reflux for 3 hours, cooled, and the solvent was distilled under reduced pressure. 20 ml of acetonitrile (1: 4) mixed solution was added to the residue to dissolve the residue, and then the residue was filtered off. The filtrate was column chromatographed on silica gel using a water-acetonitrile (1: 4) mixed solvent, and the product fraction was freeze-dried to obtain 1.84 g (90.6%) of the target compound as a white powder.

IR and NMR data of the target compound were the same as in Method A.

EXAMPLES 2-8

In the same manner as in Method A of Example 1, the compound of formula (I) was prepared.

Example 9

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3 [(2,3-cyclopentenno-1-pyridinium) methyl] -sef Preparation of Sulfate Monohydrate of 3-M-4-carboxylate

Method A

To 510 ml of methylene chloride, 68.2 ml (0.35 mol) of trimethylsilyltrifluoromethanesulfonate and 41.0 ml (0.35 mol) of 2,3-cyclopentenopyridine were added, followed by 7- [2- (2-aminothiazole-4- I) -2-cin-methoxyiminoacetamido] cephalosporanic acid 22.8 g (0.05 mol) was added.

The mixture was heated to reflux for 2 hours, and then the solvent was distilled off. 150 ml of water was added to the residue to dissolve, and the insoluble substance was filtered off. Triethylamine was added to the filtrate to adjust pH to 7.0, and 380 ml of ethyl acetate was added to separate and remove the organic layer. The water layer was adjusted to pH 4.0 with 1N sulfuric acid, activated carbon was added, stirred for about 30 minutes and filtered. 1N-sulfuric acid was added to the aqueous solution to adjust pH to 1.5, and 1250 ml of isopropyl alcohol was added dropwise at 5 ° C, and stirred for 3 hours at the same temperature. The resulting crystals were filtered and dried to afford 25.5 g (80.9%) of the title compound as pale yellow crystals.

IR (KBr, cm ¹ ): 1785 (β-lactam carbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.17-2.25 (m, 2H, cyclopentene -2H), 3.10-3.44 (m, 6H, cyclopentene-4H, -SCH _2- ), 3.88 (s, 3H, -OCH ₃ ), 5.15-5.86 (m, 4H, -CH ₂ -and lactam-2H), 6.71 ((s, 1H, thiazole-H), 7.89-8.65 (m, 3H, Pyridine ring-H).

Method B

To 81 ml of methylene chloride, 10.92 ml (56 mmol) of trimethylsilyltrifluoromethanesulfonate and 7.02 ml (60 mmol) of 2 and 3-cyclopentenopyridine were added, followed by 7- [2- (2-aminothiazole-4- Il) -2-cin-methoxyiminoacetamido] cephalosporonic acid 3.64 g (8.0 mmol) was added. After the mixture was heated to reflux for 1.5 hours, the reaction solution was cooled to 5 ° C, 16.2 ml of 2N hydrochloric acid was added dropwise, and 7.68 g of kalium iodide was added thereto, and the mixture was stirred and filtered at the same temperature for 2 hours. The crystal obtained by filtration was suspended in 20 ml of cold water, 40 ml of benzene was added, 6.06 ml of Amberlite LA-2 anion exchange resin was added, and it stirred until it became a solution state.

The solution was separated, 2N-sulfuric acid was added to the aqueous layer, adjusted to pH 4.0, 0.4 g of activated carbon was added, stirred for about 30 minutes, and filtered. The filtrate was adjusted to pH 1.5 with 2N-sulfuric acid and then 200 ml of ethanol was added dropwise at 5 ° C.

The solution was stirred at 5 ° C. for 3 hours, filtered and dried to yield 4.18 g (82.8%) of the title compound as a white powder.

IR, ¹ H-NMR data of the target compound were the same as in Method A of Example 9.

Method C

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyimino-acetamido] -3-[(2,3-cyclopenteno-1-prepared in Example 1 5.14 g (0.01 mol) of pyridinium) methyl] sef-3-m-4-carboxylate was dissolved in 200 ml of water, and 10 ml of 2N-sulfuric acid and 20 ml of ethanol were added dropwise at 5 占 폚.

Crystals formed by stirring at the same temperature for 3 hours were filtered and dried to obtain 5.55 g (88%) of the title compound.

IR, ¹ H-NMR data of the target compound were the same as in Method A.

Example 10

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl] sef Preparation of the dihydroiodide salt monohydrate of 3-m-4-carboxylate.

Method A

20 ml of methylene chloride was cooled to 5 ° C. and then 2.7 ml (0.014 mol) of trimethylsilyltrifluoromethanesulfonate was added dropwise. The solution was added dropwise with 1.8 ml (0.015 mol) of 2,3-cyclopentenolipidine while maintaining the temperature at 10-15 ° C., followed by 7- [2- (2-aminothiazol-4-yl) -2- Cin-methoxyiminoacetamido] cephalosporanic acid 0.91 g (0.002 mol) was added at the same temperature. The reaction mixture was heated to reflux for 2 hours, cooled to 5 ° C, and then added dropwise with a solution of 2 g of potassium iodide in 4 ml of 2N hydrochloric acid, followed by stirring for 2 hours.

The resulting crystals were filtered, washed with ice water and dried to obtain 1.54 g (97.6%) of the title compound as white crystals.

IR (KBr, cm ¹ ): 1785 (β-lactam carbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.10-2.40 (m, 2H, cyclopentene -2H), 3.00-3.50 (m, 6H, cyclopentene-4H, -SCH _2- ), 3.90 (s, 3H, -OCH ₃ ), 5.20-5.80 (m, 4H, -CH _2- , lactam-2H), 6.70 (s, 1H, thiazole-H), 7.90-8.60 (m, 3H, pyridine Ring-H).

Method B

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-l-prepared in Example 1 25.7 g (0.05 mol) of pyridinium) methyl] sef-3-m-4-carboxylate was dissolved in 120 ml of water, and 110 ml of 1N-HI and 240 ml of isopropyl alcohol were added dropwise at 5 ° C. The solution was stirred for 1 hour, and the resulting crystals were filtered and dried to give 38.6 g (97.9%) of the title compound as white crystals.

IR, ¹ H-NMR data of the target compound were the same as in Method A of Example 10.

Example 11

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl] sef Preparation of dihydrobromide ㆍ monohydrate of -3-m-4-carboxylate

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyimino-acetamido] -3-[(2,3-cyclopenteno-1-prepared in Example 1 5.14 g (0.05 mol) of pyridinium) methyl] sef-3-m-4-carboxylate was dissolved in 15 ml of water, and 40 ml of 1N-HBr and 120 ml of isopropyl alcohol were added dropwise at 5 ° C. The resulting crystals were stirred at the same temperature for 12 hours, filtered and dried to give 6.1 g (87.8%) of the title compound as white crystals.

IR (KBr, cm ^-1 ): 1785 (β-lactam carbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.36-2.45 (m, 2H, cyclopentene -2H), 3.20-3.55 (m, 6H, cyclopentene-4H and -SCH _2- ), 4.06 (s, 3H, -OCH ₃ ), 5.25-6.10 (m, 4H, -CH _2- , lactam-2H), 6.75 (s, 1H, thiazole-H), 7.90-8.82 (m, 3H, pyridine Ring-H).

Example 12

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl] sef Preparation of dihydrobromide ㆍ monohydrate of -3-m-4-carboxylate

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyimino-acetamido] -3-[(2,3-cyclopenteno-1-prepared in Example 1 10.28 g (0.02 mol) of pyridinium) methyl] sef-3-m-4-carboxylate was dissolved in 20 ml of water, and 10 ml of 4N hydrochloric acid and 160 ml of ethanol were added dropwise at 5 ° C. The solution was stirred for 10 hours, and the resulting crystals were filtered and dried to yield 9.7 g (80%) of the title compound as white crystals.

IR (KBr, cm ¹ ): 1785 (β-lactam carbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.37-2.47 (m, 2H, cyclopentene -2H), 3.20-3.60 (m, 6H, cyclopentene-4H and -SCH _2- ), 4.08 (s, 3H, -OCH ₃ ), 5.20-6.00 (m, 4H, -CH _2- , lactam-2H), 6.80 (s, 1H, thiazole-H), 7.89-8.70 (m, 3H, pyridine Ring-H).

Example 13

7- [2- (2-aminothiazol-4-yl) -2-cin- (2-carboxyprop-2-oxyimino) acetamido] -3- (1-pyridinium) methyl] sef- Preparation of Pentahydrate of 3-M-4-carboxylate

400 ml of methylene chloride, 4.64 (24 mmol) trimethylsilyltrifluoromethanesulfonate, 2.2 ml (27.3 mmol) of pyridine and 7- [2- (2-aminothiazol-4-yl) -2-cin- (2 -Carboxyprop-2-oxyimino) acetamido] selphalosporanic acid 2.1g (4 mmol) was added. The mixture was heated to reflux for 3 hours, the solvent was distilled off, 15 ml of water was added to the residue, dissolved, and the insoluble substance was filtered off.

30 ml of acetone was added to the filtrate, and a small amount of sodium chloride was added to dissolve it. 3 ml of concentrated hydrochloric acid was added to this mixed solution at 5 ° C, and stirred for 3 hours to filter the resulting crystals. The filtered crystals were added to 6 ml of water, dissolved, and then adjusted to pH 3.9 by addition of 4N-NaOH solution, followed by standing at 0 ° C. for 15 hours.

The resulting crystals were filtered, washed sequentially with ice water and acetone, and dried to obtain 1.8 g of the target compound.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 1.43 (s, 6H, CH ₃ -C-CH ₃ ), 3.23 and 3.52 (dd, 2H, -SCH _2- ), 5.22-5.83 ( m, 4H, -CH ₂ -and lactam-2H), 6.84 (s, 1H, thiazole-H), 8.00-8.98 (m, 5H, pyridine ring-H)

Example 14

7- [2- (2-aminothiazol-4-yl) -2-cin- (2-carboxy-prop-2-oxyimino) acetamido] -3- (1-pyridinium) methyl] sef Preparation of Pentahydrate of 3-M-4-carboxylate

40 ml of methylene chloride, 4.64 ml (24 mmol) trimethylsilyltrifluoromethanesulfonate, 2.2 ml (27.3 mmol) pyridine and 7- [2- (2-aminothiazol-4-yl) -2-cin- ( 2-t-butoxycarbonylprop-2-oxyimino) acetamido)] cellpalosporic acid was used in the same manner as in Example 13 except that 2.05 g of the target compound was obtained as white crystals.

¹ H-NMR data of the target compound were the same as in Example 13.

Example 15

7- [2- (2-aminothiazol-4-yl) -2-cin- (2-carboxyprop-2-oxyimino) acetamido] -3- (1-pyridinium) methyl] sef- Preparation of Pentahydrate of 3-M-4-carboxylate

1.16 ml (6 mmol) of trimethylsilyltrifluoromethanesulfonate, 0.57 ml (7 mmol) of pyridine and 7- [2- (2-aminothiazol-4-yl) -2-cin- (in 10 ml of methylene chloride 0.5 g (0.85 mmol) of 2-t-butoxycarbonylprop-2-oxyimino) acetamido)] selphalosporanic acid was added. The mixture was heated to reflux for 3 hours, then the solvent was distilled off, and 10 ml of acetonitrile (1: 4, v / v) solution was added to the residue, and the residue was filtered off.

The filtrate was column chromatographed on silica gel using a water-acetonitrile (1: 4, v / v) mixed solvent to obtain product fractions and then freeze-dried. To the obtained powder, 4.6 ml of 98% formic acid and 0.4 ml of concentrated ginseng were added, followed by stirring at room temperature for 1 hour. 20 ml of ether and 15 ml of isopropyl alcohol were added thereto, and the resultant crystals were filtered by stirring at room temperature for 2 hours.

The filtered crystals were dissolved in 2 ml of distilled water, and 6N-NaOH solution was added thereto to adjust the pH to 3.8 and then left at 5 ° C. for 12 hours. The resulting crystals were filtered, washed sequentially with ice water and acetone and dried to obtain 0.38 g of the target compound.

¹ H-NMR data of the target compound were the same as in Example 13.

Claims (2)

A cephalosporin compound of formula (I), characterized by reacting a pyridine derivative corresponding to Q with a compound of formula (II) in the presence of a compound of formula (III) Acceptable methods of preparing acid addition salts and solvates. Wherein R ¹ is hydrogen, methyl or Groups (R _a and R _b each represent a hydrogen or methyl group and may be the same or different). R ² is an acetoxy group or propionyloxy group, R ³ is a C _1-4 straight or branched alkyl group, X is a halogen Q such as fluoro, chloro, bromo and iodine is a 1-pyridinium group, 2, 3 -Cyclopenteno-1-pyridinium group or 2, 3-cyclohexeno-1-pyridinium group, and R ¹⁰ group is geometrically in the syn position. The process according to claim 1, wherein the compound of general formula (III) is trimethylsilyltrifluoromethanesulfonate.