KR20030015551A - THIOL DERIVATIVES AND 1-β-METHYL-CARBAPENEM DERIVATIVES WITH THE SAME - Google Patents

Abstract

PURPOSE: Provided are antibiotic 1-β-methyl-carbapenem derivatives of the formula(2) substituted with novel bicyclic thiol derivatives represented by the formula(1) which have stability against DHP-1 enzyme and are effective against resistant bacteria. CONSTITUTION: The method for preparing thiols and carbapenem derivatives comprises the steps of: carrying on the reaction scheme(1) to make thiols and combining them with carbapenem derivatives to make the final product of the formula(2). In the formula(1) and the formula(2), R1 is methyl or ethyl group and R2 is C1-6 alkyl such as methyl, ethyl, propyl, C1-6 cycloalkyl or alkyl substituted with phenyl, vinyl and hydroxyl group.

Description

THIOL DERIVATIVES AND 1-β-METHYL-CARBAPENEM DERIVATIVES WITH THE SAME}

The present invention relates to novel bicyclic thiol derivatives and 1-beta-methyl-carbapenem derivatives having them as substituents.

Carbapenem derivatives prepared according to the present invention are useful as antibiotics. Carbapenem derivative antibiotics were the first in the 1970s when Merck researchers isolated thinamycine from Streptomyces. This tyenamycin has a disadvantage in that its activity is easily degraded by dehydropeptidase-I (so-called DHP-I), which is produced in the kidney in the human body. In fact, Imipenem, developed by Merck, which is used as an antibiotic, was used in combination with Cilastatin, a DHP-I enzyme inhibitor, due to its chemically unstable structure. Because of these problems, carbapenem research was not active.

With new discoveries at Merck in the mid-1980s, Kabapenem's research began to come to life again. This was shown to be chemically stable by substituting a beta-type methyl group at the C-1 position of the carbapenem nucleus. Knowing this fact, many carbapenems having excellent efficacy have been synthesized.

As a condition of good antibiotics, it must first have strong activity, broad antimicrobial range, and strong selectivity against MRSA and Pseudomonas among pathogenic microorganisms. Therefore, developing an antibiotic that satisfies these conditions is currently the most urgent task. In this context, it is thought that carbapenem has an advantage over any antibiotic. In particular, it exhibits a wide range of potent medicinal effects on both Gram-positive bacteria and negative bacteria, and shows excellent effects on various resistant strains. The pharmacological outlook is that the growth of carbapenem antibiotics is most prominent since the 1990s. Panipenem, baiapenem, meropenem, and the like have been developed, but meropenem is currently on the market for various reasons. However, these outstanding antibiotics have encountered a problem these days that they are very weak against bacterial resistant bacteria.

In order to solve this problem, the present invention provides a thiol derivative having a novel double ring and a 1-beta-methyl-carbapenem derivative having a substituent to provide a carbapenem derivative stable and resistant to DHP-I. To provide.

The present invention relates to thiol derivatives having a novel double ring and carbapenem derivatives having them as substituents.

The present invention relates to a thiol derivative having the following formula (1).

Wherein R ¹ is a methyl group or an ethyl group and R ² is an alkyl substituted with C _1-6 cycloalkyl or phenyl, vinyl, hydroxyl groups, such as C _1-6 alkyl, cycloalkyl, such as methyl, ethyl, propyl. The thiol derivative according to the present invention has a double ring containing nitrogen at the C-2 position.

The 1-beta-methyl-carbapenem derivative substituted with the thiol derivative according to the present invention has the following formula (2).

Wherein R ¹ is a methyl group or an ethyl group and R ² is an alkyl substituted with C _1-6 cycloalkyl or phenyl, vinyl, hydroxyl groups, such as C _1-6 alkyl, cyclopropyl, such as methyl, ethyl, propyl.

New bicyclic thiol derivatives having formula (1) according to the present invention are prepared by the following reaction process and are shown in Scheme 1.

(a) protecting the amine of proline with nitrobenzylchloroformate using trans-hydroxy-L-proline (3) as starting material and then esterifying with methanol under acid catalyst to give compound (4),

(b) reacting compound (4) with mesyl chloride under trimethylamine base to give compound (5), and then reacting with ammonia in methanol solvent to synthesize compound (6) in which a methyl ester is substituted with an amide group,

(c) Compound (6) was deprotected to amine using hydrogen and a palladium catalyst, and then refluxed with dialkyl ketone (ketone having R ¹ and R ² ) to synthesize Compound (7), which is a bicyclic compound,

(d) reacting compound (7) with potassium thioacetate under solvent DMF to obtain compound (8), and then hydrolyzing it with 4N-sodium hydroxyside to give a double compound represented by the formula (1) containing nitrogen as the desired compound. A cyclic thiol compound (1) can be obtained.

3 4 5

6 7 8

One

R ¹ : a, b, c, d, e, f, g = methyl, h = ethyl

R ² : a = methyl, b = ethyl, c = propyl, d = cyclopropyl, e = allyl, f = phenyl,

g = hydroxymethyl, h = ethyl

The preparation method of 1-beta-methyl-carbapenem derivative of Formula 2 according to the present invention is as follows.

(e) Compound (9) as a starting material is reacted with diphenylchlorophosphate in the presence of a base to synthesize Compound (10), and the compound (10) is reacted with a thiol derivative of formula (1) in the presence of a base to be protected. Synthesized carbapenem compound (11),

9 10 11

(Wherein P is a para-nitrobenzyl or allyl group as protecting group)

(f) Compound (11) is deprotected with hydrogen and a palladium catalyst to give Compound (2) represented by the formula (2).

11 2

The process of step e may be prepared under the reaction conditions in preparing a carbapenem derivative in a general method, and it is preferable to use diisopropylethylamine as a base at a reaction temperature of 0-5 ° C.

In order to compare the stability of the carbapenem derivatives according to the present invention with DHP-1 of conventional imipenems and meropenems, the carbapenem derivatives DHG-5 represented by imipenem, meropenem and formula (12) according to the present invention (R1) : The stability of DHP-1 of methyl, R2: propyl) was measured by using a spectrophotometer as a change in the OD value with time, and the results of the hydrolysis half-life are shown in Table 1. 2 is shown.

OD value over time of the sample Drug name Control OD Sample OD 0 hr 0.5 hr 1 hr 2 hr 4 hr Imipenem 1.68 1.70 1.05 0.75 0.51 0.47 Meropenem 1.40 1.42 1.39 1.31 1.24 1.11 DHG-5 0.97 1.04 0.99 0.96 0.94 0.89

(Temperature: 30 ° C., substrate: 50 μg / ml, MOPS buffer: 50 mM (pH 7.0))

Hydrolysis of the sample Drug name Hydrolysis half-life (t ^½ (hr)) Hydrolysis relative half-life (t ^½ hr) Imipenem 1.79 0.19 Meropenem 9.69 1.00 DHG-5 14.75 1.52

(Temperature: 30 ° C., substrate: 50 μg / ml, MOPS buffer: 50 mM (pH 7.0),

Relative half-life represents the sample half-life as a relative value of meropenem half-life with the value of meropenem as 1.00.)

As can be seen from Table 1 and Table 2, it showed excellent stability compared to conventional imipenem and meropenem, therefore, the carbapenem derivatives according to the present invention provide antibiotics that do not require the use of a DHP-1 enzyme inhibitor in combination. can do.

In the following, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

Example 1

Synthesis of (2S, 4R) -4hydroxy-1- (para-nitrobenzyloxycarbonyl) pyrrolidine-2-carboxylic acid methyl ester (4)

Para-nitrobenzyl chloroformate (34.2 g) dissolved in trans-4-hydroxy-L-proline (3) (16.0 g, 0.12 mol) in 2N sodium hydroxide solution (153 ml) and dissolved in anhydrous methylene chloride (70 ml). , 0.16 mol) was slowly added dropwise at 0 ° C. After stirring for 2 hours in this state, methylene chloride (50 ml) and 2N sodium hydroxide solution (50 ml) were added thereto, and the organic layer was separated. The aqueous layer was transferred to a 1 L beaker and then crystallized by treatment with concentrated sulfuric acid. It was filtered and dried to obtain an off-white solid.

The compound was dissolved in methanol (30 ml), 2 ml of concentrated sulfuric acid was added, the mixture was stirred under reflux for 3 hours, methanol was distilled under reduced pressure, ethyl acetate was added, neutralized with 10% sodium bicarbonate, extraction, and yellow oily 34.0 g (95%). )

¹ H-NMR (DMSO- _d6 ): δ 2.12 (1H, m, C ₃ -Ha), 2.35 (1H, m, C ₃ -Hb), 2.62 (1H, s, OH), 3.57 (2H, m , C ₅ -Ha), 3.57 and 3.60 (3H, 2s, OCH ₃ ), 4.45 (2H, m, C ₂ -Hb, C ₄ -H), 5.25 and 5.13, 5.34 (2H, s and dd, OCH ₂ ), 8.21, 7.60 and 8.18, 7.56 (4H, 2dd, phenyl)

Example 2

Synthesis of (2S, 4R) -4-mesyloxy-1- (para-nitrobenzyloxycarbonyl) pyrrolidine-2-carboxylic acid methyl ester (5)

Compound (4) (31.7 g, 0.098 mol) was dissolved in anhydrous methylene chloride (100 ml) and stirred for 3 minutes at 0 ° C. triethylamine (14.8 ml, 0.15 mol). Methanesulfonylchloride (14.6 g, 20.5 ml, 0.146 mol) was added dropwise through a dropping funnel and stirred for 1 hour. Cold water (100 ml) was added to the reaction mixture, and the organic solvent layer and the aqueous layer were separated. The organic solvent layer was washed with 1N hydrochloric acid and water, and then distilled off under reduced pressure to obtain a light white solid 37.0 g (97%).

mp: 78.0-80.0 ℃

¹ H-NMR (CDCl ₃ ): δ2.33 (1H, m, C ₃ -Ha), 2.70 (1H, m, C ₃ -Hb), 3.06 (1H, s, SO ₂ CH ₃ ), 3.67 and 3.78 (3H, 2s, OCH ₃ ), 3.86 (2H, m, C ₅ -H), 4.01 (1H, m, C ₄ -H), 4.55 (1H, m, C ₂ -H), 5.25 and 5.13, 5.34 (2H, s and dd, OCH ₂ ), 7.49 and 8.23 (4H, 2dd, phenyl)

Example 3

Compound of (2S, 4R) -2-carbamoyl-4-mesyloxy-1- (para-nitrobenzyloxycarbonyl) pyrrolidine (6)

Ammonia water (28%, 30ml) and methanol (5ml) were added to compound (5) (10.8g, 0.0026mol), and the mixture was stirred at room temperature for 10 hours. The product was filtered dried to give 5.5 g (55%) of an off-white solid.

mp: 142-144 ℃

¹ H-NMR (DMSO- _d6 ): δ2.33 (1H, m, C ₃ -Ha), 2.70 (1H, m, C ₃ -Hb), 3.09 (1H, s, SO ₂ CH ₃ ), 3.86 ( 2H, m, C ₅ -Ha), 4.01 (1H, m, C ₄ -H), 4.55 (1H, m, C ₂ -H), 5.05 and 5.32 (2H, s and dd, OCH ₂ ), 6.90 and 7.40 (2H, ss, NH ₂ ), 7.49, and 8.23 (4H, 2dd, phenyl)

Example 4

Synthesis of (5S, 7R) -2,2-dimethyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7a)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated, acetone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 2 hours. The reaction was concentrated and separated by silica gel column to yield 1.09 g (85%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 1.45 (3H, s), 1.50 (3H, s), 2.30 (1H, m), 2.56 (1H, m), 3.10 (3H, s), 3.88 (2H, m), 4.10 (1H, m), 6.39 (1H, s)

Example 5

Synthesis of (5S, 7R) -2-ethyl-2-methyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7b)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated, 2-butanone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 5 hours. The reaction was concentrated and separated by silica gel column to give 1.06 g (78%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 1.35 (3H, s), 1.78 (2H, q), 2.00 (1H, m), 2.56 (2H, m), 3.10 (3H, s, SO ₂ CH ₃ ), 3.28 (1H, m), 4.10 (2H, m), 7.39 (1H, s)

Example 6

Synthesis of (5S, 7R) -2-methyl-2-propyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7c)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated, 2-pentanone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 5 hours. The reaction was concentrated and separated by silica gel column to give 1.08 g (76%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 1.35 (3H, s), 1.58 (2H, q), 1.68 (2H, q), 2.00 (1H, m), 2.56 (2H, m), 3.02 (3H, s), 3.28 (1H, m), 3.90 (2H, m), 7.79 (1H, s)

Example 7

Synthesis of (5S, 7R) -2-cyclopropyl-2-methyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7d)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated, cyclopropyl methyl ketone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 36 hours. The reaction was concentrated and separated by silica gel column to give 0.99 g (70%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 0.21-.82 (4H, bs), 1.25 (1H, bs), 1.45 (3H, s), 2.56 (2H, m), 3.10 (3H, s), 3.28 (1H, m), 4.10 (1H, m), 5.12 (1H, m), 7.67 (1H, s)

Example 8

Synthesis of (5S, 7R) -2-methyl-2-vinyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7e)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated and methylvinyl ketone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 1 hour. The reaction was concentrated and separated by silica gel column to give 1.22 g (90%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 2.05 (3H, s), 2.58 (2H, m), 2.68 (2H, m), 3.01 (3H, s), 3.05 (1H, m), 3.56 (1H, t), 3.62 (1H, dd), 5.01 (1H, bs), 5.50 (1H, bs), 7.79 (1H, s)

Example 9

Synthesis of (5S, 7R) -2-methyl-2-phenyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7f)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated, acetophenone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 48 hours. The reaction was concentrated and separated by silica gel column to give 1.08 g (68%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 1.45 (3H, s), 2.30 (1H, m), 2.56 (2H, m), 3.10 (3H, s), 3.88 (2H, m), 4.10 (1H, m), 6.39 (1H, s, NH), 7.2-7.5 (5H, m)

Example 10

Synthesis of (5S, 7R) -2-hydroxymethyl-2-methyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7 g)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 2 hours. The intermediate product was concentrated, 2-pentanone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 5 hours. The reaction was concentrated and separated by silica gel column to give 1.23 g (86%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 1.35 (3H, s), 2.56 (1H, m), 3.10 (3H, s), 3.36 (2H, s), 3.38 (2H, m), 4.10 (1H, m), 6.78 (1 H, s)

Example 11

Synthesis of (5S, 7R) -2,2-diethyl-7-mesyloxy-4-oxo-1,3-diazabicyclo [3.3.0] octane (7h)

Compound (6) (2.0 g, 5.17 mmol) was suspended in methanol (40 ml) and tetrahydrofuran (40 ml), followed by palladium complex call (10%, 1 g), followed by hydrogenation at 50 psi for 1 hour. The intermediate product was concentrated, 3-pentanone (20 ml) and anhydrous sodium sulfate (2 g) were added thereto, and the mixture was stirred under reflux for 6 hours. The reaction was concentrated and separated by silica gel column to give 1.17 g (86%) of the title compound.

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 0.97 (3H, t), 1.78 (4H, q), 2.20 (1H, m), 2.36 (1H, m), 3.01 (3H, s), 3.08 (1H, m), 3.18 (1H, m), 4.20 (1H, bs), 5.50 (1H, bs), 7.29 (1H, s)

Example 12

Synthesis of (5S, 7R) -2,2-dimethyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8a)

Compound 7a (1 g, 4.4 mmol) was dissolved in dimethylformamide (20 ml) and toluene (20 ml), and potassium thioacetate (2 g, 4 eq) was added thereto, followed by stirring at 70 ° C. for 3 hours. The product was extracted with ethyl acetate and purified by column chromatography to obtain 0.85 g (85%) of a yellow oil.

¹ H-NMR (CDCl ₃ ): δ 1.45 (3H, s), 1.50 (3H, s), 2.15 (1H, m), 2.30 (3H, s), 2.56 (1H, m), 2.30 (3H, s), 3.88 (2H, m), 4.10 (1H, m), 6.39 (1H, s)

Example 13

Synthesis of (5S, 7R) -2-ethyl-2-methyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8b)

Using the compound (7b), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 75%)

¹ H-NMR (CDCl ₃ ): δ 0,91 (3H, t), 1.35 (3H, s), 1.78 (2H, q), 2.00 (1H, m), 2.30 (3H, s), 2.56 (2H, m), 3.28 (1H, m), 4.10 (2H, m), 7.39 (1H, s)

Example 14

Synthesis of (5S, 7R) -2-methyl-2-propyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8c)

Using the compound (7c), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 75%)

¹ H-NMR (CDCl ₃ ): δ 0,91 (3H, t), 1.35 (3H, s), 1.58 (2H, q), 1.68 (2H, q), 2.00 (1H, m), 2.30 (3H, s), 2.56 (2H, m), 3.28 (1H, m), 3.90 (2H, m), 7.79 (1H, s)

Example 15

Synthesis of (5S, 7R) -2-cyclopropyl-2-methyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8d)

Using the compound (7d), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 75%)

¹ H-NMR (CDCl ₃ ): δ 0.21-.82 (4H, bs), 1.25 (1H, bs), 1.45 (3H, s), 2.30 (3H, s), 2.56 (2H, m), 3.28 (1H, m), 4.10 (1H, m), 5.12 (1H, m), 6.67 (1H, s)

Example 16

Synthesis of (5S, 7R) -2-methyl-2-vinyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8e)

Using the compound (7e), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 62%)

¹ H-NMR (CDCl ₃ ): δ 2.05 (3H, s), 2.58 (3H, m), 2.68 (2H, m), 3.01 (3H, s), 3.05 (1H, m), 3.56 (1H, t), 3.62 (1H, dd), 5.01 (1H, bs), 5.50 (1H, bs), 7.79 (1H, s)

Example 17

Synthesis of (5S, 7R) -2-methyl-2-phenyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8f)

Using the compound (7f), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 79%)

¹ H-NMR (CDCl ₃ ): δ 1.45 (3H, s), 2.13 (1H, m), 2.30 (3H, s), 2.56 (2H, m), 3.38 (2H, m), 4.10 (1H, m), 6.39 (1H, s, NH), 7.2-7.5 (5H, m)

Example 18

Synthesis of (5S, 7R) -2-hydroxymethyl-2-methyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8 g)

Using a compound (7 g), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 81%)

¹ H-NMR (CDCl ₃ ): δ 1.35 (3H, s), 2.14 (1H, m), 2.30 (3H, s), 2.56 (1H, m), 3.36 (2H, s), 3.88 (2H, m), 4.10 (1H, m), 6.78 (1H, s)

Example 19

Synthesis of (5S, 7R) -2,2-diethyl-7-acetylthio-4-oxo-1,3-diazabicyclo [3.3.0] octane (8h)

Using a compound (7h), a yellow oily optical mixture was obtained in the same manner as in Example 12. (Yield 81%)

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 0.97 (3H, t), 1.78 (4H, q), 2.20 (1H, m), 2.30 (3H, s), 2.36 (1H, m), 3.08 (1H, m), 3.18 (1H, m), 4.20 (1H, bs), 5.50 (1H, bs), 7.29 (1H, s)

Example 20

(5S, 7R) -2,2-dimethyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane

Synthesis of (1a)

Compound 8a (0.8 g, 3.5 mmol) was dissolved in 20 ml of methanol, and 4N sodium hydroxide (0.9 ml) was added at 0 ° C. and stirred for 20 minutes. Neutralized with 4N hydrochloric acid, dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain an off-white liquid 0,60g (95%).

¹ H-NMR (CDCl ₃ ): δ 1.45 (3H, s), 1.50 (3H, s), 2.15 (1H, m), 2.56 (1H, m), 2.30 (3H, s), 3.88 (2H, m), 4.10 (1H, m), 6.39 (1H, s)

Example 21

(5S, 7R) -2-ethyl-2-methyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane

Synthesis of (1b)

Using the compound (8b), the yellow oil phase was obtained in the same manner as in Example 20. (Yield 91%)

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 1.35 (3H, s), 1.78 (2H, q), 2.00 (1H, m), 2.56 (2H, m), 3.28 (1H, m), 4.10 (2H, m), 7.39 (1H, s)

Example 22

Synthesis of (5S, 7R) -2-methyl-2-propyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane (1c)

Using the compound (8c), the yellow oil phase was obtained in the same manner as in Example 20. (Yield 89%)

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 1.35 (3H, s), 1.58 (2H, q), 1.68 (2H, q) 2.00 (1H, m), 2.56 (2H, m ), 3.28 (1H, m), 3.90 (2H, m), 7.79 (1H, s)

Example 23

Synthesis of (5S, 7R) -2-cyclopropyl-2-methyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane (1d)

Using the compound (8d), the yellow oil phase was obtained in the same manner as in Example 20. (Yield 92%)

¹ H-NMR (CDCl ₃ ): δ 0.21-.82 (4H, bs), 1.25 (1H, bs), 1.45 (3H, s), 2.56 (2H, m), 3.28 (1H, m), 4.10 (1H, m), 5.12 (1H, m), 6.67 (1H, s)

Example 24

Synthesis of (5S, 7R) -2-methyl-2-vinyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane (1e)

Using the compound (8e), the yellow oil phase was obtained in the same manner as in Example 20. (Yield 88%)

¹ H-NMR (CDCl ₃ ): δ 2.05 (3H, s), 2.58 (3H, m), 2.68 (2H, m), 3.05 (1H, m), 3.56 (1H, t), 3.62 (1H, dd), 5.01 (1H, bs), 5.50 (1H, bs), 7.79 (1H, s)

Example 25

Synthesis of (5S, 7R) -2-methyl-2-phenyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane (1f)

Using the compound (8f), the yellow oil phase was obtained in the same manner as in Example 20. (Yield 88%)

¹ H-NMR (CDCl ₃ ): δ 1.45 (3H, s), 2.13 (1H, m), 2.56 (2H, m), 3.38 (2H, m), 4.10 (1H, m), 6.39 (1H, s, NH), 7.2-7.5 (5H, m)

Example 26

Synthesis of (5S, 7R) -2-hydroxymethyl-2-methyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane (1 g)

Using a compound (8 g), a yellow oil phase was obtained in the same manner as in Example 20. (Yield 86%)

¹ H-NMR (CDCl ₃ ): δ 1.35 (3H, s), 2.14 (1H, m), 2.56 (1H, m), 3.36 (2H, s), 3.88 (2H, m), 4.10 (1H, m), 6.78 (1 H, s)

Example 27

(5S, 7R) -2,2-diethyl-7-mercapto-4-oxo-1,3-diazabicyclo [3.3.0] octane

Synthesis of (1h)

Using the compound (8h), a yellow oil phase was obtained in the same manner as in Example 20. (Yield 91%)

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 0.97 (3H, t), 1.78 (4H, q), 2.20 (1H, m), 2.36 (1H, m), 3.08 (1H, m), 3.18 (1H, m), 4.20 (1H, bs), 5.50 (1H, bs), 7.29 (1H, s)

Example 28

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2,2-dimethyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7- Synthesis of Ilthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11a)

Diazo beta keto ester (9) (2.5 g, 5 mmol) was dissolved in a solution of ethyl acetate: nucleic acid = 3: 1 (20 ml), and rhodium acetate (15 mg) was added thereto, followed by stirring at reflux for 15 minutes. After the reaction was completed, concentrated, acetonitrile anhydrous acetonitrile (25 ml) was added to the foamed 1-methylbicyclo ketoester, and cooled to 0 ° C. under nitrogen stream, followed by N, N′-diisopropylethylamine (2.16). ml, 8 mmol) and diphenylchlorophosphate (1.6 g, 1.2 ml, 6 mmol) were added slowly. After an hour, N, N'-diisopropylethylamine (1 ml) was slowly added, and compound (IIa) (1 g, 4.7 mmol) was diluted with anhydrous acetonitrile (5 ml) and slowly added. After stirring for 5 hours, the mixture was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 1.2 g (46%) of a yellow solid.

¹ H-NMR (CDCl ₃ ): δ1.32 (3H, s, CH ₃ ), 1.43 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β − Methyl), 2.05 (1H, m), 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H ), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 29

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2-ethyl-2-methyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7 Synthesis of -ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11b)

A yellow solid was obtained in the same manner as Example 28 with compound (1b). (Yield 54%)

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 1.35 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β -methyl), 1.78 (2H, q), 2.05 (1H, m), 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 30

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2-methyl-2-propyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7 Synthesis of -ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11c)

A yellow solid was obtained in the same manner as Example 28 with compound (1c). (Yield 59%)

¹ H-NMR (CDCl ₃ ): δ 1.15 (3H, t, CH ₂ CH ₃ ), 1.32 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β -methyl), 1.78 (2H, q), 2.05 (1H, m), 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 31

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2-cyclopropyl-2-methyl-4-oxo-1,3-diazabicyclo [3.3.0] octane Synthesis of -7-ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11d)

A yellow solid was obtained in the same manner as Example 28 with compound (1d). (Yield 49%)

¹ H-NMR (CDCl ₃ ): δ 0.21-.82 (4H, bs), 1.32 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β − Methyl), 2.05 (1H, m), 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H ), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 32

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2-methyl-2-vinyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7 Synthesis of -ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11e)

A yellow solid was obtained in the same manner as Example 28 with compound (1e). (Yield 67%)

¹ H-NMR (CDCl ₃ ): δ1.32 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β -methyl), 2.05 (1H, m) , 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 6.35 (1H, m), 7.25 (1H, bs), 7.80 and 8.20 (4H, dd, phenyl)

Example 33

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2-methyl-2-phenyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7 Synthesis of -ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11f)

A yellow solid was obtained in the same manner as Example 28 with compound (1f). (Yield 51%)

¹ H-NMR (CDCl ₃ ): δ1.32 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β -methyl), 2.05 (1H, m) , 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.2-7.5 (5H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 34

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2-hydroxymethyl-2-methyl-4-oxo-1,3-diazabicyclo [3.3.0] octane Synthesis of -7-ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11 g)

A yellow solid was obtained in the same manner as Example 28 with compound (1 g). (Yield 54%)

¹ H-NMR (CDCl ₃ ): δ1.32 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d, β -methyl), 2.05 (1H, m) , 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, bs), 3.8 (2H, m, C ₅ -H), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 35

Para-nitrobenzyl (1R, 5S, 6S, 5'S, 7S ')-2- {2,2-diethyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7- Synthesis of ylthio} -6- (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylate (11h)

A yellow solid was obtained in the same manner as Example 28 with compound (1h). (Yield 59%)

¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 0.97 (3H, t) 1.32 (3H, s, CH ₃ ), 1.37 (3H, d, CH ₃ CHCOH), 1.41 (3H, d , β -methyl), 1.76 (14H, q), 2.05 (1H, m), 2.2 (1H, s, OH), 2.56 (1H, m), 3.05 (1H, m), 3.35 (2H, m), 3.8 (2H, m, C ₅ -H), 4.1 (1H, m, C ₂ -H), 4.25 (1H, m), 7.80 and 8.20 (4H, dd, phenyl)

Example 36

(1R, 5S, 6S, 5'S, 7S ')-2- {2,2-dimethyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7-ylthio}- Synthesis of 6 (1-hydroxyethyl) -1-methylcarbaphen-2-m-3-carboxylic acid (2a)

Compound (11a) (0.1 g, 0.17 mmol) was dissolved in tetrahydrofuran (10 ml) and saturated sodium phosphate solution (10 ml), and then paradium (10%, 0.1 g) was added and hydrogenated for 30 minutes at 50 psi hydrogen pressure. . After completion of the reaction, the catalyst was filtered, the filtrate was concentrated under reduced pressure, ethyl acetate was added to the semi-lyed product, washed, and the aqueous solution layer was treated with polymer chromatography (Dionion HP-20resin), and the fraction containing the desired product was lyophilized. To 20 mg (26%) of a yellow powder.

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.25 (s, 3H), 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 (d, 3H , CH3 CHOH, J = 6.2Hz), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ ₃ -Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 (t, 1 H)

Example 37

(1R, 5S, 6S, 5'S, 7S ')-2- {2-ethyl-2-methyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7-ylthio } -6 Synthesis of (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylic acid (2b)

A white white solid was obtained in the same manner as Example 36 with compound (11b). (Yield 34%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.99 (3H, t), 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 (d, 3H , CH3 CHOH, J = 6.2Hz), 1.66 (2H, q), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ ₃ -Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 (t, 1H)

Example 38

(1R, 5S, 6S, 5'S, 7S ')-2- {2-methyl-2-propyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7-ylthio } -6 Synthesis of (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylic acid (2c)

A white white solid was obtained in the same manner as Example 36 with compound (11c). (Yield 39%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.99 (3H, t), 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 (d, 3H , CH3 CHOH, J = 6.2Hz), 1.56 (2H, q), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ ₃ -Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 (t, 1H)

Example 39

(1R, 5S, 6S, 5'S, 7S ')-2- {2-cyclopropyl-2-methyl-4-oxo-1,3-diazabicyclo [3.3.0] octan-7-yl Synthesis of thio} -6 (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylic acid (2d)

A white white solid was obtained in the same manner as Example 36 with compound (11d). (Yield 34%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.21-.82 (4H, bs), 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 ( d, 3H, CH3 CHOH, J = 6.2 Hz), 1.98 (1H, m), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ ₃ -Hb), 2.80 (s, 3H ), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 (t, 1H)

Example 40

(1R, 5S, 6S, 5'S, 7S ')-2- {2-methyl-2-vinyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7-ylthio } -6 Synthesis of (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylic acid (2e)

A white white solid was obtained in the same manner as Example 36 with compound (11e). (Yield 29%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 (d, 3H, CH3 CHOH, J = 6.2 Hz), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ _3- Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 ( t, 1H), 5.67 (m, 1H), 7.01 (m, 1H)

Example 41

(1R, 5S, 6S, 5'S, 7S ')-2- {2-methyl-2-phenyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7-ylthio } -6 Synthesis of (1-hydroxyethyl) -1-methylcarbafen-2-m-3-carboxylic acid (2f)

A white white solid was obtained in the same manner as Example 36 with compound (11f). (Yield 36%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 (d, 3H, CH3 CHOH, J = 6.2 Hz), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ _3- Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 ( t, 1H), 7.2-7.5 (5H, m)

Example 42

(1R, 5S, 6S, 5'S, 7S ')-2- {2-hydroxymethyl-2-methyl-4-oxo-1,3-diazabicyclo [3.3.0] octan-7-yl Synthesis of thio} -6 (1-hydroxyethyl) -1-methylcarbaphen-2-m-3-carboxylic acid (2 g)

A white white solid was obtained in the same manner as Example 36 with compound (11 g). (Yield 31%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz), 1.45 (d, 3H, CH3 CHOH, J = 6.2 Hz), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ _3- Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.43 (s, 2H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H), 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 (t, 1 H)

Example 43

(1R, 5S, 6S, 5'S, 7S ')-2- {2,2-diethyl-4-oxo-1,3-diazabicyclo [3.3.0] octane-7-ylthio} Synthesis of -6 (1-hydroxyethyl) -1-methylcarbaphen-2-m-3-carboxylic acid (2h)

A white white solid was obtained in the same manner as Example 36 with compound (11h). (Yield 30%)

λmax: 298nm

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.91 (3H, t), 0.97 (3H, t), 1.32 (s, 3H), 1.35 (d, 3H, 1-CH _3, J = 7.2 Hz ), 1.45 (d, 3H, CH 3 CHOH, J = 6.2 Hz), 1.78 (4H, q), 2.04 (m, 1H, C ₃ -Ha), 2.46 (m, 1H, C ′ ₃ -Hb), 2.80 (s, 3H), 3.05 (m, 1H), 3.33 (dq, 1H, C ₁ -H), 3.87 (m, 2H, C ′ ₅ -H), 4.10 (m, 1H, C ′ ₄ -H) , 4.25-4.35 (m, 2H, C ₅ -H and CH ₃ CHOH), 4.43 (t, 1H)

The present invention provides novel bicyclic thiol derivatives and 1-beta-methyl-carbapenem derivatives having them as substituents. 1-beta-methyl-carbapenem derivative having a bicyclic thiol derivative according to the present invention as a substituent is stronger than that of conventional imipenem, meropenem and other carbapenem antibiotics and resistant to resistant bacteria, and has high stability against DHP-I. It has the utility that co-administration of I enzyme inhibitor is unnecessary.

Claims (4)

Double ring thiol derivative represented by the following formula (1). [Formula 1] Wherein R ¹ is a methyl group or an ethyl group and R ² is C _1-6 alkyl, C _1-6 cycloalkyl or alkyl substituted with a phenyl, vinyl, hydroxy group. The bicyclic thiol derivative according to claim 1, wherein R ² is unsubstituted or selected from methyl, ethyl, propyl or cyclopropyl substituted with a phenyl, vinyl or hydroxy group. 1-beta-methyl-carbapenem derivative represented by the following formula (2). [Formula 2] Wherein R ¹ is a methyl group or an ethyl group and R ² is C _1-6 alkyl, C _1-6 cycloalkyl or alkyl substituted with a phenyl, vinyl, hydroxy group. The 1-beta-methyl-carbapenem derivative according to claim 3, wherein R ² is unsubstituted or selected from methyl, ethyl, propyl or cyclopropyl substituted with a phenyl, vinyl or hydroxy group.