KR900004877B1 - Process for preparing of 1-carbaphenem -2-m-3-carboxyacid derivatives - Google Patents

Abstract

1-Carbapenem-2-M-3-carboxylic acid monohydrate of formula (I), having a broad spectrum antibacterial acitvity, is prepd. from a cpd. of formula (III). A cpd. of formula (III) is prepd. by reacting a cpd. of formula (II) with a cpd. of formula H2C=C(osi (R1)3)SCH2CH2NHCH= NR2. In the formulas, R1= C1-6 alkyl, phenyl or C7-12 phenylalkyl; R2= P-nitrobenzyloxycarbonyl, phenylacetyl, phenoxyacetyl or trimethylsillyl; R3= t-butyldimethylsillyl.

Description

Method for preparing 1-carbapenem-2-m-3-carboxylic acid derivative

The present invention relates to a novel industrial method for preparing 1-carbaphenin-2-m-3-carboxylic acid, monohydrate of the following structural formula (I) for use in the treatment of bacterial infections.

The compound of formula (I) prepared by the novel production method according to the present invention has a wide range of antibacterial action and potent activity, and is stable as an antibacterial substance to beta lactam degrading enzyme secreted by resistant bacteria of beta lactam antibiotics. Known compounds that can be prepared by 4,194,047, 4,292,436, 4,374,772. However, when the compound of the general formula (I) is prepared according to these known methods

First, the preparation method according to US Pat. Nos. 4,194,047 and 4,374,772 is a manufacturing method using thienamycin as a starting material, and the reaction process is complicated due to the instability of thienamycin itself with respect to the reaction temperature and the pH of the reaction solution. In addition, in the production of the starting material thienamycin, the fermentation method is used, and thus, due to problems such as facility investment costs, securing and preservation of strains, and instability of thienamycin itself, the synthesis of thienamycin produced by the fermentation is performed in the synthesis. There is an uneconomical disadvantage, such as not being able to concentrate to a moderately high concentration. Second, the method according to US Pat. No. 4,292,436 also has a complicated reaction process for preparing starting materials, and expensive reagents are needed to prepare these starting materials. In addition to the use of these compounds, the preparation of general formula (I) using these starting materials has a very low reaction yield. The reaction operation is complicated drawbacks.

Therefore, the novel preparation method of the general formula (I) according to the present invention is a method to compensate for the disadvantages of the above known method, and is also a method in which the reaction proceeds in a stable state and a target compound can be obtained in a relatively high yield.

The present invention is a novel industrial production method characterized by preparing a compound of the general formula (III), a method for producing the same, and a target compound of the general formula (I) using the same.

Wherein R ¹ = alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl of 7 to 12 carbon atoms, R ² = P-nitrobenzyloxycarbonyl, phenylacetyl, phenoxyacetyl, trimethylsilyl

The compound of formula (III) may be prepared by reacting a compound of formula (III) with a compound of formula (III) at low temperature in anhydrous organic solvent and then adding a silylating agent in the presence of a base.

Here, R ¹ , R ² are as defined above.

As the anhydrous organic solvent used in the above, a solvent such as triethylamine capable of removing an acid generated as a by-product during the reaction is suitable, and at least 2 moles of the compound of the general formula is added. desirable.

As the base used during the reaction, it is effective to use a strong base, and preferably n-butyllithium, phenyllithium or the like may be used. In this case, as the silylating agent to be added, it is suitable to add 1 to 2 mol based on the general formula (Ⅸ), and the silylating agent used is trimethylsilyl chloride, T-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, and the like.

In the reaction, the general formula (VII) is a known compound, which is a gaseous compound that can be generated using a ketene generator, and in the reaction, the compound of the general formula (1) is 1 to 2 times mole of the general formula (IX) It is appropriate to apply.

Looking at the preparation method of the compound of the general formula (I) according to the present invention to prepare a compound of the general formula (IV) by reacting the general formula (II) and the general formula (III) and then add glyoxylic acid ester ).

The phosphine derivative was further added to form a carbafein of general formula (VII) by ring closing in the presence of a catalyst via an lide of general formula (VI) to prepare a compound of general formula (I) by a known method.

In the above, R ¹ and R ² are as defined above, R ³ is t-butyldimethylsilyl, R ⁴ , R ⁵ , R ⁶ are lower alkyl, phenyl, methoxyphenyl and the like, respectively.

PNB is P-nitro benzyl.

Method of preparing general formula (IV) from general formula (II) and general formula (III) during the reaction process is to dissolve the compound of general formula (III) in alkaline solution and dropwise add the organic solvent containing general formula (II) Can be prepared by reacting for 90 minutes or more.

In the general formula (IV), the reaction for preparing the general formula (V) is preferably carried out in a nonpolar solvent. The solvents that can be used are benzene, toluene and the like. The general formula (V) produced in this case is ethyl acetate: cyclohexane. It is preferred to purify by chromatography with a mixed solvent of (1: 1.5 to 1.5: 1).

In the reaction, the process of preparing the compound of Formula (VI) may be performed using the compound of Formula (V) as anhydrous inert organic solvent, ie, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide dioxane, and the like. It is preferred that the reaction is carried out in the presence of a base, and suitable bases which can be used are 2.6-lutidine, 2-picoline, pyridine and the like.

The general formula (VII) was prepared by a ring closure ring using a direct intramolecular wittig reaction without purification of the compound of general formula (VI) produced during the reaction. Reaction at 100 ° C and suitable inert solvents are toluene, benzene and the like.

Formula (Ⅶ) in the general formula (Ⅰ) a method for producing the first, after removing the R ³ by the strong deprotection reagent by hydrogenolysis of platinum oxide catalyst under a hydrogen pressure at position 2 R ² group and the 3-position P-nitrobenzyl was removed and a compound of formula (I) was prepared by a known method.

The preparation of the compound of general formula (I) by the novel preparation method of the present invention will be described in more detail in the following examples, and the present invention is not limited to these examples.

Example 1

Preparation of N- (N-P-nitrobenzyloxycarbonyl) -formimidoyl-2-aminoethanethiol

After dissolving 14.1 g of 2-aminoethanethiol in 186 ml of acetonitrile, 36.7 g of diisopropyl was added in small portions under nitrogen pressure at 0 ° C., and 12.4 ml of acetonitrile added with 17.5 g of trimethylsilyl chloride was added dropwise over 2 minutes. After slowly raising the temperature of the reaction mixture to room temperature over 15 minutes, and cooled to 0 ℃ again to prepare a solution A.

After dissolving 8.8 g of isopropyl formimidate in 124 ml of acetonitrile, 18.6 g of diisopropylethylamine was added to a solution of 15.2 g of P-nitrobenzylchloroformate at 0 ° C. under nitrogen pressure, and the acetonitrile was maintained at 0 ° C. And dropwise to prepare Solution B.

Half of the prepared solution A was added dropwise to the solution B, and the reaction mixture was stirred at room temperature for 10 minutes and 25 ml of water was added thereto.

The vacuum residue was dissolved in 248 ml of dichloromethane and washed three times with 250 ml of water.

The dichloromethane organic layer was dried over anhydrous sodium sulfate, and then concentrated in vacuo to give the title compound. Elution with ethyl acetate in column chromatography followed by concentration under reduced pressure yielded 14 g of the title compound (yield: 79.6%).

Example 2

Preparation of 2-trimethylsilyloxy-20 [N- (N-P-nitrobenzyloxycarbonyl) -formimidoyl-2-amino] ethanethio-ethene

14 g of the title compound prepared in Example 1 was added to 200 ml of triethylamine containing 30 ml of n-butyllithium (1.6 M in Hexane), followed by the addition of 20 ml of acetone to a ketene generator. React.

When the amount of acetone in the ketene generator is reduced to less than half, the reaction is stopped and 7.5 ml of trimethylsilyl chloride is added while maintaining the temperature at 0 ° C., and the filtered filtrate is concentrated under reduced pressure for 1 to 2 hours. g is obtained (yield: 78%).

IR spectrum ^{/ KBr / 3350cm -1, 1230cm -1} , 1110cm -1, 1650cm -1

Elemental analysis

Calculated: C; 48.36, H; 5.79, N; 20.58

Theoretical: C; 48.55, H; 5.80, N; 10.40

Example 3

(3S, 4R) -3-[(1R)-(t-butyldimethylsilyloxy) ethyl-4-2-oxo-2- (N- (NP-nitrobenzyloxycarbonyl) -formimidoyl-2- Preparation of Amino) ethanethio) ethyl] -2-azetidinone

15.17 g of the title compound prepared in Example 2 was dissolved in 55 ml of 1N sodium hydroxide solution, stirred in an ice bath for 20 minutes, and reacted for at least 90 minutes by dropwise addition of 370 ml of dioxane containing 11 g of azetidinone. The reaction solution was extracted with dichloromethane, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 14.6 g of the title compound (yield: 73%).

Infrared Spectrum / KBr / 3400cm ^-1 , 1770cm ^-1 , 1730cm ^-1

Elemental analysis

Calculated: C; 52.17, H; 6.52, N; 10.14

Found: C; 52.30, H; 6.43, N; 10.25

mp: 136-140 degreeC

Example 4

P-nitrobenzyl-2-((3S, 4R) -3- (11R)-(t-butanedimethylsilyloxy) ethyl) -4- (2-oxo-2- (N- (NP-nitrobenzyloxycar Preparation of carbonyl) -formimidoyl-2-amino) ethanethio) ethyl-2-oxoazetidin-1-yl) -2-hydroxyacetate

12.9 g of P-nitrobenzylglyoxylate was added to 1.1 l of benzene, and then 14.6 g of the title compound prepared in Example 3 was added thereto, heated to reflux for 2 hours, and then the residue concentrated under reduced pressure was cyclohexane: ethyl acetate (1). : 1) Column chromatography with a mixed solvent gave 15.5 g of the title compound (yield: 83%).

Infrared Spectrum / KBr / 3400cm ^-1 , 1780cm ^-1 , 1760cm ^-1 , 1710cm ^-1 , 1604cm ^-1

Elemental analysis

Calculated: C; 52.04, H; 5.65, N; 9.20

Found: C; 52.12, H; 5.69, N; 9.28

Example 5

P-nitrobenzyl (5R, 6S) -6-((1R)-(t-butyldimethylsilyloxy) ethyl-2-((N- (NP-nitrobenzyloxycarbonyl) -formimidoyl-2-amino Preparation of) -ethanethio-2-carbafene-3-carboxylate

After dissolving 15.5 g of the title compound prepared in Example 4 in 270 ml of tetrahydrofuran, 10 ml of 2,6-lutidine is added and 11 ml of thionyl chloride is added at -30 to -10 ° C.

After stirring for 1 hour, the filtrate was concentrated under reduced pressure, and the solid was dissolved in 360 ml of dioxane, 7.97 g of triphenylphosphine and 5 ml of 2,6-lutidine were added thereto, warmed to 50-60 ° C., and stirred for 20 hours. Cool to room temperature. An appropriate amount of ethyl acetate is added and the organic layer is washed with 5% hydrochloric acid and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was dissolved in 2.0 l of toluene and a small amount of hydroquinone was added.

The mixture is stirred at 90-100 ° C. for about 20 hours and cooled. The solvent is removed under reduced pressure and the residue is chromatographed with a cyclohexane: ethyl acetate (2: 1) mixed solvent to give 6.8 g of the title compound (yield: 46%).

Infrared Spectrum / KBr / 1800cm ^-1 , 1700cm ^-1 , 1610cm ^-1 , 1580cm ^-1

Example 6

P-nitrobenzyl (5R, 6S) -6-((1R) -hydroxyethyl) -2-((NP-nitrobenzyloxycarbonyl) -formamidoyl-2-amino) -ethanethio-2- Preparation of Carbapenem-3-carboxylate

After dissolving 5.2 g of the title compound prepared in Example 5 in 260 ml of tetrahydrofuran, 3.9 ml of acetic acid and 11.5 g of tetra t-butylammonium fluoride trihydrate were reacted in an ice bath.

The reaction mixture is warmed at room temperature and stirred for 15-20 hours. Ethyl acetate is added to the reaction mixture, and the organic layer is washed with water and dried over anhydrous magnesium sulfate.

The solvent was removed under reduced pressure and the residue was chromatographed with a cyclohexane: ethyl acetate (1: 2) mixed solvent to give 4.15 g of the title compound (yield: 95%).

Elemental analysis

Calculated: C; 52.94, H; 4.25, N; 11.44

Found: C; 52.81, H; 4.34, N; 11.55

Nuclear magnetic resonance

1.23 (S, CH ₃ ), 3.4 (m, SCH ₂ ), 3.36 (d of d, 6H), 3.58 (4, -CH ₂ ), 3.7 (m, NH ₂ ), 4.14 (m, 8-H), 4.34 (m, 5-H), 5.3 (S, -OCH ₂ ), 8.62 (bs, N = CH-)

mp: 148-151 degreeC

Example 7

Preparation of (5R, 6S) -6-((1R) -hydroxyethyl) -2-((N-formimidoyl) -2-amino) ethanethio-2-carbapenem-3-carboxylic acid

4 g of the product of Example 6 is reacted with 400 ml of tetrahydrofuran, 0.5 M monopolynopropanesulphonic acid (adjusted to pH 7.0 by addition of sodium hydroxide) and 400 ml of water under a platinum oxide catalyst for 45 minutes under a hydrogen pressure of 40 psi.

The catalyst is removed by filtration, washed with water and the aqueous layer is concentrated under reduced pressure.

The concentrated solution was chromatographed and eluted first with water followed by acetone and water in addition to 2% to give 1.11 g of the title compound (yield: 59%).

Example 8

Preparation of N-formimidoylthienamycin monohydrate

1.11 g of the title compound of Example 7 was dissolved in a mixed solution of 18 ml of water and 100 ml of 95% ethanol and stirred for 15 hours in an ice bath. Then, the seeding seed was added and crystals were formed. The supernatant was removed by centrifugation, washed with ethanol, and dried under vacuum at 50 ° C. to obtain 1 g of the title compound (yield: 90%).

Claims (2)

A process for producing a compound of formula (IV) from formulas (II) and (III).

Wherein R ¹ is alkyl of ¹ to 6 carbon atoms, phenyl or phenylalkyl of 7 to 12 carbon atoms, R ² is P-nitrobenzyloxycarbonyl, phenylacetyl, phenoxyacetyl, trimethylsilyl, and R ³ is t-butyl Dimethylsilyl. The method according to claim 1, wherein the compound of formula (III) is reacted in anhydrous organic solvent, and then a silylating agent is added in the presence of a base to prepare a compound of formula (III). .

R ¹ is alkyl having 1 to 6 carbon atoms, phenyl or phenylalkyl having 7 to 12 carbon atoms, and R ² is P-nitrobenzyloxycarbonyl, phenylacetyl, phenoxyacetyl, trimethylsilyl.