KR101049267B1 - Stereoselective Preparation of Beta-Methyl Vinyl Phosphate Carbapenem - Google Patents

Abstract

In the method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) from a diazo-azetidinone of formula (1),

The present invention relates to a method for preparing beta-methyl vinyl phosphate carbapenem of formula (3), characterized by using less than 5 times of acetonitrile relative to the weight of diazo-azetidinone of formula (1).

[Formula 1]

(3)

In Formula 1 and Formula 3, PNB represents a 4-nitrobenzyl group.

According to the present invention, beta-methyl vinyl phosphate carbapenem of the formula (3) having high purity quality can be prepared in a high yield by a simple method.

Carbapenem, antibiotics, acetonitrile

Description

Stereoselective preparation of beta-methyl vinyl phosphate carbapenem {METHOD FOR THE STEREOSELECTIVE PREPARATION OF BETA-METHYL VINYL PHOSPHATE CARBAPENEM}

The present invention relates to a stereoselective process for the preparation of beta-methyl vinyl phosphate carbapenem, which is a very important intermediate in the preparation of beta-methyl carbapenem compounds.

Carbapenem antibiotics are prepared by total synthesis and are generally stereoselectively synthesized using 4-acetoxyazetidinone (Formula 4) as a key intermediate. 4-Acetoxyazetidinone is already produced in large quantities every year through three Japanese companies (Takasago, Kaneka, Nisso) and supplied to the world.

[Formula 4]

Meanwhile, beta-methyl groups are introduced from 4-acetoxyazetidinone through stereoselective reactions, and then, through multi-step reactions, key intermediates of various carbapenem antibiotics (meropenem, attapenem, viapenem, doripenem, etc.) Phosphorous beta-methyl vinyl phosphate carbapenem (Formula 3) is synthesized.

(3)

Previously reported beta-methyl carbapenem antibiotics (meropenem, attapenem, viapenem, doripenem, etc.) can be easily synthesized through the reaction of beta-methyl vinyl phosphate carbapenem with various thiol derivatives. Therefore, a technique for easily preparing beta-methyl vinyl phosphate carbapenem is very useful, and various preparation methods have been reported.

Typical of carbapenem antibiotics prepared from beta-methyl vinyl phosphate carbapenem include Meropenem (5), Ertapenem (6), Viapenem (7), and doripenem ( Doripenem (Formula 8) is mentioned.

Conventional methods for preparing beta-methyl vinyl phosphate carbapenem are concentrated on improved techniques to facilitate industrialization based on the method reported by Merck (see Scheme 1 below). The process for preparing the compound of Formula 3 can be summarized as de-nitrogen and ring closure reaction (one-step reaction) and phosphate reaction (two-step reaction), and finally beta-methyl vinyl phosphate carbapenem is separated into a stable solid form. It is important.

Scheme 1

In the prior art, WO 07/125788 (JP 2006-125478) uses expensive rhodium octanoate in a one-step reaction at a weight ratio of 1/160 to the weight of the compound of formula 1 to obtain beta-methyl vinyl phosphate carbapenem. In addition, after the two-step reaction, it discloses a complex reaction post-treatment process such as 0.3 normal hydrochloric acid solution wash, 5% sodium bicarbonate wash and additionally crystallization and purification process below 10 ℃.

WO 07/104219 (CN 2006-000396) uses an expensive rhodium caprylate in a weight ratio of 1/285 to the weight of the compound of formula 1 to obtain beta-methyl vinyl phosphate carbapenem, and reacts for a long time at a high temperature. Excess petroleum ether and sodium phosphate buffer solution are added to the resulting ethyl acetate crystals after the completion of the reaction to ripen the crystals, and the filtration process washes with the aforementioned solvents.

WO 07/031858 (IB 2006/002548) discloses a further crystallization step after completion of the phosphate reaction and a general reaction workup process which is washed with potassium phosphate buffer solution.

WO 95/019979 (US 95/000855) discloses a method of inhibiting epimerization by adding zinc bromide or magnesium chloride to selectively prepare beta-methyl isomers.

However, the above-described prior arts require a method capable of improving steric selectivity in the preparation step of keto ester carbapenem (Formula 2), which is stable in the manufacturing step of beta-methyl vinyl phosphate carbapenem. Efforts have been made to simplify complex manufacturing processes such as crystallization methods, crystal separation and purification methods for obtaining in form.

The present invention has been made to solve the above problems of the prior art, the object of the present invention is

First, to provide a method for efficiently preparing beta-methyl vinyl phosphate carbapenem of the formula (3) by the self-crystallization without a separate crystallization process in a crystalline state.

Second, there is provided a method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) which further improves stereoselectivity and economic efficiency by proceeding de-nitrogen and ring closure reaction of the diazo-azetidinone compound of formula (1) using a minimum amount of catalyst It is.

The present invention,

In the method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) from the diazo-azetidinone of formula (1),

It provides a method for producing beta-methyl vinyl phosphate carbapenem of the formula (3) characterized in that less than five times of acetonitrile relative to the weight of the diazo-azetidinone of the formula (1).

In Formula 1 and Formula 3, PNB represents a 4-nitrobenzyl group.

In the preparation method of the present invention, rhodium acetate, rhodium octanoate, rhodium acetamide, rhodium trifluoroacetate and rhodium capryleide as catalysts to the diazo-azetidinone of Chemical Formula 1 before the step of using acetonitrile At least one selected from the group consisting of the reaction is characterized in that the reaction of 1/2000 to 1/300 of the weight of the diazo-azetidinone of formula (1).

In addition, zinc chloride (ZnCl ₂ ), magnesium bromide, magnesium acetate, magnesium triplate, zinc bromide, zinc acetate, zinc triplate, acetylacetonate copper, copper chloride, copper bromide, calcium chloride and iron chloride as cocatalysts together with the catalyst One or more selected from the group consisting of may be reacted in an amount of 1/2000 to 1/400 based on the weight of the diazo-azetidinone of the formula (1).

In the preparation method of the present invention, separation of beta-methyl vinyl phosphate carbapenem of formula (3), which is precipitated in crystalline form, may be carried out by diluting and filtering only by dropwise addition of water to the reaction solution.

Since the preparation method of the present invention proceeds under solvent conditions at an optimum magnification, the beta-methyl vinyl phosphate carbapenem of the formula (3) is efficiently prepared by self-crystallization without separate crystallization process, and thus the manufacturing process is simple and very. It is economical.

Furthermore, the beta-methyl vinyl phosphate of formula 3 is simply added dropwise and filtered without the complex reaction post-treatment process used in the prior art to separate unstable beta-methyl vinyl phosphate carbapenem in solution. The manufacturing process of cabapenem is quick and simple and very economical.

In addition, since the stereoselectivity of the beta-methyl vinyl phosphate carbapenem of the formula (3) is further improved by using a minimum amount of the catalyst for the diazo-azetidinone compound of the formula (1), the production efficiency of the beta-methyl vinyl phosphate carbapenem of the formula (3) And economic efficiency is further doubled.

In addition, as described above, the very unstable beta-methyl vinyl phosphate carbapenem crystals are prepared by separating very quickly in solution, thereby producing pure beta-methyl vinyl phosphate carbapenem of the general formula 3 having excellent stereoselectivity and stability. It provides the effect obtainable in yield.

The present invention,

In the method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) from a diazo-azetidinone of formula (1),

It provides a method for producing beta-methyl vinyl phosphate carbapenem of the formula (3) characterized in that less than five times of acetonitrile relative to the weight of the diazo-azetidinone of the formula (1).

[Formula 1]

(3)

In Formula 1 and Formula 3, PNB represents a 4-nitrobenzyl group.

The preparation method of the present invention can be represented by the following Scheme 1.

In the reaction scheme, step 1 represents denitrification and ring closure and step 2 represents phosphate reaction.

Beta-methyl vinyl phosphate carbapenem of formula 3 (4R, 5R, 6S-4-nitrobenzyl 3-diphenoxyphosphoryloxy-6- (R) -1-hydroxyethyl-4-methyl-7-oxo -1-aza-bicyclo [3.2.0] heptene-2-carboxylate) is a compound used as a key intermediate of carbapenem antibiotics.

Conventional techniques for the preparation of the beta-methyl vinyl phosphate carbapenems have generally used a method of crystallization by performing a step for crystallization again after the phosphate reaction.

However, the inventors of the present invention can provide a method for preparing beta-methyl vinyl phosphate carbapenem, in which an additional step for crystallization is omitted by using an acetonitrile used as a solvent in an appropriate ratio. Therefore, the preparation method of the present invention shortens the time used in the further crystallization step by self-crystallization while maintaining the stericity of beta-methyl vinyl phosphate carbapenem, thereby reducing beta physicochemical stability in solution. Allow methyl vinyl phosphate carbapenem to be produced in crystalline form with high yield and purity. Therefore, it provides a very good effect both economically and in terms of stability and environment of the compound.

In the present invention, self-crystallization means that the crystallization of the target compound proceeds simultaneously as a series of reaction processes according to the present invention proceed without the usual separate treatment for the production of crystals. Conventional separate treatments for crystal formation refer to seeding, cooling, concentration and addition of low solubility solvents commonly used in the art.

In the preparation method of the present invention, the amount of acetonitrile used is less than 5 times the weight of the diazo-azetidinone of the formula (1). If more than 5 times of solvent is used, the crystallization rate is delayed or no crystals are formed, which requires an additional step, which negatively affects the yield and reduction of stereo alignment. In particular, when an amount exceeding 5 times is used, it is difficult to expect crystallization by self crystallization.

In consideration of the crystallization rate, stability, final yield and purity of the compound of formula (3) obtained, the more preferred amount of acetonitrile is 3 to 5 times the weight of the diazo-azetidinone of formula (1). If less than 3 times, crystallization proceeds too fast, and the unreacted intermediate keto ester carbapenem of formula (2) is impregnated with the self-crystallization of formula (3) produced by itself, resulting in a decrease in yield and content.

Even more preferably, 3.5 to less than 5 times acetonitrile based on the weight of the diazo-azetidinone of the formula (1) may be used.

However, the amount of acetonitrile to be used is not limited to the above-described range, and may be differently determined at a weight ratio of less than 5 times depending on the catalyst amount, temperature, solvent, and the like according to the preparation step of the beta-methyl vinyl phosphate carbapenem of the formula (3). have.

Since it is recognized by those skilled in the art that a solvent must be used at least five times the weight of the reactant in order to stably perform the reaction, the present invention has been achieved by the inversion of the idea.

In the production method of the present invention, at least one selected from the group consisting of rhodium acetate, rhodium octanoate, rhodium acetamide, rhodium trifluoroacetate and rhodium caprylate as a catalyst prior to the step of using acetonitrile It is characterized in that it comprises the step of reacting 1/2000 to 1/300 of the weight of the diazo-azetidinone of 1. The amount of the catalyst used is more preferably 1/2000 to 1/1000.

When the amount of the catalyst used is less than 1/2000, it is difficult to expect the effect by the catalyst, and when it exceeds 1/300, the sterics of the keto ester carbapenem of the formula (2) and the beta-methyl vinyl phosphate carbapenem of the formula (3) exceeding 1/300 Selectivity can be degraded.

It is more preferable to use rhodium acetate as a catalyst in the above.

In addition, zinc chloride (ZnCl ₂ ), magnesium bromide, magnesium acetate, magnesium triplate, zinc bromide, zinc acetate, zinc triplate, acetylacetonate copper, copper chloride, copper bromide, calcium chloride and iron chloride as cocatalysts together with the catalyst One or more selected from the group consisting of can be reacted in combination in an amount of 1/2000 to 1/400 relative to the weight of the diazo-azetidinone of formula (1), more preferably used in 1/1500 to 1/500 Do.

When the amount of the subcatalyst is less than 1/2000, it is difficult to expect the effect of the subcatalyst, and when the amount of the subcatalyst is more than 1/400, a problem may occur in which self crystallization does not occur well in a later process.

As the subcatalyst, zinc chloride (ZnCl ₂ ) is more preferable.

In the preparation method of the present invention, the step of reacting the catalyst and the subcatalyst to the diazo-azetidinone of Formula 1 may be performed using ethyl acetate, ethyl acetate, methyl acetate, dichloromethane or a mixture thereof as a solvent. It is preferable to use ethyl acetate.

In the preparation method of the present invention, the phosphate is used diphenyl chloride phosphate (DPCP) in 0.9 ~ 1.3 equivalents to 1 equivalent of diazo-azetidinone of the formula (1), the base is triethylamine, 4- Dimethylaminopyridine, diisopropylethylamine (DIPEA) or a mixture thereof can be carried out using 1.0 equivalent to 1.6 equivalents based on 1 equivalent of diazo-azetidinone of the formula (1), using diisopropylethylamine It is preferable.

In the preparation method of the present invention, separation of beta-methyl vinyl phosphate carbapenem of formula (3), which is precipitated in crystalline form, may be carried out by diluting and filtering only by dropwise addition of water to the reaction solution. Thus, a very economical and environmental aspect provides a very desirable effect.

Beta-methyl vinyl phosphate carbapenem crystals separated by the above method is a mixture of hexane and at least one selected from the group consisting of methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and ethyl acetate (EA) Purification with a solvent can yield pure beta-methyl vinyl phosphate carbapenem. In particular, it is preferable to use a mixed solvent of methyl ethyl ketone and hexane.

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

According to the production method of the present invention, by performing a one-step reaction in a short time using a minimum amount of catalyst as shown in Scheme 1, and a two-step reaction under the reagent and solvent conditions of the optimum magnification, beta-methyl vinyl of formula (3) Phosphate carbapenem can be obtained by self-crystallization from the reaction solution.

Scheme 1

In Scheme 1, the PNB is a 4-nitrobenzyl group. The reaction conditions are described by stages as follows.

One-step reaction: denitrogen and ring closure

Ethyl acetate, methyl acetate, dichloromethane or a mixture thereof may be used as the solvent, and the solvent may be used in a usual amount, but preferably 5 to 10 times the volume of the compound of Formula 1 is used. The reaction temperature is usually in the range of 40 to 80 ° C, preferably about 45 to 75 ° C, and preferably 0.5 to 3 hours, preferably 1 to 2 hours, while maintaining the temperature.

According to WO 95/019979 (US 95/000855), subcatalysts such as zinc bromide have the effect of inhibiting steric loss, but according to the results of the present inventors, it is determined that they play a role in increasing reactivity. do. In particular, the inventors of the present invention tend to increase the stericity of beta-methyl of beta-methyl vinyl phosphate carbapenem of formula (3) by reducing the amount of rhodium acetate used without using a subcatalyst as summarized in Table 1 below. It was confirmed that it represents. This result is thought to be due to the decreased use of rhodium acetate affects the beta type selectivity improvement of the keto ester carbapenem of formula (2). Table 1 below shows all the results of experiments using the same solvent without using the subcatalyst, but using only the amount of the main catalyst.

The subcatalyst is selected from the group consisting of zinc chloride (ZnCl ₂ ), magnesium bromide, magnesium acetate, magnesium triplate, zinc bromide, zinc acetate, zinc triplate, acetylacetonate copper, copper chloride, copper bromide, calcium chloride and iron chloride One or more may be used. Among these, zinc chloride is thought to affect the tendency and yield of self-crystallization after completion of the phosphate reaction. Self-crystallization is formed even when zinc chloride is not used, but the yield tends to drop to 68.4%. These results suggest that the amount of cocatalyst used affects the yield of the reaction.

The amount of rhodium acetate as the main catalyst used in the reaction is used in a weight ratio of 1/2000 to 1/300 to the weight of the compound of Formula 1, and preferably 1/2000 to 1/1000. In addition, zinc chloride is used as a subcatalyst to be used in the reaction, and the amount used is 1/2000 to 1/400 based on the weight of the compound of Formula 1, and preferably 1/1500 to 1/500.

order Main catalyst Subcatalyst yield content water One 1/1500 Rh ₂ (OAc) ₄ None 68.4 75.5 87.1 2 1/1000 Rh ₂ (OAc) ₄ 1/500 ZnCl ₂ 83.5 91.1 92.4 3 1/1750 Rh ₂ (OAc) ₄ 1/1400 ZnCl ₂ 81.0 87.2 94.2

Two stage reaction: phosphate reaction

Acetonitrile is used as a solvent in the phosphate reaction of the present invention. In the conventional conventional method, 5 to 10 times the weight of the compound of Formula 1 is used, but in the present invention, less than 5 times the weight of the compound of Formula 1 should be used for stable self-crystallization. Table 3 shows the results of testing the yield, quality, purity, and crystallization rate by varying only the amount of acetonitrile used relative to the weight of the compound of Compound 1, under the same conditions.

* The crystal production rate refers to the ratio (number of crystal formation / total number of times) that the compound of Formula 3 is produced as a crystal, the experiment was carried out a total of 20 times.

Diphenyl chloride phosphate (DPCP) may be used in an amount of 0.9 to 1.3 equivalents based on 1 equivalent of the compound of Formula 1, and preferably 1.0 to 1.1 equivalents. When the diphenyl chloride phosphate (DPCP) is used in less than 0.9 equivalents, the phosphate is not sufficiently progressed, which causes a decrease in yield. When the diphenyl chloride phosphate is less than 0.9 equivalents, the unreacted diphenyl chloride phosphate (DPCP) increases, resulting in an uneconomical effect. And adversely affect responses.

Diisopropylethylamine (DIPEA) used as the base may be used in an amount of 1.0 to 1.6 equivalents based on 1 equivalent of the compound of formula 1, with 1.1 to 1.3 equivalents being preferred.

When the diisopropylethylamine (DIPEA) is used in less than 1.0 equivalent, the phosphate may not proceed sufficiently to cause a decrease in yield, and when the diisopropylethylamine (DIPEA) is used in excess of 1.6 equivalents, the reaction solution becomes strongly basic to give a steric solid of the target compound. It causes the problem of impairing the orientation. Experimental results according to the amount of use of the base (diisopropylethylamine) are summarized in Table 4 below, and the following experimental results were performed under the same conditions except for the equivalent use of the base according to 1 equivalent of the compound of Formula 1.

The temperature of the phosphate reaction can be used in the range of -30 ~ 10 ℃, most preferably in the range of -10 ~ 5 ℃ in consideration of the stability and economic ease of the beta-methyl vinyl phosphate carbapenem of the formula (3).

As the reaction proceeds, self-crystallization is performed from the reaction solution to produce beta-methyl vinyl phosphate carbapenem of the formula (3). After the white crystals are sufficiently precipitated, the mixture is stirred for about 0.5 to 1 hour to ripen the crystals. It is more preferable to add 1 to 5 times of water to dilute the crystals, and to use 2 to 3 times of water. However, the present invention is not limited only to dilution with water, and it is also possible to separate and separate the self-crystallized compound using various solvents as follows.

Self-crystallized crystals of beta-methyl vinyl phosphate carbapenem of formula (3) were prepared by diluting various organic solvents, organic solvents and water, and an aqueous solution containing water. The relationship is shown in Table 5 below.

IPE: isopropyl ether, EA: ethyl acetate, ACN: acetonitrile

As shown in Table 5, when isopropyl ether or isopropyl ether and hexane were added, the yield was low while showing the best content and purity. Therefore, various experiments were conducted to maintain the content and purity while increasing the yield. As a result,

(i) In general, the method using an organic solvent showed a low yield since the beta-methyl vinyl phosphate carbapenem of Formula 3 was dissolved and lost in small amounts.

(ii) The yield was slightly higher when a small amount of hexane was added and water was added thereto to dilute the crystals, i.e., in a biphasic mixed solvent of organic solvent and water.

(iii) Dilution of the crystal solution using a buffer solution of pH 7.0 to adjust the pH in the reaction solution, to obtain a beta-methyl vinyl phosphate carbapenem of formula 3 in a yield of 75.3%.

(iv) The crystals were diluted with a weak basic aqueous solution of 0.3 equivalent sodium bicarbonate and filtered to obtain beta-methylvinyl phosphate carbapenem of formula 3 in a yield of 75.4%.

(v) For the sake of economic convenience, the beta-methyl vinyl phosphate carbapenem of the crystalline formula 3 having a good yield of 85.1% and a good content and purity of about 95% can be easily separated by diluting the crystal by simply adding water. there was.

The present invention is characterized in that it provides an effective production method for diluting and filtering crystals by simply adding water to self-crystallization through de-nitrogen and ring-closure reactions and phosphate reactions as described above.

In addition, since the crystal obtained by dilution and filtration by simply adding water only is purified through a combination of solvents as shown in Table 5 below, the beta-methyl vinyl phosphate carbapenem of Formula 3 can be recovered with little loss. Compounds having a content and purity of at least 99% can be prepared.

The polar solvent in the solvent used in the purification in Table 6 is methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and ethyl acetate (EA) in which beta-methyl vinyl phosphate carbapenem of Formula 3 is slightly dissolved. Among them, methyl ethyl ketone (MEK) was preferred. Hexs (hexane) was used as the non-soluble solvent, and the mixing ratio between the polar and the non-polar solvent was suitably 3/1 to 1/2, and more preferably 2/1.

As the amount of solvent used for purification, 5 to 10 times the weight of beta-methyl vinyl phosphate carbapenem of Formula 3 obtained by dropwise addition of water may be used in general, preferably 6 to 8 times. The crystal solution was selected through a minimum loss ratio through cooling, preferably -10 ~ 0 ℃.

The solvent ratio and the amount used for the purification are not limited only to the contents of Table 6, and may be determined differently according to the type, mixing ratio, and aging temperature of the polar solvent and the nonpolar solvent.

Beta-methyl vinyl phosphate carbapenem of formula 3 obtained as white crystals was analyzed using chiral high performance chromatography. At this time, the columns were Capcellpak, MG C18, 5 μm, 4.6 mm ID x 250 mm (acetonitrile and water mixed solvent), and Lichrospher 100 RP-8, 5 μm, 4.6 mm ID x 250 mm (ethyl acetate). And hexane) column, and the analysis showed a purity of 99.9% or more. The chiral isomer alpha-methyl vinyl phosphate carbapenem was present at 0.05% or less.

The present invention not only provides an efficient manufacturing method that is easy to industrialize, but also provides a method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) having excellent stereoselectivity.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are provided to illustrate the present invention, and the present invention is not limited to the following examples and may be variously modified and changed.

Example 1 4R, 5R, 6S-4-nitrobenzyl-3-diphenoxyphosphoryloxy-6- (R) -1-hydroxyethyl-4-methyl-7-oxo-1-aza-bicyclo Preparation of [3.2.0] heptene-2-carboxylate (beta-methyl vinyl phosphate carbapenem)

60.5 g (0.155 mol) of the diazo-azetidinone compound of formula 1 were stirred in 360 mL of ethyl acetate under a nitrogen stream. 40.3 mg (0.05 mol%) of rhodium acetate and 80.6 mg (0.38 mol%) of zinc chloride were added to the reaction solution, and nitrogen was removed. The reaction solution was stirred at 65 ° C. for 1.5 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and 240 mL of acetonitrile was added and stirred under a nitrogen stream. The reaction solution was cooled to -5 ° C and 32.1 mL (0.155 mol) diphenyl chloride phosphate was added. 32.5 mL (0.185 mol) of diisopropyl ethyl amine was slowly added dropwise to the reaction solution for 20 minutes, followed by stirring at the same temperature. After 20-30 minutes, white crystals were formed, and the reaction solution was stirred vigorously at the same temperature for 1 hour. 600 mL of water was slowly added to the crystal solution to dilute the crystals, and filtered. The resulting white crystals were dried in a 40 ° C. vacuum oven for 8 hours to give 83 g (86.9% yield, 96.5% content, 96.7% purity) of the compound. 240 mL of methyl ethyl ketone was added to the obtained white crystals and stirred for 1 hour. 120 mL of hexane was added thereto, stirred for 1 hour, the reaction solution was cooled to −10 ° C., filtered and washed with a small amount of hexane. The white crystals thus obtained were dried in vacuo for 3 hours to give 78.5 g (85.1% yield, 99.9% content, 99.9% purity and 99.9% stereoselectivity) of beta-methyl vinyl phosphate carbapenem of formula (3).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.132 (2H, d, J = 8.7 Hz), 7.545 (2H, d, J = 8.7 Hz), 7.373 ~ 7.163 (10H, m), 5.357 (1H, d , J = 13.5 Hz), 5.289 (1H, d, J = 13.5 Hz), 4.249 (2H, dd, J = 10.2, 3.3 Hz), 3.489 (1H, pd, J = 7.2, 2.1 Hz), 3.330 (1H , dd, J = 6.3, 2.1 Hz), 2.091 (1H, br), 1.323 (3H, d, J = 6.3 Hz), 1.227 (3H, d, J = 7.2 Hz).

¹³ C-NMR (CDCl ₃ , 125 MHz) δ 175.6, 158.8, 158.7, 156.2, 156.0, 149.9, 149.8, 149.7, 149.6, 147.4, 142.4, 129.9, 129.8, 128.1, 126.0, 125.9, 123.5, 119.8, 119.8, 118.4, 118.3, 65.29, 65.23, 60.61, 54.20, 39.50, 21.51, 14.36.

[a] ²⁵ _D = +56.199 ^o ( c 1.0, CH ₃ CN).

IR (cm ⁻¹ ): 3450, 1746, 1510, 1308, 1179, 1018, 949.8, 849.5, 771.4, 691.4.

UV: λ _max value 273 nm

Ms: [M + H] + value m / z = 595

Melting Point: 132.8 ℃

Example 2 4R, 5R, 6S-4-nitrobenzyl-3-diphenoxyphosphoryloxy-6- (R) -1-hydroxyethyl-4-methyl-7-oxo-1-aza-bicyclo Preparation of [3.2.0] heptene-2-carboxylate (beta-methyl vinyl phosphate carbapenem)

6.05 g of the diazo-azetidinone compound of formula 1 was stirred in 35 mL of ethyl acetate under a nitrogen stream. 4.0 mg (0.05 mol%) of rhodium acetate and 8.0 mg (0.38 mol%) of zinc chloride were added to the reaction solution, and nitrogen was removed. The reaction solution was stirred at 60 ° C. for 1 hour and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and then 24 mL of acetonitrile was added and stirred under a stream of nitrogen. The reaction solution was cooled to -5 ° C and 3.21 mL of diphenyl chloride phosphate was added. 3.25 mL of diisopropyl ethyl amine was slowly added dropwise to the reaction solution for 10 minutes and stirred at the same temperature. After 1 hour, white crystals were formed, and the reaction solution was stirred vigorously at the same temperature for 1 hour. 60 mL of water was added to the crystal solution to dilute the crystals, and filtered. The white crystals thus obtained were dried in a vacuum oven at 40 ° C. for 8 hours to obtain 8.3 g (86.9% yield, 96.5% content, 96.7% purity) of the compound. 25 mL of methyl ethyl ketone was added to the obtained white crystals, followed by stirring for 1 hour, 10 mL of hexane was added thereto, followed by stirring for 1 hour, the reaction solution was cooled to -10 ° C, filtered and washed with a small amount of hexane. The white crystals obtained were dried in vacuo for 3 hours to afford 7.85 g (85.1% yield, 99.9% content, 99.9% purity and 99.9% stereoselectivity) of beta-methyl vinyl phosphate carbapenem of formula (3).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.132 (2H, d, J = 8.7 Hz), 7.545 (2H, d, J = 8.7 Hz), 7.373 ~ 7.163 (10H, m), 5.357 (1H, d , J = 13.5 Hz), 5.289 (1H, d, J = 13.5 Hz), 4.249 (2H, dd, J = 10.2, 3.3 Hz), 3.489 (1H, pd, J = 7.2, 2.1 Hz), 3.330 (1H , dd, J = 6.3, 2.1 Hz), 2.091 (1H, br), 1.323 (3H, d, J = 6.3 Hz), 1.227 (3H, d, J = 7.2 Hz).

¹³ C-NMR (CDCl ₃ , 125 MHz) δ 175.6, 158.8, 158.7, 156.2, 156.0, 149.9, 149.8, 149.7, 149.6, 147.4, 142.4, 129.9, 129.8, 128.1, 126.0, 125.9, 123.5, 119.8, 119.8, 118.4, 118.3, 65.29, 65.23, 60.61, 54.20, 39.50, 21.51, 14.36.

[a] ²⁵ _D = +56.199 ^o ( c 1.0, CH ₃ CN).

IR (cm ⁻¹ ): 3450, 1746, 1510, 1308, 1179, 1018, 949.8, 849.5, 771.4, 691.4.

UV: λ _max value 273 nm

Ms: [M + H] + value m / z = 595

Melting Point: 132.8 ℃

Example 3: 4R, 5R, 6S-4-nitrobenzyl-3-diphenoxyphosphoryloxy-6- (R) -1-hydroxyethyl-4-methyl-7-oxo-1-aza-bicyclo Preparation of [3.2.0] heptene-2-carboxylate (beta-methyl vinyl phosphate carbapenem)

Under a stream of nitrogen, 57.4 g (0.155 mol) of diazo-azetidinone compound of formula 1 were stirred in 340 mL of ethyl acetate. 57.4 mg (0.08 mol%) of rhodium acetate and 0.11 g (0.56 mol%) of zinc chloride were added to the reaction solution, and nitrogen was removed. The reaction solution was stirred at 65 ° C. for 2 hours, and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and 200 mL of acetonitrile was added and stirred under a stream of nitrogen. The reaction solution was cooled to −10 ° C., and 30.5 mL of diphenyl chloride phosphate was added. 30.8 mL of diisopropyl ethyl amine was slowly added dropwise to the reaction solution for 30 minutes and stirred at the same temperature. After 30 minutes white crystals formed, and the reaction solution was stirred vigorously at the same temperature for 1 hour. 550 mL of water was slowly added to the crystal solution to dilute the crystals, filtered and washed with a mixed solution of acetonitrile and water. The resulting white crystals were dried in a 40 ° C. vacuum oven for 8 hours to give 78 g (89.1% yield, 91.5% content, 92.3% purity) of the compound. 230 mL of methyl ethyl ketone was added to the obtained white crystals and stirred for 1 hour. 110 mL of hexane was added thereto, stirred for 1 hour, and then the reaction solution was filtered and washed with a mixed solution of methyl ethyl ketone and hexane. The white crystals obtained were dried in vacuo for 3 hours to afford 70 g (80.1% yield, 99.9% content, 99.9% purity and 99.9% stereoselectivity) of beta-methyl vinyl phosphate carbapenem of formula (3).

Example 4: 4R, 5R, 6S-4-nitrobenzyl-3-diphenoxyphosphoryloxy-6- (R) -1-hydroxyethyl-4-methyl-7-oxo-1-aza-bicyclo Preparation of [3.2.0] heptene-2-carboxylate (beta-methyl vinyl phosphate carbapenem)

At room temperature, 30 g (76.85 mmol) of the diazo-azetidinone compound of formula 1 were stirred in 180 mL of ethyl acetate. 17 mg (0.05 mol%) of rhodium acetate and 21 mg (0.2 mol%) of zinc chloride were added to the reaction solution, and the reaction solution was heated to reflux at 75 ° C. for 1.5 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and then 90 mL of acetonitrile was added and stirred under a nitrogen stream. The reaction solution was cooled to 0 ° C, 17.2 mL of diphenyl chloride phosphate was added for 10 minutes, and stirred at the same temperature for 10 minutes. 16.1 mL of diisopropyl ethyl amine was added dropwise to the reaction solution for 10 minutes and stirred at the same temperature. After 30 minutes, white crystals were formed, and 30 mL of acetonitrile was further added thereto, and the reaction solution was stirred vigorously at the same temperature for 1 hour. 300 mL of water was slowly added to the crystal solution to dilute the crystals, and filtered. The white crystals obtained were dried in a vacuum oven at 40 ° C. for 8 hours to give 42 g (91.9% yield, 88.8% content, 93.1% purity) of the compound. 160 mL of methyl isobutyl ketone was added to the obtained white crystals and stirred for 1 hour. 80 mL of hexane was added thereto, stirred for 1 hour, and then the reaction solution was filtered and washed with hexane. The white crystals obtained were dried in vacuo for 3 hours to afford 36.1 g (79.0% yield, 100% content, 99.5% purity and 99.9% stereoselectivity) of beta-methyl vinyl phosphate carbapenem of formula (3).

Claims (8)

In the method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) from a diazo-azetidinone of formula (1), A first step of performing a denitrification and ring closure reaction; A second step of performing a phosphate reaction; A third step of diluting and filtering by dropwise addition of water to the reaction solution for the separation of beta-methyl vinyl phosphate carbapenem of the formula (3), The phosphate reaction is a method for preparing beta-methyl vinyl phosphate carbapenem of formula (3), characterized in that using acetonitrile less than 3.5 to 5 times the weight of the diazo-azetidinone of formula (1): [Formula 1]

(3)

In Formula 1 and Formula 3, PNB represents a 4-nitrobenzyl group. The method according to claim 1, wherein the first step is a rhodium acetate, rhodium octanoate, rhodium acetamide, rhodium trifluoroacetate and rhodium capping of 1/2000 to 1/300 of the diazo-azetidinone weight of formula (1) A method for preparing beta-methyl vinyl phosphate carbapenem of formula (3) comprising the step of reacting at least one catalyst selected from the group consisting of a relay with the diazo-azetidinone of formula (1). The method according to claim 2, wherein the catalyst is rhodium acetate, the method of producing beta-methyl vinyl phosphate carbapenem of the formula (3). The zinc chloride (ZnCl ₂ ), magnesium bromide, magnesium acetate, magnesium triplate, zinc bromide, zinc acetate, zinc triplate, acetylacetonate copper, copper chloride, brominated as a subcatalyst together with the catalyst Of beta-methyl vinyl phosphate carbapenem of formula (3), characterized in that at least one selected from the group consisting of copper, calcium chloride and iron chloride is used at 1/2000 to 1/400 of the weight of the diazo-azetidinone of formula (1). Manufacturing method. The method of claim 4, wherein the cocatalyst is zinc chloride (ZnCl ₂ ). The method of claim 1, wherein the second step uses diphenyl chloride phosphate (DPCP) in an amount of 0.9 to 1.3 equivalents based on 1 equivalent of diazo-azetidinone of Formula 1, and diisopropylethylamine (DIPEA) as a base. A method for preparing beta-methyl vinyl phosphate carbapenem of formula (3), characterized in that it is used in an amount of 1.0 to 1.6 equivalents based on 1 equivalent of diazo-azetidinone of formula (1). delete The method of claim 1, wherein in the beta-methyl vinyl phosphate carbapenem separation step of Formula 3, at least one selected from the group consisting of methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and ethyl acetate (EA); A method for preparing beta-methyl vinyl phosphate carbapenem of formula 3 further comprising the step of purifying with a mixed solvent of hexane.