KR101017944B1 - Method for preparing crystalline form ii of 1r,5r,6s-p-nitrobenzyl-2-diphenylphosphoryloxy-6-[r-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate - Google Patents

Abstract

The present invention provides ( 1R, 5R, 6S ) -p -nitrobenzyl-2- (diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] -1-methyl-carbapenem of Form I. Dissolving -3-carboxylate (MAP) in dichloromethane, chloroform or acetone, and then crystallizing the solution by dropwise addition of diethylether, isopropylether, normal hexane, normal heptane or cyclohexane. It relates to a method for preparing Form II of MAP. According to the production method of the present invention, it is possible to obtain a high purity, high yield of crystalline form II of MAP, which can be mass-produced in a simple manner without performing a separate cooling process to obtain a crystalline form.

MAP, carbapenem, polymorph, colorless needles, good solvent, non-solvent, crystalline form II.

Description

(1R, 5R, 6S) -J-nitrobenzyl-2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate ( MAP) METHOD FOR PREPARING CRYSTAL FORM II METHOD FOR PREPARING CRYSTALLINE FORM II OF 3-CARBOXYLATE}

( 1R, 5R, 6S ) -p -nitrobenzyl-2- (diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] -1- is useful as an intermediate of carbapenem derivatives. A novel process for preparing methyl-carbapenem-3-carboxylate (MAP) crystalline Form II. More specifically, the present invention relates to a method for preparing MAP of Form II of MAP which can be mass-produced in high purity in a simple manner without performing a separate cooling process to obtain a crystalline form.

MAP having the structure of Formula 1 is a compound used as a synthetic intermediate of carbapenem antibiotics:

At present, numerous studies have been conducted on the synthesis of carbapenem-based compounds, among which imipenem is used in clinical practice. Imipenem has excellent antimicrobial activity, but its resistance to renal dehydropeptidase-1 (DHP-1) is low, so it is easily inactivated in vivo, so cilastatin is a type of DHP-1 inhibitor. It is used in combination with a prescription. However, even in this case, there is still a problem that the DHP-1 inhibitor used in combination formulations is likely to have adverse effects on other tissues in vivo.

Therefore, in recent years, studies on carbapenem-based compounds having a betamethyl group have become more active, and for this reason, the development of a crystalline form of MAP, which is a key intermediate of the betamethyl carbapenem derivative, is more eagerly required.

For example, Japanese Patent No. 3080417 discloses a method for synthesizing MAP of Formula 1, a method for preparing crystalline Form I of MAP, and a method for synthesizing a carbapenem-based compound using a MAP derivative.

According to the contents disclosed in the patent, p -nitrobenzyl- ( 1R, 5R, 6S )-[( R ) -1-hydroxyethyl] -2-oxo-carbapenem-3-carboxylate is -20 to 40 Diphenylhalophosphate such as diphenylchlorophosphate and diphenylbromophosphate in the presence of a base such as diisopropylamine and triethylamine in an inert solvent such as methylene chloride, acetonitrile or dimethyl formamide at < RTI ID = 0.0 > MAP is prepared in amorphous form by reaction for about 30 minutes to 24 hours. After the reaction is completed, the reaction solution is concentrated and purified to obtain the desired MAP as a powder. In addition, the amorphous powder of MAP thus obtained is heated and dissolved in ethyl acetate, and then cooled to room temperature, or the amorphous powder of MAP is dissolved in dichloromethane and concentrated in an appropriate amount, and then normal hexane is added thereto to have a melting point of 136 to 137 ° C. Crystalline Form I of MAP in colorless acicular form can be obtained. Form I of the MAP disclosed in this patent is 6.8, 10.05, 11.0, 13.2, 14.85, 15.3, 16.55, 17.9, 20.05, 20.75, 21.1, 21.7, 22.6, 24.9, 25.5, 26.25, 29.8 in X-ray powder diffraction analysis. And a 2θ diffraction angle of 31.0, and the corresponding X-ray powder diffraction spectrum is shown in FIG. 1.

Accordingly, an object of the present invention is to provide a high-purity, high-yield ( 1R, 5R, 6S ) -p -nitrobenzyl-2- ( It is to provide a novel process for preparing diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate (MAP) crystalline Form II.

In order to achieve the above object, in the present invention, ( 1R, 5R, 6S ) -p -nitrobenzyl-2- (diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] 1-Methyl-carbapenem-3-carboxylate (MAP) is dissolved in dichloromethane, chloroform or acetone, and then diethyl ether, isopropyl ether, normal hexane, normal heptane or cyclohexane is added to the solution. 6.98, 10.24, 10.62, 11.16, 15.02, 15.50, 16.72, 20.20, 20.72, 21.26, 22.20, 22.66, 25.06, 25.64, 26.02, 26.38, 28.00, in X-ray powder diffraction analysis, which comprises the step of dropping and crystallizing. Provided are methods for preparing Form II of MAP having 2θ diffraction angles of 29.98, 31.06, 35.40, 36.80, 39.42, 45.26, 45.80 and 49.04.

According to the method of the present invention, high purity, high yield ( 1R, 5R, 6S ) -p -nitrobenzyl-2- ( Diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate (MAP) crystalline Form II can be obtained.

( 1R, 5R, 6S ) -p -nitrobenzyl-2- (diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] -1-methyl-carbapenem-3- of the present invention The method for preparing carboxylate (MAP) crystalline Form II is obtained by dissolving crystalline Form I of MAP in a specific good solvent such as dichloromethane, chloroform or acetone, and then diethyl ether, isopropyl ether, It is characterized by crystallizing by dropwise addition of a specific crystallization solvent (or anti-solvent) such as normal hexane, normal heptane or cyclohexane.

MAP crystalline Form II to be prepared by the method of the present invention is 6.98, 10.24, 10.62, 11.16, 15.02, 15.50, 16.72, 20.20, 20.72, 21.26, 22.20, 22.66, 25.06, 25.64, 26.02, 26.38 in X-ray powder diffraction analysis. , 28.00, 29.98, 31.06, 35.40, 36.80, 39.42, 45.26, 45.80 and 49.04.

Since Form I of MAP used in the crystallization of the present invention is a known material prepared by performing a known method, for example, the conventional method exemplified in Japanese Patent No. 3080417, the present invention is directed to the method of preparing Form I. There is no particular restriction on this.

In the preparation method of the present invention, the ratio of solute (crystalline form I of MAP): good solvent (dichloromethane, chloroform or acetone, etc.), dissolution conditions and crystallization conditions, etc. depend on the kind of good solvent used, For example:

(1) When dichloromethane or chloroform is used as a good solvent

In order to dissolve Form I of MAP in the good solvent, dichloromethane or chloroform is added in an amount of 2 to 10 times the volume (ml / g), preferably, by weight of Form I of MAP at a temperature of 5 to 60 ° C. MAP in an amount of 3 to 8 times the volume by weight of Form I of MAP at a temperature of 10 to 40 ° C., more preferably 3 to 6 times the volume of Form I of MAP at 20 to 30 ° C. Mix with Form I.

Next, crystallization solvent, such as diethyl ether, isopropyl ether, normal hexane, normal heptane or cyclohexane, is added dropwise to the solution. In this case, when diethyl ether or isopropyl ether is used as the crystallization solvent, the amount thereof is used in an amount of 2 to 10 times the volume, preferably 4 to 5 times the volume of the weight of the crystalline form I of MAP. . On the other hand, when using normal hexane, normal heptane or cyclohexane as the crystallization solvent, the amount thereof is 1 to 10 times the volume, preferably 2 to 5 times the volume of the weight of Form I of MAP. . The crystallization solvent is preferably added dropwise to the solution over 0.1 to 3 hours, more preferably over 0.5 to 1 hour. When the crystallization solvent is added at one time, Form II of MAP may not be produced. Further, at the time of dropwise addition, it is preferable to stir for 0.5 to 3 hours, preferably 1 to 2 hours, while maintaining the temperature at 20 to 30 ° C, preferably 23 to 28 ° C. The dropping conditions and stirring conditions of the crystallization solvent may play an important role in obtaining the desired high yield, high purity MAP Form II.

(2) When using acetone as a good solvent

In order to dissolve Form I of MAP in the above good solvent, acetone is added in an amount of 2 to 10 times the volume of the weight of Form I of MAP at a temperature of 30 to 60 ° C., preferably at a temperature of 40 to 60 ° C. It is mixed with Form I of MAP in an amount of 3 to 8 times the volume by weight of Form I, more preferably in an amount of 4 to 6 times the volume of Form I of MAP at a temperature of 45 to 55 ° C.

Next, crystallization solvent, such as diethyl ether, isopropyl ether, normal hexane, normal heptane or cyclohexane, is added dropwise to the solution. In this case, when diethyl ether or isopropyl ether is used as the crystallization solvent, the amount thereof is 2 to 20 times by volume, preferably 8 to 12 times by volume, based on the weight of crystalline form I of MAP. . When using normal hexane, normal heptane or cyclohexane as the crystallization solvent, the amount thereof is used in an amount of 2 to 20 times by volume, preferably 9 to 13 times by volume, of the weight of Form I of MAP. The crystallization solvent is preferably added dropwise to the solution over 0.1 to 3 hours, more preferably over 0.5 to 1 hour. When the crystallization solvent is added at one time, Form II of MAP may not be produced. In addition, the dropwise temperature is preferably maintained at a temperature dissolved in acetone, that is, a temperature of 30 to 60 ° C, particularly preferably at a temperature of 45 to 55 ° C. After the dropping, the mixture is stirred at room temperature (20 to 30 ° C.) for 0.5 to 3 hours, preferably for 1 to 2 hours.

If crystals are obtained according to the above procedure, the crystals are filtered and dried according to a conventional method to obtain Form II of the desired MAP. At this time, it is preferable to dry in vacuum to shorten the drying time, it can be dried for 4 to 24 hours, preferably 8 to 12 hours at a temperature of 35 to 40 ℃ usually.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are provided to aid the understanding of the present invention, and do not limit the scope of the present invention.

Example

Example 1

50 g of Form I MAP was mixed with 200 ml of dichloromethane to completely dissolve MAP of Form I, and then 200 ml of isopropylether was added dropwise to the solution for 30 minutes. After stirring for 1 hour at 20-25 ° C, the crystals were separated by filtration using a vacuum filter. After washing with 20 ml of isopropyl ether, the obtained crystals were dried in vacuo at 40 ° C. to obtain 40.2 g of crystals having a purity of 99.9%. The finally obtained product was measured by X-ray powder diffraction (XRD), and it was confirmed that it was Form II of MAP as shown in FIG.

Example 2

At room temperature, 50 g of MAP of Form I was mixed with 200 ml of dichloromethane to completely dissolve MAP of Form I, and then 100 ml of cyclohexane was added dropwise to the solution for 30 minutes. After stirring for 1 hour at 20-25 ° C, the crystals were separated by filtration using a vacuum filter. After washing with 10 ml of cyclohexane, the obtained crystals were dried in vacuo at 40 ° C. to obtain 30.4 g of crystals having a purity of 99.6%. The finally obtained product was measured by XRD and found to be Form II of MAP as shown in FIG.

Example 3

50 g of Form I MAP was mixed with 200 ml of dichloromethane to completely dissolve MAP of Form I, and then 100 ml of normal heptane was added dropwise to the solution for 25 minutes. After stirring for 1 hour at 20-25 ° C, the crystals were separated by filtration using a vacuum filter. After washing with 20 ml of normal heptane, the obtained crystals were dried in vacuo at 40 ° C. to obtain 37.5 g of crystals having a purity of 99.8%. The finally obtained product was measured by XRD, and it was confirmed that it was Form II of MAP as shown in FIG.

Example 4

At room temperature, 50 g of MAP of Form I was mixed with 180 ml of chloroform to completely dissolve MAP of Form I, and then 200 ml of isopropylether was added dropwise to this solution for 25 minutes. After stirring for 1 hour at 20 to 25 ℃, the crystals were separated by filtration using a vacuum filter. After washing with 20 ml of isopropyl ether, the obtained crystals were dried in vacuo at 40 ° C. to obtain 36.5 g, 99.8% of purity. The finally obtained product was measured by XRD and found to be Form II of MAP as shown in FIG.

Example 5

50 g of MAP of Form I at 45-50 ° C. was dissolved by mixing with 200 ml of acetone. While maintaining the temperature, 200 ml of normal hexanes were added dropwise for 40 minutes. The temperature was cooled to 20-25 [deg.] C. and then stirred for 1 hour, followed by filtration using a vacuum filter to separate the crystals. After washing with 20 ml of normal hexane, the obtained crystals were dried in vacuo at 40 ° C. to obtain 45.5 g of crystals having a purity of 99.8%. The finally obtained product was measured by XRD and found to be Form II of MAP as shown in FIG.

1 is an X-ray diffraction spectrum for Form I of MAP.

2 is an X-ray diffraction spectrum of Form II of MAP prepared in Example 1 of the present invention.

3 is an X-ray diffraction spectrum of Form II of MAP prepared in Example 2 of the present invention.

4 is an X-ray diffraction spectrum of Form II of MAP prepared in Example 3 of the present invention.

5 is an X-ray diffraction spectrum of Form II of MAP prepared in Example 4 of the present invention.

6 is an X-ray diffraction spectrum of Form II of MAP prepared in Example 5 of the present invention.

Claims (10)

( 1R, 5R, 6S ) -p -nitrobenzyl-2- (diphenylphosphoryloxy) -6-[( R ) -1-hydroxyethyl] -1-methyl-carbapenem-3- of Form I Dissolving the carboxylate (MAP) in dichloromethane, chloroform or acetone, and then crystallizing in this solution by dropwise addition of diethylether, isopropylether, normal hexane, normal heptane or cyclohexane. 6.98, 10.24, 10.62, 11.16, 15.02, 15.50, 16.72, 20.20, 20.72, 21.26, 22.20, 22.66, 25.06, 25.64, 26.02, 26.38, 28.00, 29.98, 31.06, 35.40, 36.80, 39.42, Process for the preparation of Form II of MAP with 2θ diffraction angles of 45.26, 45.80 and 49.04. The method of claim 1, The dichloromethane or chloroform is used in an amount of 2 to 10 times the volume of the MAP weight of Form I. The method of claim 1, Wherein the acetone is used in an amount of 2 to 10 times the volume of the MAP weight of Form I. 4. The method according to any one of claims 1 to 3, The diethyl ether or isopropyl ether is used in an amount of 2 to 10 times the volume of the MAP weight of Form I when using dichloromethane or chloroform, and 2 to the MAP weight of Form I when using acetone Method for producing a volume, characterized in that used in an amount of 20 times. 4. The method according to any one of claims 1 to 3, The normal hexane, normal heptane or cyclohexane is used in an amount of 1 to 10 times the volume of the MAP weight of Form I when using dichloromethane or chloroform, 2 to 20 compared to the MAP weight of Form I when using acetone A method of producing, characterized in that it is used in an amount of pear volume. The method of claim 1, MAP of Form I is dissolved in dichloromethane or chloroform at a temperature of 5 to 60 ℃. The method of claim 1, MAP of Form I is dissolved in acetone at a temperature of 30 to 60 ℃. The method according to claim 1, 6 or 7, The diethyl ether, isopropyl ether, normal hexane, normal heptane or cyclohexane is added dropwise at a temperature of 20 to 30 ℃ when using dichloromethane or chloroform, the temperature of 30 to 60 ℃ when using acetone Manufacturing method characterized in that the dropwise. The method of claim 1, The diethyl ether, isopropyl ether, normal hexane, normal heptane or cyclohexane is added dropwise for 0.1 to 3 hours. The method of claim 1, After the dropwise addition, the manufacturing method characterized in that it further comprises the step of stirring for 0.5 to 3 hours at a temperature of 20 to 30 ℃.

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