KR20090031252A - Acid addition salts of synthetic intermediates for carbapenem antibiotics and processes for preparing the same - Google Patents

Abstract

A method for manufacturing acid addition salts is provided to secure a high yield and purity for the acid addition salts used as an intermediate of a carbapenem based antibiotic in no need of a column chromatography. A method for manufacturing acid addition salts comprises the following steps of: reacting a compound represented by the formula 1 to a compound represented by the formula 2; mixing an obtained reaction mixture with a mixed solvent of water and an organic solvent; adjusting pH to a range of 1 to 5 to aciditify the obtained reaction mixture; and separating an organic layer from the reaction mixture.

Description

Acid addition salts of synthetic intermediates for carbapenem antibiotics and processes for preparing the same}

The present invention relates to acid addition salts of synthetic intermediates of novel carbapenem antibiotics and methods for their preparation. The present invention also relates to a method for preparing a carbapenem antibiotic using the acid addition salt.

The increasing use of infectious diseases worldwide has markedly increased the use of antibiotics for their treatment. Since antibiotics have been used in clinical trials since the 1980s, penicillin-resistant pneumococci (PRSP) and methicillin-resistant staphylococcus (MRSA) have become a problem all over the world, and in the 1990s, the emergence of vancomycin-resistant enterococci (VRE) The problem of resistant bacteria is a great danger to the health of the world. There is an urgent need to develop new antibiotics that can effectively cure resistant bacteria caused by abuse and overuse of antibiotics.

Carbapenem antibiotics are the fourth-generation antibiotics. In 1976, thienamycin isolated from Actinomycetes Streptomyces Cattleya by Merck researchers is effective and produces β-lactamase with excellent antimicrobial activity and broad antibacterial spectrum. It has also been very effective in showing the effect of the bacteria. Since the discovery of thienamycin, studies on the synthesis of a carbapenem compound, which is a thienamycin analogue, have been actively conducted. As a result, various derivatives such as imipenem and meropenem have been developed and marketed.

1-beta-methylcarbapenem antibiotics are particularly well known for the treatment of a broad spectrum of Gram-negative, Gram-positive infections (US Pat. No. 4,962,103, US Pat. No. 4,933,333, US Pat. No. 4,943,569, US Pat. No. 5,122,604). number). Recently, 2-arylcarbapenem compounds (L-695256 and L-742728), carbapenem antibiotics, have been reported to show good activity against MRSA and VRSA (Hugh rosen et al., Sciences, 703 (1999)). WO 99/62906 discloses that 2-benzothiazoleethenyl carbapenem has a good effect on MRSA.

Carbapenem antibiotics, which have been developed and marketed so far, are difficult to secure low oral absorption and preservation safety in the digestive tract, and thus are clinically administered only by injection. As an oral carbapenem antibiotic with increased ease of taking, L-084 from Meiji, Japan, has been developed and is currently undergoing clinical trials (see US Patent No. 5,534,510).

Meanwhile, the present inventors have developed a carbapenem antibiotic having excellent antibacterial effect against methicillin resistant strain (MRSA) and quinolone resistant strain (ERSA) (Korean Patent Registration No. 10-0599876). The carbapenem antibiotic developed by the present inventors is prepared as shown in Scheme 1 below.

Wherein R ₁ and R ₂ are, independently from each other, hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, amino, trifluoromethyl or halogen, and R ₃ is hydrogen or C ₁ Is a C ₃ alkyl group, R ₄ is a hydrogen or hydroxy protecting group, R ₅ is a carboxy protecting group, and M is a hydrogen or a counterion forming a pharmaceutically acceptable salt.

As shown in Scheme 1, an intermediate compound of Formula 3 is prepared by reacting a compound of Formula 1 with a compound of Formula 2. However, in order to obtain the compound of Formula 3 purely, it is necessary to perform the column chromatography step in the final step, there is a problem that it is difficult to apply to mass production on an industrial scale. In addition, the yield of the product obtained by performing the column chromatography step, that is, the compound of formula 3, is only about 40%. Moreover, since the compound of Formula 3 is obtained in a liquid phase, there is a problem in that it is difficult to handle.

The present inventors conducted various studies to develop a method for producing a synthetic intermediate of carbapenem antibiotics, in particular, a compound of Formula 3 in high yield, without performing a process that is difficult to apply to a production site, such as column chromatography. It was. As a result, it was found that when the pH was simply adjusted and the intermediate was crystallized in the acid addition salt form in an organic solvent, an acid addition salt of the compound of formula 3 can be prepared in high yield and purity without performing column chromatography. In addition, it was found that the acid addition salt of the compound of Formula 3 is easy to handle because it is obtained in a solid form.

It is therefore an object of the present invention to provide a process for the preparation of synthetic intermediates of carbapenem antibiotics, i.e. acid addition salts of compounds of formula (3).

Another object of the present invention is to provide an acid addition salt of the compound represented by Chemical Formula 3.

Another object of the present invention is to provide a method for preparing a compound of Formula 4 or a pharmaceutically acceptable salt thereof using an acid addition salt of the compound of Formula 3.

According to one aspect of the invention, (a) reacting a compound of formula (1) and a compound of formula (2); (b) adding a mixed solvent of water and an organic solvent to the reaction mixture obtained in step (a), acidifying the pH to 1 to 5 and separating the organic layer; And (c) adding an organic solvent to the organic layer obtained in step (b) or a concentrate obtained by concentrating the organic layer to crystallize.

In the formula, R ₁ And R ₂ , independently of one another, is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, hydroxy, amino, trifluoromethyl, and R ₃ is hydrogen or C ₁ -C ₃ alkyl group , R ₄ is hydrogen or a hydroxy protecting group, and R ₅ is a carboxy protecting group.

According to another aspect of the present invention, an acid addition salt of the compound of formula 3 is provided:

<Formula 3>

In the formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined above.

According to another aspect of the present invention, there is provided a process for preparing a compound of formula 4 or a pharmaceutically acceptable salt thereof, comprising deprotecting an acid addition salt of a compound of formula 3:

<Formula 3>

Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined above and M is hydrogen or a counterion forming a pharmaceutically acceptable salt.

Synthetic intermediates of the carbapenem antibiotic according to the present invention, that is, a method for preparing acid addition salts of the compound of formula 3 can produce acid addition salts of the compound of formula 3 in high yield and purity without performing column chromatography. Suitable for mass production of scale. In addition, the acid addition salt of the compound of Formula 3 has a solid form, so that it is easy to handle and easy to store at the production site. In addition, when the deprotection reaction is performed using the acid addition salt of the compound of Formula 3, the compound of Formula 4 or a pharmaceutically acceptable salt thereof may be prepared in high yield and purity.

The present invention comprises the steps of (a) reacting a compound of formula 1 and a compound of formula 2; (b) adding a mixed solvent of water and an organic solvent to the reaction mixture obtained in step (a), acidifying the pH to 1 to 5 and separating the organic layer; And (c) adding an organic solvent to the organic layer obtained in step (b) to crystallize.

<Formula 1>

<Formula 2>

<Formula 3>

In the formula, R ₁ And R ₂ , independently of each other, is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, hydroxy, amino, trifluoromethyl, and R ₃ is hydrogen or a C ₁ -C ₃ alkyl group , R ₄ is hydrogen or a hydroxy protecting group, and R ₅ is a carboxy protecting group.

In the method for preparing an acid addition salt of the compound of formula 3 of the present invention, the hydroxy protecting group may be a conventional hydroxy protecting group such as tert-butyldimethylsilyl group and triethylsilyl group, and the carboxy protecting group is p Conventional carboxy protecting groups such as nitrobenzyl, allyl and p-methoxybenzyl groups.

The step (a), that is, the step of reacting the compound of Formula 1 and the compound of Formula 2 may be carried out according to the results of the present inventors (Korean Patent Registration No. 10-0599876). That is, the condensation reaction of the compound of formula 1 with the compound of formula 2 is carried out by dissolving the compound of formula 2 in anhydrous organic solvent such as acetonitrile, methylene chloride, tetrahydrofuran or acetone, preferably acetonitrile. After cooling to -20 ° C to 0 ° C, and slowly adding N, N-diisopropylethylamine or triethylamine, the compound of Formula 1 was added and stirred at -20 ° C to 0 ° C for 2 to 4 hours. This can be done.

The preparation method of the present invention includes adding a mixed solvent of water and an organic solvent to the reaction mixture obtained in step (a), acidifying the pH to 1 to 5, and then separating the organic layer [step (b)]. do.

In the mixed solvent of water and the organic solvent, the ratio of water and organic solvent is not particularly limited, and may be, for example, an equivalent ratio of 1:10, and more preferably 1: 1 equivalent ratio. Ethyl acetate, tetrahydrofuran, methylene chloride, isopropyl ether, petroleum ether, or diethyl ether may be used as the organic solvent.

The acidification to pH 1 to 5, preferably about pH 3 may use a conventional organic acid or inorganic acid, preferably inorganic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. By the acid used, the form of the acid addition salt of the compound of formula 3 finally obtained is determined. That is, when hydrochloric acid is used as the acidifying agent, hydrochloride of the compound of formula 3 is obtained, and when sulfuric acid is used, sulfate of the compound of formula 3 is obtained.

The production method of the present invention includes the step of crystallizing by adding an organic solvent to the organic layer obtained from step (b) or a concentrate obtained by concentrating the organic layer (step (c)).

The organic layer obtained by performing the step (b) may be applied directly to the crystallization step of step (c), and if necessary, the organic layer is concentrated by a conventional method such as vacuum concentration, and then the obtained concentrate (ie, residue). May be used to carry out the crystallization step of step (c).

As the organic solvent used in the crystallization step, ethyl acetate, acetone, toluene, n-hexane, or isopropyl ether may be preferably used, among which ethyl acetate or acetone may be preferably used. In the crystallization step, finally, the compound of formula 3 in pure acid addition salt form can be obtained by filtration, washing, and drying.

The acid addition salt of the compound of formula (3) obtained according to the preparation method of the present invention is a novel substance, can be usefully used in the synthesis of carbapenem antibiotic of formula (4) or a pharmaceutically acceptable salt thereof. Accordingly, the present invention encompasses acid addition salts of compounds of Formula 3:

<Formula 3>

In the formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined above.

The acid addition salt may be an inorganic acid salt, more preferably hydrochloride, sulfate, or phosphate.

The present invention includes a method for preparing a compound of formula (4) or a pharmaceutically acceptable salt thereof, which is a carbepenem-based agent, from an acid addition salt of the compound of formula (3). The prior patents of the present inventors, that is, the Republic of Korea Patent Registration No. 10-0599876 uses the compound of formula 3 in free base form as an intermediate for preparing the compound of formula 4 or a pharmaceutically acceptable salt. However, as described above, the compound of the general formula (3) in free base form has a liquid form, which is difficult to handle. Furthermore, when the deprotection reaction is carried out using the compound of formula 3 in acid addition salt form, it is possible to prepare the compound of formula 4 or a pharmaceutically acceptable salt thereof in high purity of at least 98% without performing any purification step. It is very amazing.

Accordingly, the present invention includes a process for preparing a compound of formula 4 or a pharmaceutically acceptable salt thereof, comprising deprotecting an acid addition salt of a compound of formula 3:

<Formula 3>

<Formula 4>

Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined above and M is hydrogen or a counterion forming a pharmaceutically acceptable salt.

In the method for preparing the compound of Formula 4 or a pharmaceutically acceptable salt thereof, the acid addition salt of the compound of Formula 3 may be preferably used in the preparation method as described above, the acid addition salt of the compound of Formula 3 It is preferably in the form of hydrochloride, sulfate, or phosphate. The deprotection may be performed according to the conditions disclosed in the inventors' prior patent (Korean Patent Registration No. 10-0599876).

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrating the present invention, the scope of the present invention is not limited to these examples.

Example  4- Nitrobenzyl  (1R, 5S, 6S) -2- [1- (4- Fluorobenzyl )- Azetidine -3-yl-thio] -6-[(1R) -1- Hydroxyethyl ]-One- Methylcarbaphene -2-m-3- Carboxylate  Hydrochloride

4-fluorobenzyl-azetidin-3-yl-thiol (25 g, 126 mmol) was dissolved in acetonitrile (400 ml) and cooled to -5 ° C. 4-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methylcarbafen-2-m-3-car Voxylate (50 g, 84 mmol) was added at the same temperature and diisopropylethylamine (102 ml) was added slowly and stirred for another 2 hours.

1,600 ml of a mixed solvent of ethyl acetate and purified water (1: 1, equivalent ratio) was added to the reaction mixture, and the mixture was acidified to pH 3 with an aqueous solution of dilute hydrochloric acid. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, anhydrous magnesium sulfate was added to remove water, and then concentrated under reduced pressure. 200 ml of acetone was added to the obtained residue, followed by stirring for 2 hours to crystallize. The reaction mixture was filtered and the obtained solid was dried to give the title compound (38 g, 78%) as white.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.15 (d, J = 7.5 Hz, 3H), 1.34 (d, J = 6.3 Hz, 3H), 3.11 (m, 2H), 3,23 (m, 2H), 3.72 (m, 2H), 3.95 (m, 1H), 4.21 (m, 2H), 5.34 (q, J = 13.8 Hz, 77 Hz2H), 6.98 (m, 2H), 7.20 (m, 2H), 7.65 (d , J = 8.7 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H).

Example  2. 4- Nitrobenzyl  (1R, 5S, 6S) -2- [1- (4- Fluorobenzyl )- Azetidine -3-yl-thio] -6-[(1R) -1-hi Doxyrie Teal] -1- Methylcarbaphene -2-m-3- Carboxylate  sulfate

The title compound was prepared in the same manner as in Example 1 except that a diluted aqueous sulfuric acid solution was used instead of a diluted aqueous hydrochloric acid solution.

Yield: 55%

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.15 (d, J = 7.5 Hz, 3H), 1.35 (d, J = 6.3 Hz, 3H), 3.10 (m, 2H), 3,24 (m, 2H), 3.72 (m, 2H), 3.94 (m, 1H), 4.22 (m, 2H), 5.34 (q, J = 13.8 Hz, 77 Hz2H), 6.97 (m, 2H), 7.20 (m, 2H), 7.63 (d , J = 8.7 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H).

Example  3. 4- Nitrobenzyl  (1R, 5S, 6S) -2- [1- (4- Fluorobenzyl )- Azetidine -3-yl-thio] -6-[(1R) -1-hi Doxyrie Teal] -1- Methylcarbaphene -2-m-3- Carboxylate  phosphate

The title compound was prepared in the same manner as in Example 1, except that a dilute phosphoric acid aqueous solution was used instead of the dilute hydrochloric acid aqueous solution.

Yield: 51%

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.16 (d, J = 7.5 Hz, 3H), 1.34 (d, J = 6.3 Hz, 3H), 3.12 (m, 2H), 3.25 (m, 2H), 3.72 ( m, 2H), 3.96 (m, 1H), 4.25 (m, 2H), 5.34 (q, J = 13.8 Hz, 77 Hz, 2H), 6.98 (m, 2H), 7.19 (m, 2H), 7.64 (d , J = 8.7 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H).

Example  4. (1R, 5S, 6S) -2- [1- (4- Fluorobenzyl )- Azetidine -3-yl-thio] -6-[(1R) -1- Hydroxyethyl ]-One- Methylcarbaphene -2-m-3- Carboxylic acid  Potassium salt

4-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-fluorobenzyl) -azetidin-3-yl-thio] -6-[(1R) -1 prepared in Example 1 -Hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate hydrochloride (38 g, 66 mmol) was dissolved in tetrahydrofuran (380 mL) and phosphate buffer (pH 7.0, 380 mL), 10 % Palladium / carbon (3.5 g) was added. After stirring for 3 hours at 25-30 degreeC and hydrogen stream (at atmospheric pressure), the catalyst was filtered off and the aqueous layer was separated. The separated aqueous layer was washed with ethyl acetate and lyophilized to give the title compound (23.1 g, 79%, HPLC purity over 98%) as a white solid.

¹ H NMR (300 MHz, D ₂ O) δ 1.17 (d, J = 7.3 Hz, 3H), 1.31 (d, J = 6.1 Hz, 3H), 3.20 (m, 1H), 3.41 (m, 1H), 3.69 (m, 2H), 4.07 (s, 2H), 4.18 (m, 5H), 7.20 (m, 2H), 7.40 (m, 2H).

Claims (10)

(a) reacting a compound of Formula 1 with a compound of Formula 2; (b) adding a mixed solvent of water and an organic solvent to the reaction mixture obtained in step (a), acidifying the pH to 1 to 5 and separating the organic layer; And (c) crystallizing by adding an organic solvent to the organic layer obtained in step (b) or a concentrate obtained by concentrating the organic layer. Method for producing an acid addition salt of the compound of formula 3 comprising: <Formula 1>

<Formula 2>

<Formula 3>

In the formula, R ₁ And R ₂ , independently of one another, are hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, hydroxy, amino, trifluoromethyl, R ₃ is hydrogen or a C ₁ -C ₃ alkyl group, R ₄ is hydrogen or a hydroxy protecting group, R ₅ is a carboxy protecting group. The process according to claim 1, wherein the organic solvent of step (b) is ethyl acetate, tetrahydrofuran, methylene chloride, isopropyl ether, petroleum ether, or diethyl ether. The process according to claim 1, wherein the acidification of step (b) is carried out using an inorganic acid. 4. The process according to claim 3, wherein the inorganic acid is hydrochloric acid, sulfuric acid, or phosphoric acid. The process according to claim 1, wherein the organic solvent of step (c) is ethyl acetate, acetone, toluene, n-hexane, or isopropyl ether. Acid addition salts of compounds of formula 3: <Formula 3>

In the formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined in claim 1. 7. The acid addition salt of the compound of formula (I) according to claim 6, wherein the acid addition salt is hydrochloride, sulfate, or phosphate. A process for preparing a compound of formula (4) or a pharmaceutically acceptable salt thereof, comprising deprotecting an acid addition salt of a compound of formula (3): <Formula 3>

<Formula 4>

Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined in claim 1 and M is hydrogen or a counterion to form a pharmaceutically acceptable salt. The method according to claim 8, wherein the acid addition salt of the compound of formula 3 is prepared by the method according to any one of claims 1 to 5. The method according to claim 8, wherein the acid addition salt of the compound of formula 3 is a hydrochloride, sulfate, or phosphate salt of the compound of formula 3.