KR101118145B1 - Process for preparing synthetic intermediates of penem or carbapenem antibiotics - Google Patents

Abstract

The present invention provides an improved method for preparing optically active (S) -4-phenyl-3-propionyloxazolidin-2-one. The present invention also relates to (3S, 4S)-[(R) -1 '-((hydroxyprotecting group) oxy) ethyl] -4-[(R) -1-carboxyethyl], a synthetic intermediate of penem or carbapenem. Provided is an improved method for preparing 2-azetidinone (β-4-BMA). The production process according to the invention is suitable for industrial scale mass production and can produce β-4-BMA in high yield.

β-4-BMA, carbapenem

Description

Process for preparing synthetic intermediates of penem or carbapenem antibiotics

The present invention relates to an improved process for preparing optically active (S) -4-phenyl-3-propionyloxazolidin-2-one and to a process for preparing synthetic intermediates of penem or carbapenem antibiotics using the same.

Penem or carbapenem-based compounds, including meropenem, paropenem, and viapenem, are known as antibiotics with strong antimicrobial activity. For example, meropenem exhibits a broad antimicrobial spectrum against bacteria, including aerobic and anaerobic bacteria, and particularly good antimicrobial activity against gram positive bacteria. In addition, by introducing a beta-methyl group, the stability of DHP-1 is superior to that of imipenem, which is a kind of conventional carbapenem antibiotics, and it is known that cilastatin can be used alone without the need for body stability like imipenem.

Meanwhile, (3S, 4S)-[(R) -1 '-((hydroxyprotecting group) oxy) ethyl] -4-[(R) -1-carboxyethyl] -2-azetidinone represented by the following formula: (β-4-BMA) is known as a key intermediate for the synthesis of penem or carbapenem antibiotics.

In the above formula, R is a hydroxy protecting group such as hydrogen or tert-butyldimethylsilyl.

HETEROCYCES , Vol. 21, 1984, 29-40 discloses the preparation of β-4-BMA. However, the manufacturing method has to use a strong base, and the reaction must be carried out at -78 ° C of extremely low temperature, there are many problems in mass production on an industrial scale. In addition, there is a disadvantage that a large number of compounds having an undesired 1-α-methyl group are produced with a ratio of α / β of 4: 1 obtained.

In order to solve the above problems, various optically active chiral compounds such as (S) -4-phenyl-3-propionyloxazolidin-2-one, (S) -4-isopropyl A method for synthesizing β-4-BMA using chiral compounds such as -3-propionyloxazolidin-2-one has been developed.

For example, U.S. Pat.No. 5,104,984 discloses an intermediate in the form of an enol by reacting (S) -4-isopropyl-3-propionyloxazolidin-2-one with an enolating agent. A method of preparing an azetidine compound to which an oxazolidinone moiety has been introduced by reacting with an azetidine derivative having an acetoxy moiety, and finally a method of preparing β-4-BMA has been disclosed. However, the preparation method according to US Pat. No. 5,104,984 has a long problem because the reaction step has to be performed to react the enolating agent.

In addition, EP0974582 discloses chiral compounds such as (S) -4-phenyl-3-propionyloxazolidin-2-one and azetidine derivatives having a 4-acetoxy moiety and t-butylmagnesium chloride. After reacting in the presence of magnesium compounds such as to prepare an azetidine compound in which an oxazolidinone moiety is introduced, a method of finally producing β-4-BMA has been disclosed. The preparation method is relatively simple because there is no need to perform an enolation reaction separately, but there is a problem in that the yield of β-4-BMA finally obtained is very low. That is, according to the preparation method of EP0974582, the yield of the pre-stage material of β-4-BMA (i.e., the azetidine compound into which the oxazolidinone moiety is introduced) is only 59% (see Example 18). Finally, if β-4-BMA is produced, the yield becomes even lower.

In addition, Org. Pro. Res & Dev 2005, 9, 827-829 discloses the reaction of (A) -4-phenyl-3-propionyloxazolidin-2-one with an azetidine derivative having a 4-acetoxy moiety in the presence of Lewis acid and base After preparing an azetidine compound into which a zolidinone moiety is introduced, a method of finally preparing β-4-BMA has been disclosed. However, the above production method also has a very low yield of β-4-BMA of 65%.

European Patent Publication No. EP0974582 and Org. Pro. In order to prepare (S) -4-phenyl-3-propionyloxazolidin-2-one used as chiral compound in Res & Dev 2005, 9, 827-829, strong base such as n-BuLi, NaH, etc. Should be used. However, when the reaction is performed using a strong base, there is a risk of fire and dangerous handling, so it is difficult to apply to mass production on an industrial scale.

Therefore, there is a need in the art for the development of a method that is suitable for industrial scale mass production and capable of producing β-4-BMA in high yield.

The present inventors carried out various studies to solve the above problems of the prior art. As a result, when preparing (S) -4-phenyl-3-propionyloxazolidin-2-one as a chiral compound in combination with a Lewis acid and a weak base, fire risks and handling difficulties due to the use of a strong base It is found that not only is it suitable for industrial scale production, but also (S) -4-phenyl-3-propionyloxazolidin-2-one can be produced in a high yield of about 95%. It was. Furthermore, when Lewis acid was divided into two and reacted with (S) -4-phenyl-3-propionyloxazolidin-2-one and an azetidine derivative having a 4-acetoxy moiety, It was found that the yield can be increased to about 80%.

Accordingly, it is an object of the present invention to provide an improved method for preparing optically active (S) -4-phenyl-3-propionyloxazolidin-2-one.

It is also an object of the present invention to provide a method for producing β-4-BMA in high yield using (S) -4-phenyl-3-propionyloxazolidin-2-one.

According to one aspect of the invention, there is provided a process for the preparation of a compound of formula 2 comprising reacting a compound of formula 1 with propionyl halide or propionyl anhydride in the presence of a Lewis acid and a weak base:

In the formula, Ph is phenyl.

LiCl may be preferably used as the Lewis acid, and triethylamine may be preferably used as the weak base.

According to another aspect of the present invention, (a) adding 1 to 3 equivalents of Lewis acid to the compound of Formula 2 based on 1 equivalent of the compound of Formula 3, followed by adding a base; (b) adding 0.3 to 0.6 equivalents of a Lewis acid and a compound of Formula 3 to the reaction mixture of step (a) based on 1 equivalent of compound of Formula 3 is provided.

<Formula 2>

Wherein Ph is phenyl and R is a hydroxy protecting group.

According to another aspect of the present invention, (a) adding 1 to 3 equivalents of Lewis acid to the compound of Formula 2 based on 1 equivalent of the compound of Formula 3, followed by adding a base; (b) adding 0.3 to 0.6 equivalents of Lewis acid and the compound of Formula 3 to the reaction mixture of Step (a) based on 1 equivalent of the compound of Formula 3 to prepare a compound of Formula 4; And (c) adding hydrogen peroxide and LiOH or NaOH to the compound of Chemical Formula 4 to react.

<Formula 2>

<Formula 3>

<Formula 4>

Wherein Ph is phenyl and R is a hydroxy protecting group.

In the method of preparing the compound of Formula 4 or compound of Formula 5, the Lewis acid used in step (a) and step (b) is TiCl ₄ , ZnCl ₂ , ZnBr ₂ , chlorotrimethylsilane (TMSCl), tert-butyldimethylsilyltrifluoromethanesulfonate (TBDMSOTf), or boron trifluoride diethyl etherate (BF ₃ (OEt) ₂ ), preferably TiCl ₄ . In addition, the step of adding the Lewis acid and the compound of formula 3 to the reaction mixture of step (a) of step (b) is the temperature of the reaction mixture of step (a) to 20 ~ 30 ℃, more preferably about 25 ℃ It is preferably carried out by adjusting and then adding Lewis acid and the compound of formula (3). Also, step (a) and step (b) are in place ( in preferably in a situ ) reaction.

In the method of preparing the compound of Formula 4 or the compound of Formula 5, the compound of Formula 2 as a starting material is in the presence of Lewis acid, preferably LiCl, and a weak base, preferably triethylamine, as described above. It can be obtained by a process comprising the step of reacting the compound of formula (1) with propionyl halide or propionyl anhydride.

 According to the present invention, when preparing a chiral compound (S) -4-phenyl-3-propionyloxazolidin-2-one in combination with a Lewis acid and a weak base, the risk of fire caused by the use of a strong base and It is not only suitable for industrial scale production, but also produces (S) -4-phenyl-3-propionyloxa zolidin-2-one in a high yield of about 95% without causing problems of handling difficulties. It turned out. Further, according to the present invention, the Lewis acid is divided into two and reacted with an azetidine derivative having a (S) -4-phenyl-3-propionyloxazolidin-2-one and a 4-acetoxy moiety, thereby providing β-4. It has been found that the yield of -BMA (ie, compound of formula 5) can be increased to about 80%. Therefore, the preparation method of the present invention is suitable for mass production on an industrial scale, and can produce β-4-BMA (i.e., a compound of formula 5) in high yield.

The present invention provides a process for preparing a compound of formula 2 comprising reacting a compound of formula 1 with propionyl halide or propionyl anhydride in the presence of a Lewis acid and a weak base:

<Formula 1>

<Formula 2>

In the formula, Ph is phenyl.

The production method according to the present invention is suitable for production on an industrial scale by performing the reaction without using a strong base such as n-BuLi, NaH, without causing problems of fire risk and handling difficulty due to the use of the strong base. It has also been found by the present invention that the compound of formula 2 can be prepared in a high yield of about 95% when used in combination with Lewis acid and weak base. This is a conventional production method that does not use Lewis acid, that is, Org. Pro. It is surprising that the manufacturing method disclosed in Res & Dev 2005, 9, 827-829 shows a yield of 82%.

Starting compounds of Formula 1, propionyl halides (e.g., propionyl chloride, propionyl iodide, etc.), and propionyl anhydride, which are starting materials, are commercially available as known materials.

The Lewis acid includes LiCl, ZnCl ₂ , ZnBr ₂ , or boron trifluoride diethyl etherate (BF ₃ (OEt) ₂ ), preferably LiCl. In addition, the weak base includes triethylamine, diisopropylethylamine, tributylamine, diethylamine, and the like, and preferably triethylamine. The amount of the Lewis acid and the weak base is not particularly limited, but may be in the range of 1.0 to 1.2 equivalents and 1.2 to 1.5 equivalents, respectively, based on 1 equivalent of the compound of Formula 1.

The reaction of the compound of Formula 1 with propionyl halide or propionyl anhydride is carried out in a conventional organic solvent, for example, an organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile, preferably tetrahydrofuran. Can be.

In addition, the reaction of the compound of Formula 1 with propionyl halide or propionyl anhydride may be terminated using an aqueous solution of sodium bicarbonate, etc., extracted with ethyl acetate and the like, and dried according to a conventional method. The compound can be separated. The compound of formula 2 obtained as above is a known method, for example, Org. Pro. Intermediates of carbapenem or penem antibiotics ((3S, 4S)-[(R) -1 '-((hydroxyprotecting group) oxy) ethyl] -4, according to the preparation methods disclosed in Res & Dev 2005, 9, 827-829) -[(R) -1-carboxyethyl] -2-azetidinone).

The present inventors have used (3S, 4S)-[(R) -1 '-((hydroxyprotecting group) oxy) ethyl] -4-, one of the key intermediates of carbapenem or penem antibiotics, using the compound of formula (2). While studying the method of synthesizing [(R) -1-carboxyethyl] -2-azetidinone, surprisingly, when the compound of formula 2 is reacted with the compound of formula 2 by dividing Lewis acid twice, it is possible to effectively block side reactions. Core intermediates prepared via intermediates (compounds of Formula 4), i.e. (3S, 4S)-[(R) -1 '-((hydroxyprotecting group) oxy) ethyl] -4-[(R) -1-carboxyethyl ] -2-azetidinone (compound of formula 5) was found to be able to greatly improve the yield. Accordingly, the present invention encompasses an improved process for preparing a compound of formula 4 from a compound of formula 2 and an improved process for preparing a compound of formula 5 from a compound of formula 2 via a compound of formula 4.

That is, the present invention comprises the steps of: (a) adding 1 to 3 equivalents of Lewis acid to the compound of Formula 2 to 1 equivalent of the compound of Formula 3, followed by adding a base; (b) adding 0.3 to 0.6 equivalents of Lewis acid and a compound of Formula 3 to the reaction mixture of step (a) based on 1 equivalent of compound of Formula 3 to react;

<Formula 2>

<Formula 3>

<Formula 4>

Wherein Ph is phenyl and R is a hydroxy protecting group.

In addition, the present invention comprises the steps of (a) adding 1 to 3 equivalents of Lewis acid to the compound of Formula 2 to 1 equivalent of the compound of Formula 3, and then adding a base; (b) adding 0.3 to 0.6 equivalents of Lewis acid and the compound of Formula 3 to the reaction mixture of step (a) based on 1 equivalent of the compound of Formula 3 to prepare a compound of Formula 4; And (c) reacting the compound of Formula 4 with hydrogen peroxide and adding LiOH or NaOH to react the compound of Formula 5.

<Formula 2>

<Formula 3>

<Formula 4>

<Formula 5>

Wherein Ph is phenyl and R is a hydroxy protecting group.

Representation of the step of preparing a compound of Formula 5 from the compound of Formula 2 is shown in Scheme 1 below.

In said Scheme 1, Ph is phenyl and R is a hydroxy protecting group. The hydroxy protecting group includes a hydroxy protecting group conventionally used in the field of organic chemistry, for example tert-butyldimethylsilyl, trimethylsilyl, benzyl, methyl, and the like, preferably tert-butyldimethylsilyl.

In Scheme 1, the starting compound is preferably prepared as mentioned above.

In the method of preparing the compound of Formula 4 or the compound of Formula 5, the base used in step (a) includes weak bases such as diisopropylethylamine, triethylamine, tributylamine, diethylamine, and the like. Preferably diisopropylethylamine. The amount of the base used is not particularly limited, but may be used in the range of 1 to 2 equivalents, more preferably about 1.59 equivalents, based on 1 equivalent of the compound of Formula 3.

The Lewis acid used in steps (a) and (b) is TiCl ₄ , ZnCl ₂ , ZnBr ₂ , chlorotrimethylsilane (TMSCl), tert-butyldimethylsilyltrifluoromethanesulfonate, TBDMSOTf ), Or boron trifluoride diethyl etherate (BF ₃ (OEt) ₂ ), preferably TiCl ₄ . The amount of the Lewis acid used in step (a) may be in the range of 1 to 3 equivalents, more preferably about 1.6 equivalents, and the amount of the Lewis acid used in step (b) is in the range of 0.3 to 0.6 equivalents, more Preferably about 0.6 equivalents.

The amount of the compound represented by Formula 2 may be in the range of 1 to 2 equivalents, more preferably 1.2 to 1.4 equivalents, based on 1 equivalent of the compound of Formula 3.

The temperature of adding the compound of Formula 2, Lewis acid and base in step (a) may be in the range of -20 ~ 10 ℃, more preferably -5 ~ 5 ℃.

In the method for preparing the compound of Formula 4 or the compound of Formula 5, the step of adding the Lewis acid and the compound of Formula 3 to the reaction mixture of step (a) is a reaction mixture of step (a) It is preferably carried out by adjusting the temperature to 20 to 30 ° C., more preferably to room temperature (about 25 ° C.) and then adding Lewis acid and the compound of formula (3). If the temperature is less than 20 ℃ the reaction rate is slow, if it exceeds 30 ℃ may generate more impurities. The reaction time of step (b) may range from 0.5 to 1 hour.

Also, step (a) and step (b) are in place ( in is preferably carried out in a situ ) reaction, which makes the process suitable for industrial production in mass production. The method of preparing the compound of Formula 4 or the compound of Formula 5 may be performed in an organic solvent such as methylene chloride, dichloroethane, chloroform, and preferably, methylene chloride. The amount of the solvent used is not particularly limited, but may be 5 to 50 times the weight based on the amount of the compound of Formula 3.

Step (c) carried out to prepare the compound of formula 5 is a known method, for example Org. Pro. It can be carried out according to the method disclosed in Res & Dev 2005, 9, 827-829. That is, the compound of formula 5 may be obtained by adding hydrogen peroxide and LiOH or NaOH to the compound of formula 4 obtained in step (b).

When the compound of Formula 5 is prepared according to the present invention as described above, (3S, 4S)-[(R) -1 '-((hydroxyprotecting group) oxy) ethyl] -4- in a high yield of about 80% [(R) -1-carboxyethyl] -2-azetidinone can be prepared, which is less than 59% (EP0974582) or 65% (Org. Pro. Res & Dev 2005, 9, 827-829). Given the yield of), it is very surprising.

Hereinafter, the present invention will be described in more detail by way of examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1: Preparation of (S) -4-phenyl-3-propionyloxazolidin-2-one

100 g of (S) -4-phenyl-oxazolidin-2-one was dissolved in 500 ml of tetrahydrofuran, cooled to 0 ° C., 33 g of LiCl was added, and then 111 ml of triethylamine was added slowly. After stirring the reaction mixture for 30 minutes, 83 ml of propionyl anhydride was slowly added over 30 minutes. The temperature of the reaction mixture was gradually raised to room temperature and stirred for 1.5 hours. The reaction mixture was cooled to 0 ° C., 300 ml of 5% aqueous sodium bicarbonate solution was added, and then stirred for 30 minutes. 300 ml of ethyl acetate was added to the reaction mixture, followed by extraction three times. The combined organic layers were washed with 300 ml of 1.5N HCl and 300 ml of brine. The organic layer was dried and distilled to give 128 g of the title compound as a solid (yield: 95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.26-7.39 (m, 5H), 5.42 (dd ,, 1H), 4.68 (dd, 1H), 4.28 (dd, 1H), 2.95 (q, 2H), 1.11 (t, 3H)

Example 2: Preparation of (S) -4-phenyl-3-propionyloxazolidin-2-one

128 g of the title compound was obtained in the same manner as in Example 1, except that 56 g of propionyl chloride was used instead of propionyl anhydride (yield: 95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.26-7.39 (m, 5H), 5.42 (dd ,, 1H), 4.68 (dd, 1H), 4.28 (dd, 1H), 2.95 (q, 2H), 1.11 (t, 3H)

Example 3: (S) -3-((R) -2- (3-((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) prop Preparation of Panoyl) -4-phenyloxazolidin-2-one

44 g of (S) -4-phenyl-3-propionyloxazolidin-2-one is dissolved in 890 ml of methylene chloride, cooled to 0 ° C. and then TiCl ₄ 55 g was added slowly. After the reaction mixture was stirred at -5 ° C for 1 hour, 40 g of diisopropylethylamine were added, the temperature was raised to room temperature (about 25 ° C), and then (3R, 4R) -4-acetoxy-3- [ 50 g of (R) -1 '-(tert-butyldimethylsilyl) oxy) ethyl] -2-azetidinone and TiCl ₄ 28 g was added. The reaction mixture was stirred at rt for 0.5 h, then cooled to 0 ° C. and 890 ml of water were added. After separating the organic layer, MgSO ₄ Dry over and distill to give 95 g of the title compound. The product obtained was used for the next reaction without purification.

Example 4: Preparation of (3S, 4S)-[(R) -1 '-((tert-butyldimethylsilyl) oxy) ethyl] -4-[(R) -1-carboxyethyl] -2-azetidinone

(S) -3-((R) -2- (3-((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidine-2-prepared in Example 3 (I) 95 g of propanoyl) -4-phenyloxazolidin-2-one is dissolved in a mixed solvent of 350 ml of acetone and 200 ml of water, 50 ml of H ₂ O _{2 is added} , and then at 0 ° C. for 1 hour. Stirred. A solution obtained by dissolving 20 g of LiOH.H ₂ O in 150 ml of water was dissolved in the reaction mixture, added over 30 minutes, and then stirred for 1 hour. 500 ml of water and 500 ml of methylene chloride were added to the reaction mixture, and the layers were separated. The obtained organic layer was distilled off and 20 g of (S) -4-phenyl-oxazolidin-2-one was recovered. In addition, the obtained aqueous layer was adjusted to pH 2.5 using 6N HCl, and the resulting crystals were filtered to give 42 g of the title compound (yield: 80%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 6.5 (br s, 1H), 4.3 (m, 1H), 3.97 (dd, 1H), 3.05 (ddm, 1H), 2.85 (m, 1H), 1.29 (d , 3H), 1.22 (d, 3H), 0.89 (s, 9H), 0.08 (s, 6H)

Claims (13)

delete delete delete (a) adding 1 to 3 equivalents of a Lewis acid to the compound of Formula 2 based on 1 equivalent of the compound of Formula 3, followed by adding a base; And (b) adjusting the temperature of the reaction mixture of step (a) to 20 to 30 ° C., and then adding 0.3 to 0.6 equivalents of Lewis acid to 1 equivalent of the compound of Formula 3 and the compound of Formula 3 to react the same. Method for preparing a compound of formula 4 comprising: <Formula 2>

<Formula 3>

<Formula 4>

Wherein Ph is phenyl and R is a hydroxy protecting group. (a) adding 1 to 3 equivalents of a Lewis acid to the compound of Formula 2 based on 1 equivalent of the compound of Formula 3, followed by adding a base; (b) adjusting the temperature of the reaction mixture of step (a) to 20 to 30 ° C., and then adding 0.3 to 0.6 equivalents of Lewis acid to 1 equivalent of the compound of formula 3 and compound 3 to react with Preparing a compound; And (c) reacting the compound of Formula 4 with hydrogen peroxide and adding LiOH or NaOH. <Formula 2>

<Formula 3>

<Formula 4>

<Formula 5>

Wherein Ph is phenyl and R is a hydroxy protecting group. The method according to claim 4 or 5, wherein the Lewis acid used in steps (a) and (b) is TiCl ₄ , ZnCl ₂ , ZnBr ₂ , chlorotrimethylsilane, tert-butyldimethylsilyltrifluoromethanesulfonate, Or boron trifluoride diethyl etherate. 7. A process according to claim 6 wherein the Lewis acid used in steps (a) and (b) is TiCl ₄ . delete delete The method of claim 4 or 5, wherein step (a) and step (b) are in place ( in). situ ) the process characterized in that the reaction is carried out. The method according to claim 4 or 5, wherein the compound of formula 2 is obtained by a process comprising the step of reacting a compound of formula 1 with propionyl halide or propionyl anhydride in the presence of a Lewis acid and a weak base. Characteristic manufacturing method: <Formula 1>

12. The process according to claim 11, wherein said Lewis acid is LiCl. The method according to claim 11, wherein the weak base is triethylamine.