KR20200031934A - Preparation method of Penem derivatives using packed-bed continuous flow reaction - Google Patents

Abstract

The present invention provides a method for manufacturing a penem derivative using a fixed-bed continuous flow reaction. When synthesizing the penem derivative by using the fixed-bed continuous flow reaction according to the present invention, it is possible to synthesize the high-quality penem derivative which is very safe, has greatly reduced reaction time, and has high efficiency compared to a conventional batch type reaction. According to the present invention, by performing a hydrogenation reaction under reaction conditions that do not substantially include water, it is possible to greatly improve a conversion ratio (a compound 1 : a compound 2) of the hydrogenation reaction of the compound 1.

Description

Preparation method of Penem derivatives using packed-bed continuous flow reaction}

The present invention relates to a method for producing a Peten derivative using a fixed-phase continuous flow reaction.

Peten derivatives are prepared through the process of reducing a starting material having a benzyl ester to a peten derivative having a carboxylic acid through a hydrogenation reaction. Conventionally, a process of reducing these benzyl esters using metal Pd / C and hydrogen in a batch has been performed. The technique of synthesizing a peptone derivative using metal Pd / C and hydrogen is dangerous because an explosion risk is inherent. In addition, although a technique for synthesizing a peten derivative through a hydrogenation reaction using another metal catalyst is also known, this also does not solve the safety problem.

On the other hand, a fixed-phase continuous flow reaction {Continuous flow reaction} is a method of inducing a reaction by continuously supplying a small amount of a sample to be reacted into a reactor unlike a conventional batch reaction, and using this continuous flow. If it proceeds, a high-risk reaction, for example, a hydrogenation reaction, a cryogenic reaction, a high temperature reaction, an oxidation reaction, a reduction reaction, etc., can be performed with high efficiency. When the stationary phase continuous flow reaction is used, the reaction time is significantly reduced than the basic batch reaction due to excellent mixing efficiency and heat transfer efficiency, and the drug substance can be synthesized with high efficiency.

The present inventors intend to provide a technique capable of safely synthesizing peten derivatives while satisfying yield, quality, and the like.

Accordingly, the present invention provides a novel method for producing a Peten derivative through a fixed-phase continuous flow reaction.

Peten derivatives in the present invention may be represented by the compound of Formula 1.

[Formula 1]

In the above formula,

The compound of Formula 1 may be obtained by reducing the compound of Formula 2 having a benzyl ester.

[Formula 2]

The present invention comprises synthesizing a compound of formula 1 by hydrogenating a compound of formula 2 in the presence of a metal catalyst through continuous flow synthesis under substantially water-free reaction conditions,

Provided is a method for preparing a compound of Formula 1.

[Formula 1]

[Formula 2]

In the present invention, it is important to synthesize the compound of Formula 1 by hydrogenating the compound of Formula 2 in the presence of a metal catalyst through continuous flow synthesis under “substantially water-free reaction conditions”. As can be seen in the following comparative example, when the hydrogenation reaction proceeds in a conventional batch type reactor, the conversion rate of the hydrogenation reaction of the compound 1 is not good even when the hydrogenation reaction is performed using a metal catalyst of the same type as the present invention, and a related substance The production rate of was high. On the other hand, in the Examples of the present invention, the conversion of the hydrogenation reaction of the compound 1 (compound 1: compound 2) was increased to 92% to 97% by proceeding the hydrogenation reaction under a reaction condition substantially free of water. .

"Substantially under water-free reaction conditions" means, for example, that the amount of water present in the reaction conditions is less than 5% (w / v). Here, `` the amount of water present in the reaction conditions '' refers to substances introduced into the reactor for a hydrogenation reaction including a starting material, a solvent, and / or a catalyst, for example, the amount of water in 1 L of a reactant solution. It means the amount of existence. Preferably, the amount of water present in the reaction conditions is less than 3% (w / v), 2% (w / v) or 1% (w / v). More preferably, the amount of water present in the reaction conditions is less than 1% (w / v), such as 0.5% (w / v), 0.1% (w / v), 0.05% (w / v), or 0.01 less than% (w / v).

Synthesis of the compound of Formula 1 according to the present invention can be achieved by performing a hydrogenation reaction while flowing the reactant solution and hydrogen dissolving the compound of Formula 2 in a protic solvent into a reactor containing a continuous flow channel. have.

The compound of Formula 2 is used as a starting material for the stationary phase continuous flow reaction, and it is necessary to dissolve the compound of Formula 2 in a solvent to introduce it into the reactor including the continuous flow channel.

At this time, as a solvent used to dissolve the compound of Formula 2, a protic solvent may be used. For example, as a solvent, alcohols, dialkyl ketones (R = C1 to C4), tetrahydrofuran, dichloromethane, 1,4-dioxane, or mixtures thereof can be used, although not limited thereto.

In one embodiment of the invention, the protic solvent may be C _1-6 alcohol. For example, methanol, ethanol, isopropyl alcohol, butyl alcohol, and the like can be used.

The concentration of the compound of Formula 2 dissolved in the protic solvent is not limited thereto, but is 0.005 to 5% (wt / v), for example, 0.01 to 2% (wt / v) 0.01 to 1% (wt / v) ), 0.01 to 0.5% (wt / v), 0.02 to 0.2% (wt / v).

Therefore, it is preferred that the protic solvent used to dissolve the compound of Formula 2 also substantially does not contain water. For example, the purity of the protic solvent may be 95% (w / v) or more, and the moisture content in the protic solvent may be less than 5% (w / v). Preferably, the purity of the protic solvent is 99% (w / v) or more, and the moisture content in the protic solvent may be less than 0.1% (w / v).

The reactor used in the fixed bed continuous flow reaction in the present invention includes a continuous flow channel.

The reactor including the continuous flow channel may be divided into a fixed-bed flow reactor or a moving-bed flow reactor according to a method of introducing a catalyst. The process of the hydrogenation reaction after the introduction of the catalyst proceeds the same for both types.

In the fixed bed flow reactor, the catalyst is filled in the cartridge column for continuous flow reaction, and the reaction proceeds in a manner that the reactant solution passes through the cartridge column. Specifically, after filling the cartridge column with a catalyst, washing with a solvent to remove water, warming the temperature of the catalyst cartridge column, supplying hydrogen to pass hydrogen to a saturated state, and then flowing a reaction solution.

The mobile bed flow reactor is a method in which a catalyst is not fixed to a cartridge column and is introduced into a fixed bed continuous flow reactor together with a reactant solution. The catalyst is placed in a reactant solution (i.e., a mixture of starting material, base and solvent) into a continuous flow reactor and mixed uniformly. To proceed with the hydrogenation reaction, the temperature of the reactor is warmed and the reactant solution is flowed after passing hydrogen.

Fixed bed flow reactors and mobile bed flow reactors that can be used for a fixed bed continuous flow reaction are well known in the art, and there is no particular limitation on the type of reactor that can be used in the present invention. Those skilled in the art can select and use a reactor having a form and an internal structure suitable for the synthesis of the compound of Formula 1 of the present invention.

In one embodiment of the present invention, the reactor comprising a continuous flow channel may be a fixed bed flow reactor. In the examples below, a fixed bed flow reactor was used to elicit a reaction with excellent product yield and quality.

The fixed bed flow reactor is not limited thereto, and may be a columnar column reactor. The fixed bed flow reactor is not limited to this depending on the type of its internal structure, for example, CSTR, multitubular reactor, multibed reactor, Fluidizied-bed reactor, Tray-column reactor, etc. It is separated by. The type of the fixed bed flow reactor that can be used is not particularly limited, but in one embodiment of the present invention, a multibed reactor can be used as the fixed bed flow reactor.

Meanwhile, the internal pressure in the reactor may be 1 to 100 atm. The internal pressure in the reactor can affect the reaction time and reaction quality. Without being limited thereto, for example, the internal pressure in the reactor may be 1 to 50 atm, 1 to 30 atm, 1 to 20 atm, or 1 to 10 atm. In an embodiment of the invention, the internal pressure in the reactor can be adjusted, for example, 3 to 6 atm, 4 to 5 atm.

It may be desirable to give an appropriate rate when flowing a reactant solution in which a compound of Formula 2 is dissolved in a protic solvent into a reactor.

Although not limited thereto, in an embodiment of the present invention, the reactant solution may be introduced into the reactor at a flow rate of 30 to 200 μl / ml.

The flow rate of the reactant solution may be adjusted differently depending on whether the type of reactor to be used is a fixed bed flow reactor or a moving bed flow reactor. For example, when using a fixed bed flow reactor, the flow rate of the reactant solution may be, for example, 20 to 100 μl / min, 30 to 90 μl / min, 40 to 80 μl / min, or 50 to 60 μl / min Can be If a mobile bed flow reactor is to be used, the flow rate of the reactant solution may be, for example, 70 to 130 μl / min, 80 to 120 μl / min, or 90 to 110 μl / min.

Hydrogen is also introduced into the reactor in order to proceed with the hydrogenation of the compound of Formula 2 contained in the reactant solution.

Without being limited thereto, hydrogen is introduced into the reactor at a flow rate of 1 to 10 ml / min. For example, the flow rate of hydrogen can be adjusted to 3 to 8 ml / min, or 4 to 6 ml / min. In this case, the hydrogen supply pressure in the reactor can be pressurized to, for example, 1 to 10 bar, 2 to 8 bar, 3 to 6 bar, such as 5 bar or 3 bar.

Additionally, a dispenser at the inlet of the reactor to control the proper inflow / emission amount in the reactor or to maintain a uniform passage time, such that the starting material introduced first into the reactor becomes a product and is first released and the starting material introduced later is released later. It may be desirable to attach.

On the other hand, in the present invention, the catalyst used for the hydrogenation reaction can affect the yield and rate of the reaction.

Unlike the conventional method of producing Pd / C, a metal Pd / C is used as a catalyst, the present invention uses a metal catalyst.

In the present invention, the metal catalyst may be selected from the group consisting of Pd, Rh, Ru, Pt, Ni, Pd / C, Ni-Al alloy catalyst and Raney-Ni catalyst. In one embodiment of the present invention, the metal catalyst may be a Pd / C or Ni-Al alloy catalyst. Preferably, the metal catalyst may be a Raney-Ni catalyst. In particular, an example of a kind of a catalyst suitable for use in a mobile bed flow reactor is a homogeneous catalyst made of ruthenium, rhodium or a mixture thereof.

Without being limited thereto, the weight ratio of the starting material compound of Formula 2 and the catalyst may be used in a ratio of 1: 0.3 to 0.9, for example, 1: 0.4 to 0.8, 1: 0.5 to 0.7.

As described above, in the synthesis reaction of the compound of formula 1 according to the present invention, the important thing is to maintain substantially water-free conditions. Therefore, it is important that no matter what catalyst is used, it does not contain water in the entire reaction process. Metal catalysts are usually provided with water due to their reactivity. Therefore, in order to implement the present invention, before using the metal catalyst for the hydrogenation reaction, the metal catalyst is washed with a metal catalyst that is substantially free of water (for example, a protic solvent used in the reactant solution). It is important to ensure that water is not substantially included.

In the present invention, but is not limited thereto, the reaction temperature for the hydrogenation reaction may be 10 to 90 ℃. In one embodiment of the present invention, the reaction temperature for the hydrogenation reaction may be, for example, 20 to 80 ° C, 30 to 70 ° C, or 40 to 60 ° C.

Synthesis of a Peten derivative using a fixed-phase continuous flow reaction according to the present invention is very safe compared to a conventional batch type reaction, the reaction time is greatly reduced to a level of 1/5 or less, and a high quality Peten derivative with high efficiency Can be synthesized. In particular, according to the present invention, the conversion of the hydrogenation reaction of compound 1 (compound 1: compound 2) to about 83:17 to 92: 3 (compound) 1: the ratio of compound 2) can be greatly improved.

Advantages and features of the present invention, and a method of achieving them will be clarified with reference to embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various different forms, and only the embodiments allow the disclosure of the present invention to be complete, and common knowledge in the technical field to which the present invention pertains. It is provided to fully inform the holder of the scope of the invention, and the invention is only defined by the scope of the claims.

[Example]

Example 1

The cartridge column for the continuous-phase continuous flow reaction was filled with 0.67 g of a palladium hydroxide catalyst and washed with isopropyl alcohol to remove water contained in the catalyst. 1.0 g of starting material compound 1 was dissolved in 50 mL of isopropyl alcohol, and then stirred at room temperature for 10 minutes.

The temperature of the catalyst cartridge column was heated to 40 ° C., the hydrogen flow rate was supplied at 5 mL / min, and a hydrogenation reaction was performed by flowing the flow rate of the reaction solution at a rate of 100 μL / min. The temperature of the catalyst column was raised to 80 ° C. at a rate of 5 mL / min of hydrogen flow rate, and the flow rate of the reaction solution was fixed at 60 μL / min to perform a hydrogenation reaction.

It was produced in a yield of 95% of compound 1 within minutes at the end of the reaction, and the conversion rate of the hydrogenation reaction of compound 1 (of compound 1: of compound 2) was obtained from 92% to 97%.

Example 2

The cartridge column for continuous flow reaction was charged with 0.67 g of Raney Ni catalyst and water was removed using isopropyl alcohol. 1.0 g of starting material compound 1 was dissolved in 50 mL of isopropyl alcohol, and then stirred at room temperature for 10 minutes.

The temperature of the catalyst cartridge column was heated to 40 ° C., a hydrogen flow rate was supplied at 5 mL / min, and a hydrogenation reaction was performed by flowing a flow rate of the reaction solution at a rate of 60 μL / min. The temperature of the catalyst column was raised to 80 ° C. at a rate of 5 mL / min of hydrogen flow rate, and the flow rate of the reaction solution was fixed at 60 μL / min to perform a hydrogenation reaction.

Within a few minutes from the end of the reaction, Compound 1 was produced in a yield of 95%, and the conversion rate of the hydrogenation reaction of Compound 1 (of Compound 1: of Compound 2) was obtained from 92% to 97%.

Example 3

1.0 g of the starting material compound was dissolved in 50 mL of isopropyl alcohol in a general reactor and stirred at room temperature for 10 minutes. The palladium hydroxide catalyst was washed three times with 0.67 g of 10 ml of isopropyl alcohol and filtered under nitrogen atmosphere. Finally, a palladium hydroxide catalyst wet with isopropyl alcohol was added to the reaction solution and mixed uniformly. The temperature of the continuous flow reactor was warmed to 40 ° C. The flow rate of the reaction solution was flowed to the first line of the continuous flow reactor at a rate of 100 μL / min, and the hydrogen flow rate was performed by supplying hydrogen flow rate to 5 mL / min and hydrogen pressure to 5 bar in the second line. After the reaction was completed, the catalyst was filtered. Within a few minutes from the end of the reaction, Compound 1 was produced in a yield of 95%, and the conversion rate of the hydrogenation reaction of Compound 1 (of Compound 1: of Compound 2) was obtained from 92% to 97%.

Example 4

1.0 g of starting material compound 1 was dissolved in 10 mL of isopropyl alcohol in a general reactor and stirred at room temperature for 10 minutes. Under nitrogen atmosphere, the Raney Ni catalyst was washed 3 times with 0.67 g of 10 ml of isopropyl alcohol and filtered. Finally, a Raney Ni catalyst wet with isopropyl alcohol was added to the reaction solution and mixed uniformly. The temperature of the continuous flow reactor was warmed to 40 ° C. The flow rate of the reaction solution was flowed to the first line of the continuous flow reactor at a rate of 100 μL / min, and the hydrogenation reaction was performed by supplying hydrogen flow rate to 5 mL / min and hydrogen pressure at 5 bar to the second line. After the reaction was completed, the catalyst was filtered. Within a few minutes from the end of the reaction, Compound 1 was produced in a yield of 95%, and the conversion rate of the hydrogenation reaction of Compound 1 (of Compound 1: of Compound 2) was obtained from 92% to 97%.

Example 5

1.0 g of starting material compound 1 was dissolved in 50 mL of isopropyl alcohol in a general reactor and stirred at room temperature for 10 minutes. Under a nitrogen atmosphere, 0.67 g of a palladium carbon catalyst was washed with 10 mL of isopropyl alcohol, filtered and repeated three times, and the palladium carbon catalyst wet with isopropyl alcohol was added to the solution and mixed uniformly. The temperature of the continuous flow reactor is set to 40 ° C. and warmed. The flow rate of the reaction solution was flowed to the first line of the continuous flow reactor at a rate of 100 μL / min, and the hydrogen was constantly supplied while maintaining the hydrogen flow rate of 5 mL / min and the hydrogen pressure of 5 bar using the second line. After completion of the reaction, the catalyst is filtered. At the end of the reaction, within a few minutes, Compound 1 was produced in a yield of 95%, and the conversion rate of the hydrogenation reaction of Compound 1 (of Compound 1: of Compound 2) was obtained at 92-97%.

Example 6

Fill the cartridge column for continuous flow reaction with 0.67 g of palladium carbon (Pd / C) and remove water with isopropyl alcohol. 1.0 g of starting material compound 1 was dissolved in 50 mL of isopropyl alcohol and stirred at room temperature for 10 minutes. The temperature of the catalyst cartridge column was set to 40 ° C to warm it, and the hydrogen flow rate was supplied at 5 mL / min, and the flow rate of the reaction solution was flowed at a rate of 100 μL / min to perform the hydrogenation reaction. At a rate of 5 mL / min of hydrogen flow, the temperature of the catalyst column was raised to 80 ° C., and the flow rate of the reaction solution was fixed at 60 μL / min to perform hydrogenation reaction. At the end of the reaction, within a few minutes, Compound 1 was produced in a yield of 95%, and the conversion rate of the hydrogenation reaction of Compound 1 (of Compound 1: of Compound 2) was obtained at 92-97%.

Claims (8)

Comprising the synthesis of a compound of formula 1 by hydrogenating the compound of formula 2 in the presence of a metal catalyst through a continuous flow synthesis under substantially water-free reaction conditions,
Method of preparing the compound of formula 1:
[Formula 1]

; And
[Formula 2]

.
According to claim 1,
Synthesis of the compound of Formula 1 includes performing a hydrogenation reaction by flowing a reactant solution in which the compound of Formula 2 is dissolved in a protic solvent and hydrogen into a reactor including a continuous flow channel.
Method of preparing a compound of Formula 1.
According to claim 2,
The reactor including the continuous flow channel is a fixed-bed flow reactor or a moving-bed flow reactor.
Method of preparing a compound of Formula 1.
According to claim 2,
The internal pressure in the reactor is 1 to 100 atm
Method of preparing a compound of Formula 1.
According to claim 2,
The reactant solution is introduced into the reactor at a flow rate of 30 to 200 μl / min.
Method of preparing a compound of Formula 1.
According to claim 2,
Hydrogen is introduced into the reactor at a flow rate of 1 to 10 ml / min.
Method of preparing a compound of Formula 1.
According to claim 1,
The metal catalyst is selected from the group consisting of Pd, Rh, Ru, Pt, Ni, Pd / C, Ni-Al alloy catalyst and Raney-Ni catalyst
Method of preparing a compound of Formula 1.
According to claim 1,
The reaction temperature for the hydrogenation reaction is 10 to 90 ℃
Method of preparing a compound of Formula 1.