WO2022222249A1

WO2022222249A1 - Method for obtaining 1-n-ethyl gentamicin c1a by using pipeline reaction hydrolysis

Info

Publication number: WO2022222249A1
Application number: PCT/CN2021/099584
Authority: WO
Inventors: 王彬; 姜迎庆; 尤岚; 袁文俊; 李培鹏
Original assignee: 无锡济煜山禾药业股份有限公司
Priority date: 2021-04-24
Filing date: 2021-06-11
Publication date: 2022-10-27
Also published as: CN113185561A

Abstract

Involved is a method for obtaining 1-N-ethyl gentamicin C1a by using hydrolysis in a pipeline reactor. The method comprises the following steps: 1) pumping an etimicin synthesis solution and a NaOH solution into a temporary storage tank to be hydrolyzed, and mixing to obtain a reaction mixed solution; 2) opening a pipeline reactor to enable the temperature of a pipeline to reach about 100°C; 3) pumping the reaction mixed solution in step 1) into the pipeline reactor, controlling the temperatures of the inlet and outlet of a first reaction pipeline (1) to be 95-100°C, controlling the temperatures of the inlet and outlet of a second reaction pipeline (2) to be 100-110°C, keeping the temperature of the solution at 100-105°C, and performing hydrolysis for 6 hours; 4) after the reaction is completed, opening the circulating water supply valve and the circulating water return valve of a clamping sleeve on the pipeline reactor (3), and cooling to be close to room temperature; and 5) pumping a hydrolyzed reaction solution into a hydrolysis storage tank from the pipeline reactor (3).

Description

A method for obtaining 1‐N‐ethyl gentamicin C1a by hydrolysis via pipeline reaction

technical field

The invention belongs to the field of semi-synthetic chemical pharmacy, and relates to an efficient hydrolysis method of 1-N-ethyl gentamicin C1a.

Background technique

Aminoglycosides are glycosides formed by linking amino sugars and aminocyclic alcohols through oxygen bridges. There are natural aminoglycosides such as streptomycin from Streptomyces, gentamicin and other natural aminoglycosides from Micromonospora, and semi-synthetic aminoglycosides such as etimicin, all of which are broad-spectrum antibiotics.

Etimicin sulfate is a new generation of semi-synthetic aminoglycoside antibiotics with high efficiency, low toxicity and resistance to drug-resistant bacteria developed by Chinese researchers with independent intellectual property rights. It is the only one that has obtained the national first-class new drug certificate. Anti-infective drugs.

At present, the hydrolysis equipment used in the production of etimicin is a traditional reaction tank. The operation steps are: pumping the cooled synthetic solution into the hydrolysis tank, stirring, and vacuum pumping the prepared sodium hydroxide solution. Open jacket steam valve, return valve, condenser, ice water jacket inlet and outlet valve. After heating to boiling, adjust the steam valve to maintain proper reflux, control the liquid temperature to be about 100 °C, and hydrolyze for about 30 hours. The traditional equipment is large in size, high in space occupancy, inconvenient to operate, and not conducive to precise control of process parameters. It has many disadvantages such as low production yield, long cycle, and high environmental pressure when used to hydrolyze etimicin.

However, the commonly used stirred tank reactors used in the current production mainly have the following defects:

(1) The device is large, the space occupancy rate is high, the investment is huge, and the investment in large-scale production is even greater;

(2) The production capacity is limited, and the output of each kettle of the constant volume reaction is consistent;

(3) The power consumption is large and the energy consumption is high;

(4) Due to vigorous stirring and mixing, it is not conducive to the precise control of process parameters;

(5) It is difficult to realize continuous centralized control operation, and the labor cost is high.

Therefore, it is necessary to develop high-efficiency hydrolysis process equipment, react and continuously discharge materials, so as to improve product quality and promote green chemistry.

SUMMARY OF THE INVENTION

Aiming at the deficiencies of the prior art, the present invention aims to provide an efficient pipeline reactor for efficient hydrolysis to obtain 1-N-ethyl gentamicin C1a. The most critical step of etimicin hydrolysis is carried out in this pipeline reactor, the reactor is under the alkaline condition of 20% sodium hydroxide solution, boiling and refluxing, stirring and hydrolyzing to remove acetyl group and silyl group, to obtain 1 ‐N‐Ethyl gentamicin C1a hydrolyzate. The use of the reactor can improve the yield, reduce the occurrence of side reactions, and also has the characteristics of convenient operation and continuous discharge.

To this end, the present invention provides a method for obtaining 1-N-ethyl gentamicin C1a by using pipeline reaction hydrolysis, and the steps of the method are as follows:

1) The etimicin synthesis solution and the NaOH solution are drawn into the temporary storage tank to be hydrolyzed, and mixed to obtain a reaction mixture;

2) Open the pipeline reactor to make the tube temperature reach about 100℃;

3) Pump the reaction mixture in step 1) into the pipeline reactor, control the inlet and outlet temperatures of the first reaction pipeline (1) to be 95-100°C, and the inlet and outlet temperatures of the second reaction pipeline (2) to be 100-110°C. Keep the temperature at 100-105℃, hydrolyze for 6 hours;

4) After the reaction is completed, open the upper jacket of the pipeline reactor (3) to circulate the water supply and the circulation return valve, and cool down to near room temperature;

5) Pumping the hydrolyzed reaction solution from the pipeline reactor (3) into the hydrolysis storage tank.

The method of the present invention further comprises the following steps: confirming that the temperature of the chilled water is in the range of 5-10°C; confirming that the industrial steam pressure is in the range of 0.2-0.3MPa; confirming that the vacuum degree of the vacuum pump is in the range of -0.07--0.09MPa; 20% NaOH solution.

Wherein, the etimicin synthesis solution refers to the substitution and aldehyde addition reaction of P1 powder with hexamethyldisilazane and acetaldehyde, followed by reduction with potassium borohydride to obtain silylated triacetyl 1-N- Ethyl gentamicin C1a. where P1 refers to 3,2″,6″‐tri‐N‐acetyl genta C1a base (O‐3‐deoxy‐4‐C‐methyl‐3‐(methylamino)‐β‐L‐arabinopyridine) Anosyl-(1→6)-O-[2-acetamido-6-acetamido-2,3,4,6-tetradeoxy-α-D-erythro-hexopyranosyl- (1→4)]-2-Deoxy-N-3-Acetyl-D-Streptamine. Under alkaline conditions, the synthesis solution was stirred and hydrolyzed in a pipeline reactor to remove acetyl and silyl groups to obtain 1 ‐N‐Ethyl gentamicin C1a hydrolyzate.

The hydrolysis temporary storage tank is a 316L stainless steel storage tank with a stirring paddle, a steam jacket and a liquid level gauge of 1000L.

The hydrolysis storage tank is a 316L 1000L stainless steel storage tank with a liquid level gauge.

Preferably, in the method of the present invention, the steps are as follows:

1) The etimicin synthetic liquid and 20% NaOH liquid are drawn into the temporary storage tank to be hydrolyzed, and preliminary mixing is carried out;

2) Open the steam valve on the pipeline reactor, open the chilled water inlet and return valves of the condenser jacket, open the feed and discharge valves on the pipeline reactor, open the jacket steam valve, and open the steam bypass valve to the steam condensate. After ejection, close the steam bypass valve, and slowly make the temperature of the pipe reach about 100℃;

3) Turn on the feed pump on the pipeline reactor, pump the synthetic liquid into the reactor, and control the inlet and outlet temperature of the first reaction pipeline (1) to be 95-100°C by adjusting the steam feed, and the second reaction pipeline (2) The inlet and outlet temperature is 100-110°C, the liquid temperature is kept at 100-105°C, and normal hydrolysis is maintained for about 6 hours;

4) After the sampling point panel shows that the hydrolysis is complete, close the jacket steam valve, and close the chilled water inlet and return valves of the hydrolysis condenser jacket. Open the upper jacket of the pipeline reactor to circulate the feed water and the circulating return water valve, and cool down to near room temperature.

5) Pump the hydrolyzate into the metering hydrolysis storage tank.

The structure of the pipeline reactor of the present invention is shown in Figure 1.

The pipeline reactor includes a first reaction pipeline (1), a second reaction pipeline (2), and a third reaction pipeline (3), wherein each reaction pipeline includes pipelines connected end to end in sequence and distributed on the same horizontal plane. A feeding pipe (4) and a feeding pipe (5), the free end of the feeding pipe is provided with a feeding port (6), and the feeding port is provided with a feeding port for pumping the material to be reacted in the feeding pipe through the feeding port The feeding pump (7) of the first reaction pipe (1) is connected with the feeding pipe of the second reaction pipe (2) using a quick interface (8); the feeding pipe of the second reaction pipe (2) is connected to the The feeding pipes of the three reaction pipes (3) are connected by quick joints; the feeding pipes of the third reaction pipes (3) are connected to the final metering hydrolysis storage tank (9).

Wherein, the pipelines (1)-(3) of the pipeline reactor are provided with a main steam heating pipe (10) and at least two sets of auxiliary steam heating pipes (11), and the pipeline reactor (3) is jacketed with circulating feed water and circulating return water valves (12)

Preferably, there are two sets of auxiliary steam heating pipes described in the present invention.

Preferably, the auxiliary steam heating pipe described in the present invention is a casing type heating pipe.

A flow regulator (13) is arranged at the inlets of the main steam heating pipe and the auxiliary steam heating pipe in the pipeline reactor of the present invention.

The outlet of each set of auxiliary steam heating tubes described in the present invention is closer to the inlet end of the pipeline reactor than the inlet of each set of auxiliary steam heating tubes.

The present invention consists in using the pipeline reactor of the present invention to prepare etimicin.

The method of the present invention has the following main steps: firstly mixing the etimicin synthesis solution and 20% sodium hydroxide solution according to certain conditions, and then sending the mixed raw materials into the pipeline reactor from the inlet end of the pipeline reactor (1) for carrying out reaction, and finally the reaction product is sent out from the outlet end of the pipeline reactor (3).

In the method of the present invention, after the reactants pass through the area with a temperature of 80-95°C near the inlet end of the pipeline reactor (1), the temperature is controlled to react at 100-105°C, and the reaction product is sent out from the outlet end of the pipeline reactor (1). In the pipeline reactor (2) at 108-112 °C, the reactants are reacted in the region of 100-110 °C, and finally the reaction product is sent out from the outlet end of the pipeline reactor (2) and enters the cooling pipeline reactor (3).

The reaction flow diagram of the present invention is shown in accompanying drawing 2.

The temperature control described in the method of the present invention is achieved by controlling the temperature and flow of steam in the secondary steam heating tubes in each zone of the pipeline reactor.

In the method described in the present invention, the reaction time of the reactants through the zone where the temperature is controlled at 108-112°C is half of the total reaction time in the pipeline reactor.

In another method of the present invention, the reactants pass through the reaction time in the temperature zone of 80-95°C, the reaction time in the zone at the temperature of 108-110°C and the reaction time in the temperature zone at the temperature of 100-110°C respectively occupy the pipeline One third of the total reaction time of the reactants in the reactor. In order to reduce the occurrence of the above-mentioned side reactions and improve the yield, the pipeline reactor is designed in the present invention, including at least two sets of auxiliary steam heating pipes. The temperature of the tube heating area is different. The inlet of the main steam heating tube and the auxiliary steam heating tube is designed with a flow regulator. When different temperatures are required according to the reaction, it can be realized by controlling the flow and temperature of the steam. Each heating area of the auxiliary steam heating pipe is also provided with a temperature detection device to detect its temperature.

For the main steam heating pipe and the auxiliary steam heating pipe, the flow direction of the steam is opposite to the flow direction of the reactants in the pipeline reactor. The main reaction can proceed smoothly, reducing the occurrence of side reactions.

The invention utilizes pipeline reactor technology to obtain 1-N-ethyl gentamicin C1a from etimicin synthesis liquid. By adopting the method for hydrolysis to obtain etimicin, it is convenient to use, small in size and small in space occupation rate, sustainable in reaction, continuous in material discharge, short in synthesis reaction time, fast in reaction rate and high in product yield.

Description of drawings

Reference numerals: 1. Feed pipe 2. Feed pump 3. Feed pipe 4. Feed port 5. Quick interface 6 Auxiliary steam outlet 7. Feed pipe 8. Auxiliary steam inlet valve 9. Material outlet 10. Steam regulating valve 11. Steam outlet 12. Steam inlet 13. Three-way interface 14. Circulating water outlet 15. Circulating water inlet 16. Right-angle interface

Fig. 1 is the pipeline reactor structure diagram of the present invention

Fig. 2 is the reaction process flow chart of the present invention

Detailed ways:

The following examples further illustrate the present invention, but are not intended to limit the present invention.

Example 1

Put 200L of 20% lye in the temporary storage tank of hydrolyzate, pump 180L of 8907 synthetic solution (P1 powder 32.4kg moisture 0.42%), open the stirring paddle of the temporary storage tank of hydrolyzate, open the feeding pump, and put the material in the pipeline reactor 1 and the pipeline reactor 2 circulate for 5 minutes, open the main steam valve and the auxiliary steam inlet and outlet valves, adjust the steam valve, make the temperature of the pipeline reactor 1 be 100 ℃, the temperature of the pipeline reactor 2 is 110 ℃, and the flow is temporarily removed from the hydrolyzate. The storage tank enters the pipeline reactor 1 through the pump, and then enters the pipeline reactor 2, the control flow is 200L/H, and the reaction is carried out for 6 hours. When the reaction reaches 5 hours, the circulating water inlet and outlet on the pipeline reactor 3 is opened, and the temperature is lowered in advance, and the reaction is carried out for 6 hours. Afterwards, open the valve leading to the pipeline reactor 3, conduct cooling and cooling, and put the material into the hydrolysis storage tank. The volume of the measured feed liquid was 376L, the measured titer was 64800U/ml, and the product yield was 75.2%. The 8907 peak accounted for 83.6% by using ELSD to detect the hydrolyzate.

Example 2

Put 200L of 20% lye in the temporary storage tank of hydrolyzate, pump 180L of 8907 synthetic solution (P1 powder 32.6kg moisture 0.34%), open the stirring paddle of the temporary storage tank of hydrolyzate, open the feeding pump, put the material in the pipeline reactor 1 and the pipeline reactor 2 circulate for 5 minutes, open the main steam valve and the auxiliary steam inlet and outlet valves, adjust the steam valve, make the temperature of the pipeline reactor 1 be 100 ℃, the temperature of the pipeline reactor 2 is 110 ℃, and the flow is temporarily removed from the hydrolyzate. The storage tank enters the pipeline reactor 1 through the pump, and then enters the pipeline reactor 2, the control flow is 200L/H, and the reaction is carried out for 6 hours. When the reaction reaches 5 hours, the circulating water inlet and outlet on the pipeline reactor 3 is opened, and the temperature is lowered in advance, and the reaction is carried out for 6 hours. Afterwards, open the valve leading to the pipeline reactor 3, conduct cooling and cooling, and put the material into the hydrolysis storage tank. The volume of the measured feed liquid is 372L, the measured titer is 66000U/ml, the product yield is 75.3%, and the 8907 peak ratio is 84.1% using ELSD to detect the hydrolyzate.

Example 3

Put 200L of 20% lye in the hydrolyzate temporary storage tank, pump 180L of 8907 synthetic liquid (P1 powder 32.4kg moisture 0.38%), open the stirring paddle of the hydrolyzate temporary storage tank, open the feeding pump, and put the material in the pipeline reactor 1 and the pipeline reactor 2 circulate for 5 minutes, open the main steam valve and the auxiliary steam inlet and outlet valves, adjust the steam valve, make the temperature of the pipeline reactor 1 be 100 ℃, the temperature of the pipeline reactor 2 is 110 ℃, and the flow is temporarily removed from the hydrolyzate. The storage tank enters the pipeline reactor 1 through the pump, and then enters the pipeline reactor 2, the control flow is 200L/H, and the reaction is carried out for 6 hours. When the reaction reaches 5 hours, the circulating water inlet and outlet on the pipeline reactor 3 is opened, and the temperature is lowered in advance, and the reaction is carried out for 6 hours. Afterwards, open the valve leading to the pipeline reactor 3, conduct cooling and cooling, and put the material into the hydrolysis storage tank. The volume of the measured feed liquid is 373L, the measured titer is 67320U/ml, and the product yield is 77.5%. Using ELSD to detect the hydrolyzate, the 8907 peak accounts for 85.1%.

Claims

A method for obtaining 1-N-ethyl gentamicin C1a by hydrolysis in a pipeline reactor, the method steps are as follows:

1) The etimicin synthesis solution and the NaOH solution are drawn into the temporary storage tank to be hydrolyzed, and mixed to obtain a reaction mixture;

2) Open the pipeline reactor to make the tube temperature reach about 100℃;

3) Pump the reaction mixture in step 1) into the pipeline reactor, control the inlet and outlet temperatures of the first reaction pipeline (1) to be 95-100°C, and the inlet and outlet temperatures of the second reaction pipeline (2) to be 100-110°C. Keep the temperature at 100-105℃, hydrolyze for 6 hours;

4) After the reaction is completed, open the upper jacket of the pipeline reactor (3) to circulate the water supply and the circulation return valve, and cool down to near room temperature;

5) Pumping the hydrolyzed reaction solution from the pipeline reactor (3) into the hydrolysis storage tank.
The method according to claim 1, the steps are as follows:

1) The etimicin synthetic liquid and 20% NaOH liquid are drawn into the temporary storage tank to be hydrolyzed, and preliminary mixing is carried out;

2) Open the steam valve on the pipeline reactor, open the chilled water inlet and return valves of the condenser jacket, open the feed and discharge valves on the pipeline reactor, open the jacket steam valve, and open the steam bypass valve to the steam condensate. After ejection, close the steam bypass valve, and slowly make the temperature of the pipe reach about 100℃;

3) Turn on the feed pump on the pipeline reactor, pump the synthetic liquid into the reactor, and control the inlet and outlet temperature of the first reaction pipeline (1) to be 95-100°C by adjusting the steam feed, and the second reaction pipeline (2) The inlet and outlet temperature is 100-110°C, the liquid temperature is kept at 100-105°C, and normal hydrolysis is maintained for about 6 hours;

4) After the sampling point panel shows that the hydrolysis is complete, close the jacket steam valve, and close the chilled water inlet and return valves of the hydrolysis condenser jacket. Open the upper jacket of the pipeline reactor to circulate the feed water and the circulating return water valve, and cool down to near room temperature.

5) Pump the hydrolyzate into the metering hydrolysis storage tank.
The method according to claim 1, wherein the pipeline reactor comprises a first reaction pipeline (1), a second reaction pipeline (2), and a third reaction pipeline (3), wherein each reaction pipeline comprises an end-to-end connection in sequence The feeding pipe (4) and the feeding pipe (5) are distributed on the same horizontal plane, the free end of the feeding pipe is provided with a feeding port (6), and the feeding port is provided with a feeding port for passing the feeding The feeding pump (7) of the material to be reacted is pumped into the feeding pipe, and the feeding pipe of the first reaction pipe (1) and the feeding pipe of the second reaction pipe (2) are connected by a quick interface (8); The feeding pipe of the pipeline (2) is connected with the feeding pipe of the third reaction pipe (3) by a quick joint; the feeding pipe of the third reaction pipe (3) is connected to the final metering hydrolysis storage tank (9).

Wherein, the pipelines (1)-(3) of the pipeline reactor are provided with a main steam heating pipe (10) and at least two sets of auxiliary steam heating pipes (11), and the pipeline reactor (3) is jacketed with circulating feed water and circulating return water valves (12), a flow regulator (13) is provided at the inlets of the main steam heating pipe and the auxiliary steam heating pipe in the pipeline reactor.
A pipeline reactor, comprising a first reaction pipeline (1), a second reaction pipeline (2), and a third reaction pipeline (3), wherein each reaction pipeline comprises pipelines connected end to end in sequence and distributed on the same horizontal plane. A feeding pipe (4) and a feeding pipe (5), the free end of the feeding pipe is provided with a feeding port (6), and the feeding port is provided with a feeding port for pumping the material to be reacted in the feeding pipe through the feeding port The feeding pump (7) of the first reaction pipe (1) is connected with the feeding pipe of the second reaction pipe (2) using a quick interface (8); the feeding pipe of the second reaction pipe (2) is connected to the The feeding pipes of the three reaction pipes (3) are connected by quick joints; the feeding pipes of the third reaction pipes (3) are connected to the final metering hydrolysis storage tank (9).

Wherein, the pipelines (1)-(3) of the pipeline reactor are provided with a main steam heating pipe (10) and at least two sets of auxiliary steam heating pipes (11), and the pipeline reactor (3) is jacketed with circulating feed water and circulating return water valves (12), a flow regulator (13) is provided at the inlets of the main steam heating pipe and the auxiliary steam heating pipe in the pipeline reactor.
The pipeline reactor according to claim 4, wherein there are three sets of the auxiliary steam heating pipes.
The pipeline reactor according to claim 4, wherein the auxiliary steam heating pipe is a casing type heating pipe.
The pipeline reactor according to claim 4, wherein the outlet of each set of auxiliary steam heating tubes is close to the inlet end of the pipeline reactor relative to the inlet of each set of auxiliary steam heating tubes.
The method according to claim 1, the step is: firstly mixing the etimicin synthesis solution and 20% sodium hydroxide solution, then sending the mixed raw materials into the pipeline reactor from the inlet end of the pipeline reactor (1) The reaction is carried out, and finally the reaction product is sent out from the outlet end of the pipeline reactor (3).
The method according to claim 8, wherein, after the reactants pass through a zone with a temperature of 80-95°C near the inlet end of the pipeline reactor (1), the temperature is controlled to react at 100-105°C, and the reaction products are removed from the pipeline reactor (1). 1) The outlet end is sent to the pipeline reactor (2) at 108-112°C, the reactants are reacted in the area of 100-110°C, and finally the reaction product is sent out from the outlet end of the pipeline reactor (2) and enters the cooling pipeline for reaction device (3).
The method according to claim 8, wherein the reaction time of the reactants through the zone where the temperature is controlled at 108-112°C is half of the total reaction time in the pipeline reactor;

or

The reaction time of the reactants passing through the zone with a temperature of 80-95°C, the reaction time of the zone with a temperature of 108-110°C, and the reaction time of a temperature zone of 100-110°C each account for 1% of the total reaction time of the reactants in the pipeline reactor. one third.