A high-throughput polypeptide synthesis apparatus and methods of use thereof

Abstract

The present application belongs to the field of polypeptide synthesis, and particularly relates to a high-throughput polypeptide synthesis device and a use method thereof. The device comprises a 'boat'-type reactor, a fixing device, a shaking device, a waste liquid collecting device and a connecting pipe. The 'boat'-type reactor has an open cross-sectional area smaller than the cavity of the reactor at both ends. The fixing device is used to place multiple reactors in the shaking device which can keep constant temperature. The synthesis device of the present application can be used in the polypeptide synthesis process. The synthesis device can not only stably control the reaction conditions and save raw materials and reagents, but also can meet the synthesis requirements of a large amount or multiple types of polypeptides at the same time. The synthesis device is beneficial to the stability and efficient synthesis of polypeptides, and can be widely used in the field of high-throughput synthesis of polypeptides, especially difficult peptides.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of polypeptide synthesis, and particularly relates to a high-throughput polypeptide synthesis device and a method of use thereof. BACKGROUND

[0002] In the early 1980s, the first real polypeptide synthesizer appeared in the world, and since then, polypeptide solid-phase synthesis has entered rapid development and has undergone the evolution of the second and third generations of many different styles of polypeptide solid-phase synthesis devices.

[0003] In 2004, Hangzhou Zhongpeide Company disclosed a high-throughput polypeptide synthesis method and device. This high-throughput polypeptide synthesis device mainly comprises a polypeptide reactor, a polypeptide chip, and a polypeptide elution device (Li Xiang et al., High-throughput polypeptide synthesis method and device, CN1490327A, 2004.04.21). In 2018, Nanjing Peiye Biotechnology Company disclosed a high-throughput solid-phase polypeptide synthesis device, which comprises a constant-temperature tube rack, a polypeptide synthesis tube, a waste liquid collection tube, a nitrogen tank, and a waste liquid collection bottle (Xu Hongyan et al., High-throughput solid-phase polypeptide synthesis device, CN208776625U, 2019.04.23). In 2018, Runhui Biotechnology Company disclosed a continuous high-throughput polypeptide synthesis device, which solves the technical problems of complex operation, high cost, and low synthesis efficiency of existing polypeptide synthesis. It is provided with a reaction column, a vacuum pump, a waste liquid collection device, a reagent holding device, and a waste liquid flow guide pipe, and is also provided with a peristaltic pump. The reaction column is provided with an upper column, a lower column, a first sand core device, and a second sand core device. The lower column has a funnel structure (Ji Shengli et al., Continuous high-throughput polypeptide synthesis device, CN207619301U, 2018.07.17).

[0004] However, these disclosed devices have some problems or defects: 1. Under the action of static electricity, the resin will clump during the reaction, and the solid-liquid cannot be uniformly mixed, so it is necessary to increase the pressure of nitrogen to eliminate the static effect; however, higher pressure will "blow" the polypeptide-solid phase carrier above the liquid surface of the reactor, causing wall sticking, and finally the resin sticking to the wall cannot participate in the reaction; 2. Long-term nitrogen bubbling, rapid solvent evaporation, uneven solid-liquid mixing, and synthesis failure; at the same time, a large amount of solvent is evaporated, the production environment is poor, and it is not conducive to environmental protection; 3. Constant input of nitrogen during the entire process, large consumption of nitrogen, and increased operating costs. SUMMARY

[0005] In order to solve the above problems, the present application provides a polypeptide synthesis device, which comprises a reactor (9) containing a cavity, a fixing device (8) and a shaking device (7), the reactor (9) cavity is provided with a liquid discharge port (11) and a feeding port (12) at two ends respectively, the liquid discharge port (11) and the feeding port (12) are higher than the reactor (9) cavity, and a filter device (10) is arranged in the cavity and parallel to the cross section of the cavity near the liquid discharge port end; the fixing device (8) fixes the reactor (9) and is placed in the shaking device (7).

[0006] Further, the cross-sectional areas of the liquid discharge port (11) and the feeding port (12) at two ends of the reactor (9) are smaller than the cross-sectional area of the reactor (9) cavity.

[0007] Further, the cross-sectional area of the feeding port (12) is larger than the cross-sectional area of the liquid discharge port (11).

[0008] Further, the reactor (9) is in the shape of a "ship" and is made of glass casting. The reactor in the present application is in the shape of a "ship", which is not limited to the specific shape of the reactor, but refers to the cavity of the reactor being large in the middle and being tight at both ends to form the liquid discharge port and the feeding port. The cavity in the middle of the "ship" shaped reactor can be of any shape, such as rectangular, oval, etc.

[0009] Further, the heights of the liquid discharge port (11) and the feeding port (12) are consistent or inconsistent. Preferably, the heights of the liquid discharge port (11) and the feeding port (12) are consistent.

[0010] Further, the fixing device (8) sets the hole position according to the size of the reactor (9), and the reactor (9) is fixed in the hole position.

[0011] Preferably, the fixing device (8) contains 3-12 reactors (9). More preferably, the fixing device (8) contains 3-7 reactors (9). The fixing device (8) is usually placed in parallel with two or more hole positions, so that as many reactors as possible are fixed in the hole positions, achieving the purpose of high-throughput synthesis of polypeptides.

[0012] Preferably, the fixing device (8) is made of corrosion-resistant thermal insulation material, and more preferably is made of corrosion-resistant foam cotton. The fixing device (8) can be made of any corrosion-resistant and light thermal insulation material, such as foam, foam cotton, sponge, etc.

[0013] Further, the shaking device (7) contains 1-4 fixing devices (8). The shaking device can be any device that can make the reactors in the fixing device shake up and down, left and right regularly or irregularly, including a shaking table, etc.

[0014] Preferably, the shaking device (7) is a shaking table, and the rotation speed can be adjusted to 0-200 r / min.

[0015] Preferably, the shaking device (7) is a temperature-controllable shaker, preferably a temperature-controllable constant temperature shaker. The temperature of the shaker device in the present application can be set to 10-100℃, preferably 20-80℃, more preferably 25-60℃.

[0016] Further, the device comprises a waste liquid tank (4) and a vacuum pump (1), the top of the waste liquid tank (4) is provided with a first opening (13) and a second opening (14), the first opening (13) of the waste liquid tank (4) is connected with the vacuum pump (1) through a first connecting pipe (2), and the second opening (14) of the waste liquid tank (4) is connected with the liquid outlet (11) of the reactor (9) through a second connecting pipe (3).

[0017] Preferably, the waste liquid tank (4) is provided with a pressure sensing device (6) inside.

[0018] Preferably, the waste liquid tank (4) is provided with a liquid level alarm device (5) inside and close to the top.

[0019] Further, the waste liquid tank (4) is provided with a third opening (15) close to the bottom, and the third opening (15) is provided with a valve (16).

[0020] The waste liquid tank (4) in the present application is made of corrosion-resistant and high-pressure-resistant stainless steel, such as 302 stainless steel, 303 stainless steel, 304 stainless steel, etc., preferably 304 stainless steel; and the valve (6) is also made of corrosion-resistant material.

[0021] The connecting pipes connecting the reactor, the vacuum pump and the waste liquid tank in the present application can be high-pressure-resistant and corrosion-resistant rubber pipes.

[0022] The filter device in the present application refers to a device that plays a filtering function, including a filter membrane or a filter core. The filter device can be a filter sand core plate.

[0023] The present application specifically provides a polypeptide solid-phase synthesis device, which comprises a vacuum pump (1), a waste liquid tank (4), a shaker device (7), a fixing device (8) and a reactor (9) comprising a cavity:

[0024] The reactor (9) is provided with a liquid outlet (11) and a feeding port (12) at two ends respectively, the liquid outlet (11) and the feeding port (12) are higher than the cavity of the reactor (9), and a filter device (10) is arranged inside the cavity close to one end of the liquid outlet in parallel to the cross section of the cavity;

[0025] The fixing device (8) fixes the reactor (9) and is placed in the shaking device (7);

[0026] The waste liquid tank (4) is provided with a first opening (13) and a second opening (14), the first opening (13) of the waste liquid tank (4) is connected with the vacuum pump (1) through the first connecting pipe (2), and the second opening (14) of the waste liquid tank (4) is connected with the liquid outlet (11) of the reactor (9) through the second connecting pipe (3).

[0027] Further, the cross-sectional areas of the liquid outlet (11) and the feeding port (12) at both ends of the reactor (9) are smaller than the cross-sectional area of the cavity of the reactor (9).

[0028] Further, the liquid outlet (11) and the feeding port (12) have the same height, and the cross-sectional area of the feeding port (12) is larger than that of the liquid outlet (11).

[0029] Further, the reactor (9) is in the shape of a "ship" and is made of glass.

[0030] Further, the fixing device (8) is provided with a hole site according to the size of the reactor (9), and the reactor (9) is fixed in the hole site.

[0031] Preferably, the fixing device (8) contains 3-12 reactors (9).

[0032] Preferably, the fixing device (8) is made of a corrosion-resistant heat-insulating material, preferably a corrosion-resistant foam cotton.

[0033] Further, the shaking device (7) contains 1-4 fixing devices (8). Preferably, the shaking device (7) is a shaking bed, and the rotating speed can be adjusted to 0-200r / min; the shaking device (7) is a shaking bed with adjustable temperature, preferably a constant-temperature shaking bed with adjustable temperature.

[0034] The application also provides a method for synthesizing polypeptides by using the polypeptide synthesis device, comprising the following steps:

[0035] Step 1: Resin swelling

[0036] An appropriate amount of resin and solvent are added into the cavity of the reactor (9) from the feeding port (12), after the resin is swelled, the vacuum pump (1) is opened, and the residual solvent in the reactor (9) is pumped into the waste liquid tank (4), and the above operation is repeated until the appropriate swelled resin is obtained;

[0037] Step 2: Resin deprotection

[0038] The deprotection reagent is added from the feeding port (12) of the reactor (9) in step 1, and is placed in the shaking device (7), and the shaking device (7) is adjusted to the appropriate temperature and rotating speed for deprotection reaction, after the reaction is completed, the vacuum pump is opened, and filtration is performed, to obtain the resin with deprotection group;

[0039] Step 3: resin washing

[0040] An appropriate amount of washing agent is added from the charging port (12) of the reactor (9) of step 2, the shaking device (7) is set to an appropriate rotation speed, and washing is performed. After washing, the vacuum pump (1) is opened, and filtration is performed. The washing operation is repeated until the washing is complete.

[0041] Step 4: condensation of amino acids

[0042] According to the needs of polypeptide synthesis, an appropriate amount of amino acid raw material and condensation reagent is sequentially added from the charging port (12) to each reactor (9) of step 3, and the shaking device is adjusted to an appropriate temperature and rotation speed to perform the condensation reaction of amino acids. Before each addition of amino acid raw material, steps II and III are repeated until all the amino acids of the polypeptide are coupled. After opening the vacuum pump (1) for filtration, the resin peptide is obtained.

[0043] Step 5: cleavage of resin peptide

[0044] A cleavage reagent is added from the charging port (12) of the reactor (9) of step 4, and the shaking device (7) is adjusted to an appropriate temperature and rotation speed for cleavage reaction. After the reaction is complete, it is poured out from the liquid outlet (11).

[0045] The application also provides the use of the above-mentioned polypeptide synthesis device in the solid-phase synthesis of difficult peptides.

[0046] The application relates to a high-throughput solid-phase polypeptide synthesis device, which comprises polypeptide'ship' type reactors, reactor fixing devices, constant-temperature shaking tables, vacuum pumps and waste liquid tanks. The polypeptide'ship' type reactors are similar in shape to a ship, are made of glass, are internally provided with filter sand core plates, have liquid outlets at one end of the sand core plates, have charging ports which are slightly larger than the liquid outlets and have the same height, and are independent of each other and do not interfere with each other. The reactor fixing devices are made of corrosion-resistant light foam cotton, each hole has a size determined according to the size of the reactor, and each fixing device can accommodate 3-12 reactors. The waste liquid tanks are made of corrosion-resistant and high-pressure-resistant stainless steel, are internally provided with pressure devices and waste liquid high liquid level alarm devices. The polypeptide'ship' type reactors, the vacuum pumps and the waste liquid tanks are connected through high-pressure-resistant and corrosion-resistant rubber pipes. By using the constant-temperature shaking table, the polypeptide'ship' type reactors are in a constant-temperature and dry state and are shaken, so that the solid-liquid mixture is uniform, which is beneficial to the stable and efficient synthesis of polypeptides. By arranging multiple'ship' type reactors, multiple sequences can be synthesized in parallel, the production efficiency is improved, and the problems of high cost and high maintenance cost of the existing polypeptide synthesis device and complex polypeptide synthesis operation are solved. The device can be widely applied to the technical field of polypeptide synthesis.

[0047] The present application solves the above technical problems in the prior art and provides a high-throughput polypeptide synthesis device, which comprises polypeptide ''ship'' type reactors, reactor fixing devices, constant temperature shakers, vacuum pumps and waste liquid tanks.

[0048] The polypeptide ''ship'' type reactors are similar in shape to a ship, are made of glass, have filter sand core plates built-in, have discharge ports at one end of the sand core plates, have charging ports slightly larger than the discharge ports and consistent in height, and are independent of each other and do not interfere with each other.

[0049] The reactor fixing devices are made of light and corrosion-resistant foam cotton, each hole has a size determined according to the size of the reactor, and each fixing device can accommodate 3-12 reactors.

[0050] The shaker can be shaken in any direction, such as regular or irregular up-down or left-right shaking, and the rotation speed can be adjusted to 0-200 r / min, preferably 60 r / min.

[0051] The waste liquid tank is made of corrosion-resistant and high-pressure-resistant stainless steel; the upper end of the waste liquid tank is provided with a first opening and a second opening, and the lower end is provided with a third opening; the first opening is connected with the vacuum pump, the second opening is connected with the discharge port of the ''ship'' type reactor to prevent waste liquid from entering the vacuum pump; and the third opening is the discharge port of the waste liquid tank and is provided with a waste liquid valve for facilitating liquid discharge.

[0052] The polypeptide ''ship'' type reactors, the vacuum pump and the waste liquid tank are connected through high-pressure-resistant and corrosion-resistant rubber pipes.

[0053] As an improvement of the present application, the shaker is a constant temperature shaker, the polypeptide ''ship'' type reactors are in a constant temperature and dry state and are shaken, the solid-liquid mixture is uniform, which is beneficial to the stable and efficient synthesis of polypeptides.

[0054] As an improvement of the present application, the waste liquid tank is provided with a pressure device built-in, which can remind of excessive pressure and improve safety.

[0055] As an improvement of the present application, the waste liquid tank is provided with a liquid level alarm device built-in, which can remind of excessive waste liquid and improve safety.

[0056] As an improvement of the present application, the number of the polypeptide ''ship'' type reactors 9 is 4-12, and the number of the reactor fixing devices 8 is 1-4; the more the number, the higher the processing efficiency.

[0057] Beneficial technical effects:

[0058] Compared with the prior art, the polypeptide synthesis device has the following advantages: the polypeptide "ship" type reactor is beneficial to uniform shaking of reactants in the reactor, and can make the solid-liquid mixture uniform and the raw materials and reagents fully contact and react without nitrogen being introduced, and the cross-sectional area of the feeding port and the liquid discharge port is smaller than that of the cavity, so that evaporation of the reagents can be avoided to the greatest extent and cost is saved during polypeptide synthesis; the polypeptide "ship" type reactor is in a constant temperature and dry state by using the constant temperature shaking table, so that the reaction condition is more stable and easy to control, and the stability of the polypeptide is improved and the synthesis of difficult peptides is suitable; in addition, a plurality of polypeptide reactors can be stored in the shaking table, and a certain polypeptide can be synthesized efficiently and in a large amount at one time, or different types of polypeptides can be synthesized efficiently at the same time, so that cost and manpower can be greatly saved compared with the traditional manual solid-phase synthesis; therefore, the polypeptide synthesis device can stably control the reaction condition, save raw materials and reagents, and simultaneously meet the synthesis demand of a large amount or a plurality of types of polypeptides during polypeptide synthesis, and can be widely applied to high-throughput synthesis of polypeptides, especially difficult peptides. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 is a synthesis device diagram of Example 1, Figure 1 the left side is an effect diagram of the whole device, Figure 1 the right side is a partial enlarged view of the reactor (9);

[0060] Figure 2 is a synthesis device diagram of Example 3;

[0061] Figure 3 is a synthesis device diagram of Example 4. DETAILED DESCRIPTION

[0062] The following non-limiting Examples 1-6 are used to explain and illustrate the present application, but are not intended to limit the present application, and any modification and change made to the present application within the spirit and protection scope of the claims of the present application shall fall within the protection scope of the present application. The methods used in the present application are conventional methods unless otherwise specified; and the raw materials and devices used are conventional commercial products unless otherwise specified.

[0063] Example 1

[0064] As Figure 1 A high-throughput polypeptide synthesis device includes a polypeptide "ship" type reactor 9, a reactor fixing device 8, a constant temperature shaking table 7, a vacuum pump 1 and a waste liquid tank 4.

[0065] The polypeptide "ship" type reactor 9 is shaped like a "ship" and is made of glass, and a filter sand core plate 10 is arranged in the "ship" type reactor 9. A liquid outlet 11 is arranged at one end of the sand core plate 10, and a feeding port 12 is slightly larger than the liquid outlet 11 and has the same height. Each "ship" type reactor is an independent individual and does not interfere with each other.

[0066] The material of the reactor fixing device 8 is light and corrosion-resistant foam cotton. The size of each hole is determined according to the size of the reactor. Each fixing device 8 can accommodate 3-12 reactors.

[0067] The shaking bed 7 can be shaken in any direction, such as up and down, left and right, regular or irregular shaking, and the rotating speed can be adjusted to 0-200 r / min, preferably 60 r / min.

[0068] The waste liquid tank 4 is made of corrosion-resistant and high-pressure-resistant stainless steel. A first opening 13 and a second opening 14 are arranged at the upper end of the waste liquid tank 4, and a third opening 15 is arranged at the lower end. The first opening 13 is connected to the vacuum pump 1, the second opening 14 is connected to the liquid outlet 11 of the "ship" type reactor 9, and the third opening 15 is the liquid outlet of the waste liquid tank 4 and is provided with a waste liquid valve 16 for facilitating liquid discharge.

[0069] The polypeptide "ship" type reactor 9, the vacuum pump 1 and the waste liquid tank 4 are connected by high-pressure-resistant and corrosion-resistant rubber pipes 2 and 3.

[0070] The rubber pipe 3 is connected to the waste liquid tank, and the pipe opening at one end is always kept above the alarm liquid level to prevent waste liquid from entering the vacuum pump.

[0071] Example 2

[0072] As an improvement of the present application, the shaking bed is a constant temperature shaking bed. By setting the temperature, humidity and rotating speed of the shaking bed, the polypeptide "ship" type reactor 9 can be kept at a constant temperature and dry state, and can be shaken to mix the solid and liquid uniformly, which is beneficial to the stable and efficient synthesis of polypeptides.

[0073] Example 3

[0074] As an improvement of the present application, as shown in Figure 2 The waste liquid tank 4 is provided with a pressure device 6, which can remind that the negative pressure in the waste liquid tank is too large, thereby improving the safety.

[0075] Example 4

[0076] As an improvement of the present application, as shown in Figure 3 The waste liquid tank 4 is connected by a transparent corrosion-resistant rubber pipe, and is provided with a liquid level alarm device 5 to remind that there is too much waste liquid, so that it can be treated in time and the safety is improved.

[0077] Example 5

[0078] As an improvement of the present application, the number of the polypeptide "ship" type reactor 9 is 3-12, and the number of the fixing device 8 of the "ship" type reactor is 1-4. The more the number is, the higher the processing efficiency is.

[0079] Example 6

[0080] The use method of the polypeptide synthesis device is as follows:

[0081] 1. Resin swelling

[0082] The modified resin is added into the "ship" type reactor 9 from the feeding port 12, and an appropriate amount of DCM is added. After 5 minutes, the vacuum pump 1 is opened, and the filtrate is extracted from the liquid outlet 11 of the "ship" type reactor 9. Then, an appropriate amount of industrial DMF is added again, and the mixture is shaken uniformly. Then, the vacuum pump 1 is opened again, and the filtrate is extracted from the liquid outlet 11.

[0083] 2. Removing Fmoc protecting group

[0084] The "ship" type reactor 9 in step 1 is added with an appropriate amount of 20% Pip / DMF, and is placed in the constant temperature shaker 7 for reaction for 20 minutes.

[0085] 3. Resin washing

[0086] The vacuum pump 1 is opened, and the filtrate is extracted from the liquid outlet 11. Then, an appropriate amount of industrial DMF is added from the feeding port 12, and the mixture is shaken uniformly. Then, the vacuum pump 1 is opened again, and the filtrate is extracted from the liquid outlet 11. The above process is repeated for 5 times, and the washing is completed.

[0087] 4. Condensation of amino acid

[0088] The feeding port 12 of the "ship" type reactor 9 in step 3 is added with the protected amino acid to be condensed, and the condensation reagent. The mixture is placed in the constant temperature shaker 7 at 50°C for reaction for 1 hour, until the polypeptide resin is obtained by synthesizing all the amino acids. For some difficult-to-synthesize polypeptides, the condensation is easier, more time-saving, and higher in condensation efficiency in the constant temperature shaking reactor 9 provided by the device.

[0089] 5. Peptide resin cleavage

[0090] The "ship" type reactor 9 containing the peptide resin obtained in step 4 is added with an appropriate amount of specific cleavage reagent from the feeding port 12. The mixture is shaken in the constant temperature shaker 7 for 2.5 hours, and then is discharged from the liquid outlet 11.

[0091] The present application can also combine at least one of the technical features in examples 2, 3, 4, and 5 with example 1 to form a new implementation. It should be noted that the above examples are only the preferred embodiments of the present application, and are not used to limit the protection scope of the present application. Any equivalent replacement or substitution made on the basis of the above belongs to the protection scope of the present application.

Claims

1. A method for synthesizing polypeptides using a polypeptide synthesis device, the polypeptide synthesis device comprising a reactor (9) containing a cavity, a fixing device (8) and a shaking device (7), the reactor (9) being "boat" shaped, the cavity of the reactor (9) being large in the middle and narrowed at both ends to form a drain port (11) and a feed port (12), the cross-sectional areas of the drain port (11) and the feed port (12) at both ends of the reactor (9) being smaller than the cross-sectional area of ​​the cavity of the reactor (9), and the cross-sectional area of ​​the feed port (12) being larger than the cross-sectional area of ​​the drain port (11), the drain port (11) and the feed port (12) being higher than the cavity of the reactor (9), and a filter device (10) being provided inside the cavity near the drain port parallel to the cross-section of the cavity; the fixing device (8) fixing the reactor (9) and placing it in the shaking device (7); The method includes the following steps: Step 1: Resin swelling Add an appropriate amount of resin and solvent into the reactor (9) chamber of the polypeptide synthesis device through the feed port (12). After the resin swells, turn on the vacuum pump (1) to pump the residual solvent in the reactor (9) into the waste liquid tank (4). Repeat the above operation until a suitable swollen resin is obtained. Step 2: Deprotecting the resin Add the deprotection reagent from the feed port (12) of the reactor (9) in step 1, and place it into the shaking device (7) of the polypeptide synthesis device. Adjust the shaking device (7) to a suitable temperature and speed to carry out the deprotection reaction. After the reaction is completed, turn on the vacuum pump, filter, and obtain the deprotected resin. Step 3: Resin washing Add an appropriate amount of detergent from the feed port (12) of the reactor (9) described in step 2. Set the shaking device (7) to a suitable speed for washing. After washing, turn on the vacuum pump (1) of the polypeptide synthesis device, filter, and repeat the washing operation until the washing is complete. Step 4: Condensation of amino acids According to the synthesis requirements of the peptide, appropriate amounts of amino acid raw materials and condensation reagents are added sequentially from the feed port (12) to each reactor (9) in step 3. The shaking device (7) is adjusted to a suitable temperature and rotation speed to carry out the condensation reaction of amino acids. Before each addition of amino acid raw materials, steps 2 and 3 are repeated until all amino acids of the peptide are coupled. After the vacuum pump (1) is turned on and the mixture is filtered, resin peptides are obtained. Step 5: Cleavage of resin peptides Add the pyrolysis reagent into the feed port (12) of the reactor (9) described in step 4, adjust the shaking device (7) to a suitable temperature and speed to carry out the pyrolysis reaction, and discharge it from the drain port (11) after the reaction is completed.

2. The method of claim 1, wherein, The reactor (9) is made of glass enamel.

3. The method according to any one of claims 1-2, characterized in that, The fixing device (8) sets the hole position according to the size of the reactor (9), and the reactor (9) is fixed at the hole position.

4. The method according to claim 3, wherein the fixed device (8) accommodates 3-12 reactors (9).

5. The method according to any one of claims 1-2, characterized in that, The fixing device (8) is made of corrosion-resistant thermal insulation material.

6. The method of any one of claims 1-2, wherein, The fixing device (8) is made of corrosion-resistant foam cotton.

7. The method of any one of claims 1-2, wherein, The shaking device (7) accommodates 1-4 fixing devices (8).

8. The method according to any one of claims 1-2, characterized in that, The shaking device (7) is a shaking table with an adjustable speed of 0-200 r / min.

9. The method according to any one of claims 1-2, characterized in that, The shaking device (7) is a shaking table with adjustable temperature.

10. The method according to any one of claims 1-2, characterized in that, The shaking device (7) is a temperature-controlled constant temperature shaker.

11. The method according to any one of claims 1-2, characterized in that, The polypeptide synthesis apparatus further includes a waste liquid tank (4) and a vacuum pump (1). The waste liquid tank (4) has a first opening (13) and a second opening (14) at the top. The first opening (13) of the waste liquid tank (4) is connected to the vacuum pump (1) through a first connecting pipe (2), and the second opening (14) of the waste liquid tank (4) is connected to the drain port (11) of the reactor (9) through a second connecting pipe (3).

12. The method according to claim 11, characterized in that, The waste liquid tank (4) has a built-in pressure sensing device (6).

13. The method according to claim 11, characterized in that, The waste liquid tank (4) is equipped with a liquid level alarm device (5) inside and near the top.

14. The method according to claim 11, characterized in that, The waste liquid tank (4) has a third opening (15) near the bottom, and the third opening (15) is equipped with a valve (16).

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