A composite mass spectrometer

Abstract

The present invention relates to a composite mass spectrometer, comprising an ion source, a first ion guide device, a quadrupole mass analyzer, a time-of-flight mass analyzer, a second ion guide device and a high-resolution Fourier transform mass spectrometer based on image charge detection, and further comprising management and control means for the device, which can form an ion fragmentation function in the ion guide device or in a device between the quadrupole mass analyzer and the ion guide device while the high-resolution Fourier transform mass spectrometer performs signal acquisition, so that the time-of-flight mass analyzer performs secondary mass spectrometry analysis on ions fragmented by the ion fragmentation function for multiple times, thereby fundamentally resolving the conflict between high throughput and high resolution.

Description

Technical Field

[0001] The present invention relates to the technical field of mass spectrometers and mass spectrometry analysis methods, and in particular to a composite mass spectrometer. Background Art

[0002] Chromatography-mass spectrometry (LCMS) is a very effective chemical analysis technology that plays a great role in environmental, chemical, biopharmaceutical and medical clinical diagnosis. During liquid chromatography-mass spectrometry (LCMS) analysis, various chemical components are separated in the chromatographic column and then enter the mass spectrometer for analysis. For more complex samples, a mass spectrometer is also required to perform tandem mass spectrometry analysis to confirm the composition of the sample based on its chemical structure, while preventing the influence of co-distilled interfering components. With the development of mass spectrometers towards high sensitivity and high resolution, the analytical capabilities of LCMS are getting higher and higher, the instruments are more complex, and the sensitivity is getting higher and higher. Even small samples can be analyzed and detected, and quantitative results can be given.

[0003] The chemical components to be analyzed separated from the chromatograph are ionized into ions by an ion source (usually for liquid chromatography-mass spectrometry, electrospray ion sources and chemical ionization ion sources are mostly used), and the generated ions are introduced into a mass analyzer for mass spectrometry measurement. Mass analyzers are divided into quadrupole mass filters, ion trap analyzers, time-of-flight analyzers, and Fourier transform analyzers. Among them, the time-of-flight analyzer has the fastest single mass spectrometry scanning speed (less than 1ms), while the Fourier transform mass spectrometer is the slowest. At present, ultra-high-resolution mass spectrometry is obtained by detecting the Fourier transform results of the image current signal for a long time. For example, the Fourier transform ion cyclotron resonance (FTICR) mass spectrometer and orbital ion trap (Orbitrap) mass spectrometer on the market are all Fourier transform mass spectrometers. In order to obtain a high-resolution mass spectrum, the signal acquisition time is several hundred milliseconds (ms) to several seconds (s). If multiple secondary mass spectra need to be performed at the same time, the required time will increase exponentially. In particular, when using the currently popular data-independent acquisition (DIA) method, it is necessary to perform secondary mass spectrometry analysis on dozens of precursor ion mass segments, while the normal distillation peak time of liquid chromatography is only a few seconds, which poses a great challenge to multi-stage and multi-channel mass spectrometry analysis.

[0004] In order to solve the time-consuming problem of multi-stage mass spectrometry, US patent application US2008 / 0224033A1 proposes a mass spectrometer with a bifurcated ion transmission path, in which a mass spectrometer and a reaction pool for ion cracking are placed on two branches respectively. Compared with the traditional method of placing the ion source, reaction pool and analyzer along the same path, the switching time required for switching the working conditions of the reaction pool between the primary mass spectrometer and the secondary mass spectrometer is reduced. For the reaction process that requires a long time to crack, the primary mass spectrometry scanning and the dissociation of the secondary mass spectrometer can be carried out in parallel, which improves the work efficiency. However, this solution still cannot solve the problem that ultra-high resolution Fourier mass spectrometry analysis is time-consuming and there is no time to perform multiple multi-stage scanning mass spectrometry in a chromatographic peak time period. The Orbitrap Tribrid three-in-one mass spectrometer, a product of Thermo Company, adds a set of dual linear ion trap analyzers after the injector C trap of the electrostatic orbital trap, so that while the high-resolution electrostatic trap collects signals, subsequent ions can be sent to the linear ion trap for secondary mass spectrometry analysis, which improves the overall analysis efficiency. However, it still takes tens to hundreds of milliseconds for the ion trap to perform a scan, and the ions need to be cooled for 10 milliseconds before scanning. The number of secondary mass spectrometry scans that can be performed during a mass spectrometry acquisition in the orbital trap is still limited. Summary of the invention

[0005] The object of the present invention is to overcome the defects of the prior art and provide a composite mass spectrometer to solve the contradiction between the high resolution of the mass spectrometer and the spectral acquisition speed, that is, the contradiction between the requirement of ultra-high resolution of the primary mass spectrometer and the requirement of completing a sufficient number of secondary mass spectrometry acquisitions during multi-channel and multi-stage mass spectrometry analysis using a chromatography-mass spectrometer.

[0006] The technical solution to achieve the purpose of the present invention is: a composite mass spectrometer, including an ion source, a first ion guide device, a quadrupole mass analyzer, a time-of-flight mass analyzer, a second ion guide device and a high-resolution Fourier transform mass spectrometer based on image charge detection,

[0007] The device further includes management and control means for the device, which can form an ion fragmentation function in the ion guide device or in a device between the quadrupole mass analyzer and the ion guide device while the high-resolution Fourier transform mass spectrometer is collecting signals, so that the time-of-flight mass analyzer can perform secondary mass spectrometry analysis multiple times on the ions fragmented by the ion fragmentation function.

[0008] The structural order of the composite mass spectrometer proposed by the present invention can be from an atmospheric pressure ion source to an atmospheric vacuum interface and a rough vacuum ion convergence device, then to a first ion guide device, then to a quadrupole mass analyzer, then to a reaction cell or an ion trap for ion fragmentation, then to a repulsion device of a time-of-flight mass analyzer, then to a second ion guide device, and finally to a high-resolution Fourier transform mass spectrometer based on image charge detection. The second ion guide device includes a radio frequency ion guide and a radio frequency ion storage device, and the radio frequency ion storage device is used to provide ions to the high-resolution Fourier transform mass spectrometer.

[0009] The second ion guide device in the above technical solution includes a radio frequency ion guide and a radio frequency ion storage device, and the radio frequency ion storage device is used to provide ions to the high-resolution Fourier transform mass spectrometer for primary mass spectrometry analysis.

[0010] The second ion guide device of the above technical solution includes a radio frequency ion guide and a radio frequency ion storage device, which is used to provide ions for primary mass spectrometry analysis and daughter ions generated by the decomposition of at least one selected parent ion to the high-resolution Fourier transform mass spectrometer.

[0011] The time-of-flight analyzer described in the above technical solution adopts a pulse repeller, and the ion fragmentation function occurs in the ion reaction pool between the quadrupole analyzer and the pulse repeller. The second ion guide device is arranged behind the pulse repeller, and its axial direction is along the original traveling direction of the ion beam; at least in part of a working cycle, the pulse repeller is arranged to suspend orthogonal repulsion, and the second ion guide device converges and stores the parent ions or fragment ions passing through the quadrupole analyzer and the repeller for injection into a high-resolution Fourier transform mass spectrometer based on image charge detection. At least in another part of this working cycle, while the high-resolution Fourier transform mass spectrometer is collecting signals, the parent ions selected by the quadrupole analyzer are fragmented into fragment ions through the fragmentation function, and after orthogonal repulsion by the pulse repeller, the fragment ions enter the time-of-flight mass spectrometer for secondary mass spectrometry analysis.

[0012] The time-of-flight analyzer described in the above technical solution adopts a linear ion trap containing a radial extraction slot as its pulse repulsion device. At least in part of the working cycle, the linear ion trap is in a conducting transmission state, and ions with a wide mass-to-charge ratio range passing through the quadrupole analyzer enter the above-mentioned second ion guide device through the linear ion trap, and are gathered and stored therein, so as to provide pulsed ion injection into the high-resolution Fourier transform mass spectrometer based on image charge detection. In another part of the working cycle, while the high-resolution Fourier transform mass spectrometer is performing signal acquisition, the ion fragmentation function is formed in the above-mentioned linear ion trap, and the parent ions selected by the quadrupole analyzer are fragmented into fragment ions in the above-mentioned linear ion trap. After collision cooling, the fragment ions are radially repelled to the time-of-flight mass spectrometer through the extraction slot for secondary mass spectrometry analysis.

[0013] The second ion guide device of the above technical solution includes a linear ion trap and its axial extraction lens, and the linear ion trap contains a radial extraction slot for pulsed ion repulsion to the time-of-flight analyzer. At least in part of the working cycle, various ions passing through the quadrupole analyzer are gathered and stored in the linear ion trap for injection into a high-resolution Fourier transform mass spectrometer based on image charge detection. In another part of the working cycle, while the high-resolution Fourier transform mass spectrometer is performing signal acquisition, the ion fragmentation function is formed in the above linear ion trap, and the parent ions selected by the quadrupole analyzer are fragmented into fragment ions in the above linear ion trap. The fragment ions are repelled to the time-of-flight mass spectrometer after collision cooling for the above secondary mass spectrometry analysis.

[0014] The high-resolution Fourier transform mass spectrometer based on image charge detection described in the above technical solution is an ion cyclotron resonance Fourier transform mass spectrometer.

[0015] The high-resolution Fourier transform mass spectrometer based on image charge detection described in the above technical solution is an ion trap Fourier transform mass spectrometer using an electrostatic field or a hybrid of an electrostatic field and a magnetic field.

[0016] The high-resolution Fourier transform mass spectrometer based on image charge detection described in the above technical solution is one of the rotating hyperbolic logarithmic field ion trap Orbitrap, the electrostatic linear ion trap ELIT, the cylindrical or planar electrostatic ion trap or the Cassinian harmonic ion trap mass spectrometer.

[0017] The management and control means described in the above technical scheme enables the quadrupole analyzer to form a wider mass ion conductance range in the first time period of the analysis cycle, turns off the ion fragmentation function, and enables the second ion guide device to guide and store ions to provide the Fourier transform mass spectrometer; in the second time period of the analysis cycle, the quadrupole analyzer is enabled to form a narrower mass conductance range to select parent ions, turns on the ion fragmentation function, and promotes ion fragmentation; and the fragmented ions are pulsed out or introduced into the time-of-flight mass analyzer to perform secondary mass spectrometry analysis multiple times.

[0018] The space where the ion fragmentation function is located in the above technical solution is filled with collision gas when working, and in the second part of the analysis cycle, the fragmentation function is turned on, including allowing the ions to be accelerated to a kinetic energy of 5 to 100 electron volts when entering the fragmentation function space, thereby causing the ions to fragment by reacting with the collision gas.

[0019] According to the technical solution, in the second part of the analysis cycle, the activation of the fragmentation function includes injecting an electron beam, a negative ion beam or an excited atom beam into the space where the fragmentation function is located, and reacting with the ions therein to cause the ions to fragment.

[0020] The management and control means described in the above technical solution can turn off the ion fragmentation function while the high-resolution Fourier transform mass spectrometer is collecting signals, and before, during or after the time-of-flight mass analyzer performs secondary mass spectrometry analysis on the fragmented ions, so that the time-of-flight mass analyzer can collect the primary mass spectrum at least once.

[0021] The ion source described in the above technical solution is connected to a chromatograph to form a chromatograph-mass spectrometer.

[0022] The management and control means described in the above technical solution controls the quadrupole analyzer to select the mass conductance range of the parent ions in a data-independent acquisition (DIA) manner, and fragments the parent ions in this series of ranges in turn through the ion fragmentation function, and performs time-of-flight mass analysis on the fragment ions produced by the fragmentation.

[0023] After adopting the technical solution, the present invention has the following positive effects:

[0024] The composite mass spectrometer manufactured by the present invention can perform multi-stage multi-channel mass spectrometry analysis in a short time, and is most suitable for use with a chromatograph to form a set of efficient chromatograph-mass spectrometer. This chromatograph-mass spectrometer is also particularly suitable for the working mode of data-independent acquisition (DIA), that is, it can perform ultra-high resolution wide-spectrum mass analysis while controlling the quadrupole analyzer to select a series of parent ion mass conductance ranges (such as a range of tens to one or two hundred Th), and the parent ions in this series of ranges are sequentially cracked by the ion cracking function, and the fragment ions produced by the cracking are subjected to time-of-flight mass analysis. Thereby fundamentally solving the conflict between high throughput and high resolution. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments and in conjunction with the accompanying drawings, wherein

[0026] Figure 1 An embodiment of the present invention is given, which combines a quadrupole analyzer, an orthogonal extraction time-of-flight mass spectrometer and an orbital trap Fourier transform mass spectrometer to form a composite mass spectrometer.

[0027] Figure 2 Another embodiment of the present invention is given, which combines a quadrupole analyzer, a linear ion trap-time-of-flight mass spectrometer and an orbital trap Fourier transform mass spectrometer to form a composite mass spectrometer.

[0028] Figure 3 Will Figure 2 The orbital trap Fourier transform mass spectrometer is replaced by an electrostatic linear ion trap analyzer, and the same linear ion trap is directly used as the storage injector of the electrostatic linear ion trap to form another composite mass spectrometer.

[0029] Figure 4 Will Figure 3 The electrostatic linear ion trap analyzer is replaced by a magnetic cyclotron resonance Fourier transform analyzer to form another composite mass spectrometer.

[0030] Figure 5 Will Figure 2 The orbital trap Fourier transform mass spectrometer is replaced by a disk-type planar electrostatic ion trap analyzer, and the same linear ion trap is used as a pre-storage device for the disk-type planar electrostatic ion trap to form another composite mass spectrometer. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Generally, the components of the embodiments of the present invention described and shown in the drawings here can be arranged and designed in various different configurations.

[0032] (Example 1)

[0033] See Figure 1 , the ion source 1 located in the atmospheric pressure environment can be a common electrospray ion source, a nanospray source, a chemical ionization ion source, or a new type of in-situ ion source such as DESI, DART, etc. After the example is generated, it passes through a small hole or a capillary into a low vacuum chamber connected to the exhaust port 20a, is gathered by the ion funnel, and is transmitted into the next level of vacuum (connected to the exhaust port 20b). The first ion guide device 3 here continues to guide the ions to the quadrupole mass analyzer 4 located in the high vacuum chamber (connected to the exhaust port 20c). The outlet of the quadrupole analyzer is equipped with a reaction cell (or collision cell) 60 and its extraction lens 61, followed by an orthogonal time-of-flight mass analyzer including a pulse repeller 62, a flight tube 5, a reflector 51 and a detector 53. At this point, the structure of this device is basically the same as that of a general commercial quadrupole time-of-flight (Q-ToF) mass spectrometer. The quadrupole mass analyzer 4 can operate in a wide mass range pass (pure RF mode) or a mass selective pass mode; the collision cell 60 can be switched to enable or disable the ion fragmentation function to obtain the primary or secondary (MS 2 ) mass spectrometry.

[0034] As is known to all, the resolution of the above Q-ToF instrument is limited, especially when the primary mass spectrum peaks are relatively complex, the peaks between different components or between the analyzed components and the impurity chemical noise overlap and cannot be distinguished. In addition, the Q-ToF repeller generally has an ion utilization rate of <5% when analyzing a wide mass range, which reduces the sensitivity. This scheme is provided with a second ion guide device combination 63 and an ultra-high resolution electrostatic orbital ion trap Orbitrap analyzer 8 after the pulse repeller 62. The second ion guide device combination 63 includes an ion funnel 63a facing the pulse repeller, and the central axis is along the original direction of travel of the ion beam in the collision cell extraction lens, a radio frequency ion guide 63b and a C-shaped ion storage 63c for injection into the orbital trap analyzer 8. Of course, there is also a series of focusing and deflecting ion lenses 19 between the C-shaped storage 63c and the orbital trap 8, which are located in the vacuum chambers 20d and 20e for differential exhaust. Here, the differential exhaust section is exhausted by the exhaust ports 20d and 20e. The Orbitrap analysis chamber with the highest vacuum degree is exhausted through the exhaust port 20f.

[0035] With two analyzers with different characteristics, effective management and control means are needed to coordinate and control them in order to achieve the highest efficiency of multi-stage mass spectrometry analysis. Now let us refer to the management schedule given in Table 1 and assume that one full spectrum acquisition and N secondary mass spectra acquisitions of N parent ions of different masses are required in one working cycle.

[0036]

[0037] Table 1

[0038] In the first time period, the management and control means sets the front end of the instrument to the primary mass spectrometry mode. At this time, the quadrupole analyzer 4 is set to a wide mass range conduction state, the reaction cell or collision cell 60 turns off the ion fragmentation function, the above-mentioned pulse repeller 62 stops orthogonal repeller, and the ions pass through the quadrupole analyzer and the collision cell, are received by the ion funnel 63a of the second ion guide device, enter the C-shaped storage device through the radio frequency ion guide 63b, and accumulate and cool therein. After the management and control means determines that the ion accumulation reaches a preset amount, the first time period ends. After entering the second time period, the management and control means immediately injects the ions accumulated in the C-shaped storage device into the orbital trap 8 for image charge signal acquisition to obtain an ultra-high resolution Fourier transform mass spectrum. This acquisition and analysis process generally takes hundreds of ms. At the same time, the management and control means causes the quadrupole analyzer 4 to be successively set to a series (N) of narrow mass range conduction states, such as only allowing selected parent ions in the mass number range of 1-2 to pass through at a time. It is also possible to allow all parent ions in a small mass range to pass through at one time. Increase the kinetic energy of the ions entering the collision cell 60 and turn on the ion fragmentation function, that is, let the ions be accelerated and collide with the neutral gas in the collision cell to achieve fragmentation. According to different molecular ion characteristics, the acceleration voltage can be selected between 5 and 100 eV. The fragment ions drawn from the collision cell are focused by the lens 61 and then reach the pulse repeller 62. The pulse repeller repeatedly generates an orthogonal accelerating electric field to repel the fragment ions fragmented by the fragmentation function to the time-of-flight mass spectrometer for secondary mass spectrometry MS. 2Analysis. Since the time-of-flight analysis is very fast, time-of-flight ToF data collection can be performed multiple times for each parent ion selection point and averaged. For example, each repulsion interval is 0.5ms, and 20 ToFs require 10ms; if a total of N=15 segments of parent ions need to be subjected to secondary mass spectrometry, it can be completed in a 150ms period. After the time period for secondary mass spectrometry using ToF is completed, regardless of whether the image charge signal acquisition of the ultra-high resolution Fourier transform mass spectrometry is completed or not, the management program returns to the first time period and repeats the above process. It can be seen that in the above working cycle, including the first time period and the second time period, most of the time can be used for signal acquisition of the electrostatic orbital trap, so the ultra-high resolution of the Fourier transform mass spectrometry is guaranteed. At the same time, the time-of-flight mass spectrometer was also repeatedly operated many times to obtain many secondary mass spectra.

[0039] Of course, this device can also allow the ion funnel 63a and the radio frequency ion guide 63b of the second ion guide device to receive and guide the fragment ions to the C-shaped ion storage when the second-stage fragmentation function is turned on, so that the orbital trap can obtain an ultra-high resolution secondary mass spectrum; it can also receive the parent ion and a part of the daughter ions in the gap between the repeated repulsion of the pulse repeller in the first and second stages (for example, the repulsion interval is 0.5ms, and the repulsion pulse is less than 50us, so 90% of the time, the ions can still be received by the second ion guide device). This superposition spectrum of the primary mass spectrum and the secondary mass spectrum can make full use of the ultra-high resolution ability and spectral peak capacity of the Fourier transform mass spectrometry, and more information can be obtained without additional time. At the same time, the daughter ions superimposed can also be determined by selecting the time window to add the daughter ions produced by which parent ion, rather than mixing all kinds of daughter ions. This reduces the complexity of the later spectrum analysis.

[0040] Conversely, the time-of-flight mass spectrometer can also be used to perform several primary mass spectrometry measurements, that is, to orthogonally repel wide-range ions to the flight tube 5. Although the resolution is not high, it can be used to estimate the intensity of the ion flow, thereby determining the next time to accumulate ions in the C storage of the second ion guide device.

[0041] In this scheme, the design of the pulse repeller is critical. It can be a traditional parallel plate structure with a mesh on one side, but it should not be too long, otherwise the ions will diverge too much during the period when ion repeller is not used, affecting the efficiency of the second ion guide to receive ions. Of course, a radio frequency focusing field can also be added in the middle of the parallel plate, such as the one described in US Patent: US10184914B2 Figure 1 , Figure 2 or by using the method of PCT patent WO2007124667A1, when the orthogonal acceleration voltage is not applied, a high-frequency quadrupole field with a focusing effect is generated between the two planes to help ions to be transported axially.

[0042] (Example 2)

[0043] See Figure 2 The difference between this embodiment and embodiment 1 is that a multipole ion lens 2 is used here to replace the ion funnel in embodiment 1 to gather and transmit ions. Both are existing technologies, each with its own characteristics, and can be interchanged, and no further description is given here. A linear quadrupole ion trap 6 is installed at the outlet of the quadrupole mass analyzer 4, which is the key device of this scheme.

[0044] This linear ion trap has two pairs of electrodes, upper and lower, front and back, and adds mutually anti-phase radio frequency voltages to form a radio frequency electric field that traps ions. This radio frequency electric field only plays a radial trapping role on ions, and the linear ion trap in the figure is divided into three sections. If a positive DC voltage is superimposed on the electrodes of the head and tail sections, positive ions can be further trapped in the axial direction (and vice versa). If the parent ions from the quadrupole mass analyzer 4 are accelerated into the linear ion trap and collide with the collision gas molecules in the trap, the generated fragment ions will accumulate here, which forms the so-called cracking function in the linear ion trap, or the linear ion trap is set as a collision cracking pool. If the axial trapping voltage is canceled, the ions from the quadrupole mass analyzer 4 can pass through the linear ion trap smoothly and enter the second ion guide device 7. Figure 2 It is further shown that the ion trap has at least one radial extraction slot 61 on the upper electrode facing the time-of-flight analysis tube 5, and a series of extraction focusing lenses 52 are arranged outside the ion trap extraction slot. By adding a pulse dipole voltage between the upper and lower and square electrodes of the ion trap (the original radio frequency voltage must be reduced or cancelled at this time), the ions stored in the ion trap can be repelled to the time-of-flight analyzer for mass spectrometry analysis. It can be seen that the linear ion trap can realize multiple functions such as 1) ion conduction, 2) collision cleavage, 3) storage cooling, and 4) pulse repulsion radial extraction. The specific technical scheme for ion conduction, cooling, and pulse repulsion using a linear ion trap can also refer to the scheme in U.S. Patent No. 5,763,878, which will not be elaborated here.

[0045] Now we also need to use management and control means to coordinate and control the above-mentioned components to achieve the highest efficiency of multi-stage mass spectrometry. It is also assumed that a full spectrum acquisition and N secondary mass spectrometry acquisitions of N parent ions of different masses are required within a working cycle. In the first time period, the management and control means sets the quadrupole analyzer 4 to a wide mass range conduction state and the linear ion trap to an ion conduction function. The ions pass through the quadrupole analyzer and the linear ion trap, and are introduced into the C-shaped storage 7b by the radio frequency ion guide 7a of the second ion guide device, and are accumulated and cooled therein. After the management and control means determines that the ion accumulation reaches a preset amount, the first time period ends.

[0046] After entering the second time period, the management and control means, on the one hand, injects the ions accumulated in the C-shaped memory 7b into the orbital trap 8 for image charge signal collection to obtain an ultra-high resolution Fourier transform mass spectrum. At the same time, the management and control means makes the quadrupole analyzer 4 be placed in a series of (N) narrow mass range conduction states, allowing the parent ions of each small mass range to pass, and accelerates the injection of ions into the linear ion trap 6, and utilizes the ion fragmentation function to fragment the parent ions into a variety of fragment ions. The fragment ions are collision-cooled in the linear ion trap and gathered near the central axis of the ion trap. This collision cracking-aggregation cooling process generally requires 10 to 40ms according to the intensity of the parent ion flow. Afterwards, the pulse dipole voltage between the upper and lower electrodes is used to repel the ions into the flight time analyzer for secondary mass spectrometry analysis. Because the ion trap has an accumulation effect on the fragment ions, even if a flight time ToF measurement is performed for each parent ion selection point, a better secondary ion mass spectrum can be obtained (of course, the average spectrum quality will be better if the average spectrum is collected multiple times, but the time consumption increases). If a total of N = 15 parent ions need to be subjected to secondary mass spectrometry, all secondary mass spectrometry MS can be completed in the period of 150ms to 600ms. 2 After the time period of the secondary mass spectrometry using ToF is completed, the management program returns to the first time period and repeats the ion conduction collection process. Similar to the first scheme, in a working cycle, most of the time including the first time period and the second time period can be used for signal acquisition of the electrostatic orbital trap, so the ultra-high resolution of the Fourier transform mass spectrometry is guaranteed. At the same time, the time-of-flight mass spectrometer is also repeatedly operated many times to obtain many secondary mass spectra.

[0047] (Example 3)

[0048] See Figure 3, this embodiment adopts an implementation scheme of high-resolution Fourier transform mass spectrometry analysis using an electrostatic linear ion trap. Under this scheme, the linear ion trap 6 and its axial extraction lens 25 become the so-called second ion guide device. In the first period, the ions are gathered and stored in the linear ion trap 6 through the first ion guide device 3 and the quadrupole analyzer 4. After the management and control means determines that the ion accumulation reaches a preset amount, the second period is entered. After entering the second period, the management and control means first injects the ions accumulated in the linear ion trap 6 into the electrostatic linear ion trap 26 through the lens 25. Then the ions are reflected back and forth between the two reflectors 22a and 22b, and the image charge signal is collected by the detector 23 (for more than 100ms) to obtain an ultra-high resolution Fourier transform mass spectrum. At the same time, the management and control means puts the quadrupole analyzer 4 into a series (N) of narrow mass range conduction states, allowing the parent ions of each small mass range to pass through, and accelerates the ions to be injected into the linear ion trap 6. As in the above process, the parent ions are cracked and become a variety of fragment ions. The fragmented ions are cooled by collision in the linear ion trap and gathered near the central axis of the ion trap. The pulsed dipole voltage is used to repel the ions into the time-of-flight analyzer for secondary mass spectrometry analysis. After the time period of secondary mass spectrometry using ToF is completed, the management program returns to the first time period and repeats the ion conduction collection process.

[0049] (Example 4)

[0050] See Figure 4 , this embodiment adopts ion magnetic cyclotron resonance to perform high-resolution Fourier transform mass spectrometry. Similarly, the linear ion trap 6, its axial extraction lens 31 and radio frequency multipole guide 32 are used to form the so-called second ion guide device. In the first time period, the ions are gathered and stored in the linear ion trap 6 through the first ion guide device 3 and the quadrupole analyzer 4. After entering the second time period, the management and control means first injects the ions accumulated in the linear ion trap 6 through the lens 31 and the radio frequency multipole guide 32 into the ion magnetic cyclotron resonance unit 34 for ultra-high resolution Fourier transform mass spectrometry. At the same time, the management and control means puts the quadrupole analyzer 4 into a series (N) of narrow mass range conduction states. As in the above process, each parent ion is cracked in the ion trap and ToF is used for secondary mass spectrometry. After the time period of the secondary mass spectrometry is completed, the management program returns to the first time period and repeats the conduction collection process of the ions.

[0051] (Example 5)

[0052] Of course, it is understandable that there are many forms of new ultra-high resolution Fourier transform mass spectrometers, such as the Cassinian simple harmonic ion trap mass spectrometer introduced in the article International Journal of Mass Spectrometry, vol. 287, no. 1-3, pp. 114-118, and the cylindrical type proposed in US Pat. No. 9082604 and the disk type electrostatic ion trap analyzer proposed in US Pat. No. 9159544B2. Taking the latter as an example, Figure 5 The implementation scheme of using this type of analyzer for high-resolution Fourier transform mass spectrometry is given. Similarly, the linear ion trap 6 and its axial extraction lens 41 and radio frequency multipole guides 42, 43, arc pulse injector 46 constitute the so-called second ion guide device. In the first time period, the ions are collected and stored in the linear ion trap 6 through the first ion guide device 3 and the quadrupole analyzer 4. After entering the second time period, the management and control means first injects the ions accumulated in the linear ion trap 6 into the disk electrostatic ion trap analyzer 44 through the lens 41 and the radio frequency multipole guides 42, 43, and the arc pulse injector 46, and uses the image charge detection electrode 45 to collect signals for high-resolution Fourier transform mass spectrometry. At the same time, the management and control means make the quadrupole analyzer 4, the linear ion trap 6, and the ToF analyzer 5 cooperate to perform multiple secondary mass spectrometry analyses. After the time period of the secondary mass spectrometry is completed, the management program returns to the first time period and repeats the ion conduction collection process.

[0053] In Examples 3, 4, and 5, although different ultra-high resolution mass spectrometers are used, linear ion traps are used to achieve ion fragmentation, and also as a pulse repulsion device for time of flight and a part of the second ion guide for injecting ions into the Fourier transform analyzer. Figure 1 The reaction / collision cell after the quadrupole analyzer 4 realizes the ion fragmentation function, and the ions are repelled toward the time-of-flight analyzer by the orthogonal pulse repulsion device. In the first time period, a separate second ion guide device is still used to focus and accumulate ions for the primary mass spectrometry, regardless of which Fourier transform analyzer is used for ultra-high resolution mass spectrometry analysis.

[0054] As a means of parent ion fragmentation, in addition to the above-mentioned collision fragmentation with neutral gas molecules, low-energy electrons, negative ions or even excited hydrogen atoms can be injected into the gap of the ion trap or ion lens to form electron capture dissociation, electron transfer dissociation or hydrogen atom induced dissociation. The activation of the fragmentation function includes injecting an electron beam, an ion beam or an excited atom beam into the space where the fragmentation function is located, so that it reacts with the ions therein to cause the ions to fragment.

[0055] The present invention uses ultra-high resolution FTMS to obtain a very high-resolution primary mass spectrum, and it does not exclude the use of this analyzer to perform secondary ultra-high resolution mass spectrometry analysis on at least a portion of the fragment ions, and even to accumulate mixed parent ions and fragment ions for ultra-high resolution mass spectrometry analysis, which has been mentioned in the previous embodiment 1. The time-of-flight mass spectrometer only needs to perform rapid secondary mass spectrometry analysis on the fragmentation ions with relatively simple spectral peaks, so it does not require a very high resolution. For example, a ToF analyzer can be designed with a shorter flight tube. The flight tube length, including the reflector, can be designed to be within 1 meter, or even within 500 mm. The resolution ability of 2000 to 5000 can meet the requirements.

[0056] Similarly, since ultra-high resolution FTMS can be used to obtain high-resolution primary or secondary mass spectra, the quadrupole analyzer used for parent ion selection does not necessarily need a very high resolution. Especially in the non-data-dependent DIA working mode that has become increasingly popular in recent years, the quadrupole analyzer is actually a small-range bandpass filter, which can adopt a shorter and cheaper design and processing accuracy. Therefore, there is room for reducing the high cost of compound mass spectrometers caused by increasing the number of analyzers.

[0057] The combined mass spectrometer contains multiple mass spectrometers and ion guides between the analyzers. The vacuum conditions they require are different, and a reasonable differential pumping method should be designed to meet them. However, in order to save costs, the number of vacuum pumps or vacuum pumping ports should be reduced through reasonable design. Figure 1 For example, the quadrupole mass analyzer 4, the reaction / collision cell 60, the extraction lens 61 and the pulse repeller 62 are all placed in the same vacuum chamber, which is connected to a high vacuum pump (which may be a turbomolecular pump, not shown) through the exhaust port 20c, wherein the vacuum degree is about 10 -3 Pa. The gas pressure in the collision cell is relatively high, so it needs to be wrapped in a shell, and only the ion inlet and outlet are connected to the space of the vacuum chamber. The ion funnel 63a of the second ion guide and the C-shaped ion storage 63c require a relatively high pressure. A small flow of inert gas can be appropriately introduced to balance the gas pressure at 10 -2 to 10 -1 Pa. The electrostatic orbital ion trap requires 10 -7 Ultra-high vacuum below Pa is achieved through three-stage differential vacuuming of 20d, 20e, and 20f. The 20d vacuum port provides 10 -4 to 10 -5 The flight tube 5 of the time-of-flight analyzer also needs this vacuum degree, so they can share the same exhaust port. If a multi-port split-flow molecular pump is used to exhaust, the exhaust of the entire system can be achieved by two or even one molecular pump.

[0058] The combined mass spectrometer breaks through the contradiction between ultra-high resolution and rapid mass spectrometry acquisition, and is particularly suitable for high-throughput chromatograph-mass spectrometer analysis methods. When selecting ultra-high resolution Fourier transform analyzers and time-of-flight analyzers and their connecting devices, there are many possible transformation schemes, which are not listed one by one in the above implementation schemes. People in the industry can easily refer to the listed schemes for changes. However, as long as it is used to realize the functions of high-resolution primary mass spectrometry and high-speed secondary mass spectrometry in parallel, any modifications, equivalent replacements, improvements, etc. made thereto should be included in the protection scope of the present invention.

Claims

1. A composite mass spectrometer, characterized in that: The invention comprises an ion source, a first ion guide device, a quadrupole mass analyzer, a time-of-flight mass analyzer, a second ion guide device and a high-resolution Fourier transform mass spectrometer based on image charge detection, The device further comprises a management and control means for the device, which can form an ion fragmentation function in the second ion guide device or in the device between the quadrupole mass analyzer and the second ion guide device while the high-resolution Fourier transform mass spectrometer performs signal acquisition, so that the time-of-flight mass analyzer performs secondary mass spectrometry analysis on the ions fragmented by the ion fragmentation function multiple times; The structural order of the compound mass spectrometer is from an atmospheric pressure ion source to an atmospheric vacuum interface and a rough vacuum ion focusing device, then to a first ion guide device, then to a quadrupole mass analyzer, then to a reaction cell or an ion trap for ion fragmentation, then to a repeller device of a time-of-flight mass analyzer, then to a second ion guide device, and finally to a high-resolution Fourier transform mass spectrometer based on image charge detection; The time-of-flight mass analyzer adopts a pulse repeller, and the ion fragmentation function occurs in the ion reaction pool between the quadrupole analyzer and the pulse repeller. The second ion guide device is arranged behind the pulse repeller, and its axis is along the original direction of travel of the ion beam; at least in a part of a working cycle, the pulse repeller is arranged to suspend orthogonal repulsion, and the second ion guide device converges and stores the parent ions or fragment ions passing through the quadrupole analyzer and the repeller for injection into the high-resolution Fourier transform mass spectrometer based on image charge detection. At least in another part of this working cycle, while the high-resolution Fourier transform mass spectrometer is collecting signals, the parent ions selected by the quadrupole analyzer are fragmented into fragment ions through the fragmentation function. After orthogonal repulsion by the pulse repeller, the fragment ions enter the time-of-flight mass analyzer for secondary mass spectrometry analysis; or, The time-of-flight mass analyzer uses a linear ion trap containing a radial extraction slot as its pulse repulsion device. At least in part of the working cycle, the linear ion trap is in a conducting transmission state. Ions in a wide mass-to-charge ratio range passing through the quadrupole analyzer enter the above-mentioned second ion guide device through the linear ion trap, and are gathered and stored therein so as to provide pulsed ion injection into a high-resolution Fourier transform mass spectrometer based on image charge detection. In another part of the working cycle, while the high-resolution Fourier transform mass spectrometer is performing signal acquisition, the ion fragmentation function is formed in the above-mentioned linear ion trap, and the parent ions selected by the quadrupole analyzer are fragmented into fragment ions in the above-mentioned linear ion trap. After collision cooling, the fragment ions are radially repelled through the extraction slot to the time-of-flight mass analyzer for secondary mass spectrometry analysis.

2. A composite mass spectrometer according to claim 1, characterized in that: The second ion guide device includes a radio frequency ion guide and a radio frequency ion storage device, and the radio frequency ion storage device is used to provide ions to the high-resolution Fourier transform mass spectrometer for primary mass spectrometry analysis.

3. A composite mass spectrometer according to claim 1, characterized in that: The second ion guide device comprises a radio frequency ion guide and a radio frequency ion storage device, which is used to provide ions for primary mass spectrometry analysis and daughter ions generated by fragmentation of at least one selected parent ion to the high-resolution Fourier transform mass spectrometer.

4. A composite mass spectrometer according to claim 1, characterized in that: The second ion guide device comprises a linear ion trap and an axial extraction lens thereof, and the linear ion trap contains a radial extraction slot for pulsedly repelling ions to a time-of-flight mass analyzer. At least in a part of the working cycle, various ions passing through the quadrupole analyzer are gathered and stored in the linear ion trap for injection into a high-resolution Fourier transform mass spectrometer based on image charge detection. In another part of the working cycle, while the high-resolution Fourier transform mass spectrometer is collecting signals, the ion fragmentation function is formed in the linear ion trap. The parent ions selected by the quadrupole analyzer are fragmented into fragment ions in the linear ion trap. The fragment ions are repelled to the time-of-flight mass analyzer after collision cooling for the secondary mass spectrometry analysis.

5. A composite mass spectrometer according to claim 1, characterized in that: The high-resolution Fourier transform mass spectrometer based on image charge detection is an ion cyclotron resonance Fourier transform mass spectrometer.

6. A composite mass spectrometer according to claim 1, characterized in that: The high-resolution Fourier transform mass spectrometer based on image charge detection is an ion trap Fourier transform mass spectrometer of electrostatic field or a hybrid of electrostatic field and magnetic field.

7. A composite mass spectrometer according to claim 1, characterized in that: The high-resolution Fourier transform mass spectrometer based on image charge detection is one of a rotating hyperbolic logarithmic field ion trap Orbitrap, an electrostatic linear ion trap ELIT, a cylindrical or planar electrostatic ion trap or a Cassinian simple harmonic ion trap mass spectrometer.

8. A composite mass spectrometer according to claim 1, characterized in that: During the first part of the analysis cycle, the management and control means causes the quadrupole analyzer to form a wider mass ion conductance range, turns off the ion fragmentation function, and causes the second ion guide device to guide and store ions to provide the Fourier transform mass spectrometer; during the second part of the analysis cycle, the quadrupole analyzer causes the quadrupole analyzer to form a narrower mass conductance range to select parent ions, turns on the ion fragmentation function, and promotes ion fragmentation; and causes the fragmented ions to be pulsed out or introduced into the time-of-flight mass analyzer to perform secondary mass spectrometry analysis multiple times.

9. A composite mass spectrometer according to claim 1, characterized in that: The space where the ion fragmentation function is located is filled with collision gas when working, and in the second part of the analysis cycle, the fragmentation function is turned on, including allowing the ions to be accelerated to a kinetic energy of 5 to 100 electron volts when entering the fragmentation function space, prompting the ions to fragment by reacting with the collision gas.

10. A composite mass spectrometer according to claim 8, characterized in that: In the second part of the analysis cycle, the activation of the fragmentation function includes injecting an electron beam, a negative ion beam or an excited atom beam into the space where the fragmentation function is located, and reacting with the ions therein to cause the ions to fragment.

11. A composite mass spectrometer according to claim 1, characterized in that: The management and control means can turn off the ion fragmentation function while the high-resolution Fourier transform mass spectrometer is collecting signals, and before, during or after the time-of-flight mass analyzer performs secondary mass spectrometry analysis on the fragmented ions, so that the time-of-flight mass analyzer collects a primary mass spectrum at least once.

12. A composite mass spectrometer according to claim 1, characterized in that: The ion source is connected to a chromatograph to form a chromatograph-mass spectrometer.

13. A composite mass spectrometer according to claim 12, characterized in that: The management and control means controls the quadrupole analyzer to select the mass conductance range of parent ions in a data-independent acquisition (DIA) manner, and fragments the parent ions in this range in turn through the ion fragmentation function, and performs time-of-flight mass analysis on the fragment ions produced by the fragmentation.

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