1. A method for synthesizing an intermediate LND1067-L1 of an antibody-conjugated drug linker, comprising the steps of:

LND1067-L1-0 and lead tetraacetate react for 2h-4h at 60 ℃ -80 ℃ in a first solvent, the reaction solution is treated, concentrated, crystallized and pulped to obtain LND 1067-L1-1;

reacting the LND1067-L1-1 with benzyl glycolate in THF for 1h-3h, processing the reaction solution, concentrating, purifying the crude product with normal phase, and purifying to obtain LND 1067-L1-3;

LND1067-L1-0, phenylalanine tert-butyl ester hydrochloride, HATU and DIPEA are reacted in a second solvent, and the reaction solution is treated, pulped, filtered and dried to obtain LND 1067-L1-6;

reacting the LND1067-L1-6 with trifluoroacetic acid in a third solvent for 4-16h, processing a reaction solution, pulping, filtering, and drying to obtain LND 1067-L1-7;

reacting the LND1067-L1-3 with diethylamine in DMF for 0.3h-1h at 0-5 ℃ under the protection of nitrogen, concentrating, adding LND1067-L1-7 and PyBop, cooling to 0-5 ℃, adding diisopropylethylamine, reacting in a fourth solvent for 1h-5h at room temperature, completely separating liquid, extracting, drying, concentrating, and purifying in a normal phase to obtain LND 1067-L1-8;

and (3) carrying out hydrogenation reaction on the LND1067-L1-8 and palladium carbon in a fifth solvent at normal pressure for 1.5-4 h, filtering, concentrating, crystallizing and pulping to obtain an intermediate LND1067-L1 of the antibody coupling drug linker.

2. The synthesis method according to claim 1, wherein the molar equivalent ratio of LND1067-L1-0 to lead tetraacetate is 1.3eq-1.6 eq: 1 when LND1067-L1-1 is prepared.

3. The synthetic method of claim 1 wherein the molar equivalent ratio of LND1067-L1-1 to benzyl glycolate 1.5-2.5 eq: 1 in the preparation of LND 1067-L1-3;

preferably, the elution flow rate of the normal phase purification is 3L/min to 5L/min when preparing LND 1067-L1-3.

4. The synthetic method of claim 1, wherein preparing LND1067-L1-6 is performed according to the following steps:

dissolving LND1067-L1-0 in a second solvent, adding HATU, and stirring at room temperature for 5-10 min;

and (3) reducing the temperature to 0-5 ℃ under the protection of nitrogen, adding phenylalanine tert-butyl ester hydrochloride, dropwise adding DIPEA, keeping the internal temperature at 0-10 ℃ in the dropwise adding process, heating to room temperature, stirring for reaction for 0.5-2h, and stirring in ice water to obtain the LND 1067-L1-6.

5. The synthesis method according to claim 4, wherein the molar equivalent ratio of LND1067-L1-0, HATU, phenylalanine tert-butyl ester hydrochloride, DIPEA is 1.0eq, 1.3eq-1.5eq, 1.0eq, 2.5eq-3.5eq when preparing LND 1067-L1-6.

6. The synthetic process of claim 1 wherein the molar equivalent ratio of LND1067-L1-6 to trifluoroacetic acid in the preparation of LND1067-L1-7 is from 7.0eq to 9.0 eq: 1.

7. The synthetic method according to claim 1, wherein when preparing LND1067-L1-8, the molar equivalent ratio of LND1067-L1-3, diethylamine, LND1067-L1-7, PyBop, diisopropylethylamine is 1.0 eq: 4.0eq-6.0 eq: 1.0 eq: 1.5eq-2.5 eq: 2.0eq-3.0 eq.

8. The synthetic method of claim 1, wherein when preparing the intermediate LND1067-L1 of the antibody-conjugated drug linker, the amount of palladium on carbon is 5% -15% of the mass of LND 1067-L1-8.

9. The synthetic method of claim 1, wherein the first solvent is THF or toluene;

the second solvent is DMF, THF or DCM;

the third solvent is THF or DCM;

the fourth solvent is DMF, DMA, DCM.

10. The synthesis method according to claim 1, wherein the fifth solvent is a mixed solvent of methanol and THF or a mixed solvent of methanol and DCM;

preferably, the mixing volume ratio of the methanol and the THF is 30V: 10V;

the mixing volume ratio of the methanol to the DCM is 30V: 10V.

Background

Antibody Drug Conjugates (ADC) are a novel anti-tumor drug, and the principle is that cytotoxin is connected to an Antibody, and the cytotoxin is transported to a target point through recognition of a specific antigen on the surface of a cancer cell by the Antibody and entering the cancer cell through endocytosis, so that the aim of targeted therapy of malignant tumor is achieved. Compared with the traditional micromolecule antitumor drugs, the ADC has higher specificity and effectiveness due to the fact that the target recognition of the antibody and the high activity of the toxin can be used.

ADCs comprise three distinct components, namely antibodies, linkers and cytotoxins. In the linker context, the main application is the non-cleavable type, such as glycine-phenylalanine-glycine-citrulline (GGFG-Acid), which remains active after lysosomal hydrolysis and binds to an amino Acid residue via the linker region.

The existing LND1067-L1 is used as an intermediate of an important antibody coupling drug linker, and the existing synthetic route is as follows:

this synthesis method has the following problems:

1. step 1, normal phase silica gel purification is needed, and the purification is difficult and small in magnitude;

2. the 2 nd step is small in magnitude and difficult to realize commercial production;

3. the 3 rd step is small in magnitude and difficult to realize commercial production;

4. step 4, normal phase silica gel purification is needed, and the purification is difficult and small in magnitude;

5. the step 5 of synthesizing LND1067-L1-7 requires normal phase silica gel purification, which is difficult to purify and has small magnitude;

6. step 6, reverse-phase preparation and purification are needed, the purification difficulty is high, and the magnitude is small;

7. the 7 th step has small magnitude and is not separated to obtain a pure product.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide a method for synthesizing the intermediate LND1067-L1 of the antibody-conjugated drug linker, which can be synthesized efficiently and is easy to scale up and produce commercially.

In order to achieve the technical purpose, the invention provides a synthetic method of an intermediate LND1067-L1 of an antibody-coupled drug linker, which comprises the following steps:

LND1067-L1-0 reacts with lead tetraacetate in a first solvent for 2h-4h, the reaction solution is processed, concentrated, crystallized and pulped to obtain LND 1067-L1-1;

reacting LND1067-L1-1 with benzyl glycolate (LND1067-L1-2) in THF for 1h-3h, processing the reaction solution, concentrating, rapidly purifying the crude product with normal phase, and purifying to obtain LND 1067-L1-3;

LND1067-L1-0 and phenylalanine tert-butyl ester hydrochloride (LND1067-L1-5) react in a second solvent, and the reaction solution is processed, pulped, filtered and dried to obtain LND 1067-L1-6;

LND1067-L1-6 and trifluoroacetic acid react in a third solvent for 4h-16h, and after the reaction solution is treated, the LND1067-L1-7 is obtained by pulping, suction filtration and drying;

under the protection of nitrogen at 0-5 ℃, reacting LND1067-L1-3 with diethylamine in DMF for 0.3h-1h, concentrating, adding LND1067-L1-7 and PyBop, cooling to 0-5 ℃, adding diisopropylethylamine, reacting in a fourth solvent at room temperature for 1h-5h, completely separating liquid, extracting, drying, concentrating, and purifying in a normal phase to obtain LND 1067-L1-8;

and (3) carrying out hydrogenation reaction on LND1067-L1-8 and palladium carbon in a fifth solvent at normal pressure for 1.5-4 h, filtering, concentrating, crystallizing and pulping to obtain an intermediate LND1067-L1 of the antibody coupling drug linker.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the following steps:

the synthetic method of the intermediate LND1067-L1 of the antibody-coupled drug linker solves the problems of small magnitude, high production difficulty and difficult amplification of the original research route, realizes the high-efficiency synthesis of the LND1067-L1, is easy to amplify and is convenient for commercial production.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the step of preparing LND 1067-L1-1. The method comprises the following steps:

in one embodiment of the invention, the molar equivalent ratio of LND1067-L1-0 to lead tetraacetate is 1.3eq-1.6 eq: 1 when LND1067-L1-1 is prepared. Wherein the mixing ratio of the LND1067-L1-0 to the lead tetraacetate can be 500 g: 1085 g.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the step of preparing LND 1067-L1-3. The method comprises the following steps:

in one embodiment of the invention, the molar equivalent ratio of LND1067-L1-1 to benzyl glycolate 1.5-2.5 eq: 1 is used in the preparation of LND 1067-L1-3. The mixing ratio of the LND1067-L1-1 and the LND1067-L1-2 can be 400 g: 360.95 g. In addition, p-toluenesulfonic acid-hydrate may be added as a catalyst in an amount of 0.1 to 0.2 molar equivalents.

In one embodiment of the invention, the elution flow rate for normal phase purification is 3L/min to 5L/min when LND1067-L1-3 is prepared.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the step of preparing LND 1067-L1-6. The method comprises the following steps:

in one embodiment of the present invention, LND1067-L1-6 is prepared by the following steps:

dissolving LND1067-L1-0 in a second solvent, adding HATU, and stirring at room temperature for 5-10 min;

and (3) under the protection of nitrogen, cooling to 0-5 ℃, adding LND1067-L1-5, dropwise adding DIPEA, keeping the internal temperature less than 10 ℃ in the dropwise adding process (preferably 0-10 ℃), heating to room temperature, stirring for reacting for 0.5-2h, and stirring in ice water to obtain the LND 1067-L1-6.

Specifically, when LND1067-L1-6 is prepared, the molar equivalent ratio of LND1067-L1-0, HATU, LND1067-L1-5 and DIPEA is 1.0 eq: 1.3eq-1.5 eq: 1.0 eq: 2.5eq-3.5 eq. Wherein the mixing ratio of LND1067-L1-0, HATU, LND1067-L1-5 and DIPEA can be 300 g: 139.5 g: 218.22 g: 328.27 g.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the step of preparing LND 1067-L1-7. The method comprises the following steps:

in one embodiment of the invention, the molar equivalent ratio of LND1067-L1-6 to trifluoroacetic acid in the preparation of LND1067-L1-7 is from 7.0eq to 9.0 eq: 1. Wherein the mixed reaction ratio of the LND1067-L1-6 and the trifluoroacetic acid can be 475 g: 475 ml.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the step of preparing LND 1067-L1-8. The method comprises the following steps:

in one embodiment of the invention, when preparing LND1067-L1-8, the molar equivalent ratio of LND1067-L1-3, diethylamine, LND1067-L1-7, PyBop (benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate), diisopropylethylamine is 1.0 eq: 4.0eq-6.0 eq: 1.0 eq: 1.5eq-2.5 eq: 2.0eq-3.0 eq; wherein the mixing ratio of LND1067-L1-3, diethylamine, LND1067-L1-7, PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) and diisopropylethylamine can be 200 g: 200 mL: 211.3 g: 439 g: 149.3 g.

The synthetic method of the intermediate LND1067-L1 of the antibody-conjugated drug linker comprises the step of preparing LND 1067-L1. The method comprises the following steps:

in a specific embodiment of the invention, when preparing the intermediate LND1067-L1 of the antibody-conjugated drug linker, the amount of palladium carbon is 5% -15% of the mass of LND 1067-L1-8; wherein, the mixing ratio of the LND1067-L1-8 and the palladium carbon can be 65 g: 6.5 g.

In one embodiment of the invention, the first solvent is THF or toluene; the second solvent is DMF, THF or DCM; the third solvent is THF or DCM; the fourth solvent is DMF, DMA, DCM.

In a specific embodiment of the present invention, the fifth solvent is a mixed solvent of methanol and THF or a mixed solvent of methanol and DCM; wherein the mixing volume ratio of the methanol to the THF is 30V: 10V; the mixing volume ratio of methanol to DCM was 30V: 10V.

The synthetic method of the intermediate LND1067-L1 of the antibody-coupled drug linker solves the problems of small magnitude, high production difficulty and difficult amplification of the original research route; by optimizing and improving the process, the high-efficiency synthesis of LND1067-L1 is realized, the scale-up is easy, and the commercial production is convenient.

Drawings

FIG. 1 is an HPLC spectrum of LND1067-L1-1 in an example of the invention.

FIG. 2 is a LCMS spectrum of LND1067-L1-1 in an example of the invention.

FIG. 3 is an HPLC spectrum of LND1067-L1-3 in an example of the invention.

FIG. 4 is a LCMS spectrum of LND1067-L1-3 in an example of the invention.

FIG. 5 is an HPLC spectrum of LND1067-L1-6 in an example of the invention.

FIG. 6 is a LCMS spectrum of LND1067-L1-6 in an example of the invention.

FIG. 7 is an HPLC spectrum of LND1067-L1-7 in an example of the invention.

FIG. 8 is a LCMS spectrum of LND1067-L1-7 in an example of the invention.

FIG. 9 is an HPLC spectrum of LND1067-L1-8 in an example of the invention.

FIG. 10 is a LCMS spectrum of LND1067-L1-8 in an example of the invention.

FIG. 11 is an HPLC spectrum of LND1067-L1 in an example of the invention.

FIG. 12 is a LCMS spectrum of LND1067-L1 in an example of the invention.

FIG. 13 is a HNMR spectrum of LND1067-L1 in an example of the invention.

Detailed Description

Examples

The embodiment provides a synthesis method of an intermediate LND1067-L1 of an antibody-conjugated drug linker, which specifically comprises the following steps.

Synthesis of LND1067-L1-1

500g of LND1067-L1-0 was added to a 10L reactor, 5L (10V) of THF was added; 1085g (1.4eq) of lead tetraacetate and 174ml (1.2eq) of pyridine are added into the system, and reflux reaction is carried out for 2 to 4 hours at the temperature of between 70 and 80 ℃; after the reaction is complete, post-treatment: and (3) pouring out all the system, concentrating and spin-drying, adding pure water (3L) EA (5L) for extraction, adding 2L EA into a water phase for back extraction, combining EA phases, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering with a sand core funnel, spin-drying filtrate, adding 1L MTBE into a crude product, pulping for 2 hours, performing suction filtration with a Buchner funnel, washing a filter cake with MTBE, and drying a product to obtain 417.5g of a pure product, wherein the yield is as follows: 80.3 percent. 6319 HPLC: 96.0% (HPLC spectrum is shown in FIG. 1), LCMS spectrum is shown in FIG. 2.

Synthesis of LND1067-L1-3

400g of LND1067-L1-1 is added into a 10L three-necked bottle, 4L of THF is added, 360.95g (2.0eq) of benzyl glycolate and 41.32g (0.2eq) of p-toluenesulfonic acid-hydrate are added under stirring, and the mixture is stirred and reacted for 1 to 3 hours at room temperature; and (3) after the reaction is complete, post-treatment: adding 4L of EA and 1.4L of saturated sodium bicarbonate, and extracting and separating; 3L of EA back extraction of the aqueous phase, combining the EA phases, drying over anhydrous sodium sulfate, filtering through a sand-core funnel, concentrating to obtain a crude product, purifying in the normal phase (PE/EA: 1/2-/2/1) to obtain a pure product 267g, yield: 51.8 percent. HPLC: 95.1% (spectrum shown in fig. 3), LCMS: 475.34[ M + H ] + (spectrum shown in FIG. 4).

Synthesis of LND1067-L1-6

300g of LND1067-L1-0 is dissolved in 1.5L of DMF (5V), then HATU 139.5g (1.3eq) is added, stirring is carried out for 5-10min at room temperature, nitrogen protection is carried out, and the temperature is reduced by ice water bath; when the temperature is reduced to 0-5 ℃, adding 1067-L1-5218.22 g (1.0eq) of LND, beginning to dropwise add 328.27g (3.0eq) of DIPEA after the addition is finished, keeping the internal temperature less than 10 ℃ during the dropwise addition, raising the temperature to room temperature, and stirring for reaction for 0.5-2 h. After the reaction is complete, post-treatment: pouring the reaction system into 10L of ice water, mechanically stirring, separating out a large amount of white solid particles, stirring overnight, performing suction filtration, washing a filter cake with pure water, and drying to obtain a white solid, wherein a pure product 475g is obtained, and the yield is as follows: 100 percent. HPLC: 98.3% (spectrum shown in fig. 5), LCMS: 558.50[ M + H]⁺(the spectrum is shown in FIG. 6).

Synthesis of LND1067-L1-7

475g of LND1067-L1-6 was dissolved in 1.9L (4V) DCM, and 475ml of TFA (1V) was added, under nitrogen protection, and stirred at room temperature for 4-16 h; after the reaction is completed, the reaction solution is directly spin-driedAdding 2L of MTBE, mechanically stirring and pulping for 2h, carrying out suction filtration, washing a filter cake with the MTBE, and drying the filter cake to obtain 432g, wherein the yield is as follows: 101 percent. HPLC: 97.1% (as shown in FIG. 7), LCMS: 502.36[ M + H]⁺(as shown in fig. 8).

Synthesis of LND1067-L1-8

Pouring 200g of LND1067-L1-3 and 800ml of DMF (4V) into a 3L single-mouth bottle, reducing the temperature in the reaction to 0-5 ℃ under the protection of nitrogen, adding 200ml of (1V) Diethylamine (DEA), reacting for 0.3-1h, detecting by TLC, concentrating the reaction system, and directly carrying out the next reaction;

1000ml (5V) of DMF, 1067-L1-7211.3(1.0eq) and 439g (2.0) of PyBop are added into the concentrated reaction system, the temperature is reduced to 0-5 ℃, 149.3g (2.0eq) of DIPEA is added, and the reaction system is heated to room temperature for reaction for 1-5 h. And (3) after reaction is complete: adding 4.6L of EA and 3L of pure water, stirring, extracting, separating, adding 3L of EA into the water phase, performing back extraction, combining the organic phases, washing the organic phase with saturated sodium chloride for three times, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product; normal phase purification (DCM/MeOH: 1/100-4/100) gave pure 207.9g, yield: 67.1 percent. HPLC: 95.3% (as shown in FIG. 9), LCMS: 758.58[ M + Na ]]⁺(as shown in fig. 10).

Synthesis of LND1067-L1

65g of LND1067-L1-8, 650ml of DCM and 1950ml of MeOH were added to a 3L single-neck flask, and 6.5g of 10% Pd/C was added with stirring to displace hydrogen and the reaction was carried out for 1.5h-4 h. HPLC detection reaction complete post-treatment: and (3) filling diatomite into a sand core funnel, performing suction filtration, performing rotary evaporation on filtrate until a large amount of white massive solid is separated out, performing suction filtration, washing a filter cake with MeOH, and drying to obtain 42.3g of a product, wherein the yield is as follows: 74.2 percent.

HPLC: 95.4% (as shown in FIG. 11), LCMS: 668.62[ M + Na ]]⁺(as shown in fig. 12).

1H NMR (400MHz, DMSO) δ 8.58(t, J ═ 6.5Hz, 1H), 8.32(t, J ═ 5.7Hz, 1H), 8.17(d, J ═ 8.0Hz, 1H), 8.05(t, J ═ 5.4Hz, 1H), 7.95(s, 1H), 7.89(d, J ═ 7.5Hz, 2H), 7.71(d, J ═ 7.4Hz, 2H), 7.59(t, J ═ 6.0Hz, 1H), 7.41(t, J ═ 7.4Hz, 2H), 7.32(t, J ═ 7.4Hz, 2H), 7.23(d, J ═ 6.0Hz, 3H), 7.18(dd, J ═ 7.5, 5.0, 1.4H, 62, 2H), 7.7.23 (d, J ═ 6.0Hz, 3H), 7.18(dd, 7.5, 5, 1.0, 62H, 2H), 13.7.7.7.7.7.7.7.7.7.7, 13H, 3H, 2H, 7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7, 3H, 2H, 3H, and so on (d, 3H).

Comparative example

The comparative example provides a synthesis method of an intermediate LND1067-L1 of an antibody-conjugated drug linker, and specifically comprises the following steps.

500g of LND1067-L1-0 was added to a 10L reactor, 5L (10V) of THF was added; 1085g (1.4eq) of lead tetraacetate and 174ml (1.2eq) of pyridine are added into the system, and the temperature is increased and the reflux reaction is carried out for 6 hours; after the reaction is complete, post-treatment: and (3) pouring out the whole system, concentrating, spin-drying, adding pure water (3L) EA (5L) for extraction, adding 2L EA into a water phase for back extraction, combining EA phases, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering with a sand core funnel, spin-drying filtrate, adding 1L MTBE into a crude product, pulping for 2h, performing suction filtration with a Buchner funnel, washing a filter cake with MTBE, and drying the product to obtain a pure product, wherein the yield is as follows: 65 percent.

400g of LND1067-L1-1 is added into a 10L three-necked flask, 4L of THF is added, 360.95g (2.0eq) of benzyl glycolate and 41.32g (0.2eq) of p-toluenesulfonic acid-hydrate are added under stirring, and the mixture is stirred and reacted at room temperature for 0.5 h; and (3) after the reaction is complete, post-treatment: adding 4L of EA and 1.4L of saturated sodium bicarbonate, and extracting and separating; 3L of EA back extraction aqueous phase, EA phase combination, anhydrous sodium sulfate drying, sand core funnel filtration, concentration to obtain crude product, normal phase purification (PE/EA: 1/2-/2/1) to obtain pure product, yield: 42 percent.

300g of LND1067-L1-0 is dissolved in 1.5L of DMF (5V), then HATU 139.5g (1.3eq) is added, stirring is carried out for 5-10min at room temperature, nitrogen protection is carried out, and the temperature is reduced by ice water bath; when the temperature is reduced to-5 ℃, adding 1067-L1-5218.22 g (1.0eq) of LND, beginning to dropwise add 328.27g (3.0eq) after the addition is finished, keeping the internal temperature at 10 ℃ during the dropwise addition, raising the temperature to room temperature, and stirring for reaction for 3 hours. After the reaction is complete, post-treatment: pouring the reaction system into 10L of ice water, mechanically stirring, separating out a large amount of white solid particles, stirring overnight, performing suction filtration, washing a filter cake with pure water, and drying to obtain a white solid, wherein the yield is as follows: 85 percent.

475g of LND1067-L1-6 were dissolved in 1.9L (4V) DCM, and 475ml of TFA (1V) were added, under nitrogen, and stirred at room temperature for 35 h; after the reaction is completed, directly spin-drying the reaction solution, adding 2L of MTBE, mechanically stirring and pulping for 2h, carrying out suction filtration, washing a filter cake with the MTBE, and drying the filter cake to obtain a pure product, wherein the yield is as follows: 80 percent.

200g of LND1067-L1-3, 800ml of DMF (4V) is poured into a 3L single-mouth bottle, nitrogen is used for protection, the temperature in the reaction is reduced to-5 ℃, 200ml of (1V) Diethylamine (DEA) is added, the reaction is finished for 5 hours, TLC detection is carried out, the reaction system is concentrated, and then the next reaction is directly carried out; 1000ml (5V) of DMF, 1067-L1-7211.3(1.0eq) of LND and 800g of PyBop are added into the concentrated reaction system, the temperature is reduced to 0-5 ℃, 149.3g (2.0eq) of DIPEA is added, and the reaction system is heated to room temperature for reaction for 1-5 h. And (3) after reaction is complete: adding 4.6L of EA and 3L of pure water, stirring, extracting, separating, adding 3L of EA into the water phase, performing back extraction, combining the organic phases, washing the organic phase with saturated sodium chloride for three times, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product; normal phase purification (DCM/MeOH: 1/100-4/100) gave pure product in yield: 42 percent.

65g of LND1067-L1-8, 650ml of DCM and 1950ml of MeOH were added to a 3L single-neck flask, and 1g of 10% Pd/C was added with stirring to displace the hydrogen and react for 0.5 h. HPLC detection reaction complete post-treatment: filling diatomite in a sand core funnel, performing suction filtration, performing rotary evaporation on filtrate until a large amount of white massive solids are separated out, performing suction filtration, washing a filter cake with MeOH, and drying to obtain a product, wherein the yield is as follows: and 47 percent.

The above examples illustrate the synthesis method of the intermediate LND1067-L1 of the antibody-conjugated drug linker of the invention, which realizes the efficient synthesis of LND1067-L1, is easy to scale up, and is convenient for commercial production.

The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.