CN111362926A - Synthetic method of intermediate CLA-SN38 for antibody coupled drug and intermediate thereof - Google Patents
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Abstract
The invention provides a preparation method of an intermediate CLA-SN38 for an antibody drug conjugate, and also discloses an intermediate compound related to the synthesis method. The synthesis method provided by the invention has the advantages of easily available raw materials, simple operation and easy amplification. And the cyclization reaction catalyzed by copper is put in the first step, so that the residue of copper ions with toxic and side effects in a final product can be reduced, the purification difficulty is reduced, and the method is suitable for commercial production.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthetic method of an intermediate CLA-SN38 for an antibody drug conjugate and an intermediate thereof.
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. The antibody realizes targeting, the linker ensures the stability of the ADC in the blood transportation process, and after the ADC reaches an action target, the toxin plays a role in killing cancer cells. Depending on the mechanism of action, the toxins suitable for ADCs are classified into microtubule-like inhibitors (microtubuliinhibitors), DNA damaging agents (DNA damaging agents), RNA polymerase inhibitors (RNA polymerase inhibitors), and the like. Currently, the toxins used in ADCs marketed and in clinical trials are mainly microtubule inhibitors, mainly including compounds designed based on Dolastatin-based (Dolastatin-based) such as MMAE, MMAF and MMAD, and compounds designed based on Maytansine-based (Maytansine-based) such as DM1 and DM 4. In the linker context, the main applications are non-cleavable types, such as Valine-citrulline (Valine-Citriline) and cyclohexyl carboxylic acid (MCC), which remain active after lysosomal hydrolysis and bind to an amino acid residue via a linker region.
The antibody-conjugated drug IMMU-132 was developed by Seattle Gene, and is now in phase 3 clinical trials, expected to enter the market in 2020. This drug couples an antibody targeting the tumor cell TROP-2 antigen to SN-38, the metabolite of the chemotherapeutic drug irinotecan.
In the process of preparing ADC by IMMU-132, the used small molecular intermediate is CLA-SN38, the structural formula of which is shown in the specification
The preparation method adopts the following linear route:
the preparation method has low yield, complicated operation and difficult amplification, and is not beneficial to commercial production. .
Disclosure of Invention
In the prior art, the preparation method of the intermediate CLA-SN38 of the antibody drug conjugate has low yield, complex operation and difficult amplification. Aiming at the problems in the prior art, the preparation method adopts a gathering route, the raw materials are more easily obtained, and the catalytic cyclization reaction of copper is put into the first step, so that the residue of copper ions with toxic and side effects in the final product is reduced, and the purification difficulty is reduced.
One of the purposes of the invention is to provide an intermediate compound C for synthesizing an anti-antibody drug conjugate intermediate CLA-SN38, wherein the structural formula is shown in the specification
The invention also aims to provide a preparation method of the intermediate CLA-SN38 for the antibody drug conjugate, which comprises the following steps:
1) dissolving a compound A with a structural formula A and a compound B with a structural formula B in dichloromethane, generating a ring reaction under the action of a catalyst to obtain a reaction solution containing a compound C, and separating and purifying the compound C from the reaction solution for the first time.
Structural formula A is
Structural formula B is
2) Dissolving a compound D with a structural formula D and 4-dimethylamino pyridine in dichloromethane, adding trichloromethyl carbonate, and stirring to perform a first reaction to form a yellow solution. And adding a compound C into the solution to perform condensation reaction to obtain a reaction solution containing a compound E with a structural formula E, and separating and purifying the compound E from the reaction solution for the second time. Structural formula D is
The structural formula E is
3) And dissolving the compound E in a mixed solvent of dichloromethane and trifluoroacetic acid, wherein the volume ratio of the dichloromethane to the trifluoroacetic acid in the mixed solution is 4/1, removing Boc protecting groups under the action of the trifluoroacetic acid, and separating and purifying the reaction liquid for the third time to obtain a product CLA-SN 38.
Optionally, the catalyst in step 1) is selected from cuprous bromide and/or triphenylphosphine.
Further, the first reaction in step 2) is carried out for 5 minutes at the temperature of 0 ℃ under the protection of inert gas.
Further, the first separation and purification in the step 1) comprises: first, the reaction solution of Compound C was washed with water, dried over anhydrous sodium sulfate, and spin-dried. The crude product is then purified by medium pressure reverse phase purification gradient volume ratio: water/acetonitrile 90/10-10/90 for 1 hour, and the pure product was collected and lyophilized.
Further, the second separation and purification in the step 2) comprises: first, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and spin-dried. The crude product is then purified by medium pressure reverse phase purification gradient volume ratio: water/acetonitrile 90/10-10/90 for 1 hour, and the pure product was collected and lyophilized.
Further, the third separation and purification in the step 1) comprises: first, acetonitrile was added to the reaction solution to dilute it, and the volume of the solution was concentrated at low temperature. Then, purification was performed using medium pressure reverse phase, with gradient volume ratio: water/acetonitrile 90/10-10/90, for 1 hour, collecting pure product, and freeze-drying to obtain CLA-SN 38.
The method adopting the gathering route has the advantages of easily obtained raw materials, more easily obtained raw materials and simple reaction, and provides possibility for amplifying CLA-SN38 to hectogram level. In addition, the route puts the cyclization reaction catalyzed by copper in the first step, so that the residue of copper ions with toxic and side effects in the final product can be reduced, and the purification difficulty is reduced.
Drawings
FIG. 1 is a liquid chromatogram of Compound E synthesized according to the present invention.
FIG. 2 is a mass spectrum of Compound E synthesized according to the present invention.
FIG. 3 is the NMR spectrum of Compound E synthesized according to the invention.
FIG. 4 is a liquid chromatogram of intermediate CLA-SN38 synthesized according to the invention.
FIG. 5 is a mass spectrum of intermediate CLA-SN38 synthesized by the present invention.
FIG. 6 is the nuclear magnetic resonance hydrogen spectrum of intermediate CLA-SN38 synthesized by the invention
Detailed Description
The structural formula of the intermediate CLA-SN38 for the antibody drug conjugate is shown in the specification
As used herein, the abbreviations commonly used have the conventional meaning in the art, e.g., the abbreviation BOC stands for tert-butyloxycarbonyl.
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure. While the invention will be described in connection with the preferred embodiments, there is no intent to limit its features to those embodiments. On the contrary, the invention is described in connection with the embodiments for the purpose of covering alternatives or modifications that may be extended based on the claims of the present invention. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be practiced without these particulars. Moreover, some of the specific details have been left out of the description in order to avoid obscuring or obscuring the focus of the present invention.
The invention provides a synthetic method of an intermediate CLA-SN38 for an antibody drug conjugate, which comprises the following reaction route:
the synthesis method of the intermediate CLA-SN38 for the antibody drug conjugate comprises the following steps:
1) the structural formula A of the compound A is
The structural formula B of the compound B is
Dissolving a compound A and a compound B in dichloromethane, and fully performing cyclization reaction under the action of a catalyst and the protection of inert gas, wherein the catalyst can be selected from cuprous bromide and/or triphenylphosphine to obtain a reaction solution containing a compound C, and the structural formula C of the compound C is
The reaction solution was washed with water, dried over anhydrous sodium sulfate, spun-dried, and the crude product was purified by medium pressure reverse phase (80 g of commercially packed C18 reverse phase column) with gradient water/acetonitrile (90/10-10/90, v/v) for 1 hour. The pure product was collected and lyophilized to give compound C as a white solid.
2) The structural formula D of the compound D is
Dissolving the compound D and 4-dimethylaminopyridine in dichloromethane, adding trichloromethyl carbonate, and stirring and reacting at the temperature of 0 ℃ for 5 minutes under the protection of inert gas to form a yellow solution. Adding a compound C into the yellow solution to perform condensation reaction to obtain a reaction solution containing a compound E, wherein the structural formula E of the compound E is
The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, spun dry and the crude product was purified by medium pressure reverse phase (80 g of commercially packed C18 reverse phase column) with gradient water/acetonitrile (90/10-10/90, v/v) over 1 hour. The pure product was collected and lyophilized to give compound E as a white solid.
3) And dissolving the compound E in a mixed solvent of dichloromethane and trifluoroacetic acid, wherein the volume ratio of the dichloromethane to the trifluoroacetic acid in the mixed solution is 4/1, stirring at room temperature for reaction under the protection of inert gas, and finally removing the Boc protecting group under the action of the trifluoroacetic acid to obtain a reaction liquid containing CLA-SN 38. The reaction was diluted with acetonitrile, concentrated at low temperature, purified by medium pressure reverse phase (40 g of commercial packed C18 reverse phase column) and gradient water/acetonitrile (90/10-10/90, v/v) for 1 hour. Collecting pure product, lyophilizing to obtain white solid CLA-SN38
Examples
Adding compound A (1.6g, 1.52mmol), compound B (0.5g, 1.83mmol), CuBr (86mg, 0.61mmol) and PPh3(80mg, 0.31mmol) into dichloromethane (30mL), stirring at room temperature under nitrogen for 4 hours, LCMS shows that less than 3% of compound A in the reaction solution is considered as the end of the reaction, washing the reaction solution with water (2 × 50mL), drying with anhydrous sodium sulfate, spinning, purifying the crude product by medium pressure reverse phase (using 80g of industrial packed C18 reverse phase column), purifying gradient water/acetonitrile (90/10-10/90, v/v), and 1 hour, collecting the pure product, and freeze-drying to obtain compound C as a white solid (white solid, 1.6g, yield 80%).
Dissolving compound D (750mg, 1.52mmol) and 4-dimethylaminopyridine (551mg, 4.52mmol) in dichloromethane (10mL), adding trichloromethyl carbonate (225mg, 0.76mmol) under nitrogen protection at 0 deg.C, stirring for 5 minutes to obtain a yellow solution, adding compound C (2.0g, 1.52mmol), stirring for 5 minutes at 0 deg.C, LCMS shows that less than 5% of compound C in the reaction solution is regarded as reaction completion, diluting the reaction solution with 40mL dichloromethane, washing with water (2 × 50mL), drying with anhydrous sodium sulfate, spinning, purifying the crude product with medium pressure reverse phase (80 g of industrial packed C18 reverse phase column is selected), purifying gradient water/acetonitrile (90/10-10/90, v/v), collecting the pure product, lyophilizing to obtain compound E (white solid, 0.98g, yield 36%). MS: 1838.24(M + H) (M.+)
The liquid chromatogram of compound E is shown in figure 1; the mass spectrum of compound E is shown in figure 2; the NMR spectrum of compound E is shown in figure 3.
Compound E (1.0g, 0.54mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroacetic acid (10mL, 4/1, v/v), the reaction was stirred at room temperature under nitrogen for 1 hour, and LCMS showed that less than 5% of compound E in the reaction solution was regarded as the end of the reaction. Reaction solution is addedDiluted with 40mL acetonitrile, cryoconcentrated to a volume of about 10mL, and purified by medium pressure reverse phase (40 g of commercial packed C18 reverse phase column), gradient water/acetonitrile (90/10-10/90, v/v) for 1 hour. The pure product was collected and lyophilized to give CLA-SN38(280mg, 35% yield, 96% HPLC purity by UV 220nm) as a white solid. MS: 1481.44(M + H)+)
The liquid chromatogram of intermediate CLA-SN38 is shown in figure 4; the intermediate CLA-SN38 has a mass spectrum shown in figure 5; the intermediate CLA-SN38 has NMR spectrum shown in figure 6.
Claims (7)
1. An intermediate compound C with a structural formula C for synthesizing an antibody coupling drug intermediate CLA-SN38, wherein the structural formula of the intermediate CLA-SN38 is
Characterized in that the structural formula C is
2. A synthetic method for synthesizing an antibody coupling drug intermediate compound CLA-SN38 is provided, wherein the structural formula of the intermediate compound CLA-SN38 is
The synthesis method is characterized by comprising the following steps:
1) dissolving a compound A with a structural formula A and a compound B with a structural formula B in a dichloromethane solvent, generating a ring reaction under the action of a catalyst M to obtain a reaction liquid containing a compound C, and separating and purifying the compound C from the reaction liquid for the first time.
The structural formula A is
The structural formula B is
The structural formula C is
2) Dissolving a compound D with a structural formula D and 4-dimethylamino pyridine in dichloromethane, adding trichloromethyl carbonate, and stirring to perform a first reaction to form a yellow solution. And adding a compound C into the solution to perform condensation reaction to obtain a reaction solution containing a compound E with a structural formula E, and separating and purifying the compound E from the reaction solution for the second time. The structural formula D is
The structural formula E is
3) And dissolving the compound E in a mixed solvent of dichloromethane and trifluoroacetic acid, wherein the volume ratio of the dichloromethane to the trifluoroacetic acid in the mixed solvent is 4/1, removing Boc protective groups under the action of the trifluoroacetic acid, and separating and purifying the reaction liquid for the third time to obtain a product CLA-SN 38.
3. The synthesis process according to claim 2, characterized in that the catalyst M is chosen from cuprous bromide and/or triphenylphosphine.
4. The synthesis method according to claim 2, wherein the first reaction in step 2) is carried out at 0 ℃ for 5 minutes under the protection of inert gas.
5. The method of any one of claims 2-4, wherein the first separation and purification comprises:
the reaction solution containing compound C was washed with water, dried over anhydrous sodium sulfate, and spin-dried.
The crude product is purified by medium pressure reversed phase, and the volume ratio of the purification gradient is as follows: water/acetonitrile 90/10-10/90, and the pure product was collected and lyophilized.
6. The synthesis method according to any one of claims 2 to 4, wherein the second separation and purification comprises:
the reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and spin-dried.
The crude product is purified by medium pressure reversed phase, and the volume ratio of the purification gradient is as follows: water/acetonitrile 90/10-10/90, and the pure product was collected and lyophilized.
7. The method of any one of claims 2-4, wherein the third separation and purification comprises:
and adding acetonitrile into the reaction solution for dilution, and concentrating the volume of the solution at low temperature.
Purification with medium pressure reversed phase, gradient volume ratio: water/acetonitrile 90/10-10/90, and the pure product was collected and lyophilized.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113813399A (en) * | 2021-04-19 | 2021-12-21 | 联宁（苏州）生物制药有限公司 | Camptothecin compound, antibody drug conjugate thereof and application thereof |
| CN114605493A (en) * | 2022-04-06 | 2022-06-10 | 联宁（苏州）生物制药有限公司 | Synthetic method of antibody-coupled drug intermediate SET0526 |
| CN114605493B (en) * | 2022-04-06 | 2024-06-04 | 联宁（苏州）生物制药有限公司 | Synthesis method of antibody-coupled drug intermediate SET0526 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101824090A (en) * | 2002-06-14 | 2010-09-08 | 免疫医疗公司 | Monoclonal antibody hpam 4 |
| CN108853514A (en) * | 2017-08-18 | 2018-11-23 | 四川百利药业有限责任公司 | There are two types of the antibody drug conjugates of different pharmaceutical for tool |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101824090A (en) * | 2002-06-14 | 2010-09-08 | 免疫医疗公司 | Monoclonal antibody hpam 4 |
| CN108853514A (en) * | 2017-08-18 | 2018-11-23 | 四川百利药业有限责任公司 | There are two types of the antibody drug conjugates of different pharmaceutical for tool |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113813399A (en) * | 2021-04-19 | 2021-12-21 | 联宁（苏州）生物制药有限公司 | Camptothecin compound, antibody drug conjugate thereof and application thereof |
| CN114605493A (en) * | 2022-04-06 | 2022-06-10 | 联宁（苏州）生物制药有限公司 | Synthetic method of antibody-coupled drug intermediate SET0526 |
| CN114605493B (en) * | 2022-04-06 | 2024-06-04 | 联宁（苏州）生物制药有限公司 | Synthesis method of antibody-coupled drug intermediate SET0526 |
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