Method for preparing indeno[1,2-b]quinoline-10,13-dione derivatives

Abstract

The present disclosure relates to a method for preparing an indeno[1,2-b]quinoline-10,13-dione derivative. Specifically, the present disclosure relates to a method for preparing a compound of formula I, which comprises converting a compound of formula Da to a compound of formula I under acidic conditions. The method effectively realizes enrichment of the compound of formula I, improves the process yield, and is suitable for industrial production. [Formula 1] JPEG2026506043000056.jpg47143

Description

[Technical Field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to a method for preparing indeno[1,2-b]quinoline-10,13-dione derivatives. [Background technology]

[0002] The compound (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]imidazo[1,2-b]quinoline-10,13(9H,15H)-dione), a derivative of camptothecin, is a topoisomerase I inhibitor with tumor growth inhibitory and antitumor properties.

[0003] EP0495432 discloses a method for preparing the above compound, which mainly involves using compound 1 as a substrate and reacting compound 2 with compound 2 in the Friedlander reaction to form intermediate 3, then removing the acetyl group under methanesulfonic acid conditions to obtain diastereomers, and then recrystallizing the diastereomers to obtain optical products. [ka]

[0004] The overall process is achiral selective, with the dr value of the resulting diastereomer 4 being approximately 1:1. The subsequent recrystallization step also serves only to purify the optical product. Therefore, the single-step recrystallization yield is approximately 45%, and the overall process yield is less than 41%. For other synthesis literature, see CN111065621, CN115197088, and CN115197234. Summary of the Invention

[0005] The present disclosure provides methods for preparing compounds of formula I or salts thereof. [ka] wherein the method comprises the step of: forming a compound of formula I under acidic conditions from a compound of formula Da; [ka] ,Of which, P 1 is a hydroxy protecting group or hydrogen, e.g., hydrogen or a tert-butoxycarbonyl group, and R 1 is hydrogen, halogen or C 1-6 alkyl group, for example, a methyl group, and R 2 is selected from hydrogen or halogen, for example fluoro.

[0006] In some embodiments, the acid used in the reaction is selected from a hydrogen chloride (HCl) solution, hi some embodiments, the acid used in the reaction is an HCl / 1,4-dioxane solution, an HCl / ethanol solution, an HCl / ethyl acetate solution, an HCl / isopropanol solution, or an HCl / isobutanol solution.

[0007] In some embodiments, the solvent used in the reaction of the compound of Formula Da is one or more selected from isobutanol, isopropanol, 3-methyl-2-butanol, ethyl acetate, ethanol, and 1,4-dioxane.

[0008] In some other embodiments, the method further comprises reacting a compound of formula A with a compound of formula B to form a compound of formula C; [ka] , among which, R 1 , R 2 , P 1 is as defined above, and P 2 is selected from amino protecting groups, such as an acetyl group.

[0009] The amount (molar amount) of the compound of formula B used in this step is not particularly limited as long as it ensures the reaction proceeds, and is preferably 0.8 to 1.2 equivalents (eq.) based on the compound of formula A, including 0.8 equivalents, 0.9 equivalents, 1 equivalent, 1.1 equivalents, 1.2 equivalents, or any value between two of them.

[0010] In some embodiments, the reaction of the compound of formula A with the compound of formula B is carried out in the presence of an acid catalyst. Illustrative examples include pyridinium p-toluenesulfonate or methanesulfonic acid. In some embodiments, the amount (molar amount) of the acid catalyst used in this step is not particularly limited, and is preferably 0.03 to 0.3 equivalents based on the compound of formula A.

[0011] In some embodiments, the reaction of the compound of formula A with the compound of formula B is carried out in a solvent containing cresol or phenol. In some embodiments, the reaction of the compound of formula A with the compound of formula B is carried out in toluene containing o-cresol. For specific reaction conditions / procedures, see CN111065621, the contents of which are incorporated herein by reference.

[0012] In some embodiments, the reaction of the compound of formula A with the compound of formula B is carried out in a solvent containing acetic acid or toluene. In some embodiments, the reaction of the compound of formula A with the compound of formula B is carried out in toluene containing acetic acid. Compared to the presence of o-cresol or phenol, a faster reaction rate can be observed in the presence of acetic acid or toluene. For specific reaction conditions / procedures, see CN115197088, the contents of which are incorporated herein by reference.

[0013] In some embodiments, the reaction temperature between the compound of formula A and the compound of formula B is not limited as long as the reaction proceeds, and is preferably 90 to 130°C, including, but not limited to, 90°C, 100°C, 110°C, 120°C, 130°C, or any value between these two. In some embodiments, the reaction temperature between the compound of formula A and the compound of formula B is the temperature at which toluene is heated to reflux. The reaction time for this step is not limited as long as the reaction proceeds, and is preferably 16 to 64 hours.

[0014] In some embodiments, the compound of formula I is [ka] wherein the method comprises the steps of: converting a compound of formula D-1a into a compound of formula I-1 under acidic conditions; [ka] Includes:

[0015] Some embodiments provide a method of preparing a compound of Formula I or a salt thereof, [ka] wherein the compound of formula D is enriched in the presence of an acid to obtain the compound of formula I, or the compound of formula I is enriched in the presence of an acid; [ka] ,Of which, P 1 is a hydroxy protecting group or hydrogen, preferably hydrogen or a tert-butoxycarbonyl group, and R 1 is hydrogen, halogen or C 1-6 alkyl group, preferably a methyl group; R 2 is selected from hydrogen or halogen, preferably fluoro.

[0016] In some embodiments, Formula D compounds include Formula Da compounds and Formula I compounds.

[0017] The "enrichment" described in the present disclosure is different from crystal resolution of diastereomers, and its principle is to realize the phenomenon of "enrichment" of target configuration products by, for example, converting a non-target configuration product into a target configuration product through a dynamic asymmetric transformation process driven by crystallization under specific conditions, such as in the presence of an acid. For example, in some embodiments of the present disclosure, enrichment refers to converting a compound of formula Da to a compound of formula I in the presence of an acid, or in some embodiments of the present disclosure, enrichment refers to converting a compound of formula D to a compound of formula I in the presence of an acid.

[0018] In some embodiments, the compound of Formula D is a diastereomeric mixture, primarily comprising two diastereomers, Compound 5 and Compound 6, with a dr value of about 1:1. In some embodiments, the compound of Formula D effectively converts non-target configurations to target configurations in the presence of an acid, e.g., in the presence of a hydrogen chloride solution, thereby enriching the compound of Formula I. In some embodiments, the dr value of the compound of Formula D increases from 1:1 to about 9:1 in the presence of an acid, e.g., in the presence of a hydrogen chloride solution.

[0019] In some embodiments, compound 6 is converted to compound 5 (also referred to as the compound of formula I-1) in the presence of an acid. [ka] In some embodiments, the acid used in the reaction is a solution of HCl in 1,4-dioxane.

[0020] In some embodiments, the method further comprises reacting a compound of formula A-1 with a compound of formula B-1 to form a compound of formula C-1; [ka] ,Of which, P 2 is selected from amino protecting groups, preferably an acetyl group.

[0021] In some other embodiments, the method comprises converting a compound of formula C to a compound of formula D; [ka] Further includes:

[0022] In some embodiments, the reaction of a compound of Formula C is carried out in the presence of an acid, for example, in the presence of methanesulfonic acid and water, or in the presence of hydrochloric acid.

[0023] In some embodiments, the solvent used in the reaction of the compound of formula C is not particularly limited as long as it does not inhibit the reaction, and solvents including, for example, 2-methoxyethanol and ethylcyclohexane are used. In other embodiments, the reaction of the compound of formula C uses a solvent such as acetic acid or toluene. In some embodiments, the compound of formula C undergoes removal of the amino protecting group in toluene containing acetic acid.

[0024] In some embodiments, the reaction temperature for converting the compound of formula C to the compound of formula D is not limited as long as the reaction proceeds, and is preferably 90 to 130°C, including, but not limited to, 90°C, 100°C, 110°C, 120°C, 130°C, or any value between these two. In some embodiments, the reaction temperature for converting the compound of formula C to the compound of formula D is the temperature at which toluene is heated to reflux. The reaction time for this step is not limited as long as the reaction proceeds, and is preferably 16 to 32 hours.

[0025] In some embodiments, the method includes converting a compound of formula C-1 to a compound of formula D-1; [ka] Further includes:

[0026] Some embodiments provide a method for preparing a compound of Formula I or a salt thereof, comprising the steps of reacting compound 1 with compound 2 to form compound 3, and removing the amino-protecting group-acetyl group of compound 3; [ka] Includes:

[0027] The reaction / operation in this step is the same as the reaction between a compound of formula A and a compound of formula B. In some embodiments, the reaction between compound 1 and compound 2 is carried out in the presence of an acid catalyst. Illustrative examples may be pyridinium p-toluenesulfonate or methanesulfonic acid. In some embodiments, the reaction between compound 1 and compound 2 is carried out in the presence of methanesulfonic acid. Furthermore, compound 1 and compound 2 are carried out in toluene containing acetic acid. For specific reaction conditions / operations, see CN115197088, the relevant contents of which are incorporated herein for explanation.

[0028] According to another aspect, a method of preparing a compound of formula I or a salt thereof of the present disclosure comprises reacting a compound of formula A-1 with a compound of formula B-1 to form a compound of formula C-1, which then undergoes protective group removal to form a compound of formula D-1; [ka] ,Of which, P 2 is an amino protecting group, for example an acetyl group.

[0029] In some embodiments, the method for preparing a compound of Formula I or a salt thereof comprises: step 1) reacting compound 1 with compound 2 to form compound 3; Step 2) removing the amino protecting group from compound 3 to form compound 4 (also referred to as compound of formula D-1); Step 3) Enrichment of Compound 5 (also referred to as Formula I-1 compound); [ka] Includes:

[0030] In some embodiments, the step of enriching compound 5 (also referred to as the compound of formula I-1) comprises converting compound 6 to compound 5 (also referred to as the compound of formula I-1) in the presence of an acid; [ka] Includes:

[0031] In some embodiments, the acid used for enrichment is selected from a solution of hydrogen chloride, hi some embodiments, the acid used for enrichment is a solution of HCl in 1,4-dioxane, HCl in ethanol, HCl in ethyl acetate, HCl in isopropanol, or HCl in isobutanol.

[0032] According to another aspect, the present disclosure further provides a method for preparing a compound DC, said method comprising the step of preparing a compound of formula I above: [ka] , among which, R 1 , R 2 is as defined in claim 1, and R 3 , R 4 are independently hydrogen, deuterium, and C 1-3 Alkyl group or C 3-6 It is selected from cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups.

[0033] In some embodiments, the method of preparing compound DC comprises reacting a compound of formula I with compound AA to form a compound of formula DC; [ka] In some embodiments, compound AA is reacted with a compound of formula I in the presence of a basic reagent to form a compound of formula DC. Illustrative examples may be N-methylmorpholine or triethylamine. Specific reaction conditions / procedures can be found in WO2020063676, the contents of which are incorporated herein by reference.

[0034] In some embodiments, compounds of formula DC are [ka] is.

[0035] The present disclosure further provides a method for preparing compound DD, said method comprising preparing a compound of formula I above, or preparing a compound of formula DC, [ka] , among which, R 1 , R 2 is as defined in claim 1, and R 3 , R 4 are independently hydrogen, deuterium, and C 1-3 Alkyl group or C 3-6 It is selected from cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups.

[0036] In some embodiments, the method of preparing compound DD further comprises reacting a compound of formula I with compound BB to form a compound of formula DD; [ka] , among which, R 1 , R 2 is as defined above, and R 3 , R 4 are independently hydrogen, deuterium, and C 1-3 Alkyl group or C 3-6 cycloalkyl groups, such as hydrogen, deuterium, or cyclopropyl groups; P 3 is an amino-protecting group, such as Fomc-. In some embodiments, compound B is reacted with a compound of formula I in the presence of a basic reagent to form a compound of formula DD, and the base used in the reaction can be N-methylmorpholine or triethylamine. Specific reaction conditions / operations can be found in WO2020063676, the contents of which are incorporated herein by reference.

[0037] In some embodiments, the compound of formula DD is [ka] is.

[0038] In another aspect of the present disclosure, there is further provided a method for preparing a compound of formula L, said method comprising the steps of preparing a compound of formula I above, or preparing a compound of formula DC, or preparing a compound of formula DD, [ka] , among which, R 1 , R 2 is as defined above, and R 3 , R 4 are independently hydrogen, deuterium, and C 1-3 Alkyl group or C 3-6 It is selected from cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups.

[0039] In some embodiments, the method of preparing a compound of formula L further comprises reacting a compound of formula I with a compound of formula L-1: [ka] , among which, R 1 , R 2 is as defined above, and R 3 , R 4 are independently hydrogen, deuterium, and C 1-3 Alkyl group or C 3-6 It is selected from cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups.

[0040] In some embodiments, the compound of formula L is [ka] is.

[0041] The present disclosure further provides a method for preparing an antibody conjugate, said method comprising the step of preparing a compound of formula I above, or preparing a compound of formula DC, or preparing a compound of formula DD, or preparing a compound of formula DD.

[0042] The present disclosure further provides a method for preparing an antibody-conjugated ADC, said method comprising the steps of preparing a compound of formula I as described above, or preparing a compound of formula DC, or preparing a compound of formula DD, or preparing a compound of formula DD, and conjugating a compound of formula L to an antibody via a thioether bond; [ka] , among which, R 1 , R 2 is as defined above, and R 3 , R 4 are independently hydrogen, deuterium, and C 1-3 Alkyl group or C 3-6 It is selected from cycloalkyl groups, such as hydrogen, deuterium, or a cyclopropyl group; K is 1 to 10, such as 1, 2, 3, 4, or 5; and Ab is an antibody or an antigen-binding fragment thereof.

[0043] In some embodiments, the antibody or antigen-binding fragment thereof is selected from an anti-HER2 (ErbB2) antibody, an anti-EGFR antibody, an anti-B7-H3 antibody, an anti-c-Met antibody, an anti-HER3 (ErbB3) antibody, an anti-HER4 (ErbB4) antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD44 antibody, or an anti-TROP2 antibody.

[0044] In some embodiments, the antibody conjugate ADC comprises: [ka] is.

[0045] Salts of compounds / intermediates of the present disclosure include, but are not limited to, addition salts of the free form of the compound / intermediate with an acid or base, and acids used to form salts include, but are not limited to, hydrochloric acid or methanesulfonic acid. In some embodiments, salts of compounds / intermediates include, but are not limited to, hydrochloride or mesylate salts.

[0046] The terms "formation" and "conversion" do not particularly mean that the conversion reaction between two substrates is a single-step one, and may be a single-step or multi-step reaction between two substrates. When an intermediate contains a protecting group, the intermediate can be reacted with a corresponding substrate to obtain the corresponding target product after removing the protecting group in one step.

[0047] The term "antibody" encompasses a variety of antibody structures that exhibit the desired antigen-binding activity, including, but not limited to, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions). "Antigen-binding fragments" encompass single-chain antibodies (i.e., full-length heavy and light chains), Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single-domain antibodies (e.g., VH, VL, or VHH), scFv, and bivalent, trivalent, or tetravalent antibodies. Methods for producing and preparing these antigen-binding fragments are known in the art (see, e.g., Verma et al., 1998, Journal of Immunological Methods, 216, 165-181).

[0048] The term "antibody drug conjugate" refers to a ligand linked to a biologically active agent by a stable linking unit. In the present disclosure, "antibody drug conjugate" (ADC) refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug, such as exatecan or its derivatives, by a stable linking unit.

[0049] The term "drug loading" may be expressed as the ratio of the amount of drug to the amount of antibody. As a range of drug loading, each antibody (Ab) may be linked to 1 to 10 cytotoxic drugs (D). In embodiments of the present disclosure, the drug loading is expressed as DAR or k. A low drug loading reduces efficacy, while a high drug loading adversely affects pharmacokinetics and toxicity. Exemplary values ​​include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or an average value between any two values. Preferably, the value is 1 to 8, or an average value between 2 to 8, 2 to 7, 3 to 8, 3 to 7, 3 to 6, 4 to 7, 4 to 6, or 4 to 5. The average amount of drug per ADC molecule after the coupling reaction can be characterized and identified by conventional methods, such as UV / visible spectroscopy, mass spectrometry, ELISA, monoclonal antibody molecular size variant assay (CE-SDS), and HPLC.

[0050] The monoclonal antibody molecular size variant assay (CE-SDS) of the present disclosure can quantitatively determine the purity of recombinant monoclonal antibody products according to the molecular weight size under reducing and non-reducing conditions by sodium dodecyl sulfate capillary electrophoresis (CE-SDS) with ultraviolet detection, in accordance with the capillary electrophoresis method (Chinese Pharmacopoeia).

[0051] The values ​​in this disclosure are measured by instruments and have a certain degree of error, and generally, ±10% is within a reasonable error range. Of course, the context in which the value is used must be taken into consideration. For example, in the case of the particle size of an active ingredient, the value has an error variation of ±10% or less after measurement, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and preferably ±5%.

[0052] The pharmaceutically acceptable salts of the compounds described in the present disclosure or their salts may be selected from inorganic or organic salts, including "acid" addition salts and "base" addition salts. For example, salts formed by an acid-base reaction with a basic group (amino group), the acid including organic or inorganic acids.

[0053] JPEG2026506043000029.jpg33149

[0054] As used herein, an "antibody conjugate" refers to a ligand linked to a biologically active agent by a stable linking unit. As used herein, an "antibody drug conjugate" refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug, such as exatecan or a derivative thereof, by a stable linking unit.

[0055] The term "alkyl group" refers to saturated aliphatic hydrocarbon groups, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, and isopropyl groups.

[0056] The term "cycloalkyl group" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like, and polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0057] "Halogen" refers to fluoro, chlorine, bromine or iodine.

[0058] The "protecting groups" of the present disclosure, such as "hydroxy-protecting groups" and "amino-protecting groups," are groups known in the art that can be used to protect hydroxy or amino groups, and refer to amino or hydroxy-protecting groups in the literature (Protective Groups in Organic Synthesis, 5th Ed. T.W. Greene & P.G.M. Buts). Examples of amino-protecting groups include, but are not limited to, an acetyl group or Fomc. DETAILED DESCRIPTION OF THE INVENTION

[0059] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0060] Experimental methods for which specific conditions are not specified in the examples of this disclosure generally follow conventional conditions or conditions recommended by raw material or product manufacturers. Reagents for which specific sources are not specified are conventional commercially available reagents.

[0061] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are given in units of 10-6 (ppm).

[0062] For the NMR measurement, a Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used, and the measurement solvent was deuterated chloroform (CDCl3).

[0063] For MS measurements, a triple quadrupole mass spectrometer, Waters Micromass Quattro micro API, was used, scanning in positive / negative ion mode with a mass scan range of 120-1300.

[0064] HPLC conditions (applicable to Intermediate G, Intermediate H, Intermediate H-1, Intermediate H-2, Intermediate I-1, and Intermediate I-2) were as follows: Column: octadecylsilane-bonded silica gel (Agilent Zorbax Bonus-RP C18, 4.6 mm x 150 mm, 3.5 μm); Column temperature: 30°C; Detection wavelength: 240 nm; Mobile phase: phosphate buffer solution as mobile phase A and methanol as mobile phase B; Retention time of Intermediate G was approximately 17-20 min; Retention times of Intermediate H-1 and Intermediate I-1 were approximately 7-8 min; and Retention times of Intermediate H-2 and Intermediate I-2 were approximately 9-10 min.

[0065] Yantai Huanghai HSGF254 silica gel plates are used as silica gel plates for thin layer chromatography. The specifications for silica gel plates used in thin layer chromatography (TLC) are 0.2 mm ± 0.03 mm, and the specifications for separating and purifying products by thin layer chromatography are 0.4 to 0.5 mm.

[0066] Example 1: [ka] Step 1: Add 90 g of intermediate E, 86.7 g of intermediate F, 180 mL of acetic acid, 6.03 g of methanesulfonic acid, and 900 mL of toluene to a reaction flask and heat until reflux. After the reaction is complete, add 900 mL of toluene, cool to below room temperature, filter, and dry to obtain intermediate G.

[0067] Step 2: Add 3.5 L of 8 M hydrochloric acid, 750 mL of acetic anhydride, 1.5 L of toluene, and 153 g of intermediate G to a reaction flask, stir evenly, and heat to reflux. After the reaction is complete, cool to room temperature, place 300 g of diatomaceous earth in a suction funnel, filter, wash the filter cake with 3 L of a mixed solvent (methanol:purified water = 1:1), and concentrate to obtain 153 g of product H. The dr value detected by HPLC is 52%:48%.

[0068] Step 3: Add 72 g of the product from Step 2, 1080 mL of isobutanol, and 1400 mL of 1 M HCl / 1,4-dioxane solution to a reaction flask, heat to 60 °C, and stir. After the reaction is complete, cool to room temperature and concentrate under reduced pressure at 45 °C until no visible droplets are observed. A yellow crude product is obtained. The DR value (content ratio) determined by HPLC is 90%:10%.

[0069] Step 4: Add 6N hydrochloric acid solution (1080 mL) and the yellow crude product obtained in Step 3 to a reaction flask, heat to 45°C, filter through a suction funnel with 300 g of diatomaceous earth, wash the filter cake with 6N hydrochloric acid solution, transfer the filtrate to a reaction flask, heat to 45°C, add 2.88 L of methanol dropwise, and after the addition is complete, cool to room temperature and suction filter. Wash the filter cake with 50 mL of anhydrous methanol each time. Transfer the filter cake to a vacuum drying box at 20-25°C and dry for 12-15 hours to obtain 55.4 g of compound H-1. The d value detected by HPLC was 99%:1%, and the total yield of steps E to H-1 was 75%.

[0070] Example 2: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and then 20 V of isobutanol solvent (10 mL) was added. 10 V of HCl / 1,4-dioxane solution (1 M, 5 mL) was slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the ratio of diastereomers H-1 / H-2 was 92.8% / 7.2%.

[0071] Example 3: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and 15 V of isobutanol solvent (7.5 mL) was added. Then, 15 V of HCl / 1,4-dioxane solution (1 M, 7.5 mL) was slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 92.1% / 7.9%.

[0072] Example 4: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and then 15 V of isobutanol solvent (7.5 mL) was added. Then, 15 V of HCl / 1,4-dioxane solution (2 M, 7.5 mL) was slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 92.2% / 7.8%.

[0073] Example 5: [ka] 0.5 g of the product obtained in Step 2 of Example 1 was added to a reaction flask, and 15 V of HCl / isopropanol solution (4 M, 7.5 mL) was slowly added. The mixture was heated to 60°C and stirred for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 89.5% / 10.5%.

[0074] Example 6: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and 15 V of 3-methyl-2-butanol solvent (7.5 mL) was added. Then, 15 V of HCl / 1,4-dioxane solution (1 M, 7.5 mL) was slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 83.2% / 16.8%.

[0075] Example 7: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and 15 V of isobutanol solvent (7.5 mL) was added. Then, 15 V of HCl / ethyl acetate solution (4 M, 7.5 mL) was slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 84.8% / 15.2%.

[0076] Example 8: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and then 15 V of isobutanol solvent (7.5 mL) was added. Then, 15 V of HCl / ethanol solution (4 M, 7.5 mL) was slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 85.0% / 15.0%.

[0077] Example 9: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and 15 V of isobutanol solvent (7.5 mL) was added. 5 V of hydrobromic acid (content ≧40%, 2.5 mL) was then slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 62.2% / 37.8%.

[0078] Example 10: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and 15 V of isobutanol solvent (7.5 mL) was added. 5 V of concentrated sulfuric acid (2.5 mL) was then slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 52.7% / 47.3%.

[0079] Example 11: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and then 15 V of isobutanol solvent (7.5 mL) was added. 5 V of perchloric acid (2.5 mL) was then slowly added. The mixture was heated to 60°C and reacted with stirring for 20 hours. The mixture was then cooled to room temperature and concentrated. After sampling, the mixture was analyzed by HPLC, and the content ratio of diastereomers H-1 / H-2 was 52.5% / 47.5%.

[0080] Example 12: [ka] A reaction flask was charged with 0.5 g of the product obtained in Step 2 of Example 1, and 2.7 mL of methanesulfonic acid (5.4 V) and 0.6 mL of purified water (1.2 V). The mixture was heated to 45°C and stirred for 30 minutes. 10 mL of methanol (18 V) was added dropwise. After the addition was complete, the mixture was stirred for 3 hours while maintaining the temperature. The mixture was then cooled to 25°C and sampled for HPLC analysis. The diastereomer H-1 / H-2 content ratio was 51.5% / 48.5%.

[0081] Example 13: [ka] Step 1: Add 155.5 g of intermediate E, 150.0 g of intermediate F and 2.8 L of toluene to a reaction flask and stir. Add 10.5 g of methanesulfonic acid and 622 mL of acetic acid. After the reflux reaction is completed, lower the temperature and concentrate the reaction solution until the liquid basically stops dripping to obtain intermediate G.

[0082] Step 2: Add the intermediate G obtained in the previous step, 1.6 L of toluene, 3.110 L of purified water, and 1.555 L of methanesulfonic acid to a reaction flask and stir. After the reflux reaction is completed, lower the temperature to 60-65°C, filter (diatomaceous earth assisted filtration), and wash the filter cake with 2 x 1.0 L of a mixture of methanol and water (volume ratio 1:1). Combine the filtrate and wash solution and sample for HPLC detection. The content ratio of diastereomers I-1 / I-2 is 50.2% / 49.8%.

[0083] Step 3: The filtrate was concentrated under reduced pressure until the liquid stopped dripping, and the concentrated liquid was transferred to a reaction flask, stirred, and heated to 45°C. 5.597L of methanol was added dropwise, and then 311mL of purified water was added dropwise. The temperature was lowered to room temperature, and the mixture was filtered. The filter cake was washed with 2L of methanol. The filter cake was placed in a drying box and the temperature was controlled at 20-25°C. After drying for 12-15 hours, 115.0g of intermediate I-1 was obtained. The dR value detected by HPLC was 97%:3%, and the total yield of the three steps (compounds E to I-1) was 39.0%.

Claims

1. A process for preparing a compound of formula I or a salt thereof, comprising: 【Chemistry 1】 wherein the method comprises the step of: converting a compound of formula Da to a compound of formula I under acidic conditions; 【Chemistry 2】 ,Of which, P １ is a hydroxy protecting group or hydrogen, preferably hydrogen or a tert-butoxycarbonyl group, R １ is hydrogen, halogen or C １－６ alkyl group, preferably a methyl group, and R ２ is selected from hydrogen or halogen, preferably fluoro; method.

2. The acid is selected from hydrogen chloride solution; The method of claim 1.

3. The solution used in the reaction is one or more selected from isobutanol, isopropanol, 3-methyl-2-butanol, ethyl acetate, ethanol, and 1,4-dioxane.

3. The method according to claim 1 or 2.

4. further comprising reacting a compound of formula A with a compound of formula B to form a compound of formula C; 【Transformation 3】 , among which, R １ , R ２ , P １ is as defined in claim 1, and P ２ is selected from amino protecting groups, preferably an acetyl group; The method according to any one of claims 1 to 3.

5. Compounds of formula I are 【Chemistry 4】 wherein the method comprises the steps of: converting a compound of formula D-1a into a compound of formula I-1 under acidic conditions; 【Transformation 5】 Including, The method according to claims 1 to 4.

6. A process for preparing a compound of formula I or a salt thereof, comprising: 【Transformation 6】 wherein the compound of formula D is enriched in the compound of formula I in the presence of an acid; 【Transformation 7】 ,Of which, P １ is a hydroxy protecting group or hydrogen, preferably hydrogen or a tert-butoxycarbonyl group, R １ is hydrogen, halogen or C １－６ alkyl group, preferably a methyl group, and R ２ is selected from hydrogen or halogen, preferably fluoro; method.

7. reacting a compound of formula A-1 with a compound of formula B-1 to form a compound of formula C-1, which is then reacted with a compound of formula C-1 to remove a protecting group to form a compound of formula D-1; 【Transformation 8】 Among them, P １ is a hydroxy protecting group or hydrogen, preferably hydrogen or a tert-butoxycarbonyl group, P ２ is an amino protecting group, preferably an acetyl group; The method according to any one of claims 1 to 6.

8. 1. A method for preparing compound DC, comprising: The method comprises the steps of the method according to any one of claims 1 to 7, 【Chemistry 9】 , among which, R １ , R ２ is as defined in claim 1, and R ３ , R ４ are each independently hydrogen, deuterium, or C １－３ Alkyl group or C ３－６ cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups; method.

9. 1. A method for preparing compound DD, comprising: The method comprises the steps of the method according to any one of claims 1 to 8, 【Chemistry 10】 , among which, R １ , R ２ is as defined in claim 1, and R ３ , R ４ are each independently hydrogen, deuterium, or C １－３ Alkyl group or C ３－６ cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups; method.

10. A method for preparing a compound of formula L, comprising: 【Chemistry 11】 , the method comprising the steps of the method of any one of claims 1 to 8 and reacting a compound of formula I with a compound of formula L-1, 【Chemistry 12】 , among which, R １ , R ２ is as defined in claim 1, and R ３ , R ４ are each independently hydrogen, deuterium, or C １－３ Alkyl group or C ３－６ cycloalkyl groups, such as hydrogen, deuterium or cyclopropyl groups; method.

11. A method for preparing an antibody complex, comprising the steps of the method according to any one of claims 1 to 10.

12. 1. A method for preparing an antibody conjugate ADC, comprising: The method comprises the steps of the method of any one of claims 1 to 10 and a step in which Formula L is conjugated to an antibody via a thioether bond, 【Chemistry 13】 , among which, R １ , R ２ is as defined in claim 1, and R ３ , R ４ are each independently hydrogen, deuterium, or C １－３ Alkyl group or C ３－６ cycloalkyl groups, e.g., hydrogen, deuterium, or cyclopropyl groups; K is 1-10; and Ab is an antibody or antigen-binding fragment thereof. method.

13. the antibody is an anti-HER2 antibody, an anti-HER3 antibody, or an anti-TROP2 antibody; The method of claim 12.

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