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CN-121991162-A - Drug conjugate intermediate and preparation method thereof

CN121991162ACN 121991162 ACN121991162 ACN 121991162ACN-121991162-A

Abstract

The invention discloses a drug conjugate intermediate and a preparation method thereof. Specifically, the invention provides a preparation method of a compound of formula (M) or a salt thereof, which comprises the following steps of carrying out deprotection reaction on amino and carboxyl protecting groups of the compound of formula (H) or the salt thereof as shown below to obtain the compound of formula (M) or the salt thereof, wherein X 1 is-CH (CH 3 )-CH 2 -. The preparation method of the invention has the advantages of low cost, high yield and simpler operation, and is suitable for large-scale production.

Inventors

  • ZHANG YU
  • KU JIE
  • CHEN CHENG
  • LI BING
  • ZHU ZHONGYUAN

Assignees

  • 映恩生物制药（苏州）有限公司

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241106

Claims (10)

  1. 1. A process for the preparation of a compound of formula (M), characterized in that it comprises the steps of: Deprotecting the amino and carboxyl protecting groups of the compound of formula (H) or a salt thereof to give a compound of formula (M) or a salt thereof as follows: , Wherein X 1 is-CH (CH 3 )-CH 2 -; GP 2 is selected from carboxyl protecting groups; GP 3 is selected from amino protecting groups.
  2. 2. The method of claim 1, wherein at least one of the following conditions is satisfied: (1) In the definition of X 1 , -CH (CH 3 )-CH 2 -left side is linked to O as shown; (2) X 1 is in the R configuration, S configuration, or a mixture thereof, e.g 、 Or (b) ; (3) The carboxyl protecting group GP 2 is selected from methyl, ethyl, tertiary butyl, trimethyl silicon base, triethyl silicon base, tertiary butyl diphenyl silicon base, tertiary butyl dimethyl silicon base, triisopropyl silicon base, trityl, methoxymethyl, THP or benzyl, wherein the benzyl is optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, methyl, methoxy, dimethylamino, nitro, hydroxyl, cyano, carboxyl, amino, ester, aldehyde and allyl; (4) The amino protecting group GP 3 is independently selected from t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, benzyl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzenesulfonyl, p-toluenesulfonyl, 2-naphthalenesulfonyl, trimethylsilyl, trifluoroacetyl, trityl, trichloroacetyl, formyl, benzoyl, t-butyl, methoxycarbonyl or ethoxycarbonyl, preferably GP 3 is selected from benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, more preferably GP 3 is selected from 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl; (5) The deprotection reaction is as follows: The compound of formula (H) or a salt thereof is subjected to deamination protecting group GP 3 as shown below to obtain compound (L), and then the compound of formula (L) is subjected to decarboxylation protecting group GP 2 as shown below to obtain compound of formula (M) or a salt thereof, ; (6) The amino protecting group GP 3 is removed under acidic conditions, under alkaline conditions, or under the conditions of a metal reagent; For example, when the GP 3 is 9-fluorenylmethoxycarbonyl, the compound of formula (H) or a salt thereof, under basic conditions, deprotected GP 3 , preferably an organic base, preferably selected from the group consisting of piperidine, diethylamine, morpholine, diisopropylamine, DBU, triethylamine and N, N-diisopropylethylamine, more preferably DBU, piperidine, diethylamine or morpholine, e.g., DBU; The molar ratio of the base to the compound of formula (H) or salt thereof may be from 1.5:1 to 1:1.25, preferably 1.0.5:1-1:1.25; When the GP 3 is 9-fluorenylmethoxycarbonyl, the compound of formula (H) or a salt thereof removes the protecting group GP 3 under acidic conditions, the acid being selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, tin chloride and ferric chloride; When GP 3 is 9-fluorenylmethoxycarbonyl, the reaction solvent is selected from one or any combination of DMF, DMAc, NMP, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, methanol and ethanol, preferably one or any combination of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran, such as dichloromethane; (7) The temperature of the deprotection reaction is 0-30 ℃, such as 0-10 ℃, 2-12 ℃, 3-13 ℃, 4-10 ℃, 5-15 ℃ and 7-17 ℃; (8) The carboxyl protecting group GP 2 is removed in the presence of metal catalyst-hydrogen; Preferably, the metal catalyst is a palladium-based reagent or a platinum-based reagent, such as a catalyst selected from palladium on carbon, platinum dioxide, palladium hydroxide, pd/Al 2 O 3 , preferably from palladium on carbon or Pd/Al 2 O 3 ; Preferably, the reaction solvent is selected from one or any combination of water, DMF, DMAc, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, butanol, tert-butanol, and ethyl acetate, preferably from water, DMAc, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, butanol, and tert-butanol, e.g., water, methanol, water, and isopropanol, water, and tert-butanol, e.g., water to isopropanol in a volume ratio of 3:7, and water to tert-butanol in a volume ratio of 1:2; (9) Simultaneously removing the amino protecting group GP 3 and the carboxyl protecting group GP 2 , for example, when the amino protecting group GP 3 is benzyloxycarbonyl and the carboxyl protecting group GP 2 is benzyl; (10) When the amino protecting group GP 3 is benzyloxycarbonyl and the carboxyl protecting group GP 2 is benzyl, removing the protecting group GP 3 、GP 2 from the compound of formula (H) or a salt thereof under a metal reagent-hydrogen system; Preferably, the metal reagent is palladium reagent or platinum reagent, preferably palladium carbon, platinum dioxide and palladium hydroxide; Preferably, the solvent for the reaction is selected from any one of alcohols, ethers, esters, amides and water or is mixed in any ratio, preferably from methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, DMF, DMAc, NMP and water, such as methanol, water and isopropanol, DMAc, tetrahydrofuran, 2-methyltetrahydrofuran, for example, in a volume ratio of 3:7; Preferably, the temperature of the deprotection reaction is from 10 ℃ to 80 ℃, e.g., from 10 ℃ to 50 ℃, and further e.g., from 20 to 30 ℃, from 25 to 35 ℃, from 35 to 45 ℃; (11) The preparation method comprises the following steps: , 。
  3. 3. The preparation method according to claim 1 or 2, characterized in that it comprises the following steps: a compound of formula (F) or a salt thereof and a compound of formula (G) or a salt thereof are subjected to a condensation reaction as shown below to obtain a compound of formula (H) or a salt thereof, , Wherein X 1 、GP 2 and GP 3 are as defined in claim 1.
  4. 4. A method of preparation as claimed in claim 3, characterised in that it satisfies at least one of the following conditions: (1) The method comprises the steps of obtaining a compound of formula (H) or a salt thereof under the action of a condensing agent or condensing agent and/or anti-racemization agent in a solvent; Preferably, the condensing agent is selected from NDSC, TDBTU, TBTU, TOTU, HCTU, TCTU, TPTU, TNTU, HDMA, pyBOP, pyAOP, DMTMM, HATU, HBTU, EDCI, COMU, N-ethynyl-N-methyl methanesulfonamide, EEDQ, and T3P, more preferably from EDCI; Preferably, the molar ratio of the condensing agent to the compound of formula (G) or salt thereof is from 1:0.5 to 2:1, preferably 1:0.85, 2:1, 1.3:1; preferably, the anti-racemisation agent is selected from HOAt and HOBt; Preferably, the molar ratio of the anti-racemisation agent to the compound of formula (G) or salt thereof is from 0.1:1 to 2:1, preferably 0.3:1, 0.5:1, 1:1, 2:1, more preferably from 2:1; (2) The condensation reaction for preparing the compound of formula (H) or a salt thereof also reacts in the presence of any one of p-toluenesulfonic acid, diisopropylethylamine, pyridinium p-toluenesulfonate, zinc acetate, aluminum trichloride, ferric trichloride, boron trifluoride diethyl ether and ytterbium triflate, preferably p-toluenesulfonic acid, pyridinium p-toluenesulfonate, diisopropylethylamine and pyridinium p-toluenesulfonate; (3) The solvent for the condensation reaction for preparing the compound of formula (H) or a salt thereof is selected from any one of halogenated hydrocarbons, alcohols, ethers, esters, amides and water or mixed in any ratio, preferably selected from dichloromethane, methanol, ethanol, butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, DMF, DMAc, N-methyl-2-pyrrolidone NMP and water, for example, dichloromethane, DMAc and 2-MeTHF; (4) The molar ratio of the compound of formula (F) or salt thereof to the compound of formula (G) or salt thereof is from 1:1.2 to 1:0.8, preferably from 1:1 to 1:0.8; (5) The condensation reaction for preparing the compound of formula (H) or a salt thereof is carried out at a temperature of 0 ℃ to 30 ℃, for example 0 ℃ to 5 ℃, 0 ℃ to 10 ℃,10 ℃ to 20 ℃,2 to 12 ℃,3 to 13 ℃,4 to 10 ℃,5 to 15 ℃ and 7 to 17 ℃; (6) The preparation method comprises the following steps: , 。
  5. 5. the method of claim 4, comprising the steps of: The amino protecting group of the compound of formula (E) or a salt thereof is subjected to deprotection reaction as shown below to give the compound of formula (F) or a salt thereof, , Wherein X 1 and GP 2 are as defined in claim 1; GP 1 is selected from amino protecting groups.
  6. 6. The method of claim 5, wherein at least one of the following conditions is satisfied: (1) The amino protecting group GP 1 is independently selected from t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsiloxycarbonyl, benzyl or phenylsulfonyl, p-toluenesulfonyl, 2-naphthalenesulfonyl, trimethylsilyl, trifluoroacetyl, trityl, trichloroacetyl, formyl, t-butyl, methoxycarbonyl or ethoxycarbonyl, preferably GP 1 is selected from 9-fluorenylmethoxycarbonyl and allyloxycarbonyl, more preferably GP 1 is 9-fluorenylmethoxycarbonyl; (2) The amino protecting group GP 1 is removed under acidic conditions or under alkaline conditions; Preferably, when the GP 1 is 9-fluorenylmethoxycarbonyl, the compound of formula (E) or a salt thereof, under basic conditions, deprotecting GP 1 , preferably an organic base, preferably an inorganic base, selected from one or more of piperidine, diethylamine, morpholine, diisopropylamine, DBU, triethylamine and N, N-diisopropylethylamine, more preferably DBU; Preferably, when the GP 1 is 9-fluorenylmethoxycarbonyl, the compound of formula (E) or a salt thereof removes the protecting group GP 1 under acidic conditions, the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, tin chloride and ferric chloride; Preferably, when the GP1 is 9-fluorenylmethoxycarbonyl, the reaction solvent is selected from one or any combination of DMF, DMAc, NMP, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, methanol and ethanol, preferably one or any combination of acetonitrile, dichloromethane, DMAc, tetrahydrofuran and 2-methyltetrahydrofuran, such as acetonitrile, DMAc and 2-MeTHF; Preferably, the molar ratio of the compound of formula (E) or salt thereof to the base is from 1.2:1 to 1:0.5, preferably from 1:0.5 to 1:0.8; (3) The deprotection reaction to prepare the compound of formula (F) or a salt thereof is carried out at a temperature of 0℃to 30℃such as 0℃to 10℃2 to 12℃3 to 13℃4 to 10℃5 to 15℃7 to 17℃preferably 10℃to 20℃and for example 15 ℃; (4) The preparation method comprises the following steps: 。
  7. 7. a process for the preparation of a compound of formula (M), formula (H), formula (F) or a pharmaceutically acceptable salt thereof, characterized in that, (I) A process for the preparation of a compound of formula (M) or a pharmaceutically acceptable salt thereof, comprising the steps of: the amino group and the carboxyl protecting group of the compound of formula (H) or a salt thereof are subjected to deprotection reaction as shown below to obtain the compound of formula (M) or a salt thereof, , Wherein, X 1 、GP 2 and GP 3 are defined as X 1 、GP 2 and GP 3 in claim 1 or 2; (ii) A process for the preparation of a compound of formula (H) or a pharmaceutically acceptable salt thereof, comprising the steps of: a compound of formula (F) or a salt thereof and a compound of formula (G) or a salt thereof are subjected to a condensation reaction as shown below to obtain a compound of formula (H) or a salt thereof, , Wherein, the definitions of X 1 、GP 2 and GP 3 are as shown in X 1 、GP 2 and GP 3 in claim 3 or 4; (iii) A process for the preparation of a compound of formula (F) or a pharmaceutically acceptable salt thereof, comprising the steps of: The amino protecting group of the compound of formula (E) or a salt thereof is subjected to deprotection reaction as shown below to give the compound of formula (F) or a salt thereof, , Wherein, X 1 、GP 1 and GP 2 are defined as X 1 、GP 1 and GP 2 in claim 5 or 6.
  8. 8. The method according to claim 7, wherein, (I) A process for the preparation of said compound of formula (M) or a pharmaceutically acceptable salt thereof, wherein the conditions and steps in said process are as defined in any one of claims 1 to 2; (ii) A process for the preparation of said compound of formula (H) or a pharmaceutically acceptable salt thereof, wherein the conditions and steps in said process are as defined in any one of claims 3 to 4; (iii) A process for the preparation of said compound (F) or a pharmaceutically acceptable salt thereof, wherein the conditions and steps in said process are as defined in the process of claims 5-6.
  9. 9. A process for producing a compound of formula (L) or a salt thereof, characterized in that the process comprises the step of subjecting a compound of formula (H) or a salt thereof to deamination of protecting group GP 3 as shown below; , wherein X 1 is selected from cyclobutylidene; GP 2 is selected from carboxyl protecting groups; GP 3 is selected from amino protecting groups; Preferably, it satisfies at least one of the following conditions: (1) The cyclobutylidene is selected from 、 ; (2) The carboxyl protecting group GP 2 is selected from methyl, ethyl, t-butyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, triisopropylsilyl, trityl, methoxymethyl, THP, benzyl or benzyloxycarbonyl, the benzyl group being optionally substituted with one or more substituents selected from fluorine, chlorine, bromine, methyl, methoxy, dimethylamino, nitro and allyl; (3) The amino protecting group GP 3 is independently selected from the group consisting of benzyloxycarbonyl, t-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, benzyl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzenesulfonyl, p-toluenesulfonyl, 2-naphthalenesulfonyl, trimethylsilyl, trifluoroacetyl, trityl, trichloroacetyl, formyl, benzoyl, t-butyl, methoxycarbonyl, and ethoxycarbonyl, preferably GP 3 is selected from the group consisting of benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, and more preferably GP 3 is selected from the group consisting of 9-fluorenylmethoxycarbonyl; (4) GP 3 is removed under basic conditions, for example, when the GP 3 is 9-fluorenylmethoxycarbonyl, the compound of formula (H) or a salt thereof removes the protecting group GP 3 under basic conditions, the base is preferably an organic base, preferably selected from the group consisting of piperidine, diethylamine, morpholine, diisopropylamine, DBU, triethylamine and N, N-diisopropylethylamine, more preferably DBU, piperidine, diethylamine or morpholine, e.g., DBU; The molar ratio of the base to the compound of formula (H) or salt thereof may be from 1.5:1 to 1:1.2, preferably 1.05:1-1.3:1; When GP 3 is 9-fluorenylmethoxycarbonyl, the reaction solvent is selected from one or any combination of DMF, DMAc, NMP, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, methanol and ethanol, preferably one or any combination of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran, such as tetrahydrofuran and/or 2-methyltetrahydrofuran; (5) The deamination protecting group GP 3 is reacted at a temperature of 0 ℃ to 30 ℃, e.g., 0 ℃ to 10 ℃,2 to 12 ℃,3 to 13 ℃,4 to 10 ℃,5 to 15 ℃, 7 to 17 ℃; (6) The preparation method comprises the following steps: 。
  10. 10. the following compounds, isomers thereof or salts thereof: 。

Description

Drug conjugate intermediate and preparation method thereof Technical Field The application relates to the field of biological medicine, in particular to a drug conjugate intermediate and a preparation method thereof. Background In recent years, an Antibody Drug Conjugate (ADC) is used as a novel targeted therapeutic drug, gradually becomes a research hot spot, and overcomes the defects of easy nonspecific accumulation in normal tissues, obvious off-target toxicity, low tolerance, narrow therapeutic window and the like of the traditional anti-tumor chemotherapeutic drugs. The design of Antibody Drug Conjugates (ADCs) includes three key components, monoclonal antibodies, linkers and cytotoxic payloads. Monoclonal antibodies are responsible for recognizing and binding to specific antigens on the surface of cancer cells, while linkers ensure stable binding between the antibody and cytotoxic drug and release the drug at the appropriate location. By combining the monoclonal antibody with the cytotoxic drug, the high-efficiency and specific killing of cancer cells is realized. The combination utilizes the targeting advantage of the monoclonal antibody and the high killing capacity of the cytotoxic drug, thereby obviously reducing the damage to normal cells and realizing the accurate striking of cancer cells. While ADCs present great potential in clinical applications, their development still faces many challenges. For example, the preparation process of the drug conjugate is also the focus of current research because of the problems of complex preparation, low yield, complex operation, high cost and the like of the ADC. Therefore, there is an urgent need to provide a new method suitable for large-scale industrial production, which is simple, economical and high in yield. Disclosure of Invention Aiming at the defects of the existing route preparation process, the application provides a preparation method of a drug conjugate intermediate compound in a formula (M) and a preparation method of the intermediate or salt thereof. The preparation method provided by the application has the advantages of low cost, high yield and simpler operation, and is suitable for large-scale production. In one aspect, the present application provides a process for the preparation of a compound of formula (M) or a salt thereof, comprising the steps of: Deprotecting the amino and carboxyl protecting groups of the compound of formula (H) or a salt thereof to give a compound of formula (M) or a salt thereof as follows: , Wherein X 1 is-CH (CH 3)-CH2 -; GP 2 is selected from carboxyl protecting groups; GP 3 is selected from amino protecting groups. In some embodiments, in the definition of X 1, -CH (CH 3)-CH2 -left side is attached to O as shown). In some embodiments, X 1 is in the R configuration, S configuration, or a mixture thereof, e.g、、。 In some embodiments, the carboxy protecting group GP 2 is selected from methyl, ethyl, t-butyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, triisopropylsilyl, trityl, methoxymethyl, THP, or benzyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, methyl, methoxy, dimethylamino, nitro, hydroxy, cyano, carboxy, amino, ester, aldehyde, and allyl. The term "ester group" generally refers to a-C (=o) O-alkyl group, preferably a C 1-6 alkyl group, or a-C (=o) O-cycloalkyl group, preferably a 3-6 membered cycloalkyl group, preferably a-C (O) OCH 3、-C(O)OC2H5, -C (O) O-cyclopropyl group. In some embodiments, GP 2 is benzyl. In some embodiments, the amino protecting group GP 3 is independently selected from t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), benzyl (Bn), 2, 4-Dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), benzenesulfonyl (Bs), p-methylbenzenesulfonyl (Ts), 2-naphthalenesulfonyl, trimethylsilyl (TMS), trifluoroacetyl (TFA), trityl (Tr), trichloroacetyl (TCA), formyl (CHO), benzoyl (Bz), t-butyl (t-Bu), methoxycarbonyl or ethoxycarbonyl, preferably GP 3 is selected from benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), more preferably GP 3 is selected from 9-fluorenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz). In some embodiments, the deprotection reaction is: The compound of formula (H) or a salt thereof is subjected to deamination protecting group GP 3 as shown below to obtain compound (L), and then the compound of formula (L) is subjected to decarboxylation protecting group GP 2 as shown below to obtain compound of formula (M) or a salt thereof, 。 In some embodiments, the amino protecting group GP 3 is removed under acidic conditions, under basic conditions, or under conditions of a metal reagent. In some embodiments, when the GP 3 is 9-fluorenylmethoxycarbonyl (Fmoc), the compound of formula (H) or a salt thereof, under basic conditions, removes the protecting group GP 3, preferably an orga