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WO2025118133A1 - Dérivé de (s)-lenalidomide-5, son procédé de synthèse et son utilisation - Google Patents

Dérivé de (s)-lenalidomide-5, son procédé de synthèse et son utilisation Download PDF

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Publication number
WO2025118133A1
WO2025118133A1 PCT/CN2023/136370 CN2023136370W WO2025118133A1 WO 2025118133 A1 WO2025118133 A1 WO 2025118133A1 CN 2023136370 W CN2023136370 W CN 2023136370W WO 2025118133 A1 WO2025118133 A1 WO 2025118133A1
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WIPO (PCT)
Prior art keywords
compound
reaction
lenalidomide
follows
solvent
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Pending
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PCT/CN2023/136370
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English (en)
Chinese (zh)
Inventor
郑锐
向奎荣
王益锋
朱绪新
杜益辉
丁伟
舒磊
蔡磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Apeloa Shanghai Pharma Solutions Co Ltd
Zhejiang Apeloa Jiayuan Pharmaceutical Co Ltd
Apeloa Pharmaceutical Co Ltd
Original Assignee
Apeloa Shanghai Pharma Solutions Co Ltd
Zhejiang Apeloa Jiayuan Pharmaceutical Co Ltd
Apeloa Pharmaceutical Co Ltd
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Application filed by Apeloa Shanghai Pharma Solutions Co Ltd, Zhejiang Apeloa Jiayuan Pharmaceutical Co Ltd, Apeloa Pharmaceutical Co Ltd filed Critical Apeloa Shanghai Pharma Solutions Co Ltd
Priority to PCT/CN2023/136370 priority Critical patent/WO2025118133A1/fr
Publication of WO2025118133A1 publication Critical patent/WO2025118133A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention belongs to the technical field of drug synthesis, and in particular relates to a (S)-lenalidomide-5-position derivative and a synthesis method and application thereof.
  • Lenalidomide whose chemical name is 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione and whose molecular formula is C 13 H 13 N 3 O 3 , is an anti-tumor drug developed by Celgene Biopharmaceuticals, Inc. of the United States. It has multiple effects such as anti-tumor, immunomodulatory and anti-angiogenesis.
  • the lenalidomide-5-piperazine derivative in the structural formula given by the method is of S configuration
  • the inventors synthesized it according to the method they found that the product had a racemization problem, resulting in a decrease in the chiral purity of the final product, which was difficult to meet the requirements.
  • the present invention provides a (S)-lenalidomide-5-position derivative and a synthesis method and application thereof.
  • the (S)-lenalidomide-5-position derivative is used as a key intermediate for synthesizing lenalidomide and its derivatives, the purity of the product can be effectively improved and the cost can be reduced.
  • a (S)-lenalidomide-5-position derivative is a compound represented by formula (II):
  • X is CH 2 , NH, PG-N, O or S
  • PG is a N protecting group
  • the R is
  • X is CH 2 , NH, PG-N, O or S, and PG is an N protecting group.
  • the PG is Cbz-, Boc-, Fmoc-, Tos- or Trt-.
  • the present invention also provides a method for synthesizing the (S)-lenalidomide-5-position derivative, comprising: performing an amination reduction reaction on compound I and L-glutamine tert-butyl ester (H-Gln-OtBu) to obtain compound II;
  • R is defined as above.
  • the amination reduction reaction is carried out in an organic solvent, wherein the organic solvent is a mixture of one or more of a halogenated hydrocarbon solvent, a nitrile solvent or an alkyl alcohol, wherein the carbon chain in the halogenated hydrocarbon solvent, the nitrile solvent or the alkyl alcohol molecule contains 1 to 5 carbon atoms; more preferably, it is a mixture of one or more of dichloromethane, chloroform, acetonitrile, methanol and ethanol; and even more preferably, it is a mixture of one or more of dichloromethane, acetonitrile and methanol.
  • the organic solvent is a mixture of one or more of a halogenated hydrocarbon solvent, a nitrile solvent or an alkyl alcohol, wherein the carbon chain in the halogenated hydrocarbon solvent, the nitrile solvent or the alkyl alcohol molecule contains 1 to 5 carbon atoms; more preferably, it is a mixture of one or more of dichlorome
  • sodium acetate and acetic acid are added as additives in the amination reduction reaction.
  • the present invention also provides an application of the (S)-lenalidomide-5-position derivative, comprising:
  • R is defined as above.
  • the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid;
  • the ring-closing reaction is carried out in an organic solvent, and the organic solvent is at least one of an ether solvent, a C 1 -C 4 nitrile solvent or a C 1 -C 4 alkyl alcohol, and more preferably at least one of tetrahydrofuran, acetonitrile and isopropanol.
  • the organic solvent is at least one of an ether solvent, a C 1 -C 4 nitrile solvent or a C 1 -C 4 alkyl alcohol, and more preferably at least one of tetrahydrofuran, acetonitrile and isopropanol.
  • the application also includes a preparation process of compound II;
  • the compound II was obtained according to the method described above.
  • a method for synthesizing a 5-piperazine derivative of (S)-lenalidomide comprising the following steps:
  • Step A Compound 1 is subjected to a deprotection reaction under acidic conditions to obtain compound 2;
  • Step B Compound 2 is protected at N by using benzyl chloroformate in the presence of an organic amine to obtain compound 3;
  • Step C Compound 3 is subjected to an amination reduction reaction with L-glutamine tert-butyl ester (H-Gln-OtBu) to obtain compound 4;
  • Step D Compound 4 is ring-closed under acidic conditions to obtain chiral compound 5;
  • Step E Compound 5 is subjected to a hydrogenation debenzyloxycarbonylation reaction with hydrogen under acidic conditions and a hydrogenation catalyst to obtain a chiral compound 6;
  • Step F Compounds 6 and 7 are subjected to an amination reduction reaction to obtain chiral compound 8; the reaction formula is as follows:
  • step A the deprotection reaction is carried out in an organic solvent I, and the organic solvent I is dioxane or tetrahydrofuran;
  • the acid used in the acidic condition is one or more of HCl, HBr and trifluoroacetic acid, and hydrochloric acid is most preferred.
  • the acid can be pre-mixed with the organic solvent by acid gas, or the acid gas can be introduced into the reaction system during the reaction.
  • step A the temperature of the deprotection reaction is 20-40° C., and the reaction time is 3-10 h.
  • step A after the reaction is completed, the product is directly filtered and washed to obtain compound 2.
  • the organic amine is selected from at least one of triethylamine, diethylamine, diisopropylethylamine and pyridine, preferably triethylamine or diisopropylethylamine;
  • the protection is carried out in a mixed system of organic solvent II and water, and the organic solvent II is at least one of dioxane and acetone.
  • step B the reaction temperature is 20-40° C. and the reaction time is 10-15 h.
  • step B after the reaction is completed, ethyl acetate and saturated brine are added, the layers are separated, the organic phase is collected, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 3.
  • the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, potassium borohydride, and hydrogen;
  • the amination reduction reaction is carried out in an organic solvent III, and the organic solvent III is a mixture of one or more of dichloromethane, acetonitrile and methanol.
  • step C when the reducing agent is hydrogen, the reduction is carried out in the presence of a catalyst; the catalyst is selected from at least one of palladium carbon and Raney nickel.
  • step C sodium acetate and acetic acid are also added as additives in the amination reduction reaction.
  • step C the reaction temperature is 20-40° C. and the reaction time is 15-25 h.
  • step C after the reaction is completed, the organic solvent III is removed by concentration under reduced pressure, and then ethyl acetate and water are added to separate the layers, and the organic phase is collected and concentrated under reduced pressure to obtain compound 4.
  • the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid;
  • the ring-closing reaction is carried out in an organic solvent IV, and the organic solvent IV is at least one of tetrahydrofuran, acetonitrile and isopropanol.
  • step D the reaction temperature is 20-40° C. and the reaction time is 10-15 h.
  • step D after the reaction is completed, ethyl acetate and saturated water are added, the liquids are separated, the organic phase is collected, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 5.
  • the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid, and the hydrogenation catalyst is palladium on carbon or Raney nickel;
  • the hydrodebenzyloxycarbonylation reaction is carried out in an organic solvent V, and the organic solvent V is at least one of tetrahydrofuran, methanol, and isopropanol.
  • step E the reaction temperature is 20-40° C. and the reaction time is 5-10 h.
  • step E after the reaction is completed, methanol is added to dissolve, filtered to remove palladium carbon, and methanol is removed by rotary evaporation under reduced pressure to obtain compound 6.
  • the reducing agent is at least one of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and hydrogen;
  • the amination reduction reaction is carried out in an organic solvent VI, and the organic solvent VI is at least one of tetrahydrofuran, dichloromethane, methanol, and isopropanol.
  • step F the reaction temperature is 20-40° C., and the reaction time is 3-10 h.
  • step F after the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure, and then ethyl acetate and water are added to separate the layers.
  • the aqueous phase is collected and then neutralized with a base, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary dried to obtain compound 8.
  • the method for synthesizing the (S)-lenalidomide-5-position derivative of the present invention has no strict restrictions on the amount of the reaction raw materials unless otherwise specified, and the reaction is generally carried out according to the chemical reaction stoichiometric ratio, and the reaction can also be carried out in excess; the amount of the reaction solvent and the reaction reagent in each step is not strictly limited, and can be adjusted according to the amount of the reaction raw materials; the amount of the reaction solvent and the reaction reagent is increased when the reaction raw materials are more, and the amount of the reaction solvent and the reaction reagent is reduced when the reaction raw materials are less; the reaction solvent in each step can be selected according to the knowledge of those skilled in the art, such as water, alcohols, ketones, ethers, etc.; the post-treatment method in each step can be selected according to the knowledge of those skilled in the art, such as extraction, distillation, etc.
  • the present invention has the following advantages:
  • the (S)-lenalidomide-5-position derivative is prepared by the route of the present invention, which is simple to operate, simple to post-process, and has readily available raw materials and is environmentally friendly.
  • the prepared product has high chiral purity, good stability, high total yield, low production cost, and is suitable for large-scale industrial production.
  • FIG1 is a hydrogen spectrum of compound 4 obtained in step C of Example 1;
  • FIG2 is a carbon spectrum of compound 4 obtained in step C of Example 1;
  • FIG3 is a mass spectrum of compound 4 obtained in step C of Example 1 in LCMS;
  • FIG4 is a hydrogen spectrum of compound 5 obtained in step D of Example 1;
  • FIG5 is a carbon spectrum of compound 5 obtained in step D of Example 1;
  • FIG6 is a mass spectrum of compound 5 obtained in step D of Example 1 in LCMS;
  • FIG7 is a chiral LC spectrum of the reference racemate of compound 5.
  • FIG8 is a chiral LC spectrum of compound 5 obtained in step D of Example 1;
  • FIG9 is a hydrogen spectrum of compound 8 obtained in step F of Example 1;
  • FIG10 is a carbon spectrum of compound 8 obtained in step F of Example 1;
  • FIG11 is a mass spectrum of compound 8 obtained in step F of Example 1 in LCMS;
  • FIG12 is a chiral LC spectrum of the reference racemate of compound 8.
  • FIG13 is a chiral LC spectrum of compound 8 obtained in step F of Example 1.
  • Step A Add HCl in 1,4-dioxane solution (26 mL, 1.0 eq.) to a 50 mL four-necked flask, add compound 1 (6.50 g, 1.0 eq.) in 1,4-dioxane solution (13 mL) at 30 ⁇ 5°C, stir at 30 ⁇ 5°C, solid precipitates. After stirring for 4 hours, TLC monitoring shows that compound 1 is completely converted. Filter the reaction solution, wash the filter cake with 6.5 mL of 1,4-dioxane, collect the filter cake, and obtain 12.51 g of a yellow solid product, which is compound 2. It can be directly used as a feed for the next step.
  • Step B Add compound 2 (0.82 g, 1.0 eq.), 1,4-dioxane (8.2 mL), triethylamine (1.17 g, 4.0 eq.) and water to the reaction flask and stir to dissolve. Cool to 0 ⁇ 5°C, add benzyl chloroformate (0.74 g, 1.5 eq.), stir for 10 min, then heat to 30 ⁇ 5°C and stir for 12 h. Monitor by TLC, compound 2 is completely converted. Add 10 mL of ethyl acetate and 10 mL of saturated brine, separate the liquids, and collect the upper organic phase.
  • Step C Add H-Gln-OtBu.HCl (1.87 g, 1.0 eq.), methanol (60 mL) and sodium acetate (1.93 g, 3.0 eq.) to a 100 mL reaction bottle, stir at 30 ⁇ 5°C for 0.5 h, add compound 3 (3.0 g, 1.0 eq.) and acetic acid (0.71 g, 1.5 eq.). Continue stirring for 1 h, cool to 0 ⁇ 5°C, slowly add sodium cyanoborohydride (3.0 eq.), then heat to 30 ⁇ 5°C, stir for 20 h, and monitor by TLC. The raw material is completely converted and obvious product is generated.
  • Step D Add compound 4 (1.12 g, 1.0 eq.) and acetonitrile (23 mL) to a 50 mL four-necked flask, stir at 30 °C to dissolve, then add benzenesulfonic acid (0.66 g, 2.0 eq.), and stir under nitrogen protection. After 16 h of reaction, monitor by TLC and MS, the raw material is completely converted.
  • Step E Add compound 5 (0.2 g, 1.0 eq.), methanol (5 mL), tetrahydrofuran (5 mL) and dichloromethane (4 mL) to a 50 mL four-necked flask and stir to completely dissolve the material. Then add benzenesulfonic acid (79 mg, 1.0 eq.) and 10% palladium carbon (20 mg, 0.1 w/w). Replace with hydrogen three times, install a hydrogen balloon, and stir the reaction at 30 ° C for 8 h. Monitor the reaction solution with TLC, and the raw material is completely converted. After the reaction is completed, there is obvious solid precipitation.
  • Step F Add compound 6 (0.2 g, 1.0 eq.) and methanol (5 mL) to a 50 mL four-necked flask and stir for 30 minutes to completely dissolve the material. Then add compound 7 (88 mg, 1.0 eq.) and acetic acid (39 mg, 1.0 eq.) and stir the reaction at 30 ⁇ 5°C for 1 h, and cool to 0 ⁇ 5°C. Add sodium cyanoborohydride (82 mg, 1.0 eq.), raise the temperature to 30 ⁇ 5°C and stir the reaction for 6 h. Monitor the reaction solution with TLC, and the raw material is completely converted. Remove methanol by vacuum rotary evaporation.
  • steps A to C were the same as those in Example 1. Methanol was used as the solvent in step D. The other conditions were the same as those in step D in Example 1. The final result showed no reaction and no post-treatment was performed.
  • steps A to C were the same as those in Example 1, and the reaction temperature of step D was 60° C. The results showed that no ring-closure product was obtained, and only a byproduct of tert-butyl shedding was obtained.
  • step F the amount of sodium cyanoborohydride used is 3.0 eq, the amount of acetic acid used is 1.5 eq, and the other conditions are the same as those in step F of Example 1.
  • a product is generated, but part of it is racemized.
  • Steps A and B are the same as in Example 1, and step C refers to step C of Example 1, except that acetic acid is not added, and as a result, the target product is not obtained and no post-treatment is performed.
  • Example 5 shows that the substituents on the benzene ring have a significant impact on the reaction results.

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Abstract

La présente invention concerne un dérivé de (S)-lénalidomide-5, son procédé de synthèse et son utilisation. L'utilisation comprend les étapes suivantes consistant à : éliminer un groupe protecteur tert-butoxycarbonyle d'un composé 1 dans des conditions acides pour obtenir un composé 2 ; ajouter un groupe protecteur benzyloxycarbonyle au composé 2 en présence d'une amine organique pour obtenir un composé 3 ; soumettre le composé 3 à une réaction d'amination réductrice avec un ester tert-butylique de L-glutamine pour obtenir un composé 4 ; soumettre le composé 4 à une réaction de fermeture de cycle dans un état acide pour obtenir un composé 5 ; soumettre le composé 5 à une réaction d'hydrogénation et d'élimination de benzyloxycarbonyle avec de l'hydrogène dans un état acide sous l'action d'un catalyseur d'hydrogénation pour obtenir un composé 6 ; et soumettre le composé 6 à une réaction d'amination réductrice avec un composé 7 pour obtenir un composé 8. Les composés 5, 6 et 8 sont des dérivés de (S)-lenalidomide 5. Le procédé de synthèse selon la présente invention a un post-traitement simple, moins de racémisation et un rendement élevé, ne génère pas de polluants toxiques, et est respectueux de l'environnement et sûr.
PCT/CN2023/136370 2023-12-05 2023-12-05 Dérivé de (s)-lenalidomide-5, son procédé de synthèse et son utilisation Pending WO2025118133A1 (fr)

Priority Applications (1)

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PCT/CN2023/136370 WO2025118133A1 (fr) 2023-12-05 2023-12-05 Dérivé de (s)-lenalidomide-5, son procédé de synthèse et son utilisation

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060025457A1 (en) * 2004-07-28 2006-02-02 Muller George W Isoindoline compounds and methods of their use
US20060052609A1 (en) * 2004-09-03 2006-03-09 Muller George W Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines
US20060160854A1 (en) * 1999-05-07 2006-07-20 Celgene Corporation Methods for the treatment of cachexia
CN103068386A (zh) * 2010-03-12 2013-04-24 细胞基因公司 使用来那度胺治疗非霍奇金淋巴瘤的方法及作为预测因子的基因和蛋白质生物标记
US20180238886A1 (en) * 2017-01-31 2018-08-23 Celgene Corporation Methods for treating hematological cancer and the use of biomarkers as a predictor for responsiveness to treatment compounds
CN109776493A (zh) * 2019-03-20 2019-05-21 石家庄度恩医药科技有限公司 一种来那度胺的制备方法
CN113329999A (zh) * 2019-09-23 2021-08-31 冰洲石生物科技公司 具有雄激素受体降解活性的新型取代的喹啉-8-甲腈衍生物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060160854A1 (en) * 1999-05-07 2006-07-20 Celgene Corporation Methods for the treatment of cachexia
US20060025457A1 (en) * 2004-07-28 2006-02-02 Muller George W Isoindoline compounds and methods of their use
US20060052609A1 (en) * 2004-09-03 2006-03-09 Muller George W Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines
CN103068386A (zh) * 2010-03-12 2013-04-24 细胞基因公司 使用来那度胺治疗非霍奇金淋巴瘤的方法及作为预测因子的基因和蛋白质生物标记
US20180238886A1 (en) * 2017-01-31 2018-08-23 Celgene Corporation Methods for treating hematological cancer and the use of biomarkers as a predictor for responsiveness to treatment compounds
CN109776493A (zh) * 2019-03-20 2019-05-21 石家庄度恩医药科技有限公司 一种来那度胺的制备方法
CN113329999A (zh) * 2019-09-23 2021-08-31 冰洲石生物科技公司 具有雄激素受体降解活性的新型取代的喹啉-8-甲腈衍生物及其用途

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