WO2026018182A1 - Procédé de préparation d'un dérivé de cis-1,2-diaryltétraline - Google Patents

Procédé de préparation d'un dérivé de cis-1,2-diaryltétraline

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Publication number
WO2026018182A1
WO2026018182A1 PCT/IB2025/057208 IB2025057208W WO2026018182A1 WO 2026018182 A1 WO2026018182 A1 WO 2026018182A1 IB 2025057208 W IB2025057208 W IB 2025057208W WO 2026018182 A1 WO2026018182 A1 WO 2026018182A1
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WIPO (PCT)
Prior art keywords
int
compound int
solvent
charged
reactor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/057208
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English (en)
Inventor
Zebediah Clinton GIRVIN
Robert Alan Singer
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Pfizer Inc
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Pfizer Inc
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Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of WO2026018182A1 publication Critical patent/WO2026018182A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.

Definitions

  • the present invention relates to a process for preparing a cis-1,2-diaryltetralin derivative, a key chiral intermediate in the synthesis of (S)-3-(5-(4-((1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3- dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-10 naphthalenylphenyl]-4-piperid
  • Compound 1 is in clinical development as a PROTAC ® protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.
  • Compound 1 is in phase 3 clinical trials for the treatment of patients with estrogen receptor positive / human epidermal growth factor 20 receptor 2 negative (ER+/HER2-) metastatic breast cancer.
  • ER+/HER2- estrogen receptor positive / human epidermal growth factor 20 receptor 2 negative
  • the present invention provides an asymmetric route, including intermediates and synthetic steps, to a key intermediate in the process of preparing Compound 1. Chirality is introduced via a catalytic enantioselective intramolecular Corey-Chaykovsky epoxidation, with the challenging cis-1,2-diaryl motif subsequentially installed via diastereoselective hydrogenation.
  • the present invention relates to a process for preparing compound Int-2 (Int-2) comprising the step of reacting compound Int-23 and a hydrogen source and, optionally a catalyst, in a solvent.
  • the catalyst is palladium on carbon.
  • the solvent is methanol or ethyl acetate.
  • the solvent is methanol.
  • E5 The process of any one of embodiments 1 to 3, wherein the hydrogen source is hydrogen.
  • the present invention relates to a process for preparing compound Int-23 comprising the step of reacting compound Int-20 and piperidine fragment with a palladium catalyst and a base, in a solvent.
  • the palladium catalyst is Pd2(dba)3/RuPhos.
  • the base is sodium tert- butoxide.
  • the present invention relates to a process for preparing compound Int-20 comprising the step of reacting compound Int-19 with an acid in a solvent.
  • E11 The process of embodiment 10, wherein the acid is sulfuric acid, p- toluenesulfonic acid, or polyphosphoric acid.
  • E12 The process of embodiment 10, wherein the acid is sulfuric acid.
  • E13 The process of any one of embodiments 10 to 12, wherein the solvent is 2- methyltetrahydrofuran.
  • the present invention relates to a process for preparing compound Int-19 comprising the step of reacting compound Int-13 with a Grignard reagent in a solvent.
  • E15 A process of embodiment 14, wherein the Grignard reagent is 4-chlorophenyl- magnesium bromide.
  • E16 A process of embodiment 14 or embodiment 15, wherein the solvent is 2- methyltetrahydrofuran.
  • the present invention relates to a process for preparing compound Int-20 comprising the steps of: 1) reacting compound Int-19 with an acid in a solvent; and 2) reacting compound Int-13 with a Grignard reagent in a solvent, and not isolating compound Int-19.
  • E18 The process of embodiment 17, wherein the acid is sulfuric acid, p- toluenesulfonic acid, or polyphosphoric acid.
  • E19 The process of embodiment 17, wherein the acid is sulfuric acid.
  • the solvent is 2- methyltetrahydrofuran.
  • the present invention relates to a process for preparing compound of Int-13 comprising the step of reacting compound of Int-16 and isothiocineole: ( Int-16) , lithium triflate, and potassium hydroxide in a solution of dichloromethane, tert-butyl alcohol, and water.
  • the present invention relates to a process for preparing compound Int-16 with phosphorous tribromide or hydrogen bromide in a solvent.
  • the solvent is dichloromethane.
  • the present invention relates to a process for preparing compound Int-12 comprising the step of reacting compound Int-10 and allylic alcohol: with a palladium source, a ligand and a base, in a solvent.
  • a palladium source is Pd(OAc)2.
  • the ligand is catacxium A.
  • the present invention relates to a process for preparing compound Int-2 comprising the steps of: 1) reacting compound Int-10 and allylic alcohol with a Pd(OAc) 2 and catacxium A in a solvent; 2) reacting compound Int-12 with phosphorous tribromide in a dichloromethane; 3) reacting compound Int-16 and isothiocineole ( Int-16) , lithium triflate, and potassium hydroxide in a solution of dichloromethane, tert-butyl alcohol, and water; 4) reacting compound Int-13 with 4-chlorophenyl-magnesium bromide in 2-methyltetrahydrofuran; 5) reacting compound Int-19 with sulfuric acid in 2-methyltetrahydrofuran; 6) reacting compound Int-20 and a piperidine fragment with Pd2(dba)3/RuPhos and sodium tert-butoxide, in toluene; and 7) reacting compound Int-23 and
  • a temperature of about 10 °C means 10 °C ⁇ 10% i.e., it may vary between 9 °C and 11 °C.
  • solvate refers to a crystal form of a substance which contains solvent.
  • hydrate refers to a solvate wherein the solvent is water.
  • the compound of formula Int-4 may be obtained as a hydrate or may convert to an hydrate, depending on storage conditions, specifically temperature and humidity conditions.
  • Grignard compounds are popular reagents in organic synthesis for creating new carbon–carbon bonds.
  • Grignard reagents or Grignard compounds are chemical compounds with the general formula R ⁇ Mg ⁇ X, where X is a halogen and R is an organic group, normally an alkyl or aryl.
  • X is a halogen and R is an organic group, normally an alkyl or aryl.
  • all references herein to Compound 1 and intermediates used in its preparation include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.
  • Previously known synthetic routes for preparing Compound 1 proceed through a racemic intermediate followed by a classical resolution as depicted below in Scheme 2: 2.
  • the synthetic steps described in Scheme 1 present several advantages compared to previously known synthetic routes for preparing Compound 1 as shown in Scheme 2.
  • the route of the present invention introduces chirality via a catalytic, intramolecular Corey-Chaykovksy epoxidation, avoiding the classical resolution process currently used to prepare (Int-2).
  • the unprecedented enantioselective intramolecular epoxidation not only installs a key stereocenter but completes assembly of the tetralin.
  • the challenging cis-1,2-diaryl motif is installed via stereochemical relay using hydrogenation.
  • the present invention controls stereochemistry earlier in the route providing more opportunities for control of chirality as well as conventional process related impurities, while intercepting a common intermediate with the existing convergent route.
  • the synthesis commences with the S N Ar reaction of benzyl alcohol with fluoro-substituted aldehyde (8) and provides (9) in 77 % yield (2.5 kg scale).
  • the subsequent reduction of (9) in the presence of NaBH 4 delivers benzylic alcohol (10) in 90 % isolated yield after crystallization (2.75 kg scale).
  • (10) is subjected to a palladium-catalyzed Heck reaction with allylic alcohol or vinyl-benzyl alcohol (11), which may be prepared in one step via addition of vinyl Grignard to benzaldehyde.
  • Several effective ligands may be used in the Heck reaction, with catacxium ® A proving to be the most effective ligand.
  • Pd2(dba)3 was utilized as the palladium source, reaction progress often stalled when employed at ⁇ 0.5%, likely due to the inhibitory effect the dibenzylideneacetone olefin ligand can have in Heck reactions.
  • Pd(OAc)2 enables the use of 0.5 % loading, affording (Int-12) in 66 % yield on 600 g scale.
  • the Heck reaction not only generates the desired C-C sp 2 -sp 3 linkage, but also delivers the saturated ketone following tautomerization of the enol product.
  • TBAI provides a slight enhancement in overall reactivity (Entry 9-10).
  • the common enantioselectivities when using either super-stoichiometric or catalytic chiral sulfide (Int- 17) is due to the lack of competing racemic background reaction. Since (Int-13) cannot form without prior formation of 17-derived chiral sulfonium ylide, regardless of catalyst loading, a common reactive intermediate is shared in all scenarios. Analysis of the reaction mixture indicates that the two main impurities generated are derived from competing hydrolysis of (Int-16) via water or tert-butanol to generate (Int-12) and (Int- 18), both of which are unreactive species in the epoxidation (Scheme 7).
  • Non- nucleophilic solvent combinations do not suppress impurity formation and deliver worsened reaction profiles. Concentrating the reaction system and minimizing the amount of both water and tert-butanol present, suppresses hydrolysis rates to achieve conversions reaching 85 % (Entry 12). Optimal reaction conditions (Entry 13) afford a 67 % isolated yield of (Int-13) with 98.4:1.6 e.r. after crystallization from a isopropanol:acetonitrile blend. Development of crystallization conditions following epoxidation is beneficial from both an impurity purge perspective, and upgrading the enantiopurity of (Int-13). Scheme 7.
  • Ethyl acetate (4.59 L, 1.67 V) was used to back-extract the lower aqueous phase.
  • Organic phases were combined and washed with 20% sodium chloride aqueous solution (6.46 L, 2.35 V). Aqueous phase was separated, and organic phase was concentrated to 1.0 V-1.5 V at 40-50°C.
  • n-Heptane (14.9 L, 5.4 V) was added dropwise at 40-50°C, and the reaction temperature was then lowered to 0-10°C. Reaction mixture was allowed to stir for 2-3 h. The mixture was filtered and washed with n-Heptane (2.70 L, 0.98 V). Filter cake was dried at 40-50°C under vacuum.
  • TEBAC 2.3 g, 0.005 equiv.
  • the reaction mixture was heated to 95-105°C held for 3-6 h under N 2 .
  • Reaction mixture was cooled down to 20-40°C.
  • the reaction liquid was filtered through filter paper to remove the black heavy metals.
  • the ethyl acetate phase was collected. Charged ethyl acetate (3 L, 5 V) into reactor. The water phase was added back into reactor and the mixture was stirred at 20-30°C for 30 min. Reaction mixture was allowed to stand for 30 min. The ethyl acetate phase was collected and combined with the first ethyl acetate layer. Charged 15% sodium chloride solution (3 L, 5 V) into reactor and stirred the mixture at 20-30°C for 30 min. Reaction mixture was allowed to rest for 30 min. The ethyl acetate phase was collected before 15% sodium chloride solution (3 L, 5 V) was charged into reactor.
  • Example 4 Formation of 3-(5-(benzyloxy)-2-(bromomethyl)phenyl)-1- phenylpropan-1-one (Int-16) ( Int-12) (Int-16) Charged (Int-12) (440 g, 1.0 equiv.) into reactor. Charged DCM (2.2 L, 5 V) into reactor. The reaction mixture was cooled to -5-0°C and stirred for 0.5-1 h with N2. Charged PBr3 (206.1 g, 0.6 equiv.) slowly into reactor to keep the temperature at -5- 0°C. Stirred the reaction mixture at -5-0°C for 4-16 h with N 2 . Reaction mixture was cooled down to 0-10°C.
  • Example 5 Formation of (1aR,7bR)-5-(benzyloxy)-1a-phenyl-1a,2,3,7b- tetrahydronaphtho[1,2-b]oxirene (Int-13) ( Int-16) (Int-17) (Int-13) Charged (Int-16) (120 g, 1.0 equiv.) into reactor. Charged LiOTf (68.6 g, 1.5 equiv.) into reactor. Charged (Int-17) isothiocineole (5.1 g, 0.1 equiv.) into reactor. Charged TBAI (21.6 g, 0.2 equiv.) into reactor.
  • the reaction mixture indicated that the two main impurities generated were derived from competing hydrolysis of (Int-16) via water or tert-butanol to generate (Int-12) and (Int- 18), both of which were unreactive species in the epoxidation (Scheme 11). Further concentrating the reaction system and minimizing the amount of both water and tert- butanol present, hydrolysis rates were be suppressed enough to achieve conversions reaching 85 % (Entry 12). Epoxidation on 120 g scale with optimal reaction conditions (Entry 13), afforded 67 % isolated yield of (Int-13) with 98.4:1.6 e.r. after crystallization from a isopropanol:acetonitrile blend.
  • Example 8 Formation (5R,6S)-5- ⁇ 4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl ⁇ -6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Int-2) Charged (Int-23) (50 g, 1.0 equiv.) into reactor along with MeOH (750 mL, 15 V). Charged 5% Pd/C (7.5 g, 15% w/w) into reactor. The reactor was degassed with N2 three times and then with H 2 three times. Stirred the mixture at 40-45°C for 2 days with 2 MPa H2. Reaction mixture was cooled to 20-30°C.
  • Reaction mixture was filtered and the cake was washed with ice MeOH (100 mL, 2 V).
  • (Int-2) was dried at 40°C under vacuum for 6 h. Charged the solid (Int-2) into reactor. Charged 1-propanol (400 mL, 8 V) into reactor. Reaction mixture was stirred and heated to 40°C. Once the solids dissolved, charged water (50 mL, 1 V) into reactor along with (Int-2) seed (0.42 g, 0.01 equiv.). Stirred mixture at 40°C for 1 h. Charged water (350 mL, 7 V) into reactor over 6 h and stirred mixture at 40°C for 2 h. Reaction mixture was cooled to 20°C over 2 h.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un dérivé de cis-1,2-diaryltétraline, un intermédiaire chiral clé dans la synthèse du composé 1.
PCT/IB2025/057208 2024-07-19 2025-07-16 Procédé de préparation d'un dérivé de cis-1,2-diaryltétraline Pending WO2026018182A1 (fr)

Applications Claiming Priority (2)

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US202463673579P 2024-07-19 2024-07-19
US63/673,579 2024-07-19

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WO2026018182A1 true WO2026018182A1 (fr) 2026-01-22

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018102725A1 (fr) 2016-12-01 2018-06-07 Arvinas, Inc. Dérivés de tétrahydronaphtalène et de tétrahydroisoquinoléine en tant qu'agents de dégradation des récepteurs des œstrogènes
EP3705471A1 (fr) * 2017-11-02 2020-09-09 UBE Industries, Ltd. Inhibiteur de protéase à deux têtes
WO2022056368A1 (fr) 2020-09-14 2022-03-17 Arvinas Operations, Inc. Formes cristallines d'un composé pour la dégradation ciblée du récepteur des œstrogènes
WO2023009521A1 (fr) 2021-07-26 2023-02-02 Arvinas Operations, Inc. Procédés de fabrication d'un composé bifonctionnel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018102725A1 (fr) 2016-12-01 2018-06-07 Arvinas, Inc. Dérivés de tétrahydronaphtalène et de tétrahydroisoquinoléine en tant qu'agents de dégradation des récepteurs des œstrogènes
EP3705471A1 (fr) * 2017-11-02 2020-09-09 UBE Industries, Ltd. Inhibiteur de protéase à deux têtes
WO2022056368A1 (fr) 2020-09-14 2022-03-17 Arvinas Operations, Inc. Formes cristallines d'un composé pour la dégradation ciblée du récepteur des œstrogènes
WO2023009521A1 (fr) 2021-07-26 2023-02-02 Arvinas Operations, Inc. Procédés de fabrication d'un composé bifonctionnel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HEJTMANKOVA, L. ET AL., RESEARCH ON CHEMICAL INTERMEDIATES, vol. 35, 2009, pages 615 - 623
RUIZ-CASTILLO, P.BUCHWALD, S. L.: "Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions.", CHEM. REV., vol. 116, 2016, pages 12564 - 12649, XP055576488, DOI: 10.1021/acs.chemrev.6b00512

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