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WO2025020191A1 - Composé stéroïde, son procédé de préparation et son utilisation - Google Patents

Composé stéroïde, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025020191A1
WO2025020191A1 PCT/CN2023/109660 CN2023109660W WO2025020191A1 WO 2025020191 A1 WO2025020191 A1 WO 2025020191A1 CN 2023109660 W CN2023109660 W CN 2023109660W WO 2025020191 A1 WO2025020191 A1 WO 2025020191A1
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WIPO (PCT)
Prior art keywords
ethyl acetate
cyclopenta
mmol
compound
independently
Prior art date
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PCT/CN2023/109660
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English (en)
Chinese (zh)
Inventor
刘金镖
唐静洁
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.)
Cholesgen Shanghai Co Ltd
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Cholesgen Shanghai Co Ltd
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Priority to PCT/CN2023/109660 priority Critical patent/WO2025020191A1/fr
Priority to PCT/CN2024/107804 priority patent/WO2025021193A1/fr
Priority to TW113127857A priority patent/TW202506100A/zh
Publication of WO2025020191A1 publication Critical patent/WO2025020191A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to a steroid compound, a preparation method and application thereof.
  • lipid synthesis pathway of mammalian cells is an important factor in regulating lipid metabolism balance.
  • the key factor regulating the synthesis of cholesterol and fatty acids is a type of transcription factor protein, sterol response element binding protein SREBP (Sterol-Regulatory Element Binding Protein).
  • the precursors of this type of protein are first synthesized on the endoplasmic reticulum (ER), and the precursors are transported to the Golgi apparatus through SREBP cleavage-activating protein (SCAP, SREBP cleavage-activating protein), and then cleaved by two proteases (Site-1protease (S1P) and Site-2protease (S2P)) to release its N-terminal active domain, enter the cell nucleus to play the role of a transcription factor, bind to the SREBP response element (SRE) in the promoter region of the target gene, and initiate the expression of downstream genes.
  • SCAP SREBP cleavage-activating protein
  • S1P Site-1protease
  • S2P Site-2protease
  • SREBP protein The splicing and maturation of SREBP protein is strictly regulated by the level of intracellular sterols (such as cholesterol and 25-hydroxycholesterol).
  • intracellular sterols such as cholesterol and 25-hydroxycholesterol.
  • cholesterol binds to SCAP and changes the conformation of SCAP, causing the SCAP-SREBP complex to bind to the protein Insig (Insulin-induced gene), thereby blocking the transport of SREBP to the Golgi apparatus and the subsequent activation of SREBP.
  • Insig Insulin-induced gene
  • the active form of SREBP in the nucleus increases, promoting cellular lipid synthesis.
  • 25-hydroxycholesterol 25-hydroxylcholesterol, 25-HC
  • 25-HC directly binds to Insig and induces the binding of SCAP and Insig.
  • statins and fibrates are the main lipid-regulating drugs in clinical practice.
  • the mechanism of action of statins is to inhibit the cellular cholesterol synthesis pathway and promote the reverse transport of blood cholesterol. This shows that targeting the key factors of the cellular lipid synthesis pathway is an important means to effectively reduce lipid levels.
  • fatty liver disease involves multiple risk factors, such as the accumulation of triglycerides in the form of lipid droplets, which may cause fatty degeneration, and abnormal increase in cholesterol and fatty acids in cells, which can cause endoplasmic reticulum stress and mitochondrial dysfunction, leading to cell death. Death, inflammation and fibrosis.
  • free cholesterol accumulation has been reported as a key driver of the transition from simple steatosis to aggressive steatohepatitis.
  • a mouse model of fatty liver was established.
  • a simple cholesterol-free high-fat diet could only induce steatosis even after long-term feeding, while adding 1-2% cholesterol to the diet was necessary to achieve inflammation and fibrosis. Therefore, lowering cholesterol may become a new therapeutic strategy for fatty liver disease.
  • SREBPs abnormal activation of SREBPs was found in patients with fatty liver and mouse models of fatty liver; the deletion or knockout of mouse liver-specific Scap can eliminate the activation of all SREBPs, thereby preventing the occurrence of fatty liver and hyperlipidemia.
  • recent studies have shown that abnormal activation of SREBPs induced by endoplasmic reticulum stress promotes lipogenesis and fatty liver. Therefore, these evidences suggest that reducing liver triglyceride and cholesterol levels by inhibiting the SREBP pathway is an effective strategy for preventing and/or treating metabolic disorders including fatty liver.
  • the technical problem to be solved by the present invention is to provide a new compound having inhibitory activity on the SREBP pathway.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • each are independently a single bond or a double bond
  • R 4a is H; R 4b is H or OH; or, R 4a and R 4b together with the carbon atom to which they are attached form
  • R 7a and R 7b are independently H or halogen;
  • R 8a is H;
  • R 7a When there is a double bond between carbon atoms 7 and 8, R 7a does not exist, R 7b is a halogen; R 8a does not exist;
  • n1, n2, n3, n4 and n5 are independently 2, 3, 4 or 5;
  • n1, m2, m3 and m4 are independently 0, 1, 2, 3, 4 or 5;
  • Ring A, Ring B, Ring C and Ring D are independently C 6 -C 10 aryl, "5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S" or C 3 -C 6 cycloalkyl;
  • R 1 is C 1 -C 6 alkoxy, or NR 1a R 1b ;
  • R 2 and R 3 are independently H or C 1 -C 6 alkyl
  • R A , R B , R C and R D are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • Ring E is C 3 -C 6 cycloalkyl
  • n5 0, 1, 2 or 3;
  • R 1a , R 1b , Re1 and Re2 are independently H or C 1 -C 6 alkyl
  • a carbon atom with an "*" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration, or a mixture of the two;
  • a carbon atom with a "#" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration, or a mixture of the two;
  • a carbon atom with an "&" indicates that it is an R configuration, an S configuration, or a mixture of the two when it is a chiral carbon atom;
  • the compound shown in formula I is not the following compound: and its isomers.
  • certain groups in the compound of formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in some embodiments").
  • the halogen is independently F, Cl, Br or I; preferably F.
  • the C 6 -C 10 aryl group is independently phenyl or naphthyl, preferably phenyl.
  • the “heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms” is independently “heteroatom selected from 1, 2 or 3 of N, O and S, 5-6 membered heteroaryl group having 1 or 2 heteroatoms” or “heteroatom selected from O, 9-10 membered heteroaryl group having 1 or 2 heteroatoms”, preferably pyridyl (e.g. ), pyrazinyl (e.g. ), pyrimidine radicals (e.g. ), triazine groups (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. )
  • the C 3 -C 6 cycloalkyl in Ring A, Ring B, Ring C and Ring D is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl (eg ), preferably
  • the C 1 -C 6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl.
  • the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F.
  • the C1 - C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C1 - C6 haloalkyl is independently CHF2 , CH2F or CF3 .
  • the C1 - C6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
  • the C1 - C6 haloalkoxy group is independently -OCHF2 , -OCH2F or -OCF3 ; preferably -OCF3 .
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl (eg ), preferably cyclopropyl or cyclobutyl.
  • the C1 - C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
  • the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
  • n1 is 3.
  • n2 is 3.
  • n3 is 2.
  • n4 is 2.
  • n5 is 2.
  • m1 is 0, 1, 2 or 3.
  • m2 is 0, 1, 2 or 3, such as 2.
  • m3 is 1.
  • m4 is 1.
  • m5 is 1 or 2.
  • RA is independently halogen, C1 - C6 alkoxy, or C1 - C6 haloalkoxy.
  • Ring A is phenyl, pyridyl, (e.g. ), pyrazinyl (e.g. ), pyrimidine radicals (e.g. ), triazine groups (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. ),
  • RB is independently halogen, C1 - C6 alkoxy, or C1- C6 haloalkoxy; for example , halogen or C1 - C6 alkoxy.
  • Ring B is phenyl
  • R 1 is methoxy, or NH 2 .
  • RC and RD are independently halogen.
  • Ring C is phenyl
  • Ring D is phenyl
  • Ring E is cyclopropyl or cyclobutyl.
  • R 1a and R 1b are independently H.
  • Re1 and Re2 are independently C 1 -C 6 alkyl (eg, methyl).
  • a carbon atom with a "*" indicates that when it is a chiral carbon atom, it is in the S configuration.
  • a carbon atom with a "#" indicates that when it is a chiral carbon atom, it is in the R configuration.
  • R 4b is H or OH
  • R 7a and R 7b are independently H or halogen (eg, F); preferably, R 4b is OH, R 7a and R 7b are independently halogen (eg, F).
  • m 2A is 0, 1, 2, 3 or 4.
  • R22 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound represented by formula I is formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 or I-10 Compounds shown:
  • the carbon atom with "&" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;
  • Ring A, Ring B, RA , RB , m1 and m2 are as defined in any embodiment of the present invention.
  • the compound represented by formula I is any of the following compounds:
  • the present invention also provides a pharmaceutical composition, comprising the compound described in any one of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.
  • the present invention also provides a use of the compound according to any one of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above in the preparation of a drug for inhibiting the SREBP pathway.
  • the present invention also provides a method for inhibiting the SREBP pathway, comprising administering an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof to a subject.
  • substitution or “substituent” means that the hydrogen atom in the group is replaced by a specified group.
  • substitution position is not specified, the substitution can be in any position, but only a stable or chemically feasible chemical is formed. Examples are as follows: The structure indicates that the hydrogen atoms on ring A are replaced by m1 RAs . When there are multiple RAs , Each RA may be the same or different.
  • variable e.g, RA
  • haloalkyl refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen, wherein the definition of alkyl is as described above.
  • examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, etc.
  • alkoxy refers to -O-alkyl, wherein the definition of alkyl is as described above.
  • C 1 -C 4 alkoxy refers to -O-(C 1 -C 4 alkyl), wherein the definition of C 1 -C 4 alkyl is as described above, that is, C 1 -C 4 alkoxy can specifically be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (e.g., cyclohexyl, cyclopentyl, cyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclopentyl, cyclobutyl, cyclopentyl ... etc.
  • the C 3-6 cycloalkyl group may specifically be C 3 , C 4 , C 5 , or C 6 cycloalkyl group.
  • the cycloalkyl group is monocyclic.
  • the cycloalkyl group is polycyclic (eg, cyclic, spirocyclic, or bridged).
  • C 6-10 aryl refers to phenyl or naphthyl.
  • heteroaryl refers to an aromatic monocyclic or condensed ring group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from 1, 2 or 3 of N, O and S.
  • the 5-10 membered heteroaryl group may specifically be a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group, such as a 5-6 membered heteroaryl group or an 8-10 membered condensed heteroaryl group.
  • the 5-6 membered heteroaryl group is monocyclic, and specific examples include, but are not limited to, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine and pyrazine.
  • Examples of 8-10 membered fused heteroaryl groups include, but are not limited to, benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzopyrazole, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazolothiazole, pyridopyridine, pyridopyrazine, pyridopyrimidine,
  • the chemical structure Indicates the connection location. Included in cyclic groups and not specified When the ring atoms are connected, Attachment to any ring atom is possible, but is permitted only if it results in a stable or chemically feasible compound.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base and a compound, which retains the biological activity of the compound.
  • the organic acid can be any organic acid that can form a salt conventionally used in the art.
  • the inorganic acid can be any inorganic acid that can form a salt conventionally used in the art.
  • the organic base can be any organic base that can form a salt conventionally used in the art.
  • the inorganic base can be any inorganic base that can form a salt conventionally used in the art.
  • the term "subject” includes any animal, preferably a mammal, and more preferably a human.
  • the term "effective amount" refers to a sufficient amount of a drug or pharmaceutical agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance.
  • the appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive progressive effect of the present invention is that the present invention provides a new class of compounds, which have inhibitory activity on the SREBP pathway and can be used to prevent and/or treat diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, skin damage, etc.
  • diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, skin damage, etc.
  • Step 1 Dissolve (22E, 24S)-stigmaster-6(5), 22(23)-diene-3 ⁇ -ol I-1 (5.00 g, 12.11 mmol, 1.0 eq) in dichloromethane (50 mL), place the reaction system in an ice-water bath, cool to about 5°C, add acetic anhydride (3.4 mL, 36.35 mmol, 3.0 eq), 4-dimethylaminopyridine (300 mg, 2.42 mmol, 0.2 eq) and triethylamine (8 mL, 60.57 mmol, 5.0 eq) to the reaction system in sequence, and stir the reaction system at room temperature for 2 hours.
  • acetic anhydride 3.4 mL, 36.35 mmol, 3.0 eq
  • 4-dimethylaminopyridine 300 mg, 2.42 mmol, 0.2 eq
  • triethylamine 8 mL, 60.57 mmol, 5.0 eq
  • reaction solution was quenched with methanol (20 mL), the reaction solution was washed once with saturated sodium bicarbonate ( ⁇ 50 mL) and water ( ⁇ 50 mL), dried over anhydrous sodium sulfate, and concentrated. When the concentration was almost dry, methanol ( ⁇ 20 mL) was added, and the mixture was stirred for 30 minutes under ice bath, filtered, and the filter cake was rinsed with a small amount of methanol.
  • Step 2 Weigh 10.0 g, 22 mmol, 1 eq of acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E,5S)-5-ethyl-6-methylhept-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-2 and dissolve it in tetrahydrofuran (200 mL) and water (20.0 mL). Add pyridine (4.5 mL) at room temperature.
  • Step 3 (Methoxymethyl)triphenylphosphonium chloride (55.21 g, 161.052 mmol, 5.0 eq) was dissolved in anhydrous tetrahydrofuran (100 mL), the system was cooled to -10 °C in a dry ice ethyl acetate bath, sodium bis(trimethylsilyl)amide (80.526 mL, 1 mol/L, 2.5 eq) was added, and the dry ice ethyl acetate bath was stirred for 30 minutes, and acetic acid-(1R,3aS,3bS,7S,9aR,9bS, 11aS)-1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-3
  • Step 4 Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2S,3E)-4-methoxybut-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-4 (8 g, 12.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL), and dilute hydrochloric acid (5 mol/L, 50 mL) was slowly added, and the reaction mixture was stirred at room temperature for 30 minutes.
  • Step 5 (The reactant acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-5 (10.00 g, 25.87 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (150 mL ), add (triphenyl- ⁇ 5-methylphosphine) methyl acetate (51.89g, 155.21mmol, 6.0eq), and stir the reaction system at 90°C for 18h.
  • reaction raw materials were consumed by NMR monitoring. 100mL of water was added to the reaction system, extracted with ethyl acetate (100mL ⁇ 3), the organic phase was collected and washed with water (100mL ⁇ 2), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to obtain a crude product.
  • Step 6 The reactant (2E,5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hex-2-enoic acid methyl ester I-6 (10 g, 22.59 mmol, 1.0 eq) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and methanol (50 mL), nickel chloride (2.93 g, 22.59 mmol, 1.0 eq) was added, sodium borohydride (1.28 g, 33.89 mmol) was slowly added, and the reaction system was stirred at room temperature for 1 h.
  • reaction raw materials were consumed by NMR monitoring. 100 mL of water was added to the reaction system, and ethyl acetate (100 mL ⁇ 3) was used for extraction. The organic phase was collected and washed with water (100 mL ⁇ 2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Step 7 In a 250 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-7 (2.5 g, 5.62 mmol) was dissolved in chloroform (80 mL), N-methylmorpholine (1.71 g, 16.87 mmol) and selenium dioxide (1.56 g, 14.06 mmol) were added at room temperature, and then stirred at 70°C for 18 hours.
  • Step 8 The reactant (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-8 (5 g, 11.5 mmol, 1.0 eq) was dissolved in methanol (150 mL), potassium carbonate (6.37 g, 46 mmol, 4.0 eq) was added, and the reaction system was stirred at room temperature for 30 min.
  • Step 9 The reactant (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-9 (5 g, 11.9 mmol, 1 eq) was dissolved in acetone (150 mL), p-toluenesulfonic acid (1.59 g, 8.4 mmol, 0.7 eq) and 4A molecular sieves were added, and the reaction system was stirred at room temperature for 1 h.
  • Step 10 Compound (5R)-5-[(3aR,3R,5aS,9aS,9bS)-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3a,6,6-trimethyl-2,3,3a,4,5,5a,6,9,9a,9b-decahydro-1H-cyclopenta[1,2-a]naphthalen-3-yl]hexanoic acid methyl ester I-10 (3.8 g, 8.2 mmol, 1.0 eq) was dissolved in acetone (50 mL), N-hydroxyphthalimide (0.54 g, 3.3 mmol, 0.8 eq), tert-butyl hydroperoxide (12 mL, 66 mmol, 8.0 eq) and anhydrous cobalt (II) acetate (0.29 g, 1.6 mmol, 0.2 eq) were added, and the resulting mixture was stirred under N 2 , stir
  • the raw material was basically consumed, quenched with saturated sodium sulfite, water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 15 mL).
  • the organic layers were combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • Step 11 Compound (5R)-5-[(1R, 3aS, 3bS, 6R, 7S, 9aR, 9bS, 11aR)-7-acetoxy-6-hydroxy-9a, 11a-dimethyl-2, 3, 3a, 3b, 4, 6, 7, 8, 9, 9a, 9b, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-11 (2.4 g, 5.1 mmol, 1.0 eq) was dissolved in methanol (100 mL) and ethyl acetate (50 mL), and then palladium carbon (1.2 g, 11 mmol, 2.2 eq) was added and the reaction system was replaced with a hydrogen atmosphere, and the reaction system was stirred at room temperature for 1 h.
  • Step 12 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxyde-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester I-12 (1.7 g, 3.6 mmol) was dissolved in diethylaminosulfur trifluoride (10 mL), and the resulting mixture was stirred in the reaction solution at 80° C.
  • Step 13 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester I-13 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,1 A mixture of 1,2-dioxol-2,4-dihydro-1,4-dihydro-2 ...2,4-dihydro-1,4-dihydro-2,4-dihydro-2,4-dihydro-2
  • Step 14 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol I-14 and (5R)-5-[(3aS,5aR,5bR,7aR A mixture of 1,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-te
  • Step 1 Dissolve compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester I-10 (1 g, 2.18 mmol, 1.0 eq) in tetrahydrofuran (50 mL), replace with nitrogen, add lithium aluminum tetrahydride (0.12 g, 3.270 mmol, 1.5 eq), and stir at 25° C.
  • Step 2 Dissolve compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol III-1 (1 g, 2.32 mmol, 1.0 eq) in dichloromethane (50 mL), add Dess-Martin periodinane (1.18 g, 2.79 mmol, 1.2 eq), and stir at 25°C for 1 h.
  • Step 1 Dissolve compound (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-8 (150 mg, 0.326 mmol, 1.0 eq) in ethyl acetate (5 mL), add platinum dioxide (36.97 mg, 0.163 mmol, 0.5 eq), and stir the resulting mixture in H 2 at 25° C.
  • Step 2 Weigh acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-methoxy-6-oxydehexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester IV-1 (300 mg, 0.65 mol, 1.0 eq.) and dissolve in anhydrous methanol (5mL), potassium carbonate (897mg, 6.5mmol) was added, and then the temperature was raised to 25°C and stirred for 16 hours.
  • potassium carbonate 897mg, 6.5mmol
  • Step 2 reacting the reactants (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1- ⁇ 2-[(trifluoromethyl)oxy]phenyl ⁇ hexan-1-ol 1-1 and (5R)-5-[(3aS,5aR,5bR, A mixture of 7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,
  • Step 1 Dissolve the compound 1-bromo-2-fluorobenzene (195.96 mg, 1.12 mmol, 1.2 eq) in tetrahydrofuran (30 mL), cool to -78 °C in a nitrogen-protected dry ice bath, add 2.5 M n-butyl lithium solution in n-hexane (89.67 mg, 1.400 mmol, 1.5 eq), keep warm and stir for 30 minutes, then add (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R ,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal III
  • Step 2 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2- Fluorophenyl)hexan-1-ol 3-1 (400 mg, 0.76 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), acetic anhydride (0.215 mL, 2.29 mmol, 3.0 eq), triethylamine (0.530 mL, 3.81 mmol, 5.0 eq) and 4-dimethylaminopyridine (93.09 mg, 0.76
  • Step 3 Compound acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexane
  • the ester 3-2 120 mg, 0.21 mmol, 1.0 eq
  • acetone 5 mL
  • N-hydroxyphthalimide 6.92 mg, 0.042 mmol, 0.2 eq
  • tert-butyl hydroperoxide 0.170 mL, 0.848 mmol, 4.0 eq
  • anhydrous cobalt I
  • Step 4 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexyl acetate 3-3 (60 mg, 0.10 mmol) was dissolved in methanol (5 mL), palladium carbon (11 mg, 0.103 mmol) was added, and the hydrogen gas was replaced 3 times.
  • the resulting mixture was stirred in the reaction solution in hydrogen at 25 ° C for 1 h.
  • the crude product was obtained by filtration and concentration.
  • Step 5 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxyde-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexyl acetate 3-4 (250 mg, 0.43 mmol) was dissolved in diethylaminosulfur trifluoride (5 mL), and the resulting mixture was stirred in the reaction solution at 80°C for 1 h.
  • Step 6 Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexyl ester 3-5 and acetate-(5R )-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9
  • Step 7 Compounds acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl ester 3-6 and acetic acid-(5R)-5-[(1R,3aR,5aR,6R,7S,9aR,9bS,11aR)-4-fluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl ester A mixture of a,11a-dimethyl-2,3,3a,5,5a,6,7,8,
  • the first step is to weigh m-bromoanisole (109 mg, 0.6 mol, 5.0 eq.) and dissolve it in ultra-dry tetrahydrofuran (5 mL). Cool the temperature to -78 °C with dry ice-acetone, and then drop butyl lithium (1.6 M, 0.45 mL).
  • Step 2 (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal 5-1 (30 mg, 0.056 mmol) was dissolved in anhydrous methanol (10 mL), and 2 M hydrochloric acid (3 mL) was added at room temperature.
  • the compound 1-bromo-2-fluorobenzene (195.96 mg, 1.12 mmol, 1.2 eq) was dissolved in tetrahydrofuran (30 mL), cooled to -78 °C in a nitrogen-protected dry ice bath, and n-butyl lithium 2.5 M n-hexane solution (89.67 mg, 1.400 mmol, 1.5 eq) was added.
  • Step 4 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexyl acetate 11-3 (60 mg, 0.10 mmol) was dissolved in methanol (5 mL), palladium carbon (11 mg, 0.103 mmol) was added, and the atmosphere was replaced with hydrogen three times.
  • Step 5 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxyde-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexyl acetate 11-4 (250 mg, 0.43 mmol) was dissolved in diethylaminosulfur trifluoride (5 mL), and the resulting mixture was stirred in the reaction solution at 80° C.
  • Step 6 Dissolve (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-5 (130 mg, 0.23 mmol, 1.0 eq) in dichloromethane (8 mL), place the reaction system in an ice-water bath, and cool to about 5° C., add acetic anhydride (0.022 mL, 0.23 mmol, 1.0 eq), 4-dimethylaminopyridine (5.62 mg, 0.046 mmol, 0.2 eq) and triethylamine (0.064 mL, 0.46 mmol, 2.0 eq) to the reaction system in sequence, and stir the reaction system
  • Step 8 Compound (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-7 (87 mg, 0.144 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (2.5 mL) and methanol (2.5 mL), and an aqueous lithium hydroxide solution (0.5 mL, 3 mol/L) was added, and the resulting mixture was stirred at 25 °C for 1 h.
  • the first step is to weigh acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylprop-2-yl]-9a,11a-dimethyl-2,3,3a, 3b,4,6,7,8,9,9a,9b,10,11,11a-Tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-5 (300 mg, 0.776 mmol) was dissolved in tetrahydrofuran (5 mL), and zinc chloride (105.76 mg, 0.776 mmol) and methylamine tetrahydrofuran solution (1.552 mL) were added successively at room temperature, and then stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (48.77 mg, 0.776 mmol) was added.
  • Step 2 Weigh acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-dimethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 15-1 (60 mg, 0.149 mmol) and dissolve it in DCM (5 mL), add diisopropylethylamine (0.074 mL, 0.448 mmol), add o-fluorobenzoyl chloride (47.37 mg, 0.299 mmol) under stirring, and then continue to stir at room temperature.
  • Step 4 Weigh out acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-4- ⁇ [(2-fluorophenyl)carbonyl](methyl)amino ⁇ butan-2-yl]-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 15-3 (136 mg, 0.252 mmol) and dissolve it in acetic acid (3 mL).
  • Step 5 Weigh 130 mg of acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-4- ⁇ [(2-fluorophenyl)carbonyl](methyl)amino ⁇ butyl-2-yl]-6-hydroxy-5a,9a,11a-trimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 15-4 (0.234 mmol) and dissolve it in a mixture of methanol (1 mL) and tetrahydrofuran (2 mL). Add lithium hydroxide aqueous solution (2.339 mL) and continue stirring at room temperature.
  • Step 1 The reagent 2-bromo-1,3-difluorobenzene (270 mg, 1.40 mmol, 3.0 eq) was dissolved in tetrahydrofuran (5 mL), protected by nitrogen, cooled to -78 °C in a dry ice bath, and then n-butyl lithium, 2.5 M n-hexane solution (0.67 mL, 1.680 mmol, 3.6 eq) was added.
  • Step 2 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2, 6-difluorophenyl)hexan-1-ol 21-1 (180 mg, 0.332 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and acetic anhydride (0.093 mL, 0.995 mmol, 3.0 eq), triethylamine (0.230 mL, 1.658 mmol, 5.0 eq) and DMAP (8.10 mg, 0.066
  • Step 3 Compound acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2,6-difluorophenyl)hexyl ester 21-2 (150 mg, 0.257 mmol, 1.0 eq) was dissolved in acetone (5 mL), and N-hydroxyphthalimide (8.37 mg, 0.051 mmol, 0.2 eq), tert-butyl hydroperoxide (0.205 mL, 1.026 mmol, 4.0 eq) and cobalt (
  • the resulting mixture was stirred in the reaction solution under N2 at 25°C for 18 hrs.
  • the raw material was basically consumed, and saturated sodium sulfite was used for quenching.
  • Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 15 mL). The organic layers were combined and washed with saturated brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product.
  • Step 4 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluorophenyl)hexyl acetate 21-3 (90 mg, 0.150 mmol) was dissolved in methanol (5 mL), palladium carbon (10.99 mg) was added, and the hydrogen atmosphere was replaced three times.
  • Step 5 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxyde-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2,6-difluorophenyl)hexyl acetate 21-4 (800 mg, 1.332 mmol) was dissolved in DAST (30 mL), and the resulting mixture was stirred in the reaction solution under N2 at 80°C for 3 h.
  • the reaction solution was cooled to room temperature and carefully added dropwise to a mixture of ice and water.
  • the aqueous layer was extracted with ethyl acetate (3 ⁇ 100 mL).
  • the ethyl acetate layers were combined and washed with saturated brine (100 mL).
  • Step 6 Compound (5R)-1-(2,6-difluorophenyl)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexyl acetate 21-5 (600 mg, 0.963 mmol, content 10%) was dissolved in tetrahydrofuran (30 mL), added to 3 mol/L hydrochloric acid solution (5 mL), and the resulting mixture was stirred at 25 ° C for 1 h.
  • Step 7 Compound acetic acid-(5R)-1-(2,6-difluorophenyl)-5-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-6,7-dihydroxy-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexyl ester 21-6 (420 mg, 0.721 mmol, content 10%) was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL), lithium hydroxide solution (3 mL) was added, and the resulting mixture was stirred in the reaction solution at 25° C.
  • the third step the reactant (3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-8-[(2R)-6-methoxy-6-(2-methoxyphenyl)hexan-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolane 22-2 (45 mg, 0.072 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (0.5 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 40 min.
  • Step 1 Dissolve the raw material 1-bromo-4-fluoro-2-methoxybenzene (107 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • Step 2 Reaction of the crude product (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(4-fluoro-2-methoxyphenyl)hexan-1-ol 35-1 and (5R)-5-[(3aS,5aR,5b
  • the crude product 70 mg, 0.11 mmol, 1.0 eq) of 1-(4-fluoro-2-methoxyphenyl)hexan-1-ol 36-1 (R,7aR,8
  • Step 1 Dissolve the compound 1-bromo-2-methoxybenzene (1309.01 mg, 6.999 mmol, 3.0 eq) in tetrahydrofuran (50 mL), cool to -78 °C under nitrogen protection, add n-butyl lithium, 2.5 M n-hexane solution (3.359 mL, 8.398 mmol, 3.6 eq), keep warm for 1 hour, then add (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal III (1000mg, 2.333
  • the reaction solution was quenched with saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 20mL). The organic layers were combined and washed with saturated brine (15mL).
  • Step 2 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl- 4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-Tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-methoxyphenyl)hexan-1-ol 37-1 (750 mg, 1.397 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), acetic anhydride (0.197 mL, 2.096 mmol, 1.5 eq), triethylamine (0.388 mL, 2.794 mmol, 2.0 eq) and 4-dimethylaminopyridine (34.14 mg,
  • Step 3 Compound acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-methoxy)- phenyl)hexyl ester 37-2 (750 mg, 1.296 mmol, 1.0 eq) was dissolved in acetone (30 mL), N-hydroxyphthalimide (42.27 mg, 0.259 mmol, 0.2 eq), tert-butyl hydroperoxide (1.037 mL, 5.183 mmol, 4.0 eq) and anhydrous cobalt
  • Step 4 Compound acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxyde-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolane-8- [0063]-1-(2-methoxyphenyl)hexyl ester 37-3 (340 mg, 0.574 mmol) was dissolved in methanol (20 mL), palladium carbon (100 mg, 0.940 mmol) was added, and the resulting mixture was stirred in H 2 at 25°C for 1 h.
  • Step 5 Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-methoxyphenyl)hexyl acetate 37-4 (180 mg, 0.303 mmol) was dissolved in DAST (5 mL, 0.333 mmol), and the resulting mixture was stirred in the reaction solution under N 2 at 80° C.
  • Step 6 Compounds acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-methoxyphenyl)hexyl ester 37-5 and (5R)-5-((3aS,5aR , 5bR, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a, 7a-tetramethyl-3a, 5,5a, 5b, 6,7,7a, 8,9
  • Step 7 Compounds acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-methoxyphenyl)hexyl ester 37-6 and (5 A mixture of 3S, 4R, 5R, 9R, 10R, 13R, 14R, 17R)-7-fluoro-3,4-dihydroxy-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradeca
  • the reaction solution was cooled to room temperature and carefully added dropwise to a mixture of ice and water, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 25 mL).
  • the ethyl acetate layers were combined and washed with saturated brine (15 mL).
  • the ethyl acetate layer was dried over anhydrous Na2SO4 , filtered and concentrated to give the crude product.
  • Step 1 Dissolve the raw material 1-bromo-3-methoxybenzene (98 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(3-methoxyphenyl)hexan-1-ol 39-1 and (5R)-5-[(3aS,5aR,5bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,
  • Step 2 (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid 43-1 (300 mg, 0.77 mmol) was dissolved in tetrahydrofuran (5 mL) and added.
  • Step 3 (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methoxy-N-methylhexanamide 43-2 (200 mg, 0.51 mmol) was dissolved in methanol (5 mL), Pd/C (20 mg, 10%) was added to displace H 2 , and stirring was continued at room temperature overnight.
  • Step 5 Weigh o-bromotrifluoromethoxybenzene (192.8 mg, 0.8 mmol) and dissolve it in tetrahydrofuran (5 mL). Cool the mixture to -78 °C with dry ice-acetone, then drop butyl lithium (1.6 M, 1.15 mmol) and continue stirring at -78 °C for one hour.
  • Step 1 Dissolve the raw material 1-bromo-3-fluorobenzene (92 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(3-fluorophenyl)hexan-1-ol 44-1 and (5R)-5-[(3aS,5aR,5bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,
  • Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 10 mL).
  • the EA layers were combined and washed with saturated brine (3 ⁇ 10 mL).
  • the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • Step 1 Dissolve the raw material 1-bromo-3-fluoro-2-methoxybenzene (107 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • reaction system was stirred at -78 ° C for 30 min.
  • 10 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL ⁇ 3), the combined organic phases were washed with saturated sodium chloride (10 mL), the combined organic phases were dried, and concentrated to obtain colorless oily crude products of 46-1 and 48-1 (70 mg), which were then used directly in the next step.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(3-fluoro-2-methoxyphenyl)hexan-1-ol 46-1 and (5R)-5-[(3aS,5aR,5bR The crude product (70 mg, 0.11 mmol, 1.0 eq) of (7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetra
  • the first step is to weigh acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aS)-1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-3 (2 g, 5.368 mmol) and dissolve it in tetrahydrofuran (30 mL).
  • Step 2 Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-methoxy-5-oxopent-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 47-1 (1.4 g, 3.266 mmol) was dissolved in a mixed solvent of THF (5 mL) and MeOH (3 mL), and nickel chloride (0.42 g, 3.266 mmol) and sodium borohydride (0.19 g, 4.900 mmol) were added in sequence, and stirred at room temperature.
  • Step 3 Weigh out acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxopentan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 47-2 (1.1 g, 2.554 mmol) and dissolve it in chloroform (10 mL).
  • Step 4 Weigh acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxopentan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 47-3 (30 mg, 0.067 mmol) and dissolve it in acetic acid (3 mL). Add platinum dioxide (15.25 mg, 0.067 mmol) and replace with hydrogen. Then, heat the temperature to 40 °C and stir.
  • Step 5 Acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxopentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 47-4 (100 mg, 0.223 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and methanol (2 mL), and lithium hydroxide (0.669 mL, 0.669 mmol) was added at room temperature, and then stirred at room temperature.
  • Step 1 Dissolve the raw material 2-bromo-1-fluoro-3-methoxybenzene (107 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and stir at the same temperature for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(6-fluoro-2-methoxyphenyl)hexan-1-ol 49-1 and (5R)-5-[(3aS,5aR,5bS, A mixture of 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,
  • Step 1 Dissolve the raw material 4-bromo-1-methoxybenzene (98 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(4-methoxyphenyl)hexan-1-ol 50-1 and (5R)-5-[(3aS,5aR,5bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,
  • the reaction system was stirred at -78°C for 30 min.
  • 10 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL ⁇ 3), the combined organic phases were washed with saturated sodium chloride (10 mL), the combined organic phases were dried, and concentrated to obtain a white solid 54-1, which was dissolved in anhydrous tetrahydrofuran (3 mL), and 3 M aqueous hydrochloric acid solution (1 ml) was slowly added dropwise.
  • Step 1 Dissolve the raw material 1-bromo-2-fluoro-4-[(trifluoromethyl)oxy]benzene (97 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH- Cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1- ⁇ 2-fluoro-4-[(trifluoromethyl)oxy]phenyl ⁇ hexan-1-ol 62-1 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h
  • Step 1 Dissolve the raw material 1-bromo-2-fluoro-3-methoxybenzene (77 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • reaction system was stirred at -78 ° C for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluoro-3-methoxyphenyl)hexan-1-ol 63-1 and (5R)-5-[(3aS,5aR,5 The crude product (50 mg, 0.1 mmol, 1.0 eq) of 64-1 (2aR, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a
  • Step 1 Dissolve the raw material 1-bromo-2-fluoro-4-methoxybenzene (76 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78°C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and stir at the same temperature for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluoro-4-methoxyphenyl)hexan-1-ol 67-1 and (5R)-5-[(3aS,5aR,5bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b
  • Step 1 Dissolve the raw material 2-bromo-1,3,5-trifluorobenzene (79 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2,4,6-trifluorophenyl)hexan-1-ol 69-1 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 1-bromo-2,3-dimethoxybenzene (81.4 mg, 0.38 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.13 mL, 0.32 mmol, 3.0 eq), and stir at the same temperature for 30 min.
  • Step 2 The reactant (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadienyl[7,8]phenanthro[1,2-d][1,3]dioxy-8-yl)-1-(2,3-dimethoxyphenyl)hexan-1-ol 70-1 (32 mg, 0.053 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and dilute hydrochloric acid (1 mL, 3 mol/L) was added.
  • the reaction was stopped when the raw materials were consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 10 mL). The ethyl a
  • the fourth step is to mix the mixture (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethylhexahydro-
  • Step 8 Dissolve the raw material 1-bromo-2-methoxybenzene (173 mg, 0.9 mmol, 4 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (1.8 mL, 0.28 mmol, 3 eq), and stir at the same temperature for 30 min.
  • Step 9 White solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7- ⁇ [(2-methylpropan-2-yl)diphenylsilyl]oxy ⁇ hexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-methoxyphenyl)hexan-1-ol 72-8 and (5R)-5-[(1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl -7- ⁇ [(2-methylpropane-2-yl)diphenylsilyl]oxy ⁇ -2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(
  • Step 1 Dissolve the raw material 4-bromo-pyridine (118.50 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78°C, add n-butyl lithium (2.5 mL, 0.45 mmol, 3.0 eq), and stir at the same temperature for 30 min.
  • Step 2 The reactant (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadienyl[7,8]phenanthrene[1,2-d][1,3]dioxetyl)-1-(pyridin-4-yl)hexan-1-ol 76-1 (24 mg, 0.044 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 4-bromo-2,2-difluorobenzo[d][1,3]diazole (177.8 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (4 mL), cool the system to -78 °C, add n-butyl lithium (0.26 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • reaction system was stirred at -78°C for 30 min.
  • 20 mL of water was added to the reaction system, extracted with ethyl acetate (20 mL ⁇ 2), the combined organic phases were washed with saturated sodium chloride (30 mL), the combined organic phases were dried, and concentrated to obtain a crude product.
  • Step 2 The reactant (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadien[7,8]phenanthrene[1,2-d][1,3]dioxol-8-yl)-1-(2,2-difluorobenzo[d][1,3]trioxol-4-yl)hexan-1-ol 77-1 (80 mg, 0.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 3-bromo-2-methoxypyridine (141 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). The mixture was cooled to -78°C, and n-butyllithium (0.26 mL, 0.64 mmol, 3.0 eq) was added, and the temperature was maintained with stirring for 30 min.
  • Step 2 The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluoropyridin-3-yl)hexan-1-ol 80-1 (50 mg, 0.086 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 3-bromo-2-methoxypyridine (141 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.26 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aS,12bS)-11,11,12a-trifluoro-2,2,5a,7a-tetramethyl- 4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-methoxypyridin-3-yl)hexan-1-ol 81-1 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetrahydro- The crude product of methyl-4,5,5a,
  • Step 1 Dissolve the raw material 1-bromo-3-[(trifluoromethyl)oxy]benzene (126.7 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1- ⁇ 3-[(trifluoromethyl)oxy]phenyl ⁇ hexan-1-ol 84-1 and (5R)-5-[(3aS,5aR,5bR The crude product of 88-1 (70 mg, 0.11 mmol, 1.0 eq) (7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,
  • Step 1 Dissolve the raw material 1,3-thiazolinone (44.7 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7, 8-d][1,3]dioxolan-8-yl]-1-(1,3-thiazolyl-2-yl)hexan-1-ol 89-1 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10
  • Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 10 mL).
  • the EA layers were combined and washed with saturated brine (3 ⁇ 10 mL).
  • the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product.
  • Step 1 Dissolve the raw material 2-bromopyridine (118.50 mg, 0.750 mmol) in anhydrous tetrahydrofuran (5 mL), cool the system to -78 °C, add n-butyl lithium (0.257 mL, 0.643 mmol), and maintain the temperature and stir for 30 min.
  • Step 2 The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(pyridin-2-yl)hexan-1-ol 91-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 The reactant (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadienyl[7,8]phenanthrene[1,2-d][1,3]dihydroxy-8-yl)hexanoic acid methyl ester I-13 (400 mg, 0.805 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL), and dilute hydrochloric acid (3 mL, 3 mol/L) was added. The reaction system was stirred at room temperature for 1 h.
  • Step 2 At room temperature, compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 93-1 (300 mg, 0.66 mmol, 1.0 eq) was dissolved in tetrahydrofuran (15 mL), isopropyl titanate (938 mg, 3.30 mmol, 5.0 eq) was added under nitrogen protection, and ethyl magnesium bromide (1M in THF, 6.6 mL, 6.60 mmol, 10 eq) was slowly added dropwise, maintaining the temperature at 18-20°C.
  • Step 3 ((1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 93-2 (185 mg, 0.41 mmol, 1.0 eq) was dissolved in dichloromethane (4 mL) and tetrahydrofuran (2 mL) at room temperature, and triethylamine (41 mg, 1.23 mmol, 3 eq) was added.
  • Step 4 Benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-5-(hydroxycyclopropyl)pent-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 93-3 (20 mg, 0.036 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) at room temperature, potassium carbonate (25 mg, 0.18 mmol, 5.0 eq) and water (0.5 mL) were added at room temperature, and then stirred at room temperature for 4 hours.
  • the reactant (4R)-4-((3S, 8S, 9S, 10R, 13R, 14S, 17R)-3-acetoxy-4-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)pentanoic acid methyl ester 47-3 (4.5 g, 10.08 mmol, 1.0 eq) was dissolved in methanol (50 mL), potassium carbonate (6.95 g, 50.38 mmol, 5.0 eq) was added, and the reaction system was stirred at room temperature for 30 min.
  • the resulting mixture was stirred in N 2 at 25°C for 36 h.
  • the raw material was basically consumed, and saturated sodium sulfite was used for quenching.
  • Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 15 mL). The organic layers were combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • Step 4 Compound (R)-4-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR)-2,2,5a, 7a-tetramethyl-11-oxo-3a, 5,5a, 5b, 6,7,7a, 8,9,10,10a, 10b, 11,12b-tetrahydro-4H-cyclopentadienyl[7,8]phenanthrene[1,2-d][1,3]dioxacyclopent-8-yl)pentanoic acid methyl ester 95-3 (2.4 g, 5.1 mmol, 1.0 eq) was dissolved in methanol (100 mL) and ethyl acetate (50 mL), and then palladium carbon (1.2 g, 11 mmol, 2.2 eq) was added and the reaction system was replaced with a hydrogen atmosphere, and the reaction system was stirred at room temperature for 1 h.
  • Step 5 (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxyylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]pentanoic acid methyl ester 95-4 (400 mg, 0.87 mmol) was dissolved in diethylaminosulfur trifluoride (5 mL), and the resulting mixture was stirred in the reaction solution at 80 °C for 1 h.
  • the reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added to dilute the reaction system. Ice water was carefully added dropwise to quench the reaction.
  • the organic phases were collected by layers, and the aqueous layer was extracted with dichloromethane (3 ⁇ 30 mL). The combined organic phases were washed with saturated brine (40 mL), filtered and concentrated to obtain a crude product.
  • Step 6 ((4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]pentanoic acid methyl ester 95-5 and (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b
  • Step 7 (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[ 1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]pentanoic acid 95-6 and (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,1 A mixture of 2,12a,12b-tetradecahydr
  • Step 8 The raw materials (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-N-(2-fluorophenyl)pentanamide 95-7 and (4R)-4-[(3aS,5 A mixture of 2-(4-(2-fluorophenyl)pentanamide 96-3 (30 mg, 0.053 mmol, 1.0 eq) and 1-(4-(2-fluorophenyl)pentanamide) was dissolved in DMF (2 mL), and the
  • the reactant acetate-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1- ⁇ 2-[(trifluoromethyl)oxy]phenyl ⁇ hexyl ester 97-1 (190 mg, 0.28 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (1.5 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • the third step is to dissolve acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1- ⁇ 2-[(trifluoromethyl)oxy]phenyl ⁇ hexyl ester 97-2 (180 mg, 0.28 mmol, 1.0 eq) in dichloromethane (10 mL), and the reaction system is placed in an ice-water bath.
  • Acetic anhydride (0.04 mL, 0.34 mmol, 1.2 eq), 4-dimethylaminopyridine (6.97 mg, 0.06 mmol, 0.2 eq) and triethylamine (0.12 mL, 1 mmol, 3.0 eq) are added to the reaction system in sequence, and the reaction system is stirred at room temperature for 1 hour.
  • Step 4 Compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1- ⁇ 2-[(trifluoromethyl)oxy]phenyl ⁇ hexyl acetate 97-3 (140 mg, 0.2 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and Dess-Martin reagent (176 g, 0.4 mmol, 2 eq) was added, and the resulting mixture was stirred in the reaction solution under N 2 at 25° C.
  • Step 5 The reactant acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethyl-6-oxyylidene hexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1- ⁇ 2-[(trifluoromethyl)oxy]phenyl ⁇ hexyl ester 97-4 (50 mg, 0.08 mmol, 1.0 eq) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), potassium carbonate (41.
  • Step 1 Dissolve the raw material 2-bromo-1,5-difluoro-3-methoxybenzene (123 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (0.18 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • Step 2 The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(4,6-difluoro-2-methoxyphenyl)hexan-1-ol (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 1,3-oxazacyclopentane (51.8 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (0.25 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes.
  • Step 2 (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3a H-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(1,3-oxazacyclopenta-2-yl)hexan-1-ol 99-1 (70 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 4-bromo-1-fluorobenzene (65.7 mg, 0.35 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.128 mL, 0.3 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolane -8-yl]-1-(4-fluorophenyl)hexan-1-ol 100-1 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,
  • Step 1 Dissolve the raw material 1-bromo-2,4-difluorobenzene (101 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.18 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2,4-difluorophenyl)hexan-1-ol 102-1 (70 mg, 0.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.
  • Step 1 Dissolve the raw material 3-bromo-6-fluoro-2-methoxypyridine (123.61 mg, 0.6 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.2 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(6-fluoro-2-methoxypyridin-3-yl)hexan-1-ol 108-1 and (5R)-5-((3aS,5aR, A mixture of (5bR, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetramethyl-3a, 5,5a,5b,
  • Step 1 Dissolve 2-bromo-5-chloroanisole (116.28 mg, 0.525 mmol, 3.5 eq) in tetrahydrofuran (5 mL), cool the reaction system to -78 ° C, add n-butyl lithium (0.180 mL, 0.450 mmol, 2.5 mol/L, 3.0 eq) to the reaction system, maintain -78 ° C, stir for 30 min, and then add (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,1 2,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]
  • Step 2 Resuspend the raw materials (5R)-1-(4-chloro-2-methoxyphenyl)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexan-1-ol 112-1 and (5R)-1-(4-chloro-2-methoxyphenyl)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,
  • Step 1 Dissolve the raw material 2-bromo-1,3-dimethoxybenzene (129.91 mg, 0.6 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.2 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • the reaction system was stirred at -78 ° C for 30 min.
  • 10 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL ⁇ 3), and the organic phases were combined and saturated with sodium chloride (10 mL) The organic phases were washed, combined, dried, and concentrated to give a crude product.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2,6-dimethoxyphenyl)hexan-1-ol 116-1 and (5R)-1-(2,6-dimethoxyphenyl)hexan-1-ol 116-1.
  • Step 1 (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluoro-6 -methoxyphenyl)hexan-1-ol 49-1 (200 mg, 0.3 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), the reaction system was placed in an ice-water bath and cooled to about 5 ° C, trifluoroacetic anhydride (212 mL, 1 mmol, 3.0 eq),
  • Step 2 Reaction of 2,2,2-trifluoroacetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b -Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2-fluoro-6-methoxyphenyl)hexyl ester 124-1 (200 mg, 0.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL), diluted hydrochloric acid (2 mL, 3 mol/L) was added, and the reaction system was stirred
  • Step 3 Dissolve 2,2,2-trifluoroacetic acid-(5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluoro-6-methoxyphenyl)hexyl ester 124-2 (80 mg, 0.12 mmol, 1.0 eq) in dichloromethane (10 mL), place the reaction system in an ice-water bath, and add acetic anhydride (25 mg, 0.25 mmol, 2 eq), 4-dimethylaminopyridine (3 mg, 0.003 mmol, 0.2 eq) and triethylamine (38 mg, 0.37 mmol, 3.0 eq) to the reaction system in sequence, and stir the reaction
  • Step 4 Compound acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-6-methoxyphenyl)-6-[(trifluoroacetyl)oxy]hexan-2-yl]-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 124-3 (65 mg, 0.1 mmol, 1 eq) was dissolved in dichloromethane (5 mL).
  • Step 5 The reactant acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-6-methoxyphenyl)-6-[(trifluoroacetyl)oxy]hex-2-yl]-9a,11a-dimethyl-6-oxyylidene hexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 124-4 (40 mg, 0.06 mmol, 1.0 eq) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), potassium carbonate (41.
  • Step 1 Dissolve the raw material 3-bromo-4-fluoro-2-methoxypyridine (108 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.18 mL, 0.45 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH- Cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(4-fluoro-2-methoxypyridin-3-yl)hexan-1-ol 126-1 (70 mg, 0.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1.5 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h
  • Tetrahydrofuran (30 mL) is added to the reaction solution, followed by water (0.66 mL), 15% NaOH (0.66 mL) and water (2 mL), filter through diatomaceous earth, rinse with ethyl acetate (30 mL), and concentrate the filtrate to obtain a crude product. After separation by chromatography column (12 g, 0-30% ethyl acetate/petroleum ether, 30 mL/min), a colorless oil (5,8-dioxyaspirin[3.4]octan-2-yl)methanol 129-B (1.2 g, purity: 90%, yield 86%) was obtained.
  • Step 3 Dissolve methyltriphenylphosphonium bromide (2.51 g, 7.04 mmol, 2 eq) in tetrahydrofuran (15 mL) at room temperature, cool to 0°C in an ice bath, slowly dropwise add NaHMDS (1 M in THF, 7.0 mL, 7.0 mmol, 2 eq), and stir for 30 minutes. Then dropwise add a solution of the raw material 5,8-dioxaspiro[3.4]octane-2-carboxaldehyde 129-C (500 mg, 3.52 mmol, 1.0 eq) in tetrahydrofuran (5 mL). The mixture was stirred in an ice bath for 1 hour.
  • Step 4 (3S, 8S, 9S, 10R, 13S, 14S, 17R)-10,13-dimethyl-17-((S)-1-oxopropan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentaphenanthrene-3-yl acetate I-3 (1.0 g, 2.68 mmol) was dissolved in ethyl acetate (20 mL) at room temperature, 10% Pd/C (700 mg) and acetic acid (0.5 mL) were added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 40 hours. The reaction was monitored by HNMR.
  • reaction solution was diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • Step 5 At room temperature, methyl triphenylphosphonium bromide (357.22 mg, 2.30 mmol, 2 eq) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C in an ice bath, and NaHMDS (1M in THF, 2.3 mL, 2.30 mmol, 2 eq) was slowly added dropwise, and stirred for 30 min.
  • reaction solution was quenched by adding water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • Step 6 (3S, 8R, 9S, 10S, 13R, 14S, 17R)-17-((R)-but-3-ene-2-yl)-10,13-dimethylhexahydro-1H-cyclopentaphenanthrene-3-yl acetate 129-2 (200 mg, 0.537 mmol, 1 eq), 2-vinyl-5,8-dioxaspiro[3.4]octane 129-D (376 mg, 2.68 mmol, 5 eq) and Grubbs II (228 mg, 0.269 mmol, 0.5 eq) were dissolved in dichloromethane (10 mL) at room temperature, sealed and heated at 50°C for 10 hours.
  • Step 7 At room temperature, (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R)-17-((R, E)-4-(5,8-dioxyaspirin [3.4] oct-2-yl) but-3-en-2-yl)-10,13-dimethylhexahydro-1H-cyclopentaphenanthrene-3-yl acetate 129-3 (50 mg, 0.103 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (43 mg, 1.03 mmol, 10.0 eq) and water (1 mL) were added at room temperature, followed by stirring at room temperature for 1 hour.
  • Step 8 (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R)-17-((R, E)-4-(5,8-dioxyaspirin[3.4]oct-2-yl)but-3-en-2-yl)-10,13-dimethylhexahydro-1H-cyclopentaphenanthrene-3-ol 129-4 (40 mg, 0.090 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, 10% Pd/C (40 mg) was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 4 hours. The reaction was monitored by HNMR.
  • Step 9 The reactant (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R)-17-((R)-4-(5,8-dioxyaspyro[3.4]oct-2-yl)but-2-yl)-10,13-dimethylhexahydro-1H-cyclopentadienylphenanthren-3-ol 129-5 (35 mg, 0.079 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and dilute hydrochloric acid (1 mL, 3 mol/L) was added. The reaction system was stirred at room temperature for 2 hours, heated to 40°C and stirred for 1 hour.
  • Step 1 Dissolve 3-((R)-3-((3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R)-3-hydroxy-10,13-dimethylhexahydro-1H-cyclopentadienylphenanthren-17-yl)butyl)cyclobutane-1-one (8 mg, 0.020 mmol, 1.0 eq) in methanol (1 mL) at room temperature. The mixture was cooled to 0°C in an ice bath and sodium borohydride (22.66 mg, 0.599 mmol, 3.0 eq) was added. The mixture was reacted at room temperature for 1 hour.
  • the white solid (20R)-21-[(3-hydroxycyclobutyl)methyl]-20-methyl-5 ⁇ -pregnane-3 ⁇ -ol 130 (2.63 mg, purity: 84%, yield 29.44%) was obtained by chromatography column separation (4 g, 0-20% ethyl acetate/petroleum ether, 20 mL/min).
  • Embodiment 132&133
  • Compound 133 or 132 (1R, 3aR, 5aR, 6R, 7S, 9aR, 9bR, 11aR)-4-fluoro-1-[(2R, 6S)-6-(4-fluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethyl-2,3,3a, 5,5a, 6,7,8,9,9a,9b, 10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and Compound 132 or 133: Preparation of (1R, 3aR, 5aR, 6R, 7S, 9aR, 9bR, 11aR)-4-fluoro-1-[(2R, 6R)-6-(4-fluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethyl-2,3,3a, 5,5a, 6,7,8,
  • Embodiment 134
  • Embodiment 135 is a diagrammatic representation of Embodiment 135.
  • Embodiment 136 is a diagrammatic representation of Embodiment 136.
  • reaction solution was diluted with methanol (10 mL), filtered through diatomaceous earth, and the organic phase was concentrated.
  • the crude product was separated by chromatography column (4 g, 0-10% methanol/dichloromethane, 25 mL/min) to give a white solid (20R)-20-[2-(3-aminocyclobutyl)ethyl]-5 ⁇ -pregnan-3 ⁇ -ol 136 (4.80 mg, purity: 95.47%, yield: 23.71%).
  • Compound 140 or 141 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R, 6S)-6-(4-fluoro-2-methoxyphenyl)- 6-Hydroxyhexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and
  • Embodiment 145&146
  • Step 1 Dissolve the raw material 3-bromo-2,4-difluoropyridine (145 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.25 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • Step 2 (5R)-1-(2,4-difluoropyridin-3-yl)-5-(((3AS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10a,12,12a,12b-tetradecahydro-4H-cyclopentyl[7,2]phenanthro[ 1,3]dioxy-8-ol)hexan-1-ol 145-1 and (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b
  • Step 1 Dissolve the raw material 3-bromo-2,6-difluoropyridine (102 mg, 0.52 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.18 mL, 0.45 mmol, 3.0 eq), and stir at the same temperature for 30 min.
  • a mixture of hexanal II 70 mg, 0.15 mmol, 1.0 eq
  • tetrahydrofuran 2 mL
  • Step 2 (5R)-1-(2,6-difluoropyridin-3-yl)-5-(((3AS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10a,12,12a,12b-tetradecahydro-4H-cyclopentyl[7,2]phenanthro[ 1,3]dihydroxy-8-ol)hexan-1-ol 147-1 and (5R)-5-[(3As,5Ar,5Bs,7Ar,8R,10As,10Bs,12Ar,12Br)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b
  • Embodiment 149&150
  • Compound 150 Preparation of (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluoro-4-methoxypyridin-3-yl)-6-hydroxyhexan-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol
  • Step 1 3-Bromo-4-fluoro-2-methoxypyridine (139 mg, 0.68 mmol) was dissolved in THF (3 mL), and after replacing nitrogen three times, n-BuLi (37 mg, 0.58 mmol) was slowly added dropwise at -78°C and stirred for 0.5 hours.
  • Step 2 The reactants (5R)-5-((3aS, 5aR, 5bR, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-4H-cyclopentyl[7,8]phenanthren[1,2-d][1,3]dihydroxy-8-yl)-1-(2-fluoro-4-methoxypyridin-3-yl)hexan-1-ol 149-1 and (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetrade
  • Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 10 mL).
  • the EA layers were combined and washed with saturated brine (3 ⁇ 10 mL).
  • the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product.
  • Embodiment 151
  • the reaction system was stirred at -78°C for 30 min.
  • the combined organic phases were washed with saturated sodium chloride (10 mL), the combined organic phases were dried, and concentrated to obtain a white solid 151-1.
  • the crude product 151-1 was dissolved in tetrahydrofuran (3 mL), and 3 M hydrochloric acid aqueous solution (1 mL) was slowly added dropwise.
  • Embodiment 152
  • Step 1 Dissolve the raw material 5-bromo-4-methoxypyrimidine (142 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyl lithium (0.25 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 min.
  • reaction system was stirred at -78°C for 30 min.
  • Embodiment 154&155
  • Step 1 3-Bromo-2-methoxypyridine (60 mg, 0.32 mmol) was dissolved in THF (3 mL). After replacing nitrogen three times, n-butyl lithium (0.11 mL, 0.264 mmol) was slowly added dropwise at -78 °C and stirred at -78 °C for 0.5 hours.
  • Step 2 Reaction of (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopentadiene[1',2':1,2] Phenanthrene[7,8-d][1,3]dihydroxy-8-yl]-1-(3-methoxypyrazine-2-yl)hexan-1-ol (40 mg, 0.069 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol/L) was added, and the reaction system was stirred at room temperature for 1 h.

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Abstract

L'invention concerne un composé stéroïde ayant une structure représentée par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation. Le composé a une activité inhibitrice de la voie de SREBP, et peut être utilisé pour prévenir et/ou traiter des maladies telles que l'obésité, l'hyperlipidémie, la stéatose hépatique, le diabète, l'athérosclérose, les maladies cardiovasculaires et cérébrovasculaires, le cancer du foie et les lésions cutanées.
PCT/CN2023/109660 2023-07-27 2023-07-27 Composé stéroïde, son procédé de préparation et son utilisation Pending WO2025020191A1 (fr)

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PCT/CN2024/107804 WO2025021193A1 (fr) 2023-07-27 2024-07-26 Composé stéroïde, son procédé de préparation et son utilisation
TW113127857A TW202506100A (zh) 2023-07-27 2024-07-26 甾類化合物、其製備方法和應用

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