CD ring side chain-substituted vitamin d derivative

Abstract

To provide a new vitamin D derivative that is useful for treating or preventing psoriasis or cancer.SOLUTION: Examples of vitamin D derivatives disclosed herein are compounds having structures illustrated below.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to CD ring side chain substituted vitamin D derivatives and pharmaceutical compositions containing the same. [Background technology]

[0002] Active vitamin D3 (1,25-dihydroxyvitamin D3) is known to have many physiological activities, including calcium metabolism regulation, tumor cell proliferation inhibition, differentiation induction, and immunomodulation. The present inventors have synthesized 2-substituted vitamin derivatives (MART-10 and MART-11) and demonstrated that they have a high ability to induce differentiation of human leukemia cell HL-60 (Patent Document 1, Non-Patent Document 1). Note that MART-10 and MART-11 are not included in the compounds of the present invention. [ka]

[0003] The inventors synthesized novel vitamin D derivatives in which halogen atoms were introduced into the CD ring side chains of MART-10 and MART-11, and discovered that these derivatives have therapeutic effects on psoriasis in a psoriasis-induced mouse model, as well as inhibitory effects on cancer cell proliferation in human breast cancer (MCF-7) cells. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2004 / 067504 [Non-patent literature]

[0005] [Non-Patent Document 1] Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.; Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.; Kittaka, A. HL-60 cells. J. Org. Chem. 2003, 68, 7407-7415. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a novel vitamin D derivative that is useful for treating or preventing psoriasis or cancer. [Means for solving the problem]

[0007] The above-mentioned problems can be solved by the present invention as follows: [1] General formula (I): [ka] (In the formula, X represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, Y is a linear or branched alkyl group having 1 to 12 carbon atoms, which is substituted with at least one halogen atom and may be substituted with a hydroxyl group. A compound represented by the formula: [2] X is a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 1 to 5 carbon atoms which may be substituted with a hydroxyl group, The compound of [1], wherein Y is a linear or branched alkyl group having 3 to 10 carbon atoms, which is substituted with at least one halogen atom and may be substituted with a hydroxyl group. [3] X is a linear or branched alkyl group having 1 to 4 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 1 to 4 carbon atoms which may be substituted with a hydroxyl group, The compound of [1], wherein Y is a linear or branched alkyl group having 5 to 8 carbon atoms, which is substituted with at least one halogen atom and which may be substituted with a hydroxyl group. [4] X is a linear or branched alkyl group having 3 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 3 carbon atoms which may be substituted with a hydroxyl group, The compound of [1], wherein Y is a 4-hydroxyl-4-methylpentyl group substituted with at least one halogen atom. [5] Y is [ka] (wherein Z is a hydrogen atom or a hydroxyl group, R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom or a halogen atom; R5 and R6 are each independently a methyl group or an ethyl group optionally substituted with 1 to 3 halogen atoms. A compound of any one of [1] to [4], wherein the compound is a group represented by the formula: [6] A pharmaceutical composition comprising any one of the compounds of [1] to [5] as an active ingredient. [7] A pharmaceutical composition for treating or preventing psoriasis, comprising any one of the compounds according to [1] to [5] as an active ingredient. [8] A pharmaceutical composition for treating or preventing cancer, comprising any one of the compounds according to [1] to [5] as an active ingredient. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a novel vitamin D derivative that is useful for treating or preventing psoriasis or cancer. [Brief explanation of the drawings]

[0009] [Figure 1] This graph shows the effect of topical application of a vitamin D derivative on imiquimod (IMQ)-induced psoriasis model mice. The graph shows the ear thickness after treatment for 3 days with dropwise application of IMQ alone, or IMQ plus a vitamin D derivative (calcipotriol or MART10-F2) in ethanol at various concentrations. [Figure 2] 1 is a graph showing a comparison of cell numbers after 3 days of culture in the presence of 100 nmol / L of various derivatives. [Figure 3] 1 is a graph showing a comparison of cell numbers after 7 days of culture in the presence of various derivatives at 1, 10, and 100 nmol / L. [Figure 4] 1 is a graph showing the effect of 24F2-MART-10 in inhibiting the proliferation of cancer cells as a function of time in terms of the area of ​​three-dimensionally cultured cells. DETAILED DESCRIPTION OF THE INVENTION

[0010] In the definition of group X in general formula (I) herein, "a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group" means a linear or branched alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted with a hydroxyl group. The number of carbon atoms in the alkyl group is preferably 1 to 5, more preferably 1 to 4, and even more preferably 3. Examples of the unsubstituted linear or branched alkyl group having 1 to 8 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, as well as linear and branched pentyl, hexyl, heptyl, and octyl groups. Furthermore, the linear or branched alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group refers to the aforementioned unsubstituted linear or branched alkyl group having 1 to 8 carbon atoms in which any one or more hydrogen atoms have been substituted with a hydroxyl group, and examples thereof include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group, and a hydroxyoctyl group.

[0011] In the definition of group X in general formula (I) herein, "a straight-chain or branched alkenyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group" means a straight-chain or branched alkenyl group having 1 to 8 carbon atoms which is unsubstituted or substituted with a hydroxyl group. The number of carbon atoms in the alkenyl group is preferably 1 to 5, more preferably 1 to 4, and even more preferably 3. Examples of the unsubstituted straight-chain or branched alkenyl group having 1 to 8 carbon atoms include a methylene group, a vinyl group, an allyl group, an n-butenyl group, a sec-butenyl group, a pentenyl group, a heptenyl group, and an octenyl group. Furthermore, the linear or branched alkenyl group having 1 to 8 carbon atoms substituted with a hydroxyl group refers to the aforementioned unsubstituted linear or branched alkenyl group having 1 to 8 carbon atoms in which any one or more hydrogen atoms have been substituted with a hydroxyl group, and examples thereof include a hydroxymethylene group, a hydroxyallyl group, a hydroxybutenyl group, a hydroxypentenyl group, a hydroxyheptenyl group, and a hydroxyoctenyl group.

[0012] In the present specification, the configuration of the group X at the 2-position of general formula (I) may be either R or S. In the present specification, the compound in which the configuration of the group X at the 2-position of general formula (I) is S is designated as MART-10, and the compound in which the configuration is R is designated as MART-11.

[0013] In the definition of group Y in general formula (I) herein, "a linear or branched alkyl group having 1 to 12 carbon atoms, which is substituted with at least one halogen atom and may be substituted with a hydroxyl group" means an unsubstituted or hydroxyl-substituted linear or branched alkyl group having 1 to 12 carbon atoms, in which any one or more hydrogen atoms of the alkyl group have been substituted with a halogen atom. The number of carbon atoms in the alkyl group is preferably 3 to 10, more preferably 5 to 8, and even more preferably 6 or 8. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine, with fluorine being preferred.

[0014] The group Y is particularly preferably [ka] (wherein Z is a hydrogen atom or a hydroxyl group, R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom or a halogen atom; R5 and R6 are each independently a methyl group or an ethyl group optionally substituted with 1 to 3 halogen atoms. It is a group represented by the formula:

[0015] Examples of the halogen atom substitution in the CD ring side chain include, but are not limited to, a 26,27-hexahalide in which a total of six halogen atoms are introduced to the carbon atoms at the 26th and 27th positions (Production Example 1 described below), a 26,27-tetrahalide in which two halogen atoms are introduced to each of the carbon atoms at the 26th and 27th positions, for a total of four halogen atoms (Production Example 8), a 26,27-dihalide in which one halogen atom is introduced to each of the carbon atoms at the 26th and 27th positions, for a total of two halogen atoms (Production Example 9), a 24-dihalide in which two halogen atoms are introduced to the carbon atom at the 24th position (Production Example 2), Examples include 24R-monohalide and 24S-monohalide in which one halogen atom has been introduced at the carbon atom at position 24 (Production Example 3), 23-dihalide in which two halogen atoms have been introduced at the carbon atom at position 23 (Production Example 4), 23R-monohalide and 23S-monohalide in which one halogen atom has been introduced at the carbon atom at position 23 (Production Example 5), 22-dihalide in which two halogen atoms have been introduced at the carbon atom at position 22 (Production Example 7), and 22R-monohalide and 22S-monohalide in which one halogen atom has been introduced at the carbon atom at position 22 (Production Example 6).

[0016] The pharmaceutical composition of the present invention can be administered as a medicine to a subject (e.g., an animal, preferably a mammal, particularly a human) in an effective amount as the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier or diluent, or can be provided in the form of a food or drink.

[0017] When the pharmaceutical composition of the present invention is provided as a medicine, it can be administered as an oral or parenteral preparation, preferably an oral preparation. Examples of the oral preparation include liquid preparations such as suspensions, emulsions, syrups, and extracts, and solid preparations such as tablets, capsules, powders, fine granules, and granules. Examples of the parenteral preparation include injections.

[0018] Examples of pharmaceutically acceptable carriers or diluents include excipients, disintegrants, binders, flavoring agents, effervescent agents, sweeteners, flavoring agents, lubricants, buffers, antioxidants, surfactants, and fluidizing agents.

[0019] The dosage of the pharmaceutical composition of the present invention can be appropriately selected depending on, for example, the target disease, the patient's condition, body weight, age, sex, route of administration, etc., but generally the lower limit of the dosage can be selected from the range of 0.001 μg to 0.1 μg per day for an adult, and the upper limit of the dosage can be selected from the range of 100 μg to 10,000 μg per day for an adult, and the composition can be administered in 1 to 3 divided doses per day.

[0020] The pharmaceutical composition of the present invention can be used to treat or prevent psoriasis or cancer. [Example]

[0021] The present invention will be specifically described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0022] General Procedures 1 H and 13 C spectra were recorded on JEOL AL-400 NMR (400 MHz) and ECP-600 NMR (600 MHz) spectrometers. 1 The H NMR spectra were measured using (CH3)4Si (δ 0.00 ppm) as the internal standard. 13C NMR spectra were referenced to the deuterated solvent (δ 77.0 ppm for CDCl3 and 49.3 ppm for CD3OD). IR spectra were recorded on a JASCO FT-IR-800 Fourier transform infrared spectrophotometer. High-resolution mass spectra were obtained on a SHIMADZU LCMS-IT-TOF mass spectrometer using electrospray ionization (ESI or APCI). Optical rotations were measured on a JASCO DIP-370 digital polarimeter. Column chromatography was performed using silica gel 60N (Kanto Chemical Co., Ltd., 40-50 μm) or silica gel 60 (Merck, 0.040-0.063 mm). Preparative thin-layer chromatography was performed using silica gel 60F. 254 (Merck, 0.5 mm). Unless otherwise stated, all experiments were carried out under anhydrous conditions and an argon atmosphere.

[0023] Production Example 1: Synthesis of 26,27-hexafluoro compound [ka]

[0024] Synthesis of 2-{(1R,3aS,7aR,E)-7a-Methyl-1-[(2R)-7,7,7-trifluoro-6-(methoxymethoxy)-6-(trifluoromethyl)heptan-2-yl]octahydro-4H-inden-4-ylidene}ethan-1-ol (1)

[0025] The following formula: [ka] Compound 1 represented by [the formula] was synthesized by the method described in Kawagoe, F.; Mendoza, A.; Hayata, Y.; Asano, L.; Kotake, K.; Mototani, S.; Kawamura, S.; Kurosaki, S.; Akagi, Y.; Takemoto, Y.; Nagasawa, K.; Nakagawa, H.; Uesugi, M.; Kittaka, A. Discovery of a vitamin D receptor-silent vitamin D derivative that impairs sterol regulatory element-binding protein in vivo. J. Med. Chem. 2021, 64 (9), 5689-5709.

[0026] Synthesis of 2-[(2-{(1R,3aS,7aR,E)-7a-Methyl-1-[(2R)-7,7,7-trifluoro-6-(methoxymethoxy)-6-(trifluoromethyl)heptan-2-yl]octahydro-4H-inden-4-ylidene}ethyl)thio]benzo[d]thiazole (2) [Chemical formula]

[0027] To a solution of 2-mercaptobenzothiazole (25.5 mg, 0.15 mmol), Ph3P (31.3 mg, 0.119 mmol), and CD ring 1 (23.9 mg, 0.05 mmol) in CHCl (2 mL) was added diisopropyl azodicarboxylate (55 μL, 1.9 mol / L toluene solution, 0.10 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. The reaction was quenched with HO at 0 °C, and the mixture was extracted three times with CHCl. ​​The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 6:1) and repurified on a preparative silica gel TLC plate (hexane:EtOAc = 4:1) to give compound 2 (24.7 mg, 78%) as a colorless oil.

[0028] Compound 2: [α] D 27 +79.0 (c 1.90, CHCl3); IR (neat) 1459, 1432, 1284, 1221, 1152, 993, 763 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.49 (s, 3H), 0.93 (d, J = 7.2 Hz, 3H), 1.04-1.10 (m, 1H), 1.22-1.72 (m, 12H), 1.82-2.03 (m, 5H), 2.76 (dd, J = 4.5, 12.3 Hz, 1H), 3.46 (s, 3H), 4.02 (dd, J = 7.5, 12.3 Hz, 1H), 4.14 (dd, J = 8.1, 12.3 Hz, 1H), 4.91 (dd, J = 6.6, 9.6 Hz, 2H), 5.21 (t, J = 8.1 Hz, 1H), 7.28-7.30 (m, 1H), 7.40-7.42 (m, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 11.7, 18.7, 19.0, 22.1, 23.5, 27.6, 28.8, 31.3, 35.9, 36.3, 40.3, 45.6, 55.7, 56.3, 56.6, 80.2 (sept, J = HRMS (ESI + ) calcd for C 29 H 38 NO2F6S2[M+H] + 610.2243, found 610.2214.

[0029] Synthesis of 2-[(2-{(1R,3aS,7aR,E)-7a-Methyl-1-[(2R)-7,7,7-trifluoro-6-(methoxymethoxy)-6-(trifluoromethyl)heptan-2-yl]octahydro-4H-inden-4-ylidene}ethyl)sulfonyl]benzo[d]thiazole (3) [ka]

[0030] Sulfide 2 (28.4 mg, 0.05 mmol) was dissolved in EtOH (5 mL), and the solution was added with 30% hydrogen peroxide (1 mL) and (NH)MoO. 24 4H2O (44.7 mg, 0.04 mmol) was added. After stirring at room temperature for 16 h, the mixture was poured into H2O and extracted three times with EtOAc. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified on a preparative silica gel TLC plate (hexane: EtOAc = 4:1) to give compound 3 (25.4 mg, 84%) as a white powder.

[0031] Compound 3: [α] D 27-11.4 (c 1.95, CHCl3); IR (neat) 1471, 1328, 1212, 1145, 1034, 763 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.26 (s, 3H), 0.86 (d, J = 6.6 Hz, 3H), 1.01 - 1.06 (m, 1H), 1.17 - 1.60 (m, 12H), 1.78 - 2.01 (m, 5H), 2.54 - 2.57 (m, 1H), 3.45 (s, 3H), 4.20 (dd, J = 6.9, 13.8 Hz, 1H), 4.42 (dd, J = 6.0, 13.8 Hz, 1H), 4.90 (dd, J = 7.2,9.0 Hz, 2H), 5.02 (t, J = 7.8 Hz, 1H), 7.57 - 7.69 (m, 1H), 7.62 - 7.65 (m, 1H), 8.00 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 7.2 Hz); 13 13C NMR (150 MHz, CDCl3) δ 11.5, 18.6, 18.9, 22.0, 23.1, 27.4, 28.7, 29.0, 35.7, 36.2, 39.9, 45.72, 53.9, 55.9, 56.2, 56.5, 80.2 (sept, J = 28.7 Hz), 92.8, 122.2, 123.0 (q, J = 287.3 Hz), 125.8, 127.6, 127.9, 136.9, 151.9, 152.8, 165.9; HRMS (ESI + ) calcd for C 29 H 37 NO4F6S2Na [M+Na] + 664.1960, found 664.1972.

[0032] Synthesis of (3R,5R)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-{3-[(tert-butyldimethylsilyl)oxy]propyl}cyclohexan-1-one (A ring)

[0033] The following formula: [ka] The compound represented by the formula (I) was synthesized by the method described in Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.; Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.; Kittaka, A. Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination: high potency in induction of differentiation on HL-60 cells. J. Org. Chem. 2003, 68, 7407-7415.

[0034] Synthesis of MART-10-F6 and MART-11-F6 [ka]

[0035] To a solution of sulfone 3 (133.2 mg, 0.21 mmol) in THF (1.5 mL) was added LiHMDS (260 μL, 1.0 mol / L THF solution, 0.26 mmol) at −78 °C. After stirring the mixture at the same temperature for 15 min, ring A (57.6 mg, 0.11 mmol) in THF (1.5 mL) was added, and the whole mixture was stirred at the same temperature for 90 min. After quenching the reaction with saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1 to 4:1) to give the protected coupling product as an inseparable mixture of isomers. To a solution of the above coupling compound in MeOH (20 mL) and CHCl2 (10 mL) was added methanesulfonic acid (0.6 mL) at 0 °C. The mixture was stirred overnight at room temperature in air. After quenching the reaction with room temperature H2O and saturated aqueous NaHCO3, the mixture was extracted three times with CHCl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative silica gel TLC (with EtOAc only) to give MART-10-F6 and MART-11-F6 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CH3CN:H2O = 9:1 solvent system to give MART-10-F6 (22.0 mg, 37%, 2 steps) and MART-11-F6 (19.0 mg, 32%, 2 steps), respectively, as white powders.

[0036] MART-10-F6: [α] D 27 +22.1 (c 0.08, EtOH); IR (neat) 3307, 1412, 1212 cm -1 ; 1H NMR (400 MHz, CD3OD) δ 0.62 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 1.09-2.18 (m, 26H), 2.58 (dd, J = 4.6, 13.2 Hz, 1H), 2.81-2.89 (m, 1H), 3.60-3.67 (m, 3H), 4.12-4.13 (m, 1H), 5.92 (d, J = 11.0 Hz, 1H), 6.29 (d, J = 11.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 12.7, 19.6, 20.0, 23.6, 24.5, 24.8, 29.0, 30.1, 31.6, 32.8, 36.6, 37.6, 37.8, 42.2, 46.6, 47.1, 50.3, 57.8, 58.1, 63.7, 69.2, 72.0, 77.6 (sept, J = 27.8 Hz), 117.7, 123.6, 125.4 (q, J = 286.0 Hz), 134.5, 142.1; HRMS (ESI - ) calcd for C 29 H 43 O4F6[M-H] - 569.3071, found 569.3063.

[0037] MART-11-F6: [α] D 27 +17.7 (c 0.06, EtOH); IR (neat) 3358, 1464, 1212 cm -1 ; 1H NMR (600 MHz, CD3OD) δ 0.62 (s, 3H), 1.01 (d, J = 6.0 Hz, 3H), 1.11-1.17 (m, 1H), 1.32-2.08 (m, 23H), 2.34-2.39 (m, 2H), 2.87 (dd, J = 4.2, 12.6 Hz, 1H), 3.03 (dd, J = 4.5, 13.2 Hz, 1H), 3.54 (td, J = 4.8, 9.6 Hz, 1H), 3.59-3.64 (m, 2H), 4.07-4.09 (m, 1H), 5.93 (d, J = 11.4 Hz, 1H), 6.21 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.7, 19.6, 20.1, 23.6, 24.8, 24.8, 29.0, 30.2, 31.5, 32.8, 37.6, 37.8, 38.8, 42.2, 45.1, 47.1, 50.4, 57.8, 58.1, 63.7, 69.2, 71.6, 77.6 (sept, J=28.7 Hz), 117.4, 123.3, 125.4 (q, J=284.4 Hz), 134.3, 142.2; HRMS (ESI - calcd for C 30 H 45 O6F6[M+HCOO] - 615.3126, found 615.6132.

[0038] "Manufacturing Example 2: Synthesis of 24F2 Body"

change

[0039] Synthesis of 2-(1R,3aS,7aR,E)-2-(1-{(2R)-5,5-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene)ethan-1-ol (4)

[0040] The following formula of the label: [Chemical formula] Compound 4 represented by the formula was synthesized by the method described in Kawagoe, F.; Mendoza, A.; Hayata, Y.; Asano, L.; Kotake, K.; Mototani, S.; Kawamura, S.; Kurosaki, S.; Akagi, Y.; Takemoto, Y.; Nagasawa, K.; Nakagawa, H.; Uesugi, M.; Kittaka, A. Discovery of a vitamin D receptor-silent vitamin D derivative that impairs sterol regulatory element-binding protein in vivo. J. Med. Chem. 2021, 64 (9), 5689-5709.

[0041] Compound 4: [α] D 27 +42.6 (c 0.68, CHCl3); IR (neat) 3330, 1458, 1384, 1198, 1162, 1054, 738 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.56 (s, 3H), 0.60 (q, J = 7.8 Hz, 6H), 0.93-0.96 (m, 12H), 1.24-2.05 (m, 23H), 2.61-2.64 (m, 1H), 4.17-4.23 (m, 2H), 5.22 (t, J = 6.9 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.6, 6.9, 11.8, 18.6, 22.1, 23.5, 24.3, 24.6, 26.8, 27.0 (t, J = 24.5 Hz), 27.4, 28.7, 35.7, 40.3, 45.3, HRMS (ESI + ) calcd for C 26 H 48 O2F2SiNa [M+Na] + 481.3284, found 481.3254.

[0042] Synthesis of 2-{[2-((1R,3aS,7aR,E)-1-{(2R)-5,5-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene)ethyl]sulfonyl}benzo[d]thiazole (6) [ka]

[0043] To a solution of 2-mercaptobenzothiazole (455.7 mg, 2.72 mmol), Ph3P (510.9 mg, 1.95 mmol), and CD ring 4 (497.7 mg, 1.08 mmol) in CHCl (15 mL) was added diisopropyl azodicarboxylate (918 μL, 1.9 mol / L toluene solution, 0.918 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After quenching the reaction with H2O at 0 °C, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane:EtOAc = 10:1) to give sulfide 5 (704.4 mg).

[0044] The sulfide 5 (704.4 mg) was dissolved in EtOH (25 mL), and the solution was added with 30% hydrogen peroxide (5 mL) and (NH)MoO. 24 4H2O (1.02 g, 0.83 mmol) was added. After stirring at room temperature for 3 h, the mixture was poured into H2O and extracted three times with EtOAc. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified on a preparative silica gel TLC plate (hexane: EtOAc = 20:1) to give compound 6 (96.5 mg, 14%, 2 steps) as a colorless oil.

[0045] Compound 6: [α] D 27 +34.8 (c 1.82, CHCl3); IR (neat) 1475, 1332, 1201, 1157, 1061, 1013, 759, 735 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.28 (s, 3H), 0.59 (q, J = 7.8 Hz, 6H), 0.86 (d, J = 6.0 Hz, 6H), 0.94 (t, J = 7.8 Hz, 9H), 1.17-2.00 (m, 24H), 2.55-2.57 (m, 1H), 4.21 (dd, J = 6.6, 14.4 Hz, 1H), 4.43 (dd, J = 9.0, 14.4 Hz, 1H), 5.00-5.03 (m, 1H), 7.57-7.65 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.5, 6.9, 11.6, 18.5, 22.0, 23.2, 24.3, 24.5, 26.8, 27.0 (t, J = 24.5 Hz), 27.3, 29.0, 35.6, 39.9, 45.7, 53.9, 56.0, 56.2, 75.6 (t, J = 28.0 Hz), 104.2, 122.2, 125.3 (t, J = 247.7 Hz), 125.3, 127.6, 127.9, 137.0, 152.0, 152.8, 166.0; HRMS (ESI + ) calcd for C 33 H 51 NO3F2SiS2Na [M+Na] + 662.2940, found 662.2954.

[0046] Synthesis of 24F2-MART-10 and 24F2-MART-11 [ka]

[0047] To a solution of sulfone 6 (96.5 mg, 0.154 mmol) in THF (2.0 mL) was added LiHMDS (173 μL, 1.0 mol / L THF solution, 0.173 mmol) at −78 °C. After stirring the mixture at the same temperature for 30 min, ring A (23.1 mg, 0.044 mmol) in THF (2.0 mL) was added, and the whole mixture was stirred at the same temperature for 70 min and at 0 °C for 5 min. After quenching the reaction with saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give the protected coupling product as an inseparable mixture of isomers.

[0048] To a solution of the above coupling compound in MeOH (3 mL) and CHCl (1 mL) was added 10-camphorsulfonic acid (94.0 mg, 0.405 mmol). The mixture was stirred in air at room temperature for 18 h. After quenching the reaction with room temperature H2O and saturated aqueous NaHCO3, the mixture was extracted three times with CHCl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative silica gel TLC (with EtOAc only) to give 24F2-MART-10 and 24F2-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CH3CN:H2O = 4:1 solvent system to give 24F2-MART-10 (5.4 mg, 28%, 2 steps) and 24F2-MART-11 (6.6 mg, 34%, 2 steps), respectively, as white powders.

[0049] 24F2-MART-10: [α] D 27 +47.0 (c 0.27, EtOH); IR (neat) 3358, 1451, 1376, 1176, 1021, 914 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.54 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H), 1.25-1.35 (m, 12H), 1.44-2.02 (m, 19H), 2.13-2.17 (m, 1H), 2.59 (dd, J = 4.5, 12.9 Hz, 1H), 2.79-2.86 (m, 2H), 3.63-3.71 (m, 3H), 4.09-4.09 (m, 1H), 5.82 (d, J = 10.8 Hz, 1H), 6.36 (d, J = 11.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 12.8, 19.3, 22.9, 24.1, 24.1, 24.3, 27.5, 28.0 (t, J = 24.5 Hz), 28.2, 29.5, 30.7, 36.2, 36.4, 41.1, 46.0, 46.4, 49.3, 56.9, 56.9, 63.5, 69.2, 72.2, 74.1 (t, J = 26.6 Hz), 116.0, 124.6, 126.2 (t, J = 245.6 Hz), 132.1, 143.7; HRMS (ESI + ) calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3439.

[0050] 24F2-MART-11: [α] D 27 +16.6 (c 0.29, EtOH); IR (neat) 3367, 1455, 1380, 1184, 1025 cm -1 ; 1 H NMR (600 MHz, CD3OD) δ 0.62 (s, 3H), 1.01 (d, J = 7.2 Hz, 3H), 1.28-2.09 (m, 29H), 2.34-2.39 (m, 2H), 2.88 (dd, J = 4.2, 12.6 Hz, 1H), 3.03 (dd, J = 4.5, 11.7 Hz, 1H), 3.53 (td, J = 4.8, 9.9 Hz, 1H), 3.58-3.64 (m, 2H), 4.08-4.08 (m, 1H), 5.93 (d, J = 10.8 Hz, 1H), 6.21 (d, J = 11.4 Hz, 1H); 13C NMR (150 MHz, CD3OD) δ 12.7, 19.5, 23.6, 24.2, 24.2, 24.8, 24.8, 28.7 (t, J = 24.5 Hz), 28.9, 30.1, 31.5, 37.4, 38.8, 42.1, 45.1, 47.1, 50.2, 50.4, 57.7, 58.0, 63.7, 69.2, 71.6, 74.0 (t, J = 27.3 Hz), 117.4, 123.3, 127.1 (t, J = 245.6 Hz), 134.3, 142.1; HRMS (ESI + calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3428.

[0051] "Manufacturing Example 3: Synthesis of 24F1 Body"

change

[0052] Synthesis of tert-Butyl({(1R,3aR,4S,7aR)-1-[(S)-1-iodopropan-2-yl]-7a-methyloctahydro-1H-inden-4-yl}oxy)dimethylsilane (7)

[0053] Mark the following formula:

change

[0054] Synthesis of tert-Butyl({(1R,3aR,4S,7aR)-1-[(R)-hex-5-en-2-yl]-7a-methyloctahydro-1H-inden-4-yl}oxy)dimethylsilane (8) [ka]

[0055] To a solution of compound 7 (180.0 mg, 0.412 mmol) in THF (4 mL) was added allylmagnesium bromide (3.3 mL, 1.0 mol / L EtO solution, 3.3 mmol) at 0 °C, and the mixture was stirred at room temperature for 23 h. After the reaction was quenched with water and saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane only) to give compound 8 (105.1 mg, 73%) as a colorless oil.

[0056] Compound 8: [α] D 27 +52.7 (c 1.82, CHCl3); IR (neat) 1471, 1371, 1252, 1162, 1085, 1027, 837, 771 cm-1; 11H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.90 (d, J = 6.6 Hz, 3H), 0.91 (s, 3H), 0.99 - 1.13 (m, 3H), 1.21 - 1.28 (m, 2H), 1.30 - 1.43 (m, 4H), 1.46 - 1.58 (m, 2H), 1.63 - 1.70 (m, 1H), 1.74 - 1.84 (m, 2H), 1.90 - 1.97 (m, 2H), 2.08 - 2.14 (m, 1H), 3.99 - 4.00 (m, 1H), 4.90 - 4.92 (m, 1H), 4.97 - 5.04 (m, 1H), 5.80 (ddt, J = 6.0, 10.2, 16.2 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.7, 18.0, 18.5, 23.1, 25.8, 27.3, 30.5, 34.5, 34.9, 35.1, 40.7, 42.2, 53.1, 56.8, 69.5, 113.8, 139.7; HRMS (ESI + ) calcd for C 22 H 42 OSi [M] + 350.2999, found 350.2992.

[0057] Synthesis of (2R,5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexane-1,2-diol (9)

Chem.

[0058] A mixture of AD-mix β (4.62 g) in tBuOH (15 mL) and HO (15 mL) was stirred in air at 0 °C for 25 min. Compound 8 (303.5 mg, 0.255 mmol) was added to the mixture at 0 °C and stirred at the same temperature for 1 h 35 min. After quenching the reaction with water, the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 1:1) to give compound 9 (433.1 mg, 94%) as a colorless oil.

[0059] Compound 9: [α] D 27 +41.9 (c 2.05, CHCl3); IR (neat) 3294, 1223, 1076, 1026, 837, 764 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88-0.90 (m, 15H), 1.01-1.58 (m, 11H), 1.65-1.67 (m, 1H), 1.75-1.84 (m, 2H), 1.91-1.95 (m, 4H), 3.42-3.45 (m, 1H), 3.64-3.69 (m, 2H), 3.99 (dd, J = 2.4, 5.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.7, 18.0, 18.5, 23.0, 25.8, 27.3, 29.6, 31.4, 34.4, 35.1, 40.7, 42.1, 53.0, 56.5, 67.0, 69.4, 72.7; HRMS (ESI - ) calcd for C 22 H 44 O3SiCl [M+Cl] - 419.2754, found 419.2773.

[0060] Synthesis of (2S,5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexane-1,2-diol (10) [ka]

[0061] A mixture of AD-mix α (4.01 g) in tBuOH (10 mL) and HO (10 mL) was stirred in air at 0 °C for 25 min. Compound 8 (303.5 mg, 0.255 mmol) was added to the mixture at 0 °C and stirred at the same temperature for 5 h, followed by stirring at room temperature for 15 h. After quenching the reaction with water, the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane: EtOAc = 1:1) to give compound 10 (253.9 mg, 79%) as a colorless oil.

[0062] Compound 10: [α] D 27 +44.4 (c 1.55, CHCl3); IR (neat) 3402, 1645, 1469, 1374, 1265, 1160, 1066, 1032, 840, 776, 743 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88-0.90 (m, 15H), 0.98-1.12 (m, 3H), 1.20-1.43 (m, 7H), 1.47-1.58 (m, 3H), 1.64-1.67 (m, 1H), 1.75-1.83 (m, 2H), 1.92-1.95 (m, 1H), 2.27 (s, 3H), 3.41-3.44 (m, 1H), 3.62-3.67 (m, 2H), 3.98-3.99 (m, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.6, 23.0, 25.8, 27.3, 29.7, 31.5, 34.4, 35.3, 40.7, 42.1, 53.0, 56.5, 66.7, 69.4, 73.0; HRMS (APCI - ) calcd for C 22 H 44 O3SiCl [M+Cl] - 419.2754, found 419.2764.

[0063] Synthesis of (2R,5R)-2-(Benzyloxy)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexan-1-ol (13) [ka]

[0064] Benzaldehyde dimethyl acetal (39.3 mg, 39 μL, 0.258 mmol) and pyridinium p-toluenesulfonate (PPTS) (4.5 mg, 0.018 mmol) were added to a solution of compound 9 (49.6 mg, 0.129 mmol) in toluene (0.7 mL) at room temperature, and the mixture was stirred at the same temperature for 2 h. After the reaction was quenched with water and saturated aqueous NaHCO3, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give crude acetal 11. The crude acetal was used in the next reaction without further purification.

[0065] To a mixture of the crude acetal 11 in CHCl (2 mL) was added DIBAL-H (313 μL, 1.03 mol / L hexane solution, 0.32 mmol) at −40° C., and the mixture was stirred at the same temperature for 1 h, followed by stirring at room temperature for 1 h. After diluting the reaction with MeOH, H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give compound 13 (44.4 mg, 72%) as a colorless oil.

[0066] Compound 13: [α] D 27 +31.1 (c 0.91, CHCl3); IR (neat) 3332, 1462, 1369, 1257, 1076, 1030, 837, 771 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.89-0.90 (m, 15H), 1.00-1.14 (m, 3H), 1,20-1.26 (m, 2H), 1.30-1.45 (m, 6H), 1.51-1.58 (m, 2H), 1.65-1.71 (m, 2H), 1.75-1.84 (m, 2H), 1.93-1.95 (m, 1H), 3.46-3.50 (m, 1H), 3.52-3.55 (m, 1H), 3.68 (dd, J = 3.0, 12.0Hz, 1H), 3.99-4.00 (m, 1H), 4.54 (d, J = 10.8 Hz, 1H), 4.62 (d, J = 10.8 Hz, 1H), 7.28-7.32 (m, 1H), 7.35-7.36 (m, 4H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.7, 18.0, 18.6, 23.0, 25.8, 27.2, 27.3, 31.1, 34.4, 35.3, 40.7, 42.1, 53.0, 56.4, 64.4, 69.4, 71.6, 80.3, 127,7, 127.8, 128.5, 138.5; HRMS (APCI + ) calcd for C 29 H 50 NaO3Si [M+Na] + 497.3421, found 497.3450.

[0067] Synthesis of (2S,5R)-2-(Benzyloxy)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexan-1-ol (14) [ka]

[0068] Benzaldehyde dimethyl acetal (374.4 mg, 369 μL, 2.46 mmol) and pyridinium p-toluenesulfonate (PPTS) (158.6 mg, 0.63 mmol) were added to a solution of compound 10 (472.0 mg, 1.23 mmol) in toluene (15 mL) at room temperature, and the mixture was stirred at the same temperature for 2 h. After the reaction was quenched with water and saturated aqueous NaHCO3, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give crude acetal 12. The crude acetal obtained was used in the next reaction without further purification.

[0069] To a solution of the crude acetal 12 in CHCl (15 mL) was added DIBAL-H (4.8 mL, 1.03 mol / L hexane solution, 4.92 mmol) at 0 °C, and the mixture was stirred at the same temperature for 20 min. After diluting the reaction with MeOH at 0 °C, H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted four times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give compound 14 (501.1 mg, 86%) as a colorless oil.

[0070] Compound 14: [α] D 27 +49.0 (c 3.62, CHCl3); IR (neat) 3420, 1465, 1453, 1374, 1254, 1085, 1028, 840, 776, 739 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.90-0.91 (m, 15H), 0.99-1.13 (m, 3H), 1.21-1.60 (m, 10H), 1.66-1.68 (m,1H), 1.75-1.84 (m, 2H), 1.94-1.96 (m, 2H), 3.45-3.48 (m, 1H), 3.51-3.54 (m, 1H), 3.69 (dd, J = 3.0, 11.4 Hz, 1H), 4.00-4.00 (m, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.7 Hz, 1H), 7.28-7.32 (m, 1H), 7.35-7.36 (m, 4H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.5, 23.0, 25.8, 27.1, 27.3, 31.2, 34.4, 35.3, 40.7, 42.1, 53.0, 56.5, 64.2, 69.4, 71.4, 80.4, 127,7, 127.8, 128.4, 138.5; HRMS (ESI + ) calcd for C 29 H 50 NaO3Si [M+Na] + 497.3421, found 497.3433.

[0071] Synthesis of (2R,5R)-2-(Benzyloxy)-5-({1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoic acid (17) [ka]

[0072] Dess-Martin reagent (2.76 g, 6.51 mmol) was added to a mixture of compound 13 (1.03 g, 2.17 mmol) and 4 Å molecular sieves (600.0 mg) in CHCl (10 mL) at 0 °C, and the mixture was stirred at the same temperature for 2 h. Water and saturated aqueous NaHCO were added to the reaction, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The crude residue 15 was used in the next reaction without further purification.

[0073] To a mixture of the crude aldehyde 15 in HO (3 mL) and t-BuOH (6 mL), NaHPO (134.8 mg, 0.898 mmol) and NaClO (24.6 mg, 0.272 mmol) were added in air at 0 °C, and the whole mixture was stirred at the same temperature for 30 min. After the reaction was quenched with saturated aqueous NHCl and saturated aqueous sodium thiosulfate, the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 1:1) to give compound 17 (125.3 mg, quantitative yield) as a colorless oil.

[0074] Compound 17: [α] D 27 +47.1 (c 1.88, CHCl3); IR (neat) 1720, 1469, 1250, 1085, 1028, 840, 776 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.88-0.89 (m, 15H), 0.99-1.95 (m, 17H), 3,97-4.00 (m, 2H), 4.49 (d, J = 11.9 Hz, 1H), 4.71 (d, J = 11.9 Hz, 1H), 7.29-7.37 (m, 5H); 13 C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.4, 23.0, 25.8, 27.2, 28.9, 30.6, 34.4, 34.7, 40.7, 42.1, 53.0, 56.3, 69.4, 72.6, 77.8, 128,1, 128.2, 128.5, 136.9, 176.2; - ) calcd for C 29 H 47 O4Si [MH] - 487.3249, found 487.3290.

[0075] Synthesis of (2S,5R)-2-(Benzyloxy)-5-({1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoic acid (18) [ka]

[0076] Dess-Martin reagent (1.42 g, 3.35 mmol) was added to a mixture of compound 14 (490.2 mg, 1.03 mmol) and 4 Å molecular sieves (321.9 mg) in CHCl (10 mL) at 0 °C, and the mixture was stirred at the same temperature for 2 h and 5 min. Water and saturated aqueous NaHCO were added to the reaction mixture, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude aldehyde 16. The crude aldehyde was used in the next reaction without further purification.

[0077] To a mixture of the crude aldehyde 16 and NaHPO (1.216 g, 8.11 mmol) in HO (9 mL) and t-BuOH (18 mL) was added NaClO (575.9 mg, 6.37 mmol) in air at 0 °C, and the mixture was stirred at the same temperature for 30 min. The reaction was quenched with saturated aqueous NHCl and saturated aqueous sodium thiosulfate, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified twice by flash column chromatography on silica gel (hexane: EtOAc = 1:1) to give compound 18 (960.6 mg, 99%) as a colorless oil.

[0078] Compound 18: [α] D 27 +21.7 (c 1.32, CHCl3); IR (neat) 1720, 1469, 1254, 1089, 1032, 840, 780 cm-1 ; 1 1H NMR (400 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.89 - 0.90 (m, 15H), 0.99 - 1.94 (m, 17H), 3.94 - 3.99 (m, 2H), 4.50 (d, J = 11.6 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 7.29 - 7.39 (m, 5H); 13 13C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.5, 23.0, 25.8, 27.2, 29.1, 31.1, 34.4, 35.0, 40.7, 42.1, 53.0, 56.4, 69.4, 72.5, 78.3, 128.1, 128.1, 128.5, 137.0, 176.7; HRMS (ESI - ) calcd for C 29 H 47 O4Si [M - H] - 487.3249, found 487.3278.

[0079] Synthesis of Methyl (2R,5R)-2-(benzyloxy)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoate (19)

Chem.

[0080] Trimethylsilyldiazomethane (362 μL, 2.0 mol / L diethyl ether solution, 0.73 mmol) was added to a solution of compound 17 (125.3 mg, 1.03 mmol) in MeOH (1.5 mL) and CHCl (4.5 mL) at 0 °C, and the mixture was stirred at the same temperature for 20 min. After the reaction was quenched with acetic acid and saturated aqueous NaHCO, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give compound 19 (125.1 mg, 97%) as a colorless oil.

[0081] Compound 19: [α] D 27 +57.5 (c 1.71, CHCl3); IR (neat) 1750, 1471, 1253, 1029, 838, 774 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ -0.00 (s, 3H), 0.01 (s, 3H), 0.86-0.89 (m, 15H), 1.90-1.95 (m, 1H), 3.75 (s, 3H), 3.90 (dd, J = 4.6, 8.2 Hz, 1H), 3.98-3.99 (m, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 7.27-7.36 (m, 5H); 13 C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.4, 23.0, 25.8, 27.1, 29.5, 31.0, 34.4, 34.7, 40.7, 42.1, 51.8, 53.0, 56.4,69.4,72.3,78.3,127.8,128.0,128.3,137.6,173.6; + ) calcd for C 30 H 50 O4SiNa [M+Na] + 525.3371, found 525.3399.

[0082] Synthesis of Methyl (2S,5R)-2-(benzyloxy)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoate (20) [ka]

[0083] Trimethylsilyldiazomethane (1.1 mL, 2.0 mol / L diethyl ether solution, 2.16 mmol) was added to a solution of compound 18 (490.2 mg, 1.03 mmol) in MeOH (2 mL) and CHCl (6 mL) at 0 °C, and the mixture was stirred at the same temperature for 17 min. After the reaction was quenched with acetic acid and saturated aqueous NaHCO, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give compound 20 (387 mg, 100%) as a colorless oil.

[0084] Compound 20: [α] D 27 +17.0 (c 2.70, CHCl3); IR (neat) 1750, 1465, 1254, 1028, 840, 772 cm -1 ; 11H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.88 - 0.89 (m, 15H), 1.01 - 1.10 (m, 3H), 1.19 - 1.26 (m, 2H), 1.30 - 1.42 (m, 2H), 1.50 - 1.67 (m, 4H), 1.73 - 1.85 (m, 3H), 1.91 - 1.94 (m, 1H), 3.75 (s, 3H), 3.89 (dd, J = 5.4, 7.8 Hz, 1H), 3.99 - 3.99 (m, 1H), 4.41 (d, J = 11.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 7.27 - 7.31 (m, 1H), 7.33 - 7.36 (m, 4H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.5, 23.0, 25.8, 27.1, 29.6, 31.2, 34.4, 35.0, 40.7, 42.1, 51.8, 53.0, 56.4, 69.4, 72.2, 78.9, 127.8, 127.9, 128.3, 137.6, 173.4; HRMS (ESI + ) calcd for C 30 H 49 O4SiNa [M+Na] + 525.3371, found 525.3389.

[0085] Synthesis of Methyl (2R,5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-hydroxyhexanoate (21)

Chem.

[0086] To a solution of compound 19 (219.1 mg, 0.44 mmol) in isopropanol (10 mL) was added 10% Pd / C catalyst (62.9 mg). The mixture was stirred under 1 atmosphere of hydrogen at room temperature for 45 hours, then at 50 °C for 68 hours. The reaction mixture was diluted with EtOAc, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography on silica gel (hexane: EtOAc = 3:1) afforded compound 21 (136.5 mg, 76%) as a colorless oil.

[0087] Compound 21: [α] D 27 +33.2 (c 0.61, CHCl3); IR (neat) 3506, 1739, 1468, 1253, 1085, 1025, 838, 778 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88-0.90 (m, 15H), 1.00-1.12 (m, 2H), 1.20-1.27 (m, 2H), 1.30-1.45 (m, 3H), 1.49-1.58 (m, 2H), 1.65-1.71 (m, 2H), 1.75-1.83 (m, 2H), 1.92-1.95 (m, 1H), 3.78 (s, 3H), 3.99-3.99 (m, 1H), 4.17-4.18 (dd, J = 5.6, 6.0 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.7, 18.0, 18.5, 23.0, 25.8, 27.2, 30.5, 30.9, 34.4, 34.8, 40.7, 42.1, 52.4, 53.0, 56.4, 69.4, 70.7, 175.9; HRMS (ESI + ) calcd for C 23 H 44 O4Si [M+Na] + 435.2901, found 435.2887.

[0088] Synthesis of Methyl (2S,5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-hydroxyhexanoate (22) [ka]

[0089] To a solution of compound 20 (109.0 mg, 0.22 mmol) in MeOH (10 mL) and EtOAc (2 mL) was added 10% Pd / C catalyst (22.6 mg). The mixture was stirred under 1 atmosphere of hydrogen at room temperature for 45 hours, then at 50 °C for 68 hours. The reaction mixture was diluted with EtOAc and filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash column chromatography (hexane: EtOAc = 3:1) afforded compound 22 (78.0 mg, 87%) as a colorless oil.

[0090] Compound 22: [α] D 27 +44.8 (c 1.67, CHCl3); IR (neat) 3488, 1742, 1461, 1370, 1257, 1081, 1020, 840, 776, 686 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88-0.90 (m, 15H), 0.98-1.57 (m, 13H), 1.64-1.70 (m, 1H), 1.75-1.88 (m, 3H), 1.92-1.95 (m, 1H), 2.14 (brs, 1H), 3.78 (s, 3H), 3.99-4.00 (m, 1H), 4.15 (dd, J = 3.9, 6.9 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.6, 23.0, 25.8, 27.2, 30.6, 31.1, 34.4, 35.0, 40.7, 42.1, 52.4, 53.0, 56.4, 69.4, 71.0, 175.9; HRMS (ESI + ) calcd for C 23 H 44 O4SiNa [M+Na] + 435.2901, found 435.2897.

[0091] Synthesis of Methyl (2R,5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluorohexanoate (23) [ka]

[0092] DAST (195.0 mg, 173 μL, 1.21 mmol) was added to a solution of compound 22 (99.7 mg, 0.24 mmol) in CHCl (3 mL) at 0 °C, and the mixture was stirred at the same temperature for 2 h 15 min. The reaction was quenched with MeOH, HO, and saturated aqueous NaHCO at 0 °C, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane:EtOAc = 8:1) to give compound 23 (31.0 mg, 31%) as a colorless oil.

[0093] Compound 23: [α] D 27 +44.7 (c 2.39, CHCl3); IR (neat) 1769, 1746, 1465, 1445, 1370, 1254, 1208, 1081, 1024, 836, 769 cm -1 ; 11H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3 H), 0.88 - 0.90 (m, 15H), 0.99 - 1.12 (m, 2H), 1.15 - 1.26 (m, 3H), 1.29 - 1.37 (m, 3H), 1.39 - 1.48 (m, 1H), 1.51 - 1.59 (m, 2H), 1.64 - 1.68 (m, 1H), 1.73 - 1.84 (m, 3H), 1.73 - 1.84 (m, 3H), 1.86 - 1.95 (m, 2H), 3.79 (s, 3H), 3.99 - 3.99 (m, 1H), 4.89 (ddd, J = 4.2, 8.4, 49.8 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.4, 23.0, 25.8, 27.1, 29.1 (d, J = 20.1 Hz), 30.1, 34.4, 34.6, 40.7, 42.1, 52.2, 53.0, 56.3, 69.4, 89.3 (d, J = 182.4 Hz), 170.6 (d, J = 24.5 Hz); HRMS (ESI + ) calcd for C 23 H 43 O3FSiNa [M+Na] + 437.2858, found 437.2874.

[0094] Synthesis of Methyl (2S,5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluorohexanoate (24)

Chem.

[0095] DAST (48.0 mg, 43 μL, 0.30 mmol) was added to a solution of compound 21 (20.5 mg, 0.05 mmol) in CHCl (5 mL) at 0 °C, and the mixture was stirred at the same temperature for 90 min. The reaction was quenched with MeOH, HO, and saturated aqueous NaHCO at 0 °C, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 8:1) to give compound 24 (15.5 mg, 75%) as a colorless oil.

[0096] Compound 24: [α] D 27 +34.4 (c 1.03, CHCl3); IR (neat) 1766, 1746, 1469, 1442, 1378, 1254, 1212, 1089, 1024, 836, 776 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ -0.02 (s, 3H), -0.00 (s, 3H), 0.88-0.90 (m, 15H), 1.00-2.03 (m, 19H), 3.78 (s, 3H), 3.98-3.99 (m, 1H), 4.85 (ddd, J = 4.1, 7.3, 49.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.4, 23.0, 25.8, 27.1, 29.1 (d, J = 20.0 Hz), 30.3 (d, J = 2.9 Hz), 34.4, 34.9, 40.7, 42.1, 52.2, 53.0, 56.3, 69.4, 89.6 (d. + ) calcd for C 23 H 43 O3FSiNa [M+Na] + 437.2858, found 437.2869.

[0097] Synthesis of (1R,3aR,4S,7aR)-1-[(2R,5R)-5-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (25) [ka]

[0098] To a THF solution (1 mL) of compound 23, MeMgCl (150 μL, 3.0 mol / L THF solution, 0.45 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 10 min. Furthermore, MeMgCl (264 μL, 3.0 mol / L THF solution, 0.79 mmol) was added to the mixture at 0° C., and the solution was stirred at the same temperature for 10 min. After the reaction was quenched with H2O, the mixture was extracted three times with EtOAc. The organic layer was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The crude residue was used in the next reaction without further purification.

[0099] To the crude residue from above in MeOH (10 mL) and CHCl (5 mL) was added p-toluenesulfonic acid monohydrate (380.7 mg, 2.0 mmol), and the mixture was stirred in air at room temperature for 24 h. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 25 (18.8 mg, 83%, 2 steps) as a white powder.

[0100] Compound 25: [α] D 27 +43.4 (c 1.45, CHCl3); IR (neat) 3402, 1469, 1374, 1168, 1073, 994 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.91 (d, J = 6.0 Hz, 3H), 0.94 (s, 3H), 1.01 - 1.74 (m, 21H), 1.78 - 1.91 (m, 3H), 1.98 - 2.00 (m, 1H), 4.07 - 4.07 (m, 1H), 4.18 (ddd, J = 2.1, 10.5, 48.6 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 13.5, 17.4, 18.3, 22.5, 24.2 (d, J = 4.4 Hz), 25.4 (d, J = 4.4 Hz), 26.0 (d, J = 21.6 Hz), 27.1, 31.7, 33.6, 34.9, 40.4, 41.9, 52.6, 56.4, 69.4, 72.0 (d, J = 20.1 Hz), 99.9 (d, J = 170.9 Hz); HRMS (APCI - ) calcd for C 18 H 33 O2FSi [M - H] - 299.2392, found 299.2420.

[0101] Synthesis of (1R,3aR,4S,7aR)-1-[(2R,5S)-5-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (26)

Chem.

[0102] To a solution of compound 24 in THF (3 mL), MeMgCl (264 μL, 3.0 mol / L THF solution, 0.79 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 10 min. Furthermore, MeMgCl (264 μL, 3.0 mol / L THF solution, 0.79 mmol) was added to the mixture at 0° C., and the solution was stirred at the same temperature for 5 min. After the reaction was quenched with HO, the mixture was extracted three times with EtOAc. The organic layer was washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. The crude residue was used in the next reaction without further purification.

[0103] To the crude residue from above in MeOH (10 mL) and CHCl (5 mL) was added p-toluenesulfonic acid monohydrate (399.2 mg, 2.10 mmol), and the mixture was stirred in air at room temperature for 24 h. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 1:1) to give compound 26 (36.3 mg, 61%, 2 steps) as a white powder.

[0104] Compound 26: [α] D 27 +17.5 (c 1.30, CHCl3); IR (neat) 3412, 1465, 1378, 1250, 1168, 1066, 990, 731 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.92 (d, J = 6.0 Hz, 3H) , 0.94 (s, 3H), 1.03-1.17 (m, 3H), 1.20-1.21 (m, 6H), 1.29-1.36 (m, 2H), 1.42-1.90 (m, 13H), 1.98-2.01 (m, 1H), 4.07-4.08 (m, 1H), 4.14 (ddd, J = 1.8, 10.2, 48.0 Hz, 1H); 1313C NMR (150 MHz, CDCl3) δ 13.5, 17.4, 18.5, 22.5, 24.3 (d, J = 4.4 Hz), 25.3 (d, J = 4.4 Hz), 26.4 (d, J = 21.6 Hz), 27.1, 32.1, 33.6, 35.3, 40.4, 41.9, 52.6, 56.5, 69.4, 72.0 (d, J = 20.1 Hz), 100.7 (d, J = 172.4 Hz); HRMS (ESI - ) calcd for C 18 H 32 O₂FSi [M-H] - 299.2392, found 299.2388.

[0105] (1R,3aR,7aR)-1-{(2R,5R)-5-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (27) Synthesis

Chem.

[0106] 4-Methylmorpholine N-oxide (56.2 mg, 0.48 mmol) was added to a solution of compound 25 (90.3 mg, 0.30 mmol) in CHCl (3 mL), and the mixture was cooled to 0 °C. TPAP (55.5 mg, 0.16 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 75 min. The reaction was diluted with excess EtO, and the mixture was directly purified by silica gel flash column chromatography (EtO only) to obtain the crude ketone. This crude ketone was used in the next reaction without further purification. TESCl (680.5 mg, 756 μL, 4.52 mmol) was added to a solution of the crude ketone and imidazole (424.0 mg, 6.23 mmol) in CHCl (4 mL) cooled to 0 °C, and the mixture was stirred at the same temperature for 3 h. The reaction was quenched with H O at 0 °C, and the mixture was extracted three times with CHCl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 20:1) to give compound 27 (92.3 mg, 74%, 2 steps) as a colorless oil.

[0107] Compound 27: [α] D 27 +12.2 (c 2.60, CHCl3); IR (neat) 1715, 1464, 1383, 1235, 1174, 1077, 1046, 1015, 744 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.58 (q, J = 7.8 Hz), 0.64 (s, 3H), 0.94 (t, J = 7.8 Hz), 0.96 (d, J = 6.0 Hz), 1.19 (s, 3 H), 1.24 (d, J = 1.8 Hz), 1.28-1.65 (m, 9H), 1.69-1.77 (m, 1H), 1.86-1.96 (m, 2H), 1.98-2.03 (m, 1H), 2.11-2.13 (m, 1H), 2.19-2.29 (m, 2H), 2.45 (dd, J = 7.8, 11.4 Hz), 3.97-4.07 (m, 1H); 1313C NMR (150 MHz, CDCl3) δ 6.6, 7.0, 12.5, 18.5, 19.0, 24.0, 24.6 (d, J = 2.9 Hz), 25.5 (d, J = 21.0 Hz), 27.2 (d, J = 2.9 Hz), 27.5, 31.9, 35.1, 39.0, 40.0, 49.9, 56.5, 62.0, 74.0 (d, J = 23.1 Hz), 99.4 (d, J = 175.2 Hz), 212.0; HRMS (ESI + ) calcd for C 24 H 45 O2FSiNa [M+Na] + 435.3065, found 435.3051.

[0108] (1R,3aR,7aR)-1-{(2R,5S)-5-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (28) Synthesis

Chem.

[0109] 4-Methylmorpholine N-oxide (64.9 mg, 0.55 mmol) was added to a solution of compound 26 (111.1 mg, 0.38 mmol) in CHCl (3 mL), and the mixture was cooled to 0 °C. TPAP (70.9 mg, 0.20 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO, and the mixture was directly purified by silica gel flash column chromatography (EtO only) to obtain the crude ketone. This crude ketone was used in the next reaction without further purification. TESCl (858.7 mg, 954 μL, 5.70 mmol) was added to a solution of the crude ketone and imidazole (536.4 mg, 7.88 mmol) in CHCl (4 mL) cooled to 0 °C, and the mixture was stirred at the same temperature for 3 h. The reaction was quenched with H2O at 0 °C, and the mixture was extracted three times with CHCl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 20:1) to give compound 28 (138.1 mg, 88%, 2 steps) as a colorless oil.

[0110] Compound 28: [α] D 27 -8.7 (c 2.60, CHCl3); IR (neat) 1715, 1460, 1379, 1235, 1174, 1077, 1054, 1015, 744 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 8.1 Hz), 0.64 (s, 3H), 0.94 (t, J = 8.1 Hz), 0.96 (d, J = 6.0 Hz), 1.00-1.11 (m, 1H), 1.18 (d, J = 1.8 Hz), 1.24 (d, J = 1.8 Hz), 1.27-1.63 (m, 6H), 1.68-1.94 (m, 5H), 1.98-2.03 (m, 1H), 2.10-2.13 (m, 1H), 2.19-2.29 (m, 2H), 2.44 (dd, J = 6.6, 11.4 Hz), 3.98 (ddd, J = 1.8, 10.2, 49.2 Hz, 1H);13 C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 12.5, 18.7, 19.0, 24.0, 24.4, 25.7 (d, J = 21.5 Hz), 27.3 (d, J = 2.9 Hz), 27.4 32.5, 35.5, 39.0, HRMS (ESI + ) calcd for C 24 H 45 02FSiNa [M+Na] + 435.3065, found 435.3050.

[0111] Synthesis of Ethyl 2-[(1R,3aS,7aR,E)-1-{(2R,5R)-5-fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene] acetate (29) [ka]

[0112] To a suspension of NaH (85.8 mg, 60% w / w in liquid paraffin, 2.15 mmol) in THF (2 mL) was added (EtO)P(O)CHCOEt (502.1 mg, 448 μL, 2.24 mmol) at 0 °C, and the mixture was stirred at 0 °C for 20 min. Ketone 27 (92.3 mg, 0.22 mmol) was dissolved in THF, and the solution was added to the mixture at the same temperature. After stirring at room temperature for 229 h, the reaction mixture was quenched by adding HO and saturated aqueous NHCl. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give CD ring ethyl ester 29 (64.9 mg, 60%, recovery of compound 27: 33.7 mg, 37%) as a colorless oil.

[0113] Compound 29: [α] D 27 +88.9 (c 1.14, CHCl3); IR (neat) 1715, 1646, 1464, 1379, 1181, 1050, 744 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.59 (q, J = 8.0 Hz, 6H), 0.59 (s, 3H), 0.93 - 0.96 (m, 12H), 1.20 (s, 3H), 1.25 (d, 1.8 Hz, 3H), 1.26 - 1.76 (m, 16H), 1.90 - 1.97 (m, 1H), 2.00 - 2.03 (m, 1H), 2.09 - 2.13 (m, 1H), 3.84 - 3.88 (m, 1H), 3.98 - 4.08 (m, 1H), 4.11 - 4.19 (m, 2H), 5.46 (brs, 1H); 13 C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 12.1, 14.3, 18.6, 22.1, 23.8, 24.6, 25.5 (d, J = 20.1 Hz), 27.2 (d, J = 2.9 Hz), 27.4, 29.6, 31.9, 35.5, 40.1, 47.1, 56.6, 56.8, 59.5, 74.0 (d, J = 23.0 Hz), 99.5 (d, J = 175.2 Hz), 112.0, 163.3, 167.0; HRMS (ESI + ) calcd for C 28 H 51 O3FSiNa [M+Na] + 505.3484, found 505.3475.

[0114] Synthesis of Ethyl 2-[(1R,3aS,7aR,E)-1-{(2R,5S)-5-fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene] acetate (30) [ka]

[0115] To a suspension of NaH (126.5 mg, 60% w / w in liquid paraffin, 3.16 mmol) in THF (3 mL) was added (EtO)P(O)CHCOEt (750 mg, 670 μL, 3.35 mmol) at 0 °C, and the mixture was stirred at 0 °C for 20 min. Ketone 28 (138.1 mg, 0.34 mmol) was dissolved in THF, and the solution was added to the mixture at the same temperature. After stirring at room temperature for 164 h, the reaction mixture was quenched by adding H2O and saturated aqueous NH4Cl. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 8:1) to give CD ring ethyl ester 30 (142.2 mg, 88%) as a colorless oil.

[0116] Compound 30: [α] D 27 +70.9 (c 3.82, CHCl3); IR (neat) 1715, 1646, 1464, 1387, 1239, 1162, 1077, 1050, 741 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.58 (q, J = 5.9 Hz, 6H), 0.59 (s, 3H), 0.93-0.96 (m, 12H), 1.02-1.10 (m, 1H), 1.18 (s, 3H), 1.25 (d, 1.2 Hz, 3H), 1.28 (t, 7.2 Hz, 3H), 1.31-1.44 (m, 4H), 1.49-1.84 (m, 8H), 1.87-1.95 (m, 1H), 2.01-2.03 (m, 1H), 2.08-2.11 (m, 1H), 3.84-3.88 (m, 1H), 3.94-4.04 (m, 1H), 4.11-4.18 (m, 2H), 5.46 (brs, 1H); 13C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 12.1, 14.3, 18.7, 22.1, 23.8, 24.4, 25.9 (d, J = 20.1 Hz), 27.2 (d, J = 2.9 Hz), 27.3, 29.6, 32.5, 36.0, 40.1, 47.1, 56.6, 56.8, 59.5, 74.0 (d. + ) calcd for C 28 H 51 O3FSiNa [M+Na] + 505.3484, found 505.3453.

[0117] Synthesis of 2-[(1R,3aS,7aR,E)-1-{(2R,5R)-5-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (31) [ka]

[0118] To a solution of ethyl ester 29 in THF (3 mL) was added DIBAL-H (1.57 mL, 1.03 mol / L hexane solution, 1.61 mmol) at −78 °C, and the mixture was stirred at the same temperature for 100 min. After diluting the reaction with MeOH at −78 °C, H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give alcohol 31 (49.5 mg, 84%) as a colorless oil.

[0119] Compound 31: [α] D 27+67.3 (c 1.13, CH3OH); IR (neat) 3331, 1460, 1379, 1239, 1174, 1081, 1050, 1015, 748 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ 0.56 (s, 3H), 0.58 (q, J = 7.9 Hz, 6H), 0.93 - 0.96 (m, 12H), 1.05 - 1.12 (m, 1H), 1.19 (d, J = 1.4 Hz, 3H), 1.24 - 1.34 (m, 7H), 3.89 - 1.74 (m, 9H), 1.86 - 2.02 (m, 3H), 2.61 - 2.65 (m, 1H), 3.96 - 4.11 (m, 1H), 4.21 (d, J = 6.8 Hz, 2H), 5.22 (t, J = 7.1 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 6.7, 7.0, 11.8, 18.6, 22.1, 23.5, 24.6, 25.5 (d, J = 21.0 Hz), 27.2 (d, J = 2.9 Hz), 27.5, 28.7, 32.0, 35.6, 40.3, 45.3, 55.6, 56.4, 58.7, 74.0 (d, J = 21.9 Hz), 99.6 (d, J = 175.4 Hz), 119.2, 143.8; HRMS (ESI + ) calcd for C 26 H 49 O2FSiNa [M+Na] + 463.3378, found 463.3364.

[0120] Synthesis of 2-[(1R,3aS,7aR,E)-1-{(2R,5S)-5-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (32)

Chem.

[0121] To a solution of ethyl ester 30 in THF (5 mL) was added DIBAL-H (1.72 mL, 1.03 mol / L hexane solution, 1.77 mmol) at −78 °C, and the mixture was stirred at the same temperature for 10 min. DIBAL-H (2.0 mL, 1.03 mol / L in hexane solution, 1.94 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 30 min. The reaction was quenched with HO and saturated aqueous potassium sodium tartrate at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give alcohol 32 (116.1 mg, 89%) as a colorless oil.

[0122] Compound 32: [α] D 27 +43.1 (c 3.92, CHCl3); IR (neat) 3334, 1460, 1379, 1235, 1174, 1081, 1046, 1008, 744 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 0.56 (s, 3H), 0.58 (q, J = 7.9 Hz, 6H), 0.92-0.96 (m, 12H), 1.03-1.12 (m, 1H), 1.18 (s, 3H), 1.25-2.02 (m, 19H), 2.61-2.65 (m, 1H), 3.92-4.04 (m, 1H), 4.20 (d, 6.9 Hz, 2H), 5.22 (t, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 6.7, 7.0, 11.8, 18.8, 22.1, 23.5, 24.4, 25.8 (d, 21.0 Hz), 27.2 (d, 2.9 Hz), 27.5, 28.7, 32.6, 36.1, 40.3, 45.3, 55.6, 56.4, 58.7, 74.0 (d. + ) calcd for C 26 H 49 02FSiNa [M+Na] + 463.3378, found 463.3369.

[0123] Synthesis of 2-({2-[(1R,3aS,7aR,E)-1-{(2R,5R)-5-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole (35) [ka]

[0124] To a solution of 2-mercaptobenzothiazole (45.1 mg, 0.27 mmol), Ph3P (69.3 mg, 0.26 mmol), and compound 31 (49.5 mg, 0.11 mmol) in CHCl (4 mL) was added diisopropyl azodicarboxylate (118 μL, 1.9 mol / L toluene solution, 0.23 mmol) at 0 °C, and the mixture was stirred for 10 min at 0 °C. The solution was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude product 33.

[0125] The crude sulfide 33 was dissolved in EtOH (8 mL) and CHCl (4 mL), and the solution was added with 30% hydrogen peroxide (2 mL) and (NH)MoO. 244H2O (111.2 mg, 0.09 mmol) was added at 0 °C. After stirring at room temperature for 75 min, the mixture was poured into H2O and extracted three times with CHCl2. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give sulfone 35 (60.6 mg, 87%, 2 steps) as a colorless oil.

[0126] Compound 35: [α] D 27 +52.6 (c 0.95, CHCl3); IR (neat) 1471, 1333, 1243, 1150, 1050, 744 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.28 (s, 3H), 0.57 (q, J = 7.6 Hz, 6H), 0.86 (d, J = 6.0 Hz, 3H), 0.94 (t, J = 8.1 Hz, 9H), 1.18-1.60 (m, 19H), 1.83-1.91 (m, 3H), 2.55-2.57 (m, 1H), 3.95-4.05 (m, 1H), 4.21 (dd, J = 6.6, 14.4 Hz, 1H), 4.30 (dd, J = 9.0, 14.4 Hz, 1H), 5.01 (t, J = 7.8 Hz, 1H), 7.57-7.65 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 11.6, 18.5, 22.1, 23.2, 24.6, 25.5 (d, J = 21.6 Hz), 27.2 (d, J = 2.9 Hz), 27.4, 29.0, 31.9, 35.5, 39.9, 45.7, 53.9, 56.0, 56.2, 74.0 (d, J = 23.1 Hz), 99.5 (d, 176.7 Hz), 104.2, 122.2, 125.4, 127.6, 127.9, 137.0, 152.1, 152.8, 166.0; HRMS (ESI + ) calcd for C 33 H 52 NO3FSiS2Na [M+Na] + 644.3034, found 644.3049.

[0127] Synthesis of 2-({2-[(1R,3aS,7aR,E)-1-{(2R,5S)-5-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole (36) [ka]

[0128] To a solution of 2-mercaptobenzothiazole (120.4 mg, 0.72 mmol), PhP (148.7 mg, 0.57 mmol), and compound 32 (116.1 mg, 0.26 mmol) in CHCl (4 mL) was added diisopropyl azodicarboxylate (280 μL, 1.9 mol / L toluene solution, 0.53 mmol) at 0° C., and the mixture was stirred for 7 min at 0° C. The solution was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude product 34.

[0129] Crude sulfide 34 was dissolved in EtOH (12 mL), and the solution was added with 30% hydrogen peroxide (2 mL) and (NH)MoO 24 4H2O (225.3 mg, 0.18 mmol) was added at 0 °C. After stirring at room temperature for 75 min, CHCl2 (6 mL) was added to the mixture, and the mixture was stirred at the same temperature for 3 h. The mixture was poured into H2O and extracted three times with CHCl2. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give sulfone 36 (141.2 mg, 87%, two steps) as a colorless oil.

[0130] Compound 36: [α] D 27 +31.6 (c 2.09, CHCl3); IR (neat) 1475, 1336, 1235, 1154, 1077, 760, 744 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.26 (s, 3H), 0.57 (q, J = 8.0 Hz, 6H), 0.86 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 7.8 Hz, 9H), 0.97-1.06 (m, 1H), 1.17-1.60 (m, 17H), 1.65-1.90 (m, 4H), 2.54-2.57 (m, 1H), 3.91-4.01 (m, 1H), 4.20 (dd, J = 6.6, 14.4 Hz, 1H), 4.30 (dd, J = 9.0, 14.4 Hz, 1H), 5.01 (t, J = 8.1 Hz, 1H), 7.57-7.64 (m, 2H), 8.00 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 11.5, 18.7, 22.0, 23.2, 24.4, 25.8 (d, J = 20.1 Hz), 27.2 (d, J = 2.9 Hz), 27.3, 29.0, 32.5, 35.9, 39.9, 45.7, 53.9, 56.0, 56.3, 74.0 (d, J = 23.0 Hz), 100.4 (d, 176.7 Hz), 104.2, 122.2, 125.3, 127.5, 127.9, 136.9, 152.0, 152.8, 165.9; HRMS (ESI + ) calcd for C 33 H 52 NO3FSiS2Na [M+Na] + 644.3034, found 644.3039.

[0131] Synthesis of 24RF-MART-10 and 24RF-MART-11 [ka]

[0132] To a solution of sulfone 35 (60.6 mg, 0.097 mmol) in THF (0.5 mL) was added LiHMDS (108 μL, 1.0 mol / L THF solution, 0.11 mmol) at −78 °C. After stirring the mixture at the same temperature for 25 min, ring A (31.6 mg, 0.06 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 25 min. After quenching the reaction with saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1 to 3:1) to give the protected coupling product as an inseparable mixture of isomers.

[0133] p-Toluenesulfonic acid monohydrate (205.1 mg, 1.08 mmol) was added to a solution of the above coupling product in MeOH (5 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 16 h. The reaction was quenched with HO and saturated aqueous NaHCO at room temperature, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 10:1) to give 24RF-MART-10 and 24RF-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a solvent system of CHCN:HO = 4:1 to give 24RF-MART-10 (3.4 mg, 12%, 2 steps) and 24RF-MART-11 (3.0 mg, 10%, 2 steps), respectively, as white powders.

[0134] 24RF-MART-10: [α] D 27 +66.0 (c 0.26, EtOH); IR (neat) 3350, 1522, 1393, 1153, 1063, 894 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ 0.56 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H), 1.10 (s, 3H), 1.13 (d, J = 1.4 Hz, 3H), 1.21-1.66 (m, 18H), 1.86-2.03 (m, 5H), 2.43 (dd, J = 4.6, 13.3 Hz, 1H), 2.62 (dd, J = 4.1, 13.7 Hz, 1H), 2.77-2.80 (m, 1H), 3.40-3.50 (m, 3H), 3.93 (brs, 1H), 4.03-4.18 (m, 1H), 4.26-4.61 (m, 4H), 5.83 (d, J = 11.0 Hz, 1H), 6.14 (d, J = 11.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 12.9, 19.5, 22.8, 23.9, 24.0, 25.4 (d, J = 2.9 Hz), 26.1 (d, J = 21.0 Hz), 27.1 (d, J = 2.9 Hz), 28.1, 29.2, 30.0, 31.6, 32.6, 36.1, 36.4, 46.1, 46.2, 49.5, 56.6, 56.7, 62.5, 67.5, 70.1, 70.9 (d, J = 21.0 Hz), 100.3 (d, J = 172.6 Hz), 117.3, 121.7, 136.1, 140.1; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3528.

[0135] 24RF-MART-11: [α] D 27 +26.2 (c 0.23, EtOH); IR (neat) 3355, 1451, 1391, 1173, 1053, 985 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ 0.55 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H), 1.09-1.13 (m, 6H), 1.27-1.68 (s, 18H), 1.77 (t, J = 11.7 Hz, 1H), 1.86-2.05 (m, 3H), 2.18-2.26 (m, 2H), 2.76-2.86 (m, 2H), 3.37-3.43 (m, 3H), 3.90 (brs, 1H), 3.99-4.18 (m, 2H), 4.36-4.61 (m, 3H), 5.84 (d, J = 11.0 Hz, 1H), 6.06 (d, J = 11.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 12.8, 19.5, 22.8, 24.1, 24.2, 25.4 (d, J = 2.9 Hz), 26.1 (d, J = 20.1 Hz), 27.1 (d, J = 2.9 Hz), 28.2, 29.3, 30.0, 31.4, 32.6, 36.1, 38.8, 44.9, 46.1, 49.7, 56.6, 56.7, 62.5, 67.5, 69.9, 70.9 (d, J = 21.0 Hz), 100.2 (d, J = 173.5 Hz), 116.9, 121.5, 135.8, 140.3; HRMS (ESI + ) calcd for C 29 H 49 OFNa [M+Na] + 503.3507, found 503.3526.

[0136] Synthesis of 24SF-MART-10 and 24SF-MART-11 [ka]

[0137] To a solution of sulfone 36 (141.2 mg, 0.23 mmol) in THF (1.0 mL) was added LiHMDS (289 μL, 1.0 mol / L THF solution, 0.29 mmol) at −78 °C. After stirring the mixture at the same temperature for 20 min, ring A (61.8 mg, 0.12 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 75 min. After quenching the reaction with saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1 to 3:1) to give the protected coupling product as an inseparable mixture of isomers.

[0138] p-Toluenesulfonic acid monohydrate (383.8 mg, 2.02 mmol) was added to a solution of the above coupling product in MeOH (10 mL) and CHCl (10 mL). The mixture was stirred in air at room temperature for 4 h. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (from EtOAc pure to EtOAc:MeOH = 10:1) to give 24SF-MART-10 and 24SF-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO = 1:1 solvent system to give 24SF-MART-10 (15.2 mg, 27%, 2 steps) and 24SF-MART-11 (12.8 mg, 23%, 2 steps), respectively, as white powders.

[0139] 24SF-MART-10: [α] D 27 +24.9 (c 1.17, CH3Cl); IR (neat) 3390, 1459, 1380, 1173, 1057, 993 cm -1 ; 1 H NMR (600 MHz, CD3OD) δ 0.62 (s, 3H), 1.01 (d, J = 6.0 Hz, 3H), 1.10-1.18 (m, 1H), 1.21 (s, 3H), 1.23 (d, J = 1.2 Hz, 3H), 1.36-1.83 (m, 17H), 1.94-2.01 (m, 1H), 2.05-2.18 (m, 5H), 2.58 (dd, J = 5.1, 13.2 Hz, 1H), 2.84 (dd, J = 4.5, 14.4 Hz, 1H), 2.87 (dd, J = 3.9, 12.0 Hz, 1H), 3.60-3.65 (m, 3H), 4.05-4.15 (m, 2H), 5.92 (d, J = 11.4 Hz, 1H), 6.29 (d, J = 11.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 12.7, 19.7, 23.6, 24.6, 24.8, 25.0 (d, J = 3.0 Hz), 26.0 (d, J = 2.9 Hz), 27.7 (d, J = 21.6 Hz), 29.0, 30.1, 31.6, 34.0, 36.7, 37.8, 42.2, 46.6, 47.1, 50.3, 57.8, 58.1, 63.7, 69.3, 72.0, 72.7 (d, J = 21.5 Hz), 101.6 (d, J = 173.7 Hz), 117.7, 123.6, 134.5, 142.2; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3531.

[0140] 24SF-MART-11: [α] D 27 +7.6 (c 0.99, EtOH); IR (neat) 3363, 1447, 1384, 1173, 1049, 993 cm -1 ; 1 H NMR (600 MHz, DMSO-d6) δ 0.54 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.07-1.14 (m, 7H), 1.25-1.82 (s, 18H), 1.87-2.04 (m, 3H), 2.19-2.25 (m, 2H), 2.77-2.85 (m, 2H), 3.33-3.42 (m, 3H), 3.85-3.91 (m, 1H), 4.06 (ddd, J = 1.2, 10.2, 48.0 Hz, 1H), 4.16 (d, J = 4.2 Hz, 1H), 4.16 (d, J = 4.2 Hz, 1H), 4.36 (t, J = 4.8 Hz, 1H), 4.53 (d, J = 5.4 Hz, 1H), 4.61 (s, 1H), 5.84 (d, J = 12.0 Hz, 1H), 6.06 (d, J = 11.4 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 12.8, 19.7, 22.8, 24.0, 24.2, 25.2 (d, J = 2.9 Hz), 26.4 (d, J = 20.1 Hz), 27.3 (d, J = 2.9 Hz), 28.1, 29.3, 31.4, 33.1, 36.6, 38.7, 44.9, 46.1, 49.6, 56.6, 56.7, 62.5, 67.5, 69.9, 70.9 (d, J = 21.6 Hz), 101.1 (d, J = 173.9 Hz), 116.9, 121.4, 135.8, 140.3; HRMS (ESI + calcd for C 29 H 49 O4FNa [M+Na] + 503.3507 was found.

[0141] "Manufacturing Example 4: Synthesis of 23F2 Body"

change

[0142] Synthesis of (S)-2-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}propanal (37)

[0143] Mark the following formula:

change

[0144] Synthesis of Methyl 2-(diethoxyphosphoryl)-2-[(triethylsilyl)oxy]acetate

[0145] The following formula: [ka] The compound represented by the formula (I) was synthesized by the method described in Kawagoe F.; Mototani S.; Yasuda K.; Nagasawa K.; Uesugi M.; Sakaki T.; Kittaka A. Introduction of fluorine atoms to vitamin D3 side-chain and synthesis of 24,24-difluoro-25-hydroxyvitamin D3. J. Steroid Biochem. Mol. Biol. 2019, 195, 105477.

[0146] Synthesis of Methyl (R)-4-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2,2-difluoropentanoate (40) [ka]

[0147] To a solution of Horner-Emmons reagent (2.35 g, 7.24 mmol) in THF (3.5 mL), LDA (lithium diisopropylamide) (3.5 mL, 2 mol / L THF / heptane / ethylbenzene solution, 1.75 mmol) was added at -40 °C. The mixture was stirred at the same temperature for 20 min, and a solution of compound 37 (977.0 mg, 3.01 mmol) in THF (3.5 mL) was added. The reaction mixture was stirred at 0 °C for 20 min. After quenching with H2O at 0 °C, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane:EtOAc = 3:1, 1% Et3N) to give crude coupling product 38 (43.7 mg). The crude coupling product obtained was used in the next reaction without further purification.

[0148] To the crude residue of compound 38 in CHCl (7 mL) was added AcOH (1.03 mL), followed by tetrabutylammonium fluoride (4.8 mL, 1 mol / L THF solution, 4.8 mmol) in air at 0 °C, and the mixture was stirred at room temperature for 15 min. After the reaction was quenched with H0 at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 10:1) to give the crude residue of compound 39.

[0149] To a solution of the crude residue of compound 39 (1.10 g) in CHCl (6.5 mL), N,N-diethylaminosulfur trifluoride (DAST) (2.8 mL, 3.4 g, 21.1 mmol) was slowly added at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was cooled to 0 °C, and MeOH and H2O were slowly added. The mixture was extracted three times with CHCl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give compound 40 (747.0 mg, 59%, 3 steps) as a colorless oil.

[0150] Compound 40: [α] D 27 +36.5 (c 1.90, CHCl3); IR (neat) 1774, 1471, 1253, 1097, 1077, 1029, 838 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 0.90 (d, J = 5.4 Hz, 3H), 0.91 (s, 3H), 1.03 (q, J = 9.6 Hz, 1H), 1.10 (td, J =3.6, 13.2 Hz, 1H), 1.17 - 1.27 (m, 2H), 1.31 - 1.38 (m, 2H), 1.43 - 1.49 (m, 1H), 1.51 - 1.59 (m, 2H), 1.65 - 1.67 (m, 1H), 1.74 - 1.84 (m, 2H), 1.88 - 1.98 (m, 2H), 2.04 - 2.16 (m,1H), 3.86 (s, 3H), 3.98 - 4.00 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.6, 18.0, 18.3, 23.0, 25.8, 27.0, 27.1, 31.1 (t, J = 22.3 Hz), 34.4, 34.5, 40.6, 42.1, 53.0, 53.2, 56.0, 69.4, 116.8 (t, J = 248.5 Hz), 165.0 (t, J = 33.8 Hz); HRMS (ESI - ) calcd for C 22 H 39 O3F2Si [M - H] - 417.2642, found 417.2662.

[0151] Synthesis of (R)-4-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2,2-difluoro-N-methoxy-N-methylpentanamide (41) [ka]

[0152] To a solution of compound 40 (1.01 g, 2.41 mmol) and Me(MeO)NH HCl (934.3 mg, 9.58 mmol) in THF (20 mL), isopropylmagnesium chloride (19.0 mL, 1 mol / L in THF, 19.0 mmol) was added at 0 °C, and the mixture was stirred at the same temperature for 23 h. After the reaction was quenched with water and saturated aqueous NH Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 6:1) to give compound 41 (933.9 mg, 87%) as a colorless oil.

[0153] Compound 41: [α] D 27 +39.9 (c 3.47, CHCl3); IR (neat) 1685, 1464, 1379, 1252, 1085, 1039, 984, 837 cm -1 ; 11H NMR (600 MHz, CDCl3) δ -0.02 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.92 (s, 3H), 1.02 (d, J = 6.6 Hz, 3H), 1.06 - 1.13 (m, 2H), 1.21 - 1.26 (m, 2H), 1.30 - 1.37 (m, 3H), 1.51 - 1.59 (m, 1H), 1.64 - 1.66 (m, 1H), 1.74 - 1.87 (m, 4H), 1.94 - 1.96 (m, 1H), 2.22 - 2.32 (m, 1H), 3.24 (brs, 3H), 3.72 (s, 3H), 3.98 - 3.99 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.5, 17.6, 18.0, 20.2, 23.0, 25.8, 27.4, 30.6, 33.1, 34.3, 40.1 (t, J = 20.8 Hz), 40.6, 42.2, 53.1, 56.9, 61.9, 69.4, 118.6 (t, J = 249.2 Hz), 164.7 (t, J = 27.9 Hz); HRMS (ESI + ) calcd for C 23 H 43 NO3F2SiNa [M+Na] + 470.2872, found 470.2856.

[0154] (6R)-6-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-4,4-difluoro-2-methylhept-1-en-3-yl acetate (44) Synthesis

Chem.

[0155] To a solution of compound 41 (251.5 mg, 0.56 mmol) in THF (20 mL) was added isopropenylmagnesium bromide (2.25 mL, 0.5 mol / L in THF, 1.12 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. After quenching the reaction with water, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 20:1) to give crude product 42.

[0156] NaBH4 (45.1 mg, 1.19 mmol) was added to a solution of crude 42 and CeCl3·6H2O in EtOH (3 mL) and MeOH (3 mL) at 0 °C, and the mixture was stirred at the same temperature for 5 min. After quenching the reaction with water, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. Crude 43 was used in the next reaction without further purification.

[0157] N,N-Dimethyl-4-aminopyridine (464.5 mg, 3.68 mmol) and (Ac)O (1.85 g, 2 mL, 18.1 mmol) were added to a solution of crude 43 in pyridine (4 mL) at 0 °C, and the mixture was stirred at room temperature for 10 min. The reaction was quenched with water at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1) to give compound 44 (a mixture of diastereomers) (201.8 mg, 76%, 3 steps) as a colorless oil.

[0158] Compound 44: [α] D 27 +33.7 (c 2.30, CHCl3); IR (neat) 1755, 1468, 1375, 1235, 1085, 1039, 841, 775 cm -1 ; 11H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 0.94 (s, 3H), 1.04 - 1.15 (m, 5H), 1.17 - 1.27 (m, 2H), 1.30 - 1.38 (m, 3H), 1.46 - 1.60 (m, 2H), 1.65 - 1.67 (m, 1H), 1.71 - 2.03 (m, 7H), 2.13 - 2.14 (m, 3H), 3.98 - 4.00 (m, 1H), 5.10 - 5.11 (m, 2H), 5.25 - 5.32 (m, 1H); 13 1C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.5, 13.5, 17.6, 18.0, 19.4, 19.7, 20.4, 20.5, 20.8, 23.0, 25.8, 27.5, 27.5, 30.3, 30.4, 34.3, 38.5 (t, J = 22.3 Hz), 38.7 (t, J = 22.3 Hz), 40.7, 42.2, 53.1, 57.0, 57.0, 69.​​​​​​​​​​​​​​​​​​

[0160] To a solution of sodium formate (155.8 mg, 2.29 mmol) and Pd(PPh3)4 (423.2 mg, 0.37 mmol) in dioxane (1.5 mL) was added nBu3P (345.5 mg, 427.0 μL, 1.77 mmol) at room temperature, and the mixture was stirred at 90 °C for 10 min. Acetyl derivative 44 (201.8 mg, 0.43 mmol) was dissolved in dioxane (1.5 mL), and the solution was added to the mixture. After stirring at the same temperature for 17 h, the reaction mixture was quenched with H2O at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was partially purified by flash column chromatography on silica gel (hexane: EtOAc = 100:1) and repurified by flash column chromatography on silica gel (hexane only) to give compound 45 (111.9 mg, 63%) as a colorless oil.

[0161] Compound 45: [α] D 27 +36.0 (c 0.69, CHCl3); IR (neat) 1471, 1379, 1255, 1166, 1085, 1023, 837, 775 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.95 (s, 3H), 1.04 (d, J = 7.2 Hz, 3H), 1.07 (q, J = 9.6 Hz, 1H), 1.12 (td, J =3.6, 13.2 Hz, 1H), 1.21-1.27 (m, 2H), 1.31-1.38 (m, 3H), 1.46-1.61 (m, 2H), 1.66-1.68 (m, 1H), 1.75-1.86 (m, 6H), 1.89-2.00 (m, 2H), 2.48-2.59 (m, 2H), 3.99-4.00 (m, 1H), 4.84 (brs, 1H), 4.59 (brs, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.5, 17.6, 18.0, 20.3, 23.0, 23.3, 25.8, 27.5, 30.9, 34.4, 40.7, 41.7 (t, J = 23.0 Hz), 42.2, HRMS (ESI + ) calcd for C 24 H 44 OF2SiNa [M+Na] + 437.3022, found 437.3033.

[0162] Synthesis of (1R,3aR,4S,7aR)-1-[(2R)-4,4-Difluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (48) [ka]

[0163] mCPBA (286.1 mg, 1.66 mmol) was added to a mixture of compound 45 (111.9 mg, 0.27 mmol) and NaHCO (131.9 mg, 1.57 mmol) in CHCl (2 mL) at 0 °C, and the mixture was stirred in air at the same temperature for 100 min. The reaction was quenched with H O and saturated aqueous NaHCO at room temperature, and the mixture was extracted three times with CHCl. ​​The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 20:1) to give crude product 46.

[0164] LiAlH (14.0 mg, 0.37 mmol) was added to a solution of the crude product 46 in EtO (3 mL) at 0 °C, and the mixture was stirred at the same temperature for 15 min and at room temperature for 20 min. The reaction was quenched with MeOH, water, and saturated aqueous potassium sodium tartrate, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The crude alcohol 47 was used in the next reaction without further purification.

[0165] p-Toluenesulfonic acid monohydrate (981.0 mg, 5.16 mmol) was added to a solution of the crude alcohol 47 in MeOH (20 mL), and the mixture was stirred in air at room temperature for 25 h. The reaction was quenched with H2O and saturated aqueous NaHCO3 at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 48 (63.8 mg, 74%, 3 steps) as a colorless oil.

[0166] Compound 48: [α] D 27 +26.9 (c 2.20, CHCl3); IR (neat) 3412, 1471, 1375, 1170, 987, 864 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.97 (s, 3H), 1.04 (d, J = 6.6 Hz, 3H), 1.08-1.18 (m, 2H), 1.23-1.38 (m, 8H), 1.39-1.49 (m, 3H), 1.54-1.88 (m, 8H), 1.92-2.12 (m, 4H), 4.06-4.08 (m, 1H); 1313C NMR (150 MHz, CDCl3) δ 13.3, 17.4, 20.3, 22.4, 27.5, 30.2, 30.4, 31.0, 33.5, 40.3, 41.9, 44.1 (t, J = 23.0 Hz), 48.6 (t, J = 23.0 Hz), 52.7, 56.8, 69.3, 69.9, 126.6 (t, J = 241.3 Hz); HRMS (ESI + ) calcd for C 18 H 32 O2F2Na [M+Na] + 341.2263 found 341.2249.

[0167] (1R,3aR,7aR)-1-{(2R)-4,4-Difluoro-6-methyl-6[(triethylsilyl)oxy] heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (49) Synthesis

Chem.

[0168] 4-Methylmorpholine N-oxide (36.6 mg, 0.31 mmol) was added to a solution of compound 48 (63.8 mg, 0.20 mmol) in CHCl (2 mL), and the mixture was cooled to 0 °C. TPAP (37.8 mg, 0.11 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO. The mixture was directly purified by silica gel flash column chromatography (EtO only) to give the crude ketone, which was used in the next reaction without further purification. TESCl (211.0 mg, 234 μL, 1.4 mmol) was added to a solution of the crude ketone and imidazole (130.6 mg, 1.92 mmol) in CHCl (5 mL) cooled at 0 °C, and the mixture was stirred at room temperature for 28 h. The reaction was quenched with H O at 0 °C, and the mixture was extracted three times with CHCl. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 20:1 to 10:1) to give compound 49 (76.1 mg, 88%, 2 steps) as a colorless oil.

[0169] Compound 49: [α] D 27 +6.4 (c 2.36, CHCl3); IR (neat) 1715, 1464, 1387, 1371, 1239, 1177, 1042, 748 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.58 (q, J = 7.8 Hz, 6H), 0.68 (s, 3H), 0.95 (t, J = 7.8 Hz, 9H), 1.10 (d, J = 6.0 Hz, 3H), 1.31-1.37 (m, 7H), 1.46 (q, J = 9.6 Hz, 1H), 1.50-1.78 (m, 4H), 1.82-2.06 (m, 7H), 2.12-2.16 (m, 1H), 2.19-2.30 (m, 2H), 2.46 (dd, J = 7.8, 12.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 12.3, 19.1, 21.0, 23.9, 27.7, 30.7, 30.9, 38.9, 40.9, 43.1 (t, J = 23.0 Hz), 49.8, 51.2 (t, J = HRMS (ESI + ) calcd for C 24 H 44 O2F2SiNa [M+Na] + 453.2971 found 453.2953.

[0170] Synthesis of Ethyl 2-[(1R,3aS,7aR,E)-1-{(2R)-4,4-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene] acetate (50) [ka]

[0171] To a suspension of NaH (63.8 mg, 60% w / w in liquid paraffin, 1.59 mmol) in THF (2 mL) was added (EtO)P(O)CHCOEt (396.7 mg, 1.7 mL, 1.77 mmol) at 0 °C, and the mixture was stirred at 0 °C for 20 min. Ketone 49 (76.1 mg, 0.18 mmol) was dissolved in THF (2 mL), and the solution was added to the above mixture at the same temperature. After stirring at room temperature for 182 h, the reaction mixture was quenched with HO and saturated aqueous NHCl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 10:1 to 5:1) to give compound 50 (53.8 mg, 61%, recovery of compound 49: 24.5 mg, 32%) as a colorless oil.

[0172] Compound 50: [α] D 27 +90.9 (c 2.84, CHCl3); IR (neat) 1717, 1642, 1461, 1386, 1164, 1040 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ 0.58 (q, J = 7.8 Hz, 6H), 0.62 (s, 3H), 0.95 (t, J = 7.8 Hz, 9H), 1.08 (d, J = 6.4 Hz, 3H), 1.25 - 1.42 (m, 12H), 1.48 - 2.14 (m, 13H), 3.83 - 3.89 (m, 1H), 4.09 - 4.20 (m, 2H), 5.45 (brs, 1H); 13 13C NMR (100 MHz, CDCl3) δ 6.7, 7.1, 11.9, 14.3, 21.1, 22.1, 23.7, 27.6, 29.5, 30.7, 30.9, 31.2, 40.1, 43.3 (t, J = 23.4 Hz), 47.0, 51.2 (t, J = 24.3 Hz), 56.9, 57.0, 59.5, 72.2, 112.1, 125.4 (t, J = 240.7 Hz), 163.0, 166.9; HRMS (ESI + ) calcd for C 28 H 50 O3F2SiNa [M+Na] + 523.3390 found 523.3367.

[0173] Synthesis of 2-(1R,3aS,7aR,E)-2-(1-{(2R)-4,4-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene)ethan-1-ol (51)

Chem.

[0174] To a solution of ethyl ester 50 (73.0 mg, 0.15 mmol) in THF (4 mL) was added DIBAL-H (708 μL, 1.03 mol / L hexane solution, 0.73 mmol) at −78 °C, and the mixture was stirred at the same temperature for 2 h. After diluting the reaction with MeOH at −78 °C, HO and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give alcohol 50 (58.5 mg, 87%) as a colorless oil.

[0175] Compound 51: [α] D 27 +64.0 (c 2.62, CHCl3); IR (neat) 3319, 1461, 1371, 1205, 1175, 1040, 743 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.59 (q, J = 8.4 Hz, 6H), 0.95 (t, J = 8.1 Hz, 9H), 1.70 (d, J = 6.6 Hz, 3H), 1.15 (brs, 1H), 1.27-1.33 (m, 9H), 1.42-1.74 (m, 7H), 1.81-1.92 (m, 2H), 1.95-2.07 (m, 5H), 2.61-2.64 (m, 1H), 4.18-4.23 (m, 2H), 5.22 (t, J = 6.9 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 6.7, 7.1, 11.7, 21.1, 22.2, 23.4, 27.8, 28.6, 30.7, 30.9, 31.3, 40.3, 43.4 (t, J = 23.0 Hz), 45.3, 51.2 HRMS (ESI + ) calcd for C 26 H48 O2F2SiNa [M+Na] + 481.3284, found 481.3246.

[0176] Synthesis of 2-{[2-((1R,3aS,7aR,E)-1-{(2R)-4,4-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene)ethyl]sulfonyl}benzo[d]thiazole (53) [ka]

[0177] To a solution of 2-mercaptobenzothiazole (57.2 mg, 0.34 mmol), Ph3P (81.8 mg, 0.31 mmol), and CD ring 51 (58.5 mg, 0.13 mmol) in CHCl (2 mL) was added diisopropyl azodicarboxylate (134 μL, 1.9 mol / L in toluene, 0.26 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After the reaction was quenched with HO at 0 °C, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude sulfide 52.

[0178] The crude sulfide 52 was dissolved in EtOH (12 mL) and CHCl (6 mL), and the resulting solution was added with 30% hydrogen peroxide (3 mL) and (NH)MoO. 24 4H2O (131.4 mg, 0.11 mmol) was added to the solution at 0 °C. After stirring at room temperature for 4 h, the mixture was poured into H2O and extracted three times with CHCl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give compound 53 (71.1 mg, 87%, 2 steps) as a colorless oil.

[0179] Compound 53: [α] D 27 +43.8 (c 1.68, CHCl3); IR (neat) 1472, 1330, 1205, 1149, 1037, 852, 743 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.28 (s, 3H), 0.59 (q, J = 7.8 Hz, 6H), 0.86 (d, J = 6.0 Hz, 6H), 0.94 (t, J = 7.8 Hz, 9H), 1.17-2.00 (m, 24H), 2.55-2.57 (m, 1H), 4.21 (dd, J = 6.6, 14.4 Hz, 1H), 4.43 (dd, J = 9.0, 14.4 Hz, 1H), 5.00-5.03 (m, 1H), 7.57-7.65 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 11.4, 21.0, 22.1, 23.1, 27.7, 28.9, 30.7, 30.9, 31.1, 39.9, 43.3 (t, J = 23.0 Hz), 45.7, 51.2 (t, J = 23.7 Hz), 53.9, 56.0, 56.7, 72.1, 104.4, 122.2, 125.3 (t, J = 240.6 Hz), 125.3, 127.6, 127.9, 136.9, 151.8, 152.8, 165.9; HRMS (ESI + calcd for C 33 H 51 NO3F2SiS2Na [M+Na] + 662.2940, found 662.2947.

[0180] Synthesis of 23F2-MART-10 and 23F2-MART-11

change

[0181] To a solution of sulfone 53 (71.1 mg, 0.11 mmol) in THF (1.0 mL) was added LiHMDS (122 μL, 1.0 mol / L THF solution, 0.12 mmol) at −78 °C. After stirring the mixture at the same temperature for 25 min, ring A (31.1 mg, 0.059 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 100 min. After quenching the reaction with saturated aqueous NH4Cl and HO, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1 to 3:1) to give the protected coupling product as an inseparable mixture of isomers.

[0182] p-Toluenesulfonic acid monohydrate (191.4 mg, 1.01 mmol) was added to a solution of the above coupling compound in MeOH (5 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 210 minutes. The reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 10:1) to give 23F2-MART-10 and 23F2-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO = 4:1 solvent system to give 23F2-MART-10 (3.5 mg, 13%, 2 steps) and 23F2-MART-11 (3.5 mg, 13%, 2 steps), respectively, as white powders.

[0183] 23F2-MART-10: [α] D 27 +67.7 (c 0.27, EtOH); IR (neat) 3360, 1435, 1379, 1164, 1051, 914 cm -1 ; 1H NMR (400 MHz, DMSO-d6) δ 0.58 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 1.21 (s, 6H), 1.27-2.23 (m, 24H), 2.43 (dd, J = 4.1, 12.8 Hz, 1H), 2.62 (dd, J = 4.6, 13.8 Hz, 1H), 2.77-2.80 (m, 1H), 3.41-3.52 (m, 3H), 3.93 (s, 1H), 4.26 (brs, 1H), 3.47 (t, J = 4.8 Hz, 1H), 4.45-4.50 (m, 2H), 5.83 (d, J = 11.5 Hz, 1H), 6.14 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 12.7, 21.5, 22.7, 24.0, 24.2, 28.4, 29.2, 31.2, 31.4, 31.4, 32.0, 38.8, 43.7 (t, J = 22.2 Hz), 44.9, 46.1, 49.7, 49.9 (t, J = 23.0 Hz), 56.7, 57.2, 62.5, 67.5, 68.6, 69.9, 117.0, 121.4, 127.0 (t, J = 239.9 Hz), 135.9, 140.1; HRMS (ESI + ) calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3423.

[0184] 23F2-MART-11: [α] D 27 +32.8 (c 0.27, EtOH); IR (neat) 3350, 1439, 1379, 1168, 1047 cm -1 ; 1H NMR (600 MHz, DMSO-d6) δ 0.57 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.22 (s, 6H), 1.25-1.80 (m, 24H), 1.88 (m, 1H), 1.99-2.26 (m, 7H), 2.77-2.85 (m, 2H), 3.35-3.41 (m, 3H), 3.90 (s, 1H), 4.16 (brs, 1H), 3.36 (t, J = 4.2 Hz, 1H), 4.51-4.54 (m, 2H), 5.84 (d, J = 10.8 Hz, 1H), 6.06 (d, J = 11.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 12.7, 21.5, 22.8, 23.8, 23.9, 28.3, 29.1, 31.1, 31.4, 31.6, 32.0, 36.4, 43.7 (t, J = 22.9 Hz), 46.0, HRMS (ESI + calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3413.

[0185] "Manufacturing Example 5: Synthesis of 23F1 Body"

change

[0186] Synthesis of (1R,3aR,4S,7aR)-1-[(2R,4R)-4-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (54)

[0187] Mark the following formula: [ka] Compound 54 was synthesized by the method described in Kawagoe, F.; Yasuda, K.; Mototani, S.; Sugiyama, T.; Uesugi, M.; Sakaki, T.; Kittaka, A.; Synthesis and CYP24A1-dependent metabolism of 23-fluorinated vitamin D3 analogues, ACS Omega 2019, 4, 11332-11337.

[0188] Synthesis of (1R,3aR,4S,7aR)-1-[(2R,4S)-4-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (55)

[0189] The following formula: [ka] Compound 55 was synthesized by the method described in Kawagoe, F.; Yasuda, K.; Mototani, S.; Sugiyama, T.; Uesugi, M.; Sakaki, T.; Kittaka, A.; Synthesis and CYP24A1-dependent metabolism of 23-fluorinated vitamin D3 analogues, ACS Omega 2019, 4, 11332-11337.

[0190] Synthesis of Ethyl 2-{(1R,3aS,7aR,E)-1-[(2R,4R)-4-fluoro-6-(methoxymethoxy)-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene} acetate (58) [ka]

[0191] 4-Methylmorpholine N-oxide (50.7 mg, 0.43 mmol) was added to a solution of compound 54 (101.8 mg, 0.34 mmol) in CHCl (4 mL), and the mixture was cooled to 0 °C. TPAP (61.7 mg, 0.18 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 90 min. The reaction was diluted with excess EtO. The mixture was directly purified by flash column chromatography on silica gel (EtO only) to give the crude ketone, which was used in the next reaction without further purification.

[0192] MOMCl (136.5 mg, 129 μL, 1.70 mmol) was added to a solution of the crude ketone and diisopropylethylamine (262.9 mg, 354 μL, 2.03 mmol) in CHCl (4 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 19 h. The reaction was quenched with HO and saturated aqueous NHCl at 0 °C, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 1:1) to give crude MOM-protected ketone 56.

[0193] To a suspension of NaH (135.6 mg, 60 w / w in liquid paraffin, 3.39 mmol) in THF (1 mL) was added (EtO)P(O)CHCOEt (836.2 mg, 747 μL, 3.73 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The crude ketone 56 from above was dissolved in THF (4 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 120 h, the reaction was quenched with H2O and saturated aqueous NH4Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 3:1) to give ethyl ester 58 (111.6 mg, 63%, 3 steps) as a colorless oil.

[0194] Compound 58: [α] D 27 +90.5 (c 3.11, CHCl3); IR (neat) 1714, 1642, 1464, 1384, 1152, 1038 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.59 (s, 3H), 1.00 - 1.12 (m, 4H), 1.25 - 1.40 (m, 12H), 1.50 - 1.91 (m, 10H), 2.02 - 2.04 (m, 1H), 2.08 - 2.11 (m, 1H), 3.35 (s, 3H), 3.83 - 3.87 (m, 1H), 4.10 - 4.17 (m, 2H), 4.67 (d, J = 7.8 Hz, 1H), 4.73 (d, J = 7.2 Hz, 1H), 4.87 (dddt, J = 2.4, 9.0, 19.2, 51.6 Hz, 1H), 5.45 (brs, 1H); 13 13C NMR (150 MHz, CDCl3) δ 12.1, 14.3, 18.7, 22.1, 23.8, 25.9, 27.4, 27.5, 29.6, 32.2, 40.1, 42.8 (d, J = 21.5 Hz), 47.1, 47.9 (d, J = 20.1 Hz), 55.1, 56.8, 57.0, 59.5, 75.3, 88.5 (d, J = 165.2 Hz), 91.0, 112.1, 163.1, 166.9; HRMS (ESI + ) calcd for C 24 H<H 41 O4FNa [M+Na] + 435.2881 found 435.2888.

[0195] Synthesis of Ethyl 2-{(1R,3aS,7aR,E)-1-[(2R,4S)-4-fluoro-6-(methoxymethoxy)-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene} acetate (59)

Chem.

[0196] 4-Methylmorpholine N-oxide (87.8 mg, 0.75 mmol) was added to a solution of compound 55 (111.1 mg, 0.37 mmol) in CHCl (4 mL), and the mixture was cooled to 0 °C. TPAP (72.5 mg, 0.21 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 90 min. The reaction was diluted with excess EtO. The mixture was directly purified by flash column chromatography on silica gel (EtO only) to give the crude ketone, which was used in the next reaction without further purification.

[0197] MOMCl (107.2 mg, 101 μL, 1.33 mmol) was added to a solution of the crude ketone and diisopropylethylamine (258.1 mg, 348 μL, 2.00 mmol) in CHCl (5 mL) cooled to 0 °C, and the mixture was stirred at 0 °C for 25 min and at room temperature for 19 h. The reaction was quenched with HO and saturated aqueous NHCl at 0 °C, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane:EtOAc = 1:1) to give crude MOM-protected ketone 57.

[0198] To a suspension of NaH (106.5 mg, 60% w / w in liquid paraffin, 2.66 mmol) in THF (2 mL) was added (EtO)P(O)CHCOEt (671.3 mg, 599 μL, 3.0 mmol) at 0 °C, and the mixture was stirred at 0 °C for 15 min. The crude ketone 57 was dissolved in THF (2 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 93 h, the reaction mixture was quenched with HO and saturated aqueous NHCl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give the ethyl ester 59 (64.3 mg, 42%, 3 steps) as a colorless oil.

[0199] Compound 59: [α] D 27 +83.8 (c 0.59, CHCl3); IR (neat) 1714, 1647, 1468, 1384, 1152, 1041 cm -1 ; 1 1H NMR (400 MHz, CDCl3) δ 0.59 (s, 3H), 1.02 (d, J = 6.0 Hz, 3H), 1.26 - 1.81 (m, 21H), 1.89 - 2.03 (m, 2H), 2.10 (t, J = 9.4 Hz, 1H), 3.36 (s, 3H), 3.83 - 3.88 (m, 1H), 4.09 - 4.20 (m, 2H), 4.69 (d, J = 7.2 Hz, 1H), 4.73 (d, J = 7.2 Hz, 1H), 4.74 - 4.93 (m, 1H), 5.45 (brs, 1H); 13 13C NMR (100 MHz, CDCl3) δ 12.0, 14.3, 19.0, 22.1, 23.7, 25.8, 27.5, 27.6, 29.5, 34.2 (d, J = 4.8 Hz), 40.1, 42.2 (d, J = 20.0 Hz), 47.0, 47.5 (d, J = 20.0 Hz), 55.1, 56.7, 56.9, 59.4, 75.2, 90.7 (d, J = 164.9 Hz), 90.9, 112.7, 163.0, 166.9; HRMS (ESI + ) calcd for C 24 1H 41 O4FNa [M+Na] + 435.2881 found 435.2894.

[0200] Synthesis of 2-{(1R,3aS,7aR,E)-1-[(2R,4R)-4-Fluoro-6-(methoxymethoxy)-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene}ethan-1-ol (60) [ka]

[0201] To a solution of ethyl ester 58 (111.6 mg, 0.27 mmol) in toluene (10 mL) was added DIBAL-H (788 μL, 1.03 mol / L hexane solution, 0.811 mmol) at −78 °C, and the mixture was stirred at room temperature for 10 min. The reaction was quenched with HO and saturated aqueous potassium sodium tartrate at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 60 (88.2 mg, 88%) as a colorless oil.

[0202] Compound 60: [α] D 27 +65.8 (c 2.19, CHCl3); IR (neat) 3423, 1464, 1384, 1148, 1038 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.57 (s, 3H), 0.99-1.12 (m, 4H), 1.24-2.03 (m, 22H), 3.36 (s, 3H), 4.15-4.23 (m, 2H), 4.68 (d, J = 7.2 Hz, 1H), 4.74 (d, J = 7.2 Hz, 1H), 4.88 (dddt, J = 2.4, 8.4, 10.8, 51.6 Hz, 1H), 5.21 (t, J = 6.9 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 11.8, 18.8, 22.2, 23.4, 25.9, 27.6, 28.7, 32.4, 40.4, 42.9 (d, J = 20.1 Hz), 45.4, 47.9 (d, J = 20.1 Hz), 55.2, 55.6, 56.9, 58.7, 75.3, 88.6 (d. +) calcd for C 22 H 39 O3FNa [M+Na] + 393.2775, found 393.2789.

[0203] Synthesis of 2-{(1R,3aS,7aR,E)-1-[(2R,4S)-4-Fluoro-6-(methoxymethoxy)-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene}ethan-1-ol (61) [ka]

[0204] To a solution of ethyl ester 59 (64.3 mg, 0.16 mmol) in toluene (5 mL) was added DIBAL-H (450 μL, 1.03 mol / L hexane solution, 0.47 mmol) at −78 °C, and the mixture was stirred at room temperature for 10 min. The reaction was quenched with HO and saturated aqueous potassium sodium tartrate at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 61 (50.3 mg, 87%) as a colorless oil.

[0205] Compound 61: [α] D 27 +51.7 (c 1.97, CHCl3); IR (neat) 3411, 1468, 1384, 1145, 1041 cm -1 ; 11H NMR (400 MHz, CDCl3) δ 0.56 (s, 3H), 1.01 (d, J = 6.0 Hz, 3H), 1.19 - 2.01 (m, 24H), 2.60 - 2.64 (m, 1H), 3.35 - 3.36 (m, 3H), 4.15 - 4.24 (m, 2H), 4.69 (dd, J = 1.0, 7.2 Hz, 1H), 4.72 (dd, J = 1.0, 6.6 Hz, 1H), 4.75 - 4.93 (m, 1H), 5.21 (t, J = 6.9 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 11.7, 19.5, 22.1, 23.4, 25.8, 27.5, 27.8, 28.6, 34.3 (d, J = 5.7 Hz), 40.3, 42.3 (d, J = 20.0 Hz), 45.3, 47.5 (d, J = 20.0 Hz), 55.1, 55.5, 56.8, 58.6, 75.3, 90.8 (d, J = 165.0 Hz), 90.9, 119.4, 143.4; HRMS (ESI + ) calcd for C 22 H 39 O3FNa [M+Na] + 393.2775, found 393.2789.

[0206] Synthesis of 2-[(2-{(1R,3aS,7aR,E)-1-[(2R,4R)-4-Fluoro-6-(methoxymethoxy)-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene}ethyl)sulfonyl]benzo[d]thiazole (64)

Chem.

[0207] To a solution of 2-mercaptobenzothiazole (78.7 mg, 0.47 mmol), PhP (159.0 mg, 0.61 mmol), and CD ring 60 (88.1 mg, 0.238 mmol) in CHCl (8 mL) was added diisopropyl azodicarboxylate (250 μL, 1.9 mol / L toluene solution, 0.48 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 5:1) to give crude sulfide 62.

[0208] The crude sulfide 62 was dissolved in EtOH (5 mL), and the solution was diluted with 30% hydrogen peroxide (1 mL) and (NH)MoO 24 4H2O (299.5 mg, 0.24 mmol) was added. After stirring at room temperature for 2 h, the mixture was poured into H2O and extracted three times with EtOAc. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 3:1) to give compound 64 (103.6 mg, 79%, 2 steps) as a colorless oil.

[0209] Compound 64: [α] D 27 +48.9 (c 2.03, CHCl3); IR (neat) 1471, 1332, 1148, 1041, 918, 759, 739 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.25 (s, 3H), 0.90 (d, J = 6.6 Hz, 3H), 1.01 (dddd, J = 1.8, 10.2, 14.4, 40.2 Hz, 1H), 1.16 - 1.90 (m, 21H), 2.53 - 2.55 (m, 1H), 3.33 (s, 3H), 4.19 (dd, J = 6.3, 14.4 Hz, 1H), 4.42 (dd, J = 9.0, 14.4 Hz, 1H), 4.65 (d, J = 7.2 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 4.94 (ddt, J = 1.8, 10.8, 51.6 Hz, 2H), 4.98 - 5.01 (m, 1H), 7.56 - 7.63 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 11.5, 18.6, 22.0, 23.1, 25.9, 27.4, 27.5, 28.9, 32.2, 39.9 42.7 (d, J = 5.9 Hz), 45.7, 47.8 (d, J = 20.1 Hz), 53.8, 55.1, 55.9, 56.6, 75.2, 88.5 (d, J = 165.2 Hz), 90.9, 104.3, 122.2, 125.3, 127.5, 127.8, 136.9, 151.8, 152.8, 165.9; HRMS (ESI + ) calcd for C 29 H 42 NO4FS2Na [M+Na] + 574.2432, found 574.2460.

[0210] Synthesis of 2-[(2-{(1R,3aS,7aR,E)-1-[(2R,4S)-4-Fluoro-6-(methoxymethoxy)-6-methylheptan-2-yl]-7a-methyloctahydro-4H-inden-4-ylidene}ethyl)sulfonyl]benzo[d]thiazole (65) [ka]

[0211] To a solution of 2-mercaptobenzothiazole (27.8 mg, 0.17 mmol), Ph3P (39.7 mg, 0.15 mmol), and CD ring 61 (24.2 mg, 0.065 mmol) in CHCl (5 mL) was added diisopropyl azodicarboxylate (69 μL, 1.9 mol / L toluene solution, 0.13 mmol) at 0 °C, and the mixture was stirred at 0 °C for 15 min. After quenching the reaction with HO at 0 °C, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give crude sulfide 63 (25.8 mg).

[0212] The crude sulfide 63 (25.8 mg) was dissolved in EtOH (10 mL), and the solution was added with 30% HO (2 mL) and (NH)MoO. 24 4H2O (60.5 mg, 0.049 mmol) was added. After stirring at room temperature for 20 h, the mixture was poured into H2O and extracted three times with EtOAc. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified on a preparative silica gel TLC plate (hexane: EtOAc = 3:1) to give compound 65 (26.7 mg, 79%, 2 steps) as a colorless oil.

[0213] Compound 65: [α] D 27 +41.2 (c 2.05, CHCl3); IR (neat) 1471, 1380, 1324, 1141, 1089, 1041, 918, 767, 735 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.27 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H), 1.17-1.91 (m, 22H), 2.54-2.56 (m, 1H), 3.35 (s, 3H), 4.20 (dd, J = 6.6, 14.4 Hz, 1H), 4.42 (dd, J = 9.0, 14.4 Hz, 1H), 4.68 (d, J = 7.8 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 5.00-5.03 (m, 1H), 7.57-7.65 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.2, 20.1, 22.8, 23.8, 26.5, 28.2, 28.4, 29.7, 34.9 (d, J = 5.9 Hz), 40.6, 43.0 (d, J = 20.1 Hz), 46.4, 48.2 (d, J = 20.1 Hz), 54.6, 55.8, 56.6, 57.3, 76.0, 91.5 (d, J = 165.2 Hz), 91.7, 105.0, 122.9, 126.0, 128.3, 128.6, 137.6, 152.6, 153.5, 166.6; HRMS (ESI + calcd for C 29 H 42 NO4FS2Na [M+Na] + 574.2432, found 574.2443.

[0214] Synthesis of 23RF-MART-10 and 23RF-MART-11

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[0215] To a solution of sulfone 64 (103.6 mg, 0.19 mmol) in THF (1.0 mL) was added LiHMDS (289 μL, 1.0 mol / L THF solution, 0.29 mmol) at −78 °C. After stirring the mixture at the same temperature for 20 min, ring A (58.7 mg, 0.11 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 1 h. After quenching the reaction with saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1 to 3:1) to give the protected coupling product as an inseparable mixture of isomers.

[0216] p-Toluenesulfonic acid monohydrate (1.14 g, 6.0 mmol) was added to a solution of the above coupling compound in MeOH (50 mL) and CHCl (10 mL). The mixture was stirred in air at room temperature for 17 h. After the reaction was quenched with HO and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative silica gel TLC (with EtOAc only) to give 23RF-MART-10 and 23RF-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO = 9:1 solvent system to give 23RF-MART-10 (10.2 mg, 19%, 2 steps) and 23RF-MART-11 (6.6 mg, 12%, 2 steps), respectively, as white powders.

[0217] 23RF-MART-10: [α] D 27 +58.8 (c 0.79, EtOH); IR (neat) 3379, 1615, 1440, 1384, 1157, 1049 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.56 (s, 3H), 1.00-1.30 (m, 4H), 1.26-2.17 (m, 31H), 2.60 (dd, J = 4.2, 13.2 Hz, 1H), 2.79-2.86 (m, 2H), 3.64-3.70 (m, 3H), 4.10 (brs, 1H), 4.95 (dt, J = 10.2, 51.0 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 6.36 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.1, 18.8, 22.3, 23.4, 27.6, 28.8, 29.8, 29.8, 30.0, 32.4, 35.5, 40.5, 42.7 (d, J = 20.1 Hz), 45.3, 45.8, 48.6, 48.7 (d, J = 18.8 Hz), 56.3, 56.8, 62.9, 68.6, 70.2, 71.6, 90.0 (d, J = 162.3 Hz), 115.3, 123.9, 131.3, 142.9; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3520.

[0218] 23RF-MART-11: [α] D 27 +21.4 (c 0.51, CHCl3); IR (neat) 3355, 1615, 1451, 1376, 1157, 1053 cm -1 ; 1H NMR (600 MHz, CD3OD) δ 0.63 (s, 3H), 1.06-1.19 (m, 4H), 1.26-2.09 (m, 32H), 2.34-2.39 (m, 2H), 2.88 (dd, J = 4.2, 12.6 Hz, 1H), 3.03 (dd, J = 4.2, 13.2 Hz, 1H), 3.54 (td, J = 4.2, 10.2 Hz, 1H), 3.62 (t, J = 12.0 Hz, 2H), 4.08-4.08 (m, 1H), 4.87-4.98 (m, 1H), 5.93 (d, J = 11.4 Hz, 1H), 6.21 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CD3OD) δ 12.7, 19.6, 23.6, 24.8, 24.8, 29.0, 29.1, 30.2, 31.3, 31.5, 34.1, 38.8, 42.2, 44.5 (d, J = 21.6 Hz), 45.1, 47.2, 50.4, 50.6 (d, J = 20.1 Hz), 57.8, 58.5, 63.7, 69.1, 70.9, 71.6, 90.1 (d, J = 162.3 Hz), 117.5, 123.2, 134.3, 142.1; HRMS (ESI + calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3512.

[0219] Synthesis of 23SF-MART-10 and 23SF-MART-11

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[0220] To a solution of sulfone 65 (114.4 mg, 0.21 mmol) in THF (1.0 mL) was added LiHMDS (332 μL, 1.0 mol / L THF solution, 0.33 mmol) at −78 °C. After stirring the mixture at the same temperature for 20 min, ring A (68.7 mg, 0.13 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 1 h. After quenching the reaction with saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1 to 3:1) to give the protected coupling product as an inseparable mixture of isomers.

[0221] p-Toluenesulfonic acid monohydrate (1.24 g, 6.52 mmol) was added to a solution of the above coupling compound in MeOH (50 mL) and CHCl (10 mL). The mixture was stirred in air at room temperature for 17 h. After the reaction was quenched with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative silica gel TLC (with EtOAc only) to give 23SF-MART-10 and 23SF-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CH3CN:HO = 9:1 solvent system to give 23SF-MART-10 (14.6 mg, 24%, 2 steps) and 23SF-MART-11 (14.8 mg, 24%, 2 steps), respectively, as white powders.

[0222] 23SF-MART-10: [α] D 27 +37.7 (c 1.12, CH3Cl); IR (neat) 3371, 1440, 1376, 1157, 1049, 909 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.54 (s, 3H), 1.00 (d, J = 6.6 Hz, 3H), 1.21-2.04 (m, 31H), 2.13-2.17 (m, 2H), 2.60 (dd, J = 4.2, 12.3 Hz, 1H), 2.78-2.81 (m, 1H), 2.84 (dd, J = 4.2, 13.8 Hz, 1H), 3.63-3.74 (m, 3H), 4.09-4.10 (m, 1H), 4.67-4.99 (m, 1H), 5.81 (d, J = 11.4 Hz, 1H), 6.36 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.0, 19.4, 22.2, 23.4, 23.4, 27.9, 28.8, 29.6, 29.9, 30.0, 34.3 (d, J = 5.7 Hz), 35.5, 40.4, 42.2 (d, J = 20.1 Hz), 45.3, 45.8, 48.0 (d, J = 20.1 Hz), 48.7, 56.2, 56.8, 62.9, 68.6, 70.2, 71.5, 92.3 (d, J = 162.3 Hz), 115.4, 123.9, 131.4, 142.9; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3526.

[0223] 23SF-MART-11: [α] D 27 +19.4 (c 1.14, EtOH); IR (neat) 3323, 1440, 1384, 1157, 1041, 993 cm -1 ; 1H NMR (600 MHz, CD3OD) δ 0.62 (s, 3H), 1.07 (d, J = 6.0 Hz, 3H), 1.27-1.83 (m, 18H), 1.88-1.92 (m, 1H), 1.97-2.09 (m, 3H), 2.33-2.39 (m, 2H), 2.87 (dd, J = 4.2, 12.0 Hz, 1H), 3.03 (dd, J = 4.8, 13.2 Hz, 1H), 3.54 (td, J = 3.6, 9.6 Hz, 1H), 3.58-3.63 (m, 2H), 4.08-4.08 (m, 1H), 4.80-4.93 (m, 1H), 5.93 (d, J = 10.8 Hz, 1H), 6.20 (d, J = 10.8 Hz, 1H); 13 C NMR (150 MHz, CD3OD) δ 12.6, 20.5, 23.6, 24.8, 29.1, 29.2, 30.1, 31.2, 31.5, 36.0 (d, J = 5.7 Hz), 38.8, 42.2, 35.5, 40.4, 44.0 , 123.2, 134.4, 142.1; HRMS (ESI + calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3512.

[0224] "Manufacturing Example 6:22-Synthesis of Monoflurane"

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[0225] 参考文献1:Grzywacz, P.;Plum, L. A.;Sicinski, R. R.;Clagett-Dame, M.;DeLuca, H. F. 2-亚甲基-19-去甲-1α,25-二羟基维生素D3(2MD)上25-羟基的甲基取代降低了活性,但具有骨选择性。《生物化学与生物物理学报》,2007年,第460卷,第274 - 284页。 参考文献2:Wovkulich, P. M.;Barcelos, F.;Batcho, A. D.;Sereno, J. F.;Baggiolini, E. G.;Hennessy, B. M.;Uskokovic, M. R. 1α,25S,26-三羟基胆钙化醇的立体选择性全合成。《四面体》,1984年,第40卷(12期),第2283 - 2296页。

[0226] (3R,4S)-4-{(1R,3aR,4S,7aR)-4-[(叔丁基二甲基甲硅烷基)氧基]-7a-甲基八氢-1H-茚-1-基}戊-1-烯-3-醇(103)

Chem.

[0227] To a solution of compound 101 [see Ref. 1 above] (3.06 g, 9.42 mmol) in diethyl ether (26 mL) was added vinylmagnesium bromide (28.3 mL, 1.0 mol / L THF solution, 28.3 mmol) at 0 °C, and the mixture was stirred at 0 °C for 5 minutes. The reaction was quenched with HO and saturated aqueous NH4Cl, and the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (CHCl2:Et2O = 20:1) to give compound 102 [see Ref. 2 above] (1.51 g, 45%) (less polar) and compound 103 (243.8 mg, 7%) (more polar), respectively, as white powders.

[0228] Compound 103: [α] D 27 +54.7 (c 3.12, CHCl3); IR (neat) 3368, 1471, 1253, 1169, 1085, 1021, 830, 778 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.90 (d, J = 6.6 Hz, 3H), 0.94 (s, 3H), 0.98-1.04 (m, 1H), 1.08-1.12 (m, 1H), 1.21 (ddd, J = 3.0, 6.6, 13.2 Hz, 1H), 1.31-1.39 (m, 4H), 1.55-1.47 (m, 6H), 1.93 (dt, J = 3.0, 12.6 Hz, 1H), 3.98-4.00 (m, 1H), 4.18-4.19 (m, 1H), 5.15-5.17 (m, 1H), 5.22-5.25 (m, 1H), 5.85 (ddd, J = 6.0, 10.2, 17.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 12.3, 13.7, 17.6, 18.0, 23.1, 25.8, 26.7, 34.4, 40.6, 41.4, 42.3, 52.7, 53.6, 69.3, 74.7, 116.1, 137.1; HRMS (ESI + ) calcd for C 21 H 40 O2SiNa [M+Na] + 375.2690, found 375.2683.

[0229] (2S,3R,4S)-4-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-3-[(triethylsilyl)oxy]pentane-1,2-diol (104) [ka]

[0230] TESCl (641.0 mg, 712 μL, 4.25 mmol) was added to a solution of compound 102 (507.5 mg, 1.44 mmol) and imidazole (387.0 mg, 5.68 mmol) in CHCl (8 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 16 h 40 min. After quenching the reaction with H2O and saturated aqueous NH4Cl, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane only) to give the crude product.

[0231] A mixture of AD-mix β (9.9 g) in tBuOH (15 mL) and HO (15 mL) was stirred at 0 °C for 30 min. The crude product obtained above was added to the mixture at 0 °C and stirred at the same temperature for 1 h, followed by stirring at room temperature overnight in air. After quenching the reaction with HO, the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane: EtOAc = 2:1) to give compound 104 (568.4 mg, 80%, 2 steps) as a colorless oil.

[0232] Compound 104: [α] D 27 +18.8 (c 1.40, CHCl3); IR (neat) 3355, 1464, 1249, 1101, 1025, 842, 739 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.63 (q, J = 7.8 Hz, 6H), 0.88 (s, 9H), 0.91 (d, J = 7.2 Hz, 3H), 0.94 (s, 3H), 0.97 (t, J = 8.4 Hz, 9H), 1.10 (td, J = 3.6, 13.2 Hz, 1H), 1.19-1.27 (m, 2H), 1.30-1.40 (m, 4H), 1.54-1.69 (m, 3H), 1.77-1.98 (m, 6H), 3.57-3.65 (m, 2H), 3.67-3.75 (m, 2H), 3.99-4.00 (m, 1H); 13 C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 5.5, 7.0, 13.0, 13.3, 17.6, 18.0, 23.1, 25.8, 27.8, 34.4, 38.1, 40.7, 42.2, 53.0, 53.3, 64.4, 69.4, 73.5, 75.4; HRMS (ESI + ) calcd for C 27 H 56 O4Si2Na [M+Na] +523.3609, found 523.3622.

[0233] (2S,3S,4S)-4-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-3-[(triethylsilyl)oxy]pentane-1,2-diol (105) [ka]

[0234] TESCl (282.0 mg, 313 μL, 1.87 mmol) was added to a solution of compound 103 (220.9 mg, 0.62 mmol) and imidazole (184.6 mg, 2.71 mmol) in CHCl (2 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 15 min. The reaction was quenched with H2O and saturated aqueous NH4Cl, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 100:1) to give the crude product.

[0235] A mixture of AD-mix β (4.88 g) in tBuOH (8 mL) and HO (8 mL) was stirred at 0 °C for 30 min. The crude product obtained above was added to the mixture at 0 °C and stirred at the same temperature for 1 h, followed by stirring at room temperature for 18 h in air. After quenching the reaction with HO, the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 3:1) to give compound 105 (183.3 mg, 59%, 2 steps) as a colorless oil.

[0236] Compound 105: [α] D 27 +38.8 (c 2.98, CHCl3); IR (neat) 3390, 1471, 1253, 1081, 1029, 838, 746 cm-1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.62 (q, J = 7.8 Hz, 6H), 0.89 (s, 9H), 0.90 (d, J = 9.6 Hz, 3H), 0.96 - 0.99 (m, 12H), 1.13 (td, J = 3.6, 13.2 Hz, 1H), 1.21 - 1.39 (m, 6H), 1.54 - 1.62 (m, 1H), 1.66 - 1.72 (m, 2H), 1.75 - 1.88 (m, 2H), 1.92 - 1.96 (m, 1H), 2.19 (brs, 2H), 3.67 (q, J = 4.2 Hz, 1H), 3.70 - 3.76 (m, 2H), 3.92 (t, J = 4.2 Hz, 1H), 3.99 - 4.01 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.1, -4.8, 5.0, 6.8, 13.1, 13.3, 17.6, 18.0, 23.0, 25.8, 26.7, 34.4, 40.6, 41.2, 42.5, 52.5, 53.7, 65.2, 69.3, 71.0, 77.3; HRMS (ESI + ) calcd for C 27 H 56 O4Si2Na [M + Na] + 523.3609, found 523.3627.

[0237] (2R,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-hydroxybutanoic acid (108)

Chem.

[0238] Sodium periodate (1.67 g, 7.80 mmol) was added to a solution of diol 104 (568.4 mg, 1.13 mmol) in MeOH (15 mL) and HO (3 mL), and the mixture was stirred in air at room temperature for 3 h. After quenching the reaction with HO at room temperature, the mixture was extracted three times with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 10:1) to give crude aldehyde 106.

[0239] To a mixture of the crude aldehyde 106 in HO (6 mL) and tBuOH (12 mL), NaHPO (4.30 g, 28.7 mmol), 2-methyl-2-butene (216.7 mg, 328 μL, 3.09 mmol), and NaClO (1.03 g, 11.4 mmol) were added in air at 0 °C, and the whole mixture was stirred at the same temperature for 20 min. After the reaction was quenched with saturated aqueous NHCl and saturated aqueous sodium thiosulfate, the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated to give a crude residue. The crude residue was used in the next reaction without further purification.

[0240] To the crude residue in CHCl (8 mL) was added tetrabutylammonium fluoride (4.5 mL, 1 mol / L THF solution, 4.5 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 min. After the reaction was quenched with H0 and saturated aqueous NHCl at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 1:1) to give compound 108 (267.9 mg, 64%, 3 steps) as a colorless oil.

[0241] Compound 108: [α] D 27 +10.5 (c 1.51, CHCl3); IR (neat) 3450, 1714, 1253, 1093, 838, 770 cm -1 ;1 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.87 - 0.89 (m, 12H), 0.96 (s, 3H), 1.16 (td, J = 3.2, 12.8 Hz, 1H), 1.29 - 1.51 (m, 6H), 1.57 - 1.69 (m, 2H), 1.74 - 1.99 (m, 4H), 4.00 - 4.01 (m, 1H), 4.33 (d, J = 1.8 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 12.9, 13.7, 17.6, 18.0, 22.8, 25.8, 26.8, 34.3, 39.0, 40.5, 41.9, 52.4, 53.0, 69.3, 73.2, 179.9; HRMS (ESI - ) calcd for C 20 H 38 O4Si [M - H] - 369.2467, found 369.2454.

[0242] (2S,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-hydroxybutanoic acid (109)

Chem.

[0243] Sodium periodate (1.30 g, 6.08 mmol) was added to a solution of diol 105 (486.2 mg, 0.97 mmol) in MeOH (20 mL) and HO (4 mL), and the mixture was stirred in air at room temperature for 80 min. After quenching the reaction with HO at room temperature, the mixture was extracted three times with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 10:1) to give crude aldehyde 107.

[0244] To a mixture of the crude aldehyde 107 in HO (10 mL) and tBuOH (10 mL), NaHPO (3.64 g, 24.3 mmol), 2-methyl-2-butene (408.0 mg, 619 μL, 5.82 mmol), and NaClO (146.4 mg, 1.62 mmol) were added in air at 0 °C, and the whole mixture was stirred at the same temperature for 20 min. After the reaction was quenched with saturated aqueous NHCl and saturated aqueous sodium thiosulfate, the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated to give a crude residue. The crude residue was used in the next reaction without further purification.

[0245] To the crude residue in CHCl (10 mL) was added tetrabutylammonium fluoride (3.9 mL, 1 mol / L THF solution, 3.9 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 min. After the reaction was quenched with H0 and saturated aqueous NHCl at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 1:1) to give compound 109 (178.2 mg, 50%, 3 steps) as a colorless oil.

[0246] Compound 109: [α] D 27 +52.1 (c 0.42, CHCl3); IR (neat) 3283, 1730, 1249, 1077, 834, 774 cm -1 ;1 1H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.94 (s, 3H), 0.98 (d, J = 6.6 Hz, 3H), 1.15 (td, J = 3.6, 13.2 Hz, 1H), 1.25 - 1.41 (m, 7H), 1.46 - 1.51 (m, 1H), 1.56 - 1.63 (m, 1H), 1.66 - 1.68 (m, 1H), 1.76 - 1.83 (m, 1H), 1.90 - 1.97 (m, 3H), 4.00 - 4.01 (m, 1H), 4.28 (d, J = 2.4 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.6, 14.5, 17.6, 18.0, 23.1, 25.8, 26.6, 34.4, 40.5, 41.0, 42.3, 52.1, 52.7, 69.3, 73.6, 177.5; HRMS (ESI - ) calcd for C 20 18 38 H36O4Si [M - H] - 369.2467, found 369.2467.

[0247] Methyl (2R,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-hydroxybutanoate (110)

Chem.

[0248] Trimethylsilyldiazomethane (574 μL, 2.0 mol / L diethyl ether solution, 1.15 mmol) was added to a solution of compound 108 (142.0 mg, 0.38 mmol) in MeOH (1 mL) and CHCl (3 mL) at 0 °C, and the mixture was stirred at the same temperature for 1 h. After the reaction was quenched with acetic acid and saturated aqueous NaHCO, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane:EtOAc = 5:1) to give compound 110 (113.6 mg, 77%) as a colorless oil.

[0249] Compound 110: [α] D 27 +6.6 (c 6.90, CHCl3); IR (neat) 3526, 1734, 1253, 1097, 838, 774 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.80 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H), 0.95 (s, 3H), 1.16 (td, J = 3.0, 13.2 Hz, 1H), 1.31-1.50 (m, 6H), 1.55-1.68 (m, 2H), 1.76-1.97 (m, 4H), 3.79 (s, 3H), 3.99-4.01 (m, 1H), 4.25 (d, J = 2.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 12.8, 13.8, 17.6, 18.0, 22.9, 25.8, 26.9, 34.3, 40.5, 41.0, 41.9, 52.3, 52.5, 53.0, 69.4, 73.3, 176.1; HRMS (ESI + ) calcd for C 21 H 40 O4SiNa [M+Na] + 407.2588, found 407.2605.

[0250] Methyl (2S,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-hydroxybutanote (111) [ka]

[0251] Trimethylsilyldiazomethane (1.24 mL, 2.0 mol / L diethyl ether solution, 2.48 mmol) was added to a solution of compound 109 (306.5 mg, 0.83 mmol) in MeOH (2 mL) and CHCl (6 mL) at 0 °C, and the mixture was stirred at the same temperature for 15 min. The reaction was quenched with acetic acid and saturated aqueous NaHCO, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give compound 111 (274.1 mg, 86%) as a colorless oil.

[0252] Compound 111: [α] D 27 +61.5 (c 2.31, CHCl3); IR (neat) 3530, 1734, 1256, 1085, 1021, 842, 778 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.93 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H), 1.12 (td, J = 3.6, 12.8 Hz, 1H), 1.24-1.41 (m, 6H), 1.53-1.70 (m, 3H), 1.73-1.96 (m, 4H), 3.79 (s, 3H), 3.99-4.01 (m, 1H), 4.18 (d, J = 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.5, 14.9, 17.6, 18.0, 23.1, 25.8, 26.5, 34.4, 40.5, 41.0, 42.3, 52.1, 52.2, 52.7, 69.3, 74.0, 175.4; HRMS (ESI + ) calcd for C 21 H 40 O4SiNa [M+Na] + 407.2588, found 407.2589.

[0253] Methyl (2R,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluorobutanote (112) [ka]

[0254] DAST (70.1 mg, 55 μL, 0.43 mmol) was added to a solution of compound 111 (23.9 mg, 0.062 mmol) in THF (0.5 mL) at 0 °C, and the mixture was stirred at room temperature for 45 h 30 min. The reaction was quenched with MeOH, HO, and saturated aqueous NaHCO at 0 °C, and the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 7:1) to give compound 112 (6.0 mg, 24%) as a colorless oil.

[0255] Compound 112: [α] D 27+17.1 (c 2.18, CHCl3); IR (neat) 1770, 1281, 1097, 1041, 842 cm-1; 1H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 0.93 (d, J = 7.2 Hz, 3H), 0.95 (s, 3H), 1.14-1.19 (m, 1H), 1.25-1.48 (m, 5H), 1.53-2.02 (m, 7H), 3.79 (s, 3H), 4.00-4.01 (m, 1H), 4.96 (dd, J = 1.5, 49.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.1 (d, J = 4.2 Hz), 13.6, 17.6, 18.0, 22.8, 25.8, 26.7, 34.2, 38.7 (d, J = 20.3 Hz), 40.4, 41.9, 51.9, 52.1, 52.9, 69.2, 91.9 (d, J = 186.8 Hz), 170.7 (d, J = 24.3 Hz); HRMS (ESI+) calcd for C 21 H 39 O3FSiNa [M+Na] + 409.2545, found 409.2552.

[0256] [[ID=,10]]Methyl (2S,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluorobutanoate (113)

Chem.

[0257] DAST (222.3 mg, 182 μL, 1.38 mmol) was added to a solution of compound 110 (23.9 mg, 0.062 mmol) in CHCl (1.5 mL) at 0 °C, and the mixture was stirred at the same temperature for 3 h 40 min. The reaction was quenched with MeOH, HO, and saturated aqueous NaHCO at 0 °C, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give compound 113 (33.7 mg, 44%) as a colorless oil.

[0258] Compound 113: [α] D 27 +25.1 (c 0.40, CHCl3); IR (neat) 1742, 1253, 1089, 1021, 838 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.94 (s, 3H), 1.01 (d, J = 6.6 Hz, 3H), 1.11-1.16 (m, 1H), 1.25-1.95 (m, 11H), 2.05-2.12 (m, 1H), 3.79 (s, 3H), 4.00-4.01 (m, 1H), 4.96 (dd, J = 3.3, 48.0 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.5, 14.6, 17.6, 18.0, 23.1, 25.8, 26.5, 34.3, 39.6 (d, J = 18.8 Hz), 40.4, 42.4, 51.6 (d, J = HRMS (ESI + ) calcd for C 21 H 39 O3FSiNa [M+Na] +409.2545, found 409.2543.

[0259] (2R,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluoro-N-methoxy-N-methylbutanamide (114) [ka]

[0260] To a solution of compound 112 (399.8 mg, 1.03 mmol) and Me(MeO)NH HCl (416.2 mg, 4.26 mmol) in THF (10 mL) was added isopropylmagnesium chloride (8.3 mL, 1 mol / L THF solution, 8.3 mmol) at 0 °C, and the mixture was stirred at the same temperature for 7 min. The reaction was quenched with HO and saturated aqueous NH Cl, and the mixture was extracted three times with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane: EtOAc = 4:1) to give compound 114 (337.8 mg, 85%) as a colorless oil.

[0261] Compound 114: [α] D 27 +2.0 (c 1.02, CHCl3); IR (neat) 1690, 1464, 1384, 1249, 1169, 1081, 1025, 982, 834, 770 cm -1 ; 11H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 0.94 (s, 3H), 0.98 (d, J = 7.3 Hz, 3H), 1.17 (td, J = 3.6, 12.8 Hz, 1H), 1.25 - 2.01 (m, 13H), 3.21 (s, 3H), 3.69 (s, 3H), 4.01 - 4.02 (m, 1H), 5.22 (d, J = 49.9 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 12.5 (d, J = 5.7 Hz), 13.5, 14.6, 17.5, 18.0, 22.8, 25.8, 26.4, 32.3, 34.3, 37.7 (d, J = 21.0 Hz), 40.4, 41.9, 52.3, 52.9, 61.0, 69.2, 90.9 (d, J = 179.3 Hz), 170.3 (d, J = 25.7 Hz); HRMS (ESI + ) calcd for C 22 H 42 NO3FSiNa [M+Na] + 438.2810, found 438.2834.

[0262] (2S,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-z-fluoro-N-methoxy-N-methylbutanamide (115)

Chem.

[0263] To a solution of compound 113 (35.1 mg, 0.091 mmol) and Me(MeO)NH HCl (39.1 mg, 0.40 mmol) in THF (1 mL) was added isopropylmagnesium chloride (1.5 mL, 1 mol / L THF solution, 1.5 mmol) at 0 °C, and the mixture was stirred at the same temperature for 2 h. After the reaction was quenched with HO and saturated aqueous NH Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 3:1) to give compound 115 (24.8 mg, 66%) as a colorless oil.

[0264] Compound 115: [α] D 27 +33.7 (c 0.32, CHCl3); IR (neat) 1683, 1471, 1253, 1165, 1085, 1025, 838, 774 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.94 (s, 3H), 1.05 (d, J = 7.2 Hz, 3H), 1.15 (td, J = 3.6, 13.2 Hz, 1H), 1.21-1.25 (m, 1H), 1.31-1.41 (m, 5H), 1.54-1.61 (m, 1H), 1.64-1.67 (m, 1H), 1.74-1.83 (m, 1H), 1.85-1.94 (m, 2H), 2.10-2.18 (m, 1H), 3.21 (brs, 3H), 3.71 (s, 3H), 3.99-4.00 (m, 1H), 5.02 (dd, J = 4.8, 48 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ -5.1, -4.8, 13.4, 15.1, 17.6, 18.0, 23.3, 25.8, 26.8, 32.2, 34.4, 39.2 (d, J = 20.1 Hz), 40.5, 42.8, 52.4, 52.7, 61.4, 69.3, 92.4 (d, J = 179.6 Hz), 170.0 (d, J = 24.3 Hz); HRMS (ESI + ) calcd for C 22 H 42 NO3FSiNa [M+Na] + 438.2810, found 438.2823.

[0265] Ethyl (4R,5S,E)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-4-fluorohex-2-enoate (118) [ka]

[0266] To a solution of compound 115 (24.8 mg, 0.06 mmol) in THF (1 mL) was added lithium aluminum hydride (7.3 mg, 0.19 mmol) at −78° C., and the mixture was stirred at 0° C. for 70 minutes. After diluting the reaction with MeOH at 0° C., H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 117 as a colorless oil.

[0267] To a suspension of NaH (7.9 mg, liquid paraffin 60% w / w, 0.20 mmol) in THF (0.5 mL) was added (EtO)P(O)CHCOEt (44.0 mg, 39 μL, 0.20 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. The crude product 117 was dissolved in THF (1 mL), and the solution was added to the mixture at 0 °C. After stirring at the same temperature for 10 min, the reaction was quenched with H O and saturated aqueous NH Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 3:1) to give compound 118 (17.8 mg, 85%, 2 steps) as a colorless oil.

[0268] Compound 118: [α] D 27 +44.8 (c 1.69, CHCl3); IR (neat) 1726, 1464, 1304, 1264, 1038, 838 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.00 (s, 3H), 0.89 (s, 9H), 0.90 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H), 1.05 (q, J = 9.6 Hz, 1H), 1.12 (td, J = 4.2, 13.2 Hz, 1H), 1.19-1.42 (m, 10H), 1.58-1.69 (m, 2H), 1.72-1.83 (m, 2H), 1.90-1.92 (m, 1H), 2.03-2.08 (m, 1H), 4.00-4.01 (m, 1H), 4.22 (q, J = 6.6 Hz, 2H), 5.12 (dtd, J = 1.8, 4.2, 46.8 Hz, 1H), 6.08 (d, J = 15.0 Hz, 1H), 6.88 (ddd, J = 4.2, 9.6, 22.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 12.7 (d, J = 2.9 Hz), 13.7, 14.2, 17.6, 18.0, 23.1, 25.8, 26.6, 34.3, 40.1 (d, J = 18.6 Hz), 40.5, HRMS (ESI + ) calcd for C 24 H 43 O3FSiNa [M+Na] + 449.2858, found 449.2878.

[0269] Ethyl (4S,5S,E)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-4-fluorohex-2-enoate (119) [ka]

[0270] To a solution of compound 114 (397.1 mg, 0.96 mmol) in THF (3 mL) was added lithium aluminum hydride (112.8 mg, 2.97 mmol) at −78° C., and the mixture was stirred at 0° C. for 50 minutes. After diluting the reaction with MeOH at 0° C., H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 116 as a colorless oil.

[0271] To a suspension of NaH (234.4 mg, liquid paraffin 60% w / w, 4.13 mmol) in THF (2 mL) was added (EtO)P(O)CHCOEt (864.0 mg, 771 μL, 3.84 mmol) at 0 °C, and the mixture was stirred at 0 °C for 20 min. The crude product 116 was dissolved in THF (4 mL), and the solution was added to the mixture at 0 °C. After stirring at the same temperature for 5 min, the reaction was quenched with H O and saturated aqueous NH Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 10:1) to give compound 119 (349.3 mg, 82%, 2 steps) as a colorless oil.

[0272] Compound 119: [α] D 27 +15.5 (c 0.68, CHCl3); IR (neat) 1726, 1475, 1308, 1268, 1041, 834 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.91 (d, J = 7.2 Hz, 3H), 0.92 (s, 3H), 1.16 (td, J = 3.0, 12.6 Hz, 1H), 1.25-1.49 (m, 11H), 1.57-1.69 (m, 6H), 1.74-1.83 (m, 1H), 1.90-1.96 (m, 2H), 2.03-2.08 (m, 1H), 4.00-4.01 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 5.14-5.23 (m, 1H), 6.05 (dd, J = 1.8, 15.6 Hz, 1H), 6.82 (ddd, J = 2.7, 15.6, 24.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 12.5 (d, J = 5.7 Hz), 13.5, 14.2, 17.6, 18.0, 22.9, 25.8, 26.8, 34.3, 39.8 (d, J = 20.1 Hz), 40.5, 42.0, 52.5, 52.9, 60.5, 69.3, 93.7 (d. + ) calcd for C 24 H 43 O3FSiNa [M+Na] + 449.2858, found 449.2842.

[0273] (1R,3aR,4S,7aR)-1-[(2S,3R)-3-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (122) [ka]

[0274] To a solution of compound 118 (197.2 mg, 0.46 mmol) in MeOH (10 mL) was added 10% Pd / C catalyst (43.2 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen for 24 hours. The reaction mixture was diluted with MeOH, filtered through a Celite pad, and concentrated under reduced pressure to give crude product 120. Crude product 120 was used in the next reaction without further purification.

[0275] To a solution of the crude product 120 in THF (10 mL) was added MeMgCl (1.54 mL, 3.0 mol / L THF solution, 4.62 mmol) at −78° C., and the mixture was stirred at −78° C. for 5 minutes and at 0° C. for 25 minutes. After the reaction was quenched with HO and saturated aqueous NH4Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was used in the next reaction without further purification.

[0276] To the crude residue in MeOH (20 mL) was added p-toluenesulfonic acid monohydrate (886.6 mg, 4.66 mmol), and the mixture was stirred in air at room temperature for 21 h. The reaction was quenched with H2O and saturated aqueous NaHCO3 at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 1:1) to give compound 122 (75.4 mg, 54%, 3 steps) as a white powder.

[0277] Compound 122: [α] D 27 +20.9 (c 0.38, CHCl3); IR (neat) 3407, 1459, 1376, 1260, 1221, 1165, 946 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.95 (d, J = 6.6 Hz, 3H), 0.97 (s, 3H), 1.07 (q, J = 9.6 Hz, 1H), 1.15-1.25 (m, 7H), 1.30-1.72 (m, 12H), 1.75-1.86 (m, 3H), 1.93-2.00 (m, 2H), 4.08-4.09 (m, 1H), 4.41-4.51 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 12.6, 13.4, 17.3, 22.5, 23.2 (d, J = 21.6 Hz), 26.2, 28.9, 29.7, 33.6, 39.5 (d, J = 18.6 Hz), 40.1, 40.3, 42.2, 52.0, 53.1 (d, J = 8.7 Hz), 69.0, 70.6, 97.1 (d, J = 168.0 Hz); + ) calcd for C 18 H 33 OFNa [M+Na] + 323.2357, found 323.2344.

[0278] (1R,3aR,4S,7aR)-1-[(2S,3S)-3-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (123) [ka]

[0279] To a solution of compound 119 (349.3 mg, 0.79 mmol) in MeOH (15 mL) was added 10% Pd / C catalyst (79.6 mg). The mixture was stirred at room temperature under 1 atm of hydrogen for 42 hours. The reaction mixture was diluted with MeOH, filtered through a Celite pad, and concentrated under reduced pressure to give crude product 121. Crude product 121 was used in the next reaction without further purification.

[0280] To a solution of crude 121 in THF (10 mL) was added MeMgCl (1.3 mL, 3.0 mol / L THF solution, 3.93 mmol) at −78° C., and the mixture was stirred at −78° C. for 5 minutes and at 0° C. for 1 hour. The reaction was quenched with HO and saturated aqueous NH4Cl at 0° C., and the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was used in the next reaction without further purification.

[0281] To the crude residue in MeOH (15 mL) was added p-toluenesulfonic acid monohydrate (943.0 mg, 4.96 mmol), and the mixture was stirred in air at room temperature for 71 h. After the reaction was quenched with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with CHCl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 1:1) to give compound 123 (158.4 mg, 67%, 3 steps) as a white powder.

[0282] Compound 123: [α] D 27 +7.3 (c 0.19, CHCl3); IR (neat) 3403, 1464, 1268, 1165, 950 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.91 (s, 3H), 0.93 (d, J = 6.0 Hz, 3H), 1.17-1.64 (m, 20H), 1.75-1.87 (m, 3H), 1.92-1.97 (m, 2H), 4.06-4.07 (m, 1H), 4.44-4.54 (m, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.0 (d, J = 4.4 Hz), 13.3, 17.4, 22.4, 26.6, 27.4 (d, J = 20.1 Hz), 29.1, 29.4, 33.5, 39.5 (d, J = 20.1 Hz), 39.9 (d, J = 4.2Hz), 40.3, 41.6, 52.4, 52.5, 69.2, 70.5, 96.8 (d, J = 169.5Hz) + ) calcd for C 18 H 34 O2F [M+H] + 301.2537, found 301.2538.

[0283] (1R,3aR,7aR)-1-{(2S,3R)-3-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (126) [ka]

[0284] 4-Methylmorpholine N-oxide (120.4 mg, 1.03 mmol) was added to a solution of compound 122 (156.9 mg, 0.52 mmol) in CHCl (12 mL), and the mixture was cooled to 0 °C. TPAP (91.2 mg, 0.26 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO, and the mixture was directly purified by flash column chromatography on silica gel (EtO only) to give crude product 124, which was used in the next reaction without further purification.

[0285] TESCl (1.18 g, 1.31 mL, 7.83 mmol) was added to a solution of crude 124 and imidazole (724.2 mg, 10.6 mmol) in CHCl (8 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 90 min. After quenching the reaction with H2O, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1) to give compound 126 (186.9 mg, 87%, 2 steps) as a colorless oil.

[0286] Compound 126: [α] D 27 +6.9 (c 0.68, CHCl3); IR (neat) 1718, 1464, 1380, 1221, 1049, 743 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 8.4 Hz, 6H), 0.67 (s, 3H), 0.95 (t, J = 7.8 Hz, 9H), 1.00 (d, J = 6.6 Hz, 3H), 1.21 (s, 3H), 1.24 (s, 3H), 1.38 - 1.67 (m, 9H), 1.70 - 1.82 (m, 3H), 1.87 - 1.99 (m, 2H), 2.01 - 2.05 (m, 1H), 2.12 - 2.14 (m, 1H), 2.21 - 2.32 (m, 2H), 2.40 - 2.43 (m, 1H), 4.43 (ddd, J = 2.4, 3.6, 47.4 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.8, 7.1, 12.4, 12.9 (d, J = 3.0 Hz), 19.2, 23.3 (d, J = 21.6 Hz), 24.0, 26.6, 29.4, 30.5, 39.0, 39.8 (d, J = 18.8 Hz), 40.9, 41.4, 50.1, 53.5 (d, J = 8.6 Hz), 61.4, 73.0, 97.1 (d, J = 168.0 Hz), 211.5; HRMS (ESI + ) calcd for C 24 H 45 O2FSiNa [M+Na] + 435.3065, found 435.3089.

[0287] (1R,3aR,7aR)-1-{(2S,3S)-3-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (127)

Chem.

[0288] 4-Methylmorpholine N-oxide (43.0 mg, 0.37 mmol) was added to a solution of compound 123 (35.2 mg, 0.12 mmol) in CHCl (3 mL), and the mixture was cooled to 0 °C. TPAP (23.2 mg, 0.07 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO, and the mixture was directly purified by flash column chromatography on silica gel (EtO only) to give crude product 125, which was used in the next reaction without further purification.

[0289] TESCl (264.5 mg, 294 μL, 1.76 mmol) was added to a solution of crude 125 and imidazole (158.9 mg, 2.33 mmol) in CHCl (3 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 1 h. After quenching the reaction with H2O, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1) to give compound 127 (45.7 mg, 95%, 2 steps) as a colorless oil.

[0290] Compound 127: [α] D 27 -5.0 (c 0.51, CHCl3); IR (neat) 1714, 1464, 1380, 1240, 1053, 739 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 8.4 Hz, 6H), 0.65 (s, 3H), 0.94 (t, J = 7.8 Hz, 9H), 1.01 (d, J = 7.2 Hz, 3H), 1.21 (s, 3H), 1.22 (s, 3H), 1.31-1.95 (m, 12H), 1.99-2.06 (m, 2H), 2.10-2.12 (m, 1H), 2.21-2.31 (m, 2H), 2.49-2.52 (m, 1H), 4.47 (ddd, J = 3.6, 9.0, 48.0Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.7, 7.1, 12.2 (d, J = 5.7 Hz), 12.3, 19.0, 24.0, 27.0, 27.4 (d, J = 21.5 Hz), 29.7, 30.1, 38.9, 39.8 (d, J = HRMS (ESI + ) calcd for C 24 H 45 O2FSiNa [M+Na] + 435.3065, found 435.3026.

[0291] Ethyl 2-[(1R,3aS,7aR,E)-1-{(2S,3R)-3-fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]acetate (128) [ka]

[0292] To a suspension of NaH (167.5 mg, liquid paraffin 60% w / w, 4.19 mmol) in THF (3 mL) was added (EtO)P(O)CHCOEt (1.02 g, 909 μL, 4.53 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. Ketone 26 (186.9 mg, 0.45 mmol) was dissolved in THF (3 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 19 h, the reaction was quenched with H2O and saturated aqueous NH4Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give compound 128 (206.8 mg, 95%) as a colorless oil.

[0293] Compound 128: [α] D 27 +90.7 (c 1.96, CHCl3); IR (neat) 1714, 1647, 1464, 1388, 1236, 1193, 1157, 1045, 743 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 7.8 Hz, 6H), 0.61 (s, 3H), 0.94 (t, J = 8.1 Hz, 9H), 0.97 (d, J = 6.0 Hz, 3H), 1.20 (s, 3H), 1.23 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.30 - 1.44 (m, 4H), 1.47 - 1.78 (m, 9H), 1.91 - 1.99 (m, 1H), 2.01 - 2.03 (m, 1H), 2.05 - 2.08 (m, 1H), 3.85 - 3.89 (m, 1H), 4.11 - 4.18 (m, 2H), 4.38 - 4.49 (m, 1H), 5.46 (brs, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.8, 7.1, 12.0, 12.9 (d, J = 2.9 Hz), 14.3, 22.2, 23.3 (d, J = 20.1 Hz), 23.7, 26.5, 29.4, 29.6, 30.5. 40.1, 40.2 (d, J = 18.8 Hz), 41.5, 47.3, 53.5 (d, J = 8.6 Hz), 56.3, 59.5, 73.0, 100.5 (d, J = 168.2 Hz), 112.3, 162.6, 166.9; HRMS (ESI + ) calcd for C 28 H 51 O3FSiNa [M+Na] + 505.3484, found 505.3479.

[0294] Ethyl 2-[(1R,3aS,7aR,E)-1-{(2S,3S)-3-fluoro-6-methyl-6-[(triethyl silyl)oxy]heptane-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene] acetate (129) [ka]

[0295] To a suspension of NaH (214.2 mg, liquid paraffin 60% w / w, 5.36 mmol) in THF (4 mL) was added (EtO)P(O)CHCOEt (1.26 g, 1.13 mL, 5.6 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. Ketone 127 (231.6 mg, 0.56 mmol) was dissolved in THF (4 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 43 h, the reaction was quenched with H2O and saturated aqueous NH4Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give compound 129 (234.8 mg, 87%) as a colorless oil.

[0296] Compound 129: [α] D 27 +73.8 (c 6.28, CHCl3); IR (neat) 1714, 1651, 1459, 1380, 1236, 1193, 1157, 1049, 743 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.56 (q, J = 7.8 Hz, 6H), 0.59 (s, 3H), 0.94 (t, J = 7.8 Hz, 9H), 0.98 (d, J = 6.0 Hz, 3H), 1.21 (s, 3H), 1.22 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.31 - 1.66 (m, 12H), 1.71 - 1.78 (m, 4H), 1.99 - 2.05 (m, 2H), 2.15 - 2.18 (m, 1H), 3.84 - 3.88 (m, 1H), 4.11 - 4.19 (m, 2H), 4.42 - 4.52 (m, 1H), 5.46 (brs, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.7, 7.1, 11.9, 12.2 (d, J = 4.4 Hz), 14.3, 22.1, 23.8, 26.9, 27.4 (d, J = 21.5 Hz), 29.6, 29.6, 30.1, 40.1, 40.1 (d, J = 20.1 Hz), 41.5 (d, J = 4.4 Hz), 46.8, 52.7, 56.6, 59.5, 72.9, 96.9 (d, J = 171.0 Hz), 112.1, 163.0, 166.9; HRMS (ESI + ) calcd for C 28 H 51 O3FSiNa [M+Na] + 505.3484, found 505.3478.

[0297] 2-[(1R,3aS,7aR,E)-1-{(2S,3R)-3-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (130)

Chem.

[0298] To a solution of ethyl ester 128 (206.8 mg, 0.43 mmol) in THF (5 mL) was added DIBAL-H (2.5 mL, 1.03 mol / L hexane solution, 2.57 mmol) at −78 °C, and the mixture was stirred at the same temperature for 10 min. The mixture was diluted with MeOH at −78 °C, and then HO and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give alcohol 130 (172.0 mg, 91%) as a colorless oil.

[0299] Compound 130: [α] D 27 +51.4 (c 3.55, CHCl3); IR (neat) 3240, 1464, 1240, 1045, 743 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.56 (q, J = 7.8 Hz, 6H), 0.57 (s, 3H), 0.94 (t, J = 7.8 Hz, 9H), 0.96 (d, J = 6.6 Hz, 3H), 1.20 (s, 3H), 1.23 (s, 3H), 1.24-1.43 (m, 5H), 1.46-1.76 (m, 9H), 1.90-2.02 (m, 3H), 2.62-2.66 (m, 1H), 4.18-4.23 (m, 2H), 4.38-4.49 (m, 1H), 5.22 (t, J = 7.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 6.8, 7.1, 11.7, 12.9 (d, J = 2.9 Hz), 22.2, 23.2 (d, J = 21.5 Hz), 23.4, 26.7, 28.7, 29.4, 30.5, 40.3, 40.4 HRMS (ESI + ) calcd for C 26 H 49 02FSiNa [M+Na] + 463.3378, found 463.3367.

[0300] 2-[(1R,3aS,7aR,E)-1-{(2S,3S)-3-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (131) [ka]

[0301] To a solution of ethyl ester 129 (234.8 mg, 2.92 mmol) in THF (5 mL) was added DIBAL-H (2.8 mL, 1.03 mol / L hexane solution, 2.92 mmol) at −78 °C, and the mixture was stirred at the same temperature for 40 min. The mixture was diluted with MeOH at −78 °C, and then HO and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give alcohol 131 (194.0 mg, 91%) as a colorless oil.

[0302] Compound 131: [α] D27 +38.8 (c 3.54, CHCl3); IR (neat) 3363, 1468, 1236, 1049, 739 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.56 (s, 3H), 0.56 (q, J = 7.8 Hz, 6H), 0.94 (t, J = 7.8 Hz, 9H), 0.97 (d, J = 6.6 Hz, 3H), 1.20 - 1.58 (m, 16H), 1.62 - 1.72 (m, 3H), 1.79 - 1.87 (m, 1H), 1.97 - 2.04 (m, 3H), 2.61 - 2.64 (m, 1H), 4.18 - 4.23 (m, 2H), 4.42 - 4.53 (m, 1H), 5.22 (t, J = 7.2 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.7, 7.1, 11.6, 12.2 (d, J = 5.7 Hz), 22.1, 23.4, 27.1, 27.4 (d, J = 21.5 Hz), 28.7, 29.6, 30.1, 40.1, 40.2, 41.0 (d, J = 4.4 Hz), 45.1, 52.5, 55.4, 58.6, 72.9, 97.0 (d, J = 169.5 Hz), 119.3, 143.4; HRMS (ESI + ) calcd for C 26 H 49 O2FSiNa [M+Na] + 463.3378, found 463.3336.

[0303] 2-({2-[(1R,3aS,7aR,E)-1-{(2S,3R)-3-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole (134)

Chem.

[0304] To a solution of 2-mercaptobenzothiazole (175.4 mg, 1.05 mmol), Ph3P (230.7 mg, 0.88 mmol), and CD ring 130 (172.0 mg, 0.39 mmol) in CHCl (4 mL) was added diisopropyl azodicarboxylate (411 μL, 1.9 mol / L toluene solution, 0.78 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude sulfide 132, which was used in the next reaction without further purification.

[0305] The crude sulfide 132 was dissolved in EtOH (12 mL) and CHCl (3 mL), and the solution was added with 30% aqueous HO (3 mL) and (NH)MoO 24 4H2O (437.0 mg, 0.35 mmol) was added. After stirring at room temperature for 2 hours and 30 minutes, the mixture was poured into H2O and extracted three times with EtOAc. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 4:1) to give compound 134 (188.7 mg, 78%, 2 steps) as a colorless oil.

[0306] Compound 134: [α] D 27 +36.8 (c 2.30, CHCl3); IR (neat) 1471, 1333, 1235, 1154, 1042, 760 cm -1 ; 11H NMR (400 MHz, CDCl3) δ 0.28 (s, 3H), 0.55 (q, J = 7.9 Hz, 6H), 0.89 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.8 Hz, 9H), 1.18 - 1.74 (m, 19H), 1.81 - 1.89 (m, 3H), 2.55 - 2.59 (m, 1H), 4.20 (dd, J = 6.8, 14.2 Hz, 1H), 4.31 - 4.34 (m, 1H), 4.41 - 4.46 (m, 1H), 5.03 (t, J = 8.0 Hz, 1H), 7.56 - 7.65 (m, 2H), 8.00 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 6.7, 7.1, 11.4, 12.8 (d, J = 2.9 Hz), 22.1, 23.1, 23.2 (d, J = 22.9 Hz), 26.5, 29.0, 29.4, 30.5, 39.9, 40.1 (d, J = 19.1 Hz), 41.4, 46.1, 53.1 (d, J = 8.6 Hz), 53.8, 55.4, 73.0, 97.3 (d, J = 167.8 Hz), 104.5, 122.2, 125.3, 1,27.6, 127.9, 136.9, 151.6, 152.8, 165.9; HRMS (ESI + ) calcd for C 33 H 52 NO3FSiS2Na [M+Na] + 644.3034, found 644.3062.

[0307] 2-({2-[(1R,3aS,7aR,E)-1-{(2S,3S)-3-Fluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole (135)

Chem.

[0308] To a solution of 2-mercaptobenzothiazole (138.7 mg, 0.83 mmol), PhP (243.6 mg, 0.93 mmol), and compound 131 (194.0 mg, 0.44 mmol) in CHCl (4 mL) was added diisopropyl azodicarboxylate (440 μL, 1.9 mol / L toluene solution, 0.84 mmol) at 0 °C, and the mixture was stirred for 30 min at 0 °C. The solution was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude sulfide 133.

[0309] The crude sulfide 133 was dissolved in EtOH (12 mL) and CHCl (3 mL), and the solution was added with 30% aqueous HO (3 mL) and (NH)MoO. 24 4H2O (405.1 mg, 0.33 mmol) was added at 0 °C. After stirring at room temperature for 2 h, the mixture was poured into H2O and extracted three times with Et2O. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 4:1) to give sulfone 135 (161.0 mg, 57%, 2 steps) as a colorless oil.

[0310] Compound 135: [α] D 27 +34.5 (c 4.55, CHCl3); IR (neat) 1471, 1332, 1236, 1152, 1041, 735 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.28 (s, 3H), 0.55 (q, J = 8.0 Hz, 6H), 0.90 (d, J = 7.2 Hz, 3H), 0.93 (t, J = 7.8 Hz, 9H), 1.19 - 1.69 (m, 18H), 1.75 - 1.84 (m, 2H), 1.92 - 1.98 (m, 2H), 2.54 - 2.57 (m, 1H), 4.20 (dd, J = 6.3, 14.4 Hz, 1H), 4.37 - 4.47 (m, 1H), 4.43 (dd, J = 9.0, 14.4 Hz, 1H), 5.03 (dd, J = 7.8, 9.0 Hz, 1H), 7.56 - 7.64 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 11.3, 12.2 (d, J = 5.7 Hz), 21.9, 23.1, 26.9, 27.3 (d, J = 21.6 Hz), 29.0, 29.6, 30.0, 39.8, 40.0 (d, J = 20.1 Hz), 40.9, 41.0, 45.5, 52.4, 53.8, 55.7, 72.8, 96.8 (d, J = 171.0 Hz), 104.3, 122.2, 125.3, 127.5, 127.8, 136.9, 151.8, 152.8, 165.9; HRMS (ESI + ) calcd for C 33 H 52 NO3FSiS2Na [M+Na] + 644.3034, found 644.3048.

[0311]

Chem.

[0312] To a solution of sulfone 134 (188.7 mg, 0.30 mmol) in THF (1.5 mL) was added LiHMDS (331 μL, 1.0 mol / L THF solution, 0.33 mmol) at −78 °C. After stirring the mixture at the same temperature for 30 min, ring A (74.2 mg, 0.14 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 3 h 30 min. After quenching the reaction with saturated aqueous NH4Cl and HO, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1 to 4:1) to give the protected coupling product as an inseparable mixture of isomers.

[0313] p-Toluenesulfonic acid monohydrate (514.4 mg, 2.71 mmol) was added to a solution of the above coupling compound in MeOH (5 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 5 hours and 30 minutes. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 10:1) to give 22RF-MART-10 and 22RF-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO = 4:1 solvent system to give 22RF-MART-10 (17.5 mg, 26%, 2 steps) and 22RF-MART-11 (18.9 mg, 28%, 2 steps), respectively, as white powders.

[0314] 22RF-MART-10: [α] D 27 +75.5 (c 1.35, EtOH); IR (neat) 3373, 1441, 1375, 1220, 1050, 906, 732 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.56 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.24-1.41 (m, 10H), 1.46-1.80 (m, 17H), 1.93-2.00 (m, 3H), 2.12-2.27 (m, 4H), 2.59 (dd, J = 3.9, 13.2 Hz, 1H), 2.79-2.85 (m, 2H), 3.63-3.69 (m, 3H), 4.09 (brs, 1H), 4.47 (ddd, J = 3.3, 10.2, 47.4 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 6.35 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.0, 12.9 (d, J = 2.9 Hz), 22.3, 23.2 (d, J = 20.1 Hz), 23.4, 26.7, 28.9, 29.0, 29.9, 30.0, 35.5, 40.2, 40.3, 40.4, 45.3, 46.1, 48.6, 53.0 (d, J = 8.7 Hz), 55.7, 62.8, 68.5, 70.7, 71.4, 97.1 (d, J = 168.0 Hz), 115.5, 123.8, 131.7, 142.5; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3519.

[0315] 22RF-MART-11: [α] D 27 +41.2 (c 1.45, EtOH); IR (neat) 3381, 1444, 1383, 1220, 1050, 910, 732 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.57 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.23 - 2.00 (m, 33H), 2.33 - 2.39 (m, 2H), 2.79 - 2.89 (m, 3H), 3.06 (dd, J = 4.2, 12.0 Hz), 2.52 (td, J = 4.2, 9.6 Hz, 1H), 3.62 - 3.69 (m, 2H), 4.03 (brs, 1H), 4.42 - 4.53 (m, 1H), 5.87 (d, J = 11.4 Hz, 1H), 6.22 (d, J = 12.0 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 11.9, 12.9 (d, J = 2.9 Hz), 22.3, 23.2 (d, J = 21.6 Hz), 23.4, 23.6, 26.7, 28.9, 29.7, 29.8, 37.8, 40.2, 40.2, 40.3, 40.4, 43.9, 46.1, 48.8, 53.0 (d, J = 8.6 Hz), 55.7, 62.6, 68.2, 70.7, 70.8, 97.1 (d, J = 168.0 Hz), 115.6, 123.1, 131.8, 142.1; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3506.

[0316]

Chem.

[0317] To a solution of sulfone 135 (161.0 mg, 0.26 mmol) in THF (1.0 mL) was added LiHMDS (285 μL, 1.0 mol / L THF solution, 0.29 mmol) at −78 °C. After stirring the mixture at the same temperature for 20 min, ring A (72.9 mg, 0.14 mmol) in THF (1.0 mL) was added, and the whole mixture was stirred at the same temperature for 3 h. After quenching the reaction with saturated aqueous NH4Cl and HO, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1 to 4:1) to give the protected coupling product as an inseparable mixture of isomers.

[0318] p-Toluenesulfonic acid monohydrate (426.3 mg, 2.24 mmol) was added to a solution of the above coupling compound in MeOH (5 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 3 hours and 30 minutes. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 10:1) to give 22SF-MART-10 and 22SF-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO = 4:1 solvent system to give 22SF-MART-10 (30.6 mg, 46%, 2 steps) and 22SF-MART-11 (19.0 mg, 29%, 2 steps), respectively, as white powders.

[0319] 22SF-MART-10: [α] D 27 +40.8 (c 1.35, EtOH); IR (neat) 3363, 1451, 1380, 1217, 1049, 914, 739 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.56 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.24-1.41 (m, 10H), 1.46-1.80 (m, 17H), 1.93-2.00 (m, 3H), 2.12-2.27 (m, 4H), 2.59 (dd, J = 3.9, 13.2 Hz, 1H), 2.79-2.85 (m, 2H), 3.63-3.69 (m, 3H), 4.09 (brs, 1H), 4.47 (ddd, J = 3.3, 10.2, 47.4 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 6.35 (d, J = 11.4 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 11.9, 12.3 (d, J = 4.4 Hz), 22.2, 23.3, 23.4, 27.1, 27.5 (d, J = 21.5 Hz), 28.8, 29.2, 29.4, 29.8, 35.4, 39.9 (d, J = 4.4 Hz), 40.3 (d, J = 17.4 Hz), 40.3, 45.2, 45.5, 48.5, 52.5, 56.0, 62.5, 68.4, 70.6, 71.2, 96.9 (d, J = 170.9 Hz), 115.4, 123.6, 131.7, 142.6; HRMS (ESI + ) calcd for C 29 H 49 O4FNa [M+Na] + 503.3507, found 503.3512.

[0320] 22SF-MART-11: [α] D 27 +11.1 (c 1.46, EtOH); IR (neat) 3363, 1455, 1380, 1212, 1049, 914, 735 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.55 (s, 3H), 0.99 (d, J = 6.6 Hz), 1.24-1.39 (m, 9H), 1.23-2.00 (m, 19H), 1.98-2.08 (m, 3H), 2.34-2.42 (m, 2H), 2.80 (dd, J = 4.2, 11.4 Hz), 3.09 (dd, J = 4.2, 12.6 Hz, 1H), 3.56 (td, J = 4.8, 10.8 Hz, 1H), 3.67-3.73 (m, 2H), 4.05-4.06 (m, 1H), 4.47-4.57 (m, 1H), 5.87 (d, J = 12.0 Hz, 1H), 6.25 (d, J = 12.0 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 11.9 12.3 (d, J = 5.7 Hz), 22.2, 23.5, 23.7, 27.1, 27.5 (d, J = 21.6 Hz), 28.9, 29.2, 29.4, 29.8, 37.8, 39.9 (d, J = 4.4 Hz), 40.3, 40.4 (d, J = 18.8 Hz), 44.0, 45.6, 48.9, 52.5, 56.1, 62.9, 68.3, 70.7, 71.1, 96.9 (d, J = 169.5 Hz), 115.4, 123.4, 131.3, 142.8; HRMS (ESI + calcd for C 29 H 49 O4FNa [M+Na] + 503.3507 was found; 503.3508 was also found.

[0321] "Manufacturing Example 7: Synthesis of 22F2 Body"

change

change

[0322] Ref. 3: Yu, OB; Mutchie, TR; Di Milo, ES; Arnold, LA Synthesis and biological evaluation of calcioic acid. Steroids 2020, 154, 108536.

[0323] Methyl (3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2,2-difluorobutanoate (137) [ka]

[0324] To a solution of compound 136 [see Ref. 3 above] (102.7 mg, 0.28 mmol) in THF (400 μL) and hexamethylphosphoric triamide (HMPA) (200 μL), LDA (lithium diisopropylamide) (176 μL, 2 mol / L THF / heptane / ethylbenzene solution, 0.35 mmol) was added at −78°C. The mixture was stirred at the same temperature for 1 hour, and N-fluorobenzenesulfonimide (NFSI) (116.5 mg, 0.37 mmol) was added to the mixture. After stirring at the same temperature for 2 hours, the reaction was quenched with HO and saturated aqueous NH4Cl at −78°C. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:CH2Cl2=2:1) ​​to give compound 112 (88.6 mg, 82%) as a colorless oil.

[0325] To a solution of compound 112 (1.49 g, 5.02 mmol) in THF (8 mL) and hexamethylphosphoric triamide (HMPA) (4 mL), LDA (lithium diisopropylamide) (10.9 mL, 2 mol / L THF / heptane / ethylbenzene solution, 21.8 mmol) was added at −78 °C. The mixture was stirred at the same temperature for 1 h, and N-fluorobenzenesulfonimide (NFSI) (2.18 g, 6.91 mmol) was added to the mixture. After stirring at the same temperature for 2 h, the reaction was quenched with HO and saturated aqueous NH4Cl at −78 °C. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane:CHCl=2:1) ​​to give compound 137 (1.28 g, 63%) as a colorless oil.

[0326] Compound 137: [α] D 27 +14.0 (c 0.69, CHCl3); IR (neat) 1774, 1468, 1259, 1073, 1031, 841 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 0.95 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.14-1.27 (m, 2H), 1.31-1.48 (m, 5H), 1.53-1.96 (m, 5H), 2.19-2.33 (m, 1H), 3.86 (s, 3H), 3.99-4.02 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.2 (t, J = 6.2 Hz), 13.3, 17.6, 18.0, 23.3, 25.8, 26.2, 26.2, 40.6 (t, J = 20.0 Hz), 40.6, 43.1, 50.6, 52.1, 53.0, 69.2, 118.6 (t, J = 252.7 Hz), 165.4 (t, J = 33.9 Hz); HRMS (ESI+ ) calcd for C 21 H 38 O3F2SiNa [M+Na] + 427.2451, found 427.2487.

[0327] (3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyl octahydro-1H-inden-1-yl}-2,2-difluoro-N-methoxy-N-methylbutanamide (138) [ka]

[0328] To a solution of compound 137 (69.0 mg, 0.17 mmol) and Me(MeO)NH HCl (67.9 mg, 0.70 mmol) in THF (2 mL), isopropylmagnesium chloride (1.37 mL, 1 mol / L THF solution, 1.37 mmol) was added at 0 °C, and the mixture was stirred at the same temperature for 13 min. After the reaction was quenched with HO and saturated aqueous NH Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 5:1) to give compound 138 (56.9 mg, 77%) as a colorless oil.

[0329] Compound 138: [α] D 27 +16.7 (c 2.10, CHCl3); IR (neat) 1692, 1464, 1252, 1166, 1073, 1031, 841, 779 cm -1 ; 11H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.95 (s, 3H), 1.05 (d, J = 7.2 Hz, 3H), 1.18 (td, J = 3.6, 12.6 Hz, 1H), 1.18 (ddd, J = 2.4, 6.6, 13.8 Hz, 1H), 1.33 - 1.40 (m, 4H), 1.47 - 1.67 (m, 3H), 1.74 - 1.82 (m, 1H), 1.87 - 1.95 (m, 2H), 1.65 - 1.82 (m, 3H), 1.86 - 1.90 (m, 1H), 1.92 - 1.95 (m, 1H), 2.12 - 2.19 (m, 1H), 2.41 - 2.51 (m, 1H), 3.24 (s, 3H), 3.72 (s, 3H), 3.99 - 4.01 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.2, 13.3, 17.6, 18.0, 23.5, 25.8, 26.6, 26.6, 33.2, 34.3, 40.6, 40.6 (d, J = 20.9 Hz), 43.1, 50.2, 52.1, 61.7, 69.3, 120.1 (d, J = 252.0 Hz), 165.2 (d, J = 32.3 Hz); HRMS (ESI + ) calcd for C 22 H 41 NO3F2SiNa [M+Na] + 456.2716, found 456.2717.

[0330] Ethyl (5S,E)-5-{(1R,3aR,4S,7aR)-4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-4,4-difluorohex-2-enoate (140)

Chem.

[0331] To a solution of amide 138 (1.36 g, 3.14 mmol) in CHCl (10 mL) was added DIBAL-H (4.6 mL, 1.03 mol / L hexane solution, 4.71 mmol) at −78 °C, and the mixture was stirred at the same temperature for 15 min. The reaction mixture was diluted with MeOH at −78 °C, and then H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude aldehyde 139 was used in the next reaction without further purification.

[0332] To a suspension of NaH (645.6 mg, liquid paraffin 60% w / w, 16.1 mmol) in THF, (EtO)P(O)CHCOEt (4.22 g, 3.8 mL, 18.8 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 50 min. The crude aldehyde was dissolved in THF (10 mL), and the solution was added to the mixture at 0 °C. After stirring at the same temperature for 10 min, the reaction was quenched with H O and saturated aqueous NH Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 20:1) to give compound 140 (1.10 g, 79%, 2 steps) as a colorless oil.

[0333] Compound 140: [α] D 27 +41.5 (c 0.41, CHCl3); IR (neat) 1734, 1475, 1308, 1260, 1038, 834 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 0.95 (s, 3H), 1.05 (d, J = 7.2 Hz, 3H), 1.13 - 1.25 (m, 3H), 1.30 - 1.41 (m, 6H), 1.49 - 1.64 (m, 4H), 1.66 - 1.68 (m, 1H), 1.74 - 1.83 (m, 2H), 1.93 - 1.95 (m, 1H), 2.02 - 2.11 (m, 1H), 3.99 - 4.01 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 6.23 - 6.26 (m, 1H), 6.76 - 6.83 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.4, 14.1 (t, J = 5.9 Hz), 14.2, 17.6, 18.0, 23.3, 25.8, 27.1, 27.2, 34.3, 40.7, 43.1 (t, J = 21.5 Hz), 43.2, 51.5, 51.5, 52.4, 61.1, 69.2, 123.1 (t, J = 242.7 Hz), 125.0 (t, J = 8.6 Hz), 138.7 (t, J = 27.3 Hz), 165.3; HRMS (ESI + ) calcd for C 24 H 42 O3F2SiNa [M+Na] + 467.2764, found 467.2766.

[0334] (1R,3aR,4S,7aR)-1-[(2S)-3,3-Difluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (142)

Chem.

[0335] To a solution of compound 140 (1.10 g, 2.47 mmol) in MeOH (20 mL) and EtOAc (5 mL) was added 10% Pd / C catalyst (208.8 mg). The mixture was stirred at room temperature under 1 atm of hydrogen for 24 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give crude ester 141, which was used in the next reaction without further purification.

[0336] To a solution of the crude ester 141 in THF (20 mL) was added MeMgCl (8.2 mL, 3.0 mol / L THF solution, 24.7 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. The reaction was quenched with HO and saturated aqueous NH Cl at 0 °C, and the mixture was extracted three times with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated. The crude residue was used in the next reaction without further purification.

[0337] To the crude residue in MeOH (50 mL) and CHCl (10 mL) was added p-toluenesulfonic acid monohydrate (5.03 g, 26.4 mmol), and the mixture was stirred in air at room temperature for 44 h. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 2:1) to give compound 142 (674.2 mg, 86%, 3 steps) as a white powder.

[0338] Compound 142: [α] D 27 +8.2 (c 3.32, CHCl3); IR (neat) 3407, 1475, 1232, 1169, 961 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.95 (s, 3H), 1.04 (d, J = 7.2 Hz, 3H), 1.71-1.61 (m, 16H), 1.64-1.67 (m, 2H), 1.80-2.03 (m, 7H), 4.07-4.08 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 13.1, 14.8 (t, J = 5.7 Hz), 17.4, 22.8, 27.4 (t, J = 25.1 Hz), 29.2, 29.4, 33.5, 34.7, 40.5, 42.5 (t, J = 21.5 Hz), 42.8, 51.8, 51.8, 51.9, 69.1, 70.2, 127.6 (t, J = 243.4 Hz); - ) calcd for C 19 H 33 O4F2[M+HCOO] - 363.2352, found 363.2345.

[0339] (1R,3aR,7aR)-1-{(2S)-3,3-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (144) [ka]

[0340] 4-Methylmorpholine N-oxide (120.9 mg, 1.03 mmol) was added to a solution of compound 142 (219.8 mg, 0.69 mmol) in CHCl (2 mL), and the mixture was cooled to 0 °C. TPAP (117.1 mg, 0.33 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO. The mixture was directly purified by flash column chromatography on silica gel (EtO only) to give crude ketone 143, which was used in the next reaction without further purification.

[0341] TESCl (211.0 mg, 578 μL, 3.45 mmol) was added to a solution of the crude ketone 143 and imidazole (347.4 mg, 5.10 mmol) in CHCl (15 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 18 h. After quenching the reaction with H2O, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give compound 144 (290.4 mg, 98%, 2 steps) as a colorless oil.

[0342] Compound 144: [α] D 27 -12.1 (c 2.81, CHCl3); IR (neat) 1714, 1464, 1380, 1225, 1061, 743 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 7.8 Hz, 6H), 0.67 (s, 3H), 0.94 (t, J = 7.8 Hz, 9H), 1.09 (d, J = 6.6 Hz, 3H), 1.22 (s, 3H), 1.22 (s, 3H), 1.49-1.67 (m, 6H), 1.71-1.80 (m, 2H), 1.85-2.05 (m, 6H), 2.13-2.17 (m, 1H), 2.21-2.31 (m, 2H), 2.41-2.44 (m, 1H); 13 C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 12.3, 14.8 (t, J = 6.5 Hz), 19.4, 23.9, 27.5, 27.9 (d, J = 25.1 Hz), 29.9, 29.9, 36.0, 39.0, 40.9, HRMS (ESI + ) calcd for C 24 H 44 O2F2SiNa [M+Na] + 435.3065, found 435.3026.

[0343] Ethyl 2-[(1R,3aS,7aR,E)-1-{(2S)-3,3-difluoro-6-methyl-6-[(triethyl silyl)oxy]heptane-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene] acetate (145) [ka]

[0344] To a suspension of NaH (234.4 mg, liquid paraffin 60% w / w, 5.86 mmol) in THF (3 mL) was added (EtO)P(O)CHCOEt (1.51 g, 1.4 mL, 6.74 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Ketone 144 (290.4 mg, 0.64 mmol) was dissolved in THF (3 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 92 h, the reaction mixture was quenched with H2O and saturated aqueous NH4Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give compound 145 (309.0 mg, 89%) as a colorless oil.

[0345] Compound 145: [α] D 27 +68.7 (c 2.35, CHCl3); IR (neat) 1718, 1647, 1464, 1388, 1244, 1161, 1057, 743 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 8.4 Hz, 6H), 0.62 (s, 3H), 0.94 (t, J = 8.4 Hz, 9H), 1.08 (d, J = 6.6 Hz, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.43 (td, J = 4.2, 13.2 Hz, 1H), 1.50 - 1.78 (m, 9H), 1.84 - 2.13 (m, 6H), 3.85 - 3.88 (m, 1H), 4.11 - 4.18 (m, 2H), 5.48 (s, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.7, 7.1, 11.9, 14.3, 14.9 (t, J = 5.9 Hz), 22.4, 23.7, 27.3, 27.8 (t, J = 25.1 Hz), 29.6, 29.9, 29.9, 36.0, 40.2, 43.0 (t, J = 22.3 Hz), 47.7, 51.9, 51.9, 56.1, 59.5, 72.4, 112.4, 127.7 (t, J = 243.5 Hz), 162.6, 166.9; HRMS (ESI + ) calcd for C 28 H 50 O3F2SiNa [M+Na] + 523.3390, found 523.3363.

[0346] 2-[(1R,3aS,7aR,E)-1-{(2S)-3,3-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (146)

Chem.

[0347] To a solution of ethyl ester 145 (300.9 mg, 0.60 mmol) in THF (10 mL) was added DIBAL-H (2.9 mL, 1.03 mol / L hexane solution, 3.0 mmol) at −78 °C, and the mixture was stirred at the same temperature for 2 h. After diluting the reaction with MeOH at −78 °C, HO and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give alcohol 146 (253.9 mg, 92%) as a colorless oil.

[0348] Compound 146: [α] D 27 +37.3 (c 4.18, CHCl3); IR (neat) 3339, 1459, 1380, 1225, 1161, 1069, 746 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.57 (q, J = 7.8 Hz, 6H), 0.59 (s, 3H), 0.94 (t, J = 7.8 Hz, 9H), 1.07 (d, J = 6.6 Hz, 3H), 1.22 (s, 3H), 1.22 (s, 3H), 1.32-1.37 (m, 2H), 1.44-1.68 (m, 9H), 1.82-2.04 (m, 6H), 2.62-2.65 (m, 1H), 4.17-4.23 (m, 2H), 5.24 (t, J = 7.2 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 11.6, 14.9 (t, J = 6.5 Hz), 22.4, 23.4, 27.5, 27.8 (t, J = 25.1 Hz), 28.7, 29.9, 36.0, 40.4, 43.2 HRMS (ESI -) calcd for C 26 H 48 O2F2SiCl [M+Cl] - 493.3086, found 493.3080.

[0349] 2-({2-[(1R,3aS,7aR,E)-1-{(2S)-3,3-Difluoro-6-methyl-6-[(triethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole (148) [ka]

[0350] To a solution of 2-mercaptobenzothiazole (219.7 mg, 1.31 mmol), Ph3P (302.1 mg, 1.15 mmol), and CD ring 146 (253.9 mg, 0.55 mmol) in CHCl (5 mL) was added diisopropyl azodicarboxylate (583 μL, 1.9 mol / L toluene solution, 1.11 mmol) at 0 °C, and the mixture was stirred at 0 °C for 45 min. The mixture was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude sulfide 147, which was used in the next reaction without further purification.

[0351] The crude sulfide 147 was dissolved in EtOH (15 mL) and CHCl (15 mL), and the solution was added with 30% aqueous HO (6 mL) and (NH)MoO 24 4H2O (474.8 mg, 0.38 mmol) was added. After stirring at room temperature for 17 h, the mixture was poured into H2O and extracted three times with EtOAc. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified on a preparative silica gel TLC plate (hexane: EtOAc = 4:1) to give compound 148 (295.4 mg, 83%, 2 steps) as a colorless oil.

[0352] Compound 148: [α] D 27 +27.4 (c 3.84, CHCl3); IR (neat) 1471, 1332, 1240, 1148, 1069, 759, 731 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.31 (s, 3H), 0.56 (q, J = 7.8 Hz, 6H), 0.93 (t, J = 7.8 Hz, 9H), 0.99 (d, J = 7.2 Hz, 3H), 1.18 - 1.29 (m, 2H), 1.20 (s, 3H), 1.21 (s, 3H), 1.42 - 1.59 (m, 8H), 1.81 - 1.90 (m, 6H), 2.56 - 2.59 (m, 1H), 4.20 (dd, J = 6.9, 13.8 Hz, 1H), 4.43 (dd, J = 9.0, 14.4 Hz, 1H), 5.04 (t, J = 7.8 Hz, 1H), 7.50 - 7.60 (m, 1H), 7.61 - 7.65 (m, 1H), 8.00 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.7, 7.0, 11.2, 14.9 (t, J = 5.7 Hz), 22.3, 23.1, 27.3, 27.8 (t, J = 25.1 Hz), 29.0, 29.9, 36.0, 40.0, 43.0 (t, J = 2​​​​​​​​​​​22F2-MART-10 and 22F2-MART-11 [ka]

[0354] To a solution of sulfone 148 (294.5 mg, 0.46 mmol) in THF (3.0 mL) was added LiHMDS (506 μL, 1.0 mol / L THF solution, 0.51 mmol) at −78 °C. After stirring the mixture at the same temperature for 30 min, ring A (62.5 mg, 0.12 mmol) in THF (2.0 mL) was added, and the whole mixture was stirred at the same temperature for 90 min. After quenching the reaction with saturated aqueous NH4Cl and HO, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1 to 4:1) to give the protected coupling product as an inseparable mixture of isomers.

[0355] p-Toluenesulfonic acid monohydrate (236.2 mg, 1.24 mmol) was added to a solution of the coupling compound in MeOH (5 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 5 hours and 30 minutes. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 100:1 to 10:1) to give 22F2-MART-10 and 22F2-MART-11 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO = 4:1 solvent system to give 22F2-MART-10 (13.7 mg, 24%, 2 steps) and 22F2-MART-11 (16.9 mg, 29%, 2 steps), respectively, as white powders.

[0356] 22F2-MART-10: [α] D 27+56.6 (c 1.05, EtOH); IR (neat) 3395, 1440, 1380, 1228, 1053, 954 cm -1 ; 1 H NMR (600 MHz, DMSO-d6) δ 0.58 (s, 3H), 1.07 (d, J = 6.6 Hz, 3H), 1.13 (s, 3H), 1.13 (s, 3H), 1.29-1.67 (m, 15H), 1.85-2.03(m, 8H), 2.43 (dd, J = 3.9, 12.9 Hz, 1H), 2.63 (dd, J = 4.5, 14.1 Hz, 1H), 2.78-2.81 (m, 1H), 3.41-3.49 (m, 3H), 3.93 (s, 1H), 4.25 (d, J = 4.2 Hz, 1H), 4.28 (brs, 1H), 4.35 (brs, 1H), 4.45 (d, J = 5.4 Hz, 1H), 5.85 (d, J = 10.8 Hz, 1H), 6.15 (d, J = 10.8 Hz, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 12.6, 15.7 (t, J = 5.8 Hz), 23.1, 23.9, 24.0, 28.2, 28.3 (t, J = 25.1 Hz), 29.2, 30.2, 30.3, 31.6, 35.6, 36.4, 43.8 (t, J = 21.5 Hz), 46.2, 46.9, 49.5, 51.9, 55.8, 62.5, 67.5, 69.0, 70.1, 117.5, 121.7, 129.1 (t, J = 242.8 Hz), 136.3, 139.8; HRMS (ESI + ) calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3405.

[0357] 22F2-MART-11: [α] D 27+15.9 (c 1.30, EtOH); IR (neat) 3379, 1451, 1332, 1268, 1089, 1049 cm -1 ; 1 H NMR (600 MHz, DMSO-d6) δ 0.58 (s, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.13 (s, 3H), 1.13 (s, 3H), 1.23-1.68 (m, 16H), 1.77 (t, J = 11.7 Hz, 1H), 1.86-2.05 (m, 6H), 2.19-2.26 (m, 2H), 2.78-2.85 (m, 2H), 3.33-3.50 (m, 3H), 3.91 (brs, 1H), 4.16 (brs, 1H), 4.29 (s, 1H), 4.36-4.40 (m, 1H), 4.54 (d, J = 4.8 Hz, 1H), 5.86 (d, J = 10.8 Hz, 1H), 6.06 (d, J = 10.8 Hz, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 12.5, 15.7 (t, J = 5.8 Hz), 23.1, 24.0, 24.2, 28.2, 28.3 (t, J = 24.5 Hz), 29.3, 30.2, 30.3, 31.4, 35.6, 38.8, 43.8 (t, J = 21.6 Hz), 44.9, 46.9, 49.6, 51.9, 55.8, 57.0, 62.5, 67.5, 69.0, 69.9, 117.2, 121.4, 129.1 (t, J = 242.8 Hz), 136.0, 139.9; HRMS (ESI + calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3413.

[0358] "Manufacturing Example 8: Synthesis of 26, 26, 27, 27-F4 body"

change

[0359] Ref. 4: Nicoletti, D.; Mourino, A.; Torneiro, MS Synthesis of 25-hydroxyvitamin D3and 26,26,26,27,27,27-hexadeutero-25-hydroxyvitamin D3on solid support. J. Org. Chem. 2009, 74, 4782-4786.

[0360] (5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoic acid (150) [ka]

[0361] Aqueous KOH (25 mL, 7.1 mol / L solution) was added to a solution of methyl ester 149 (2.0 g, 5.05 mmol) [see Ref. 4 above] in dioxane (50 mL), and the mixture was stirred at 60 °C for 19 h. After quenching the reaction with HO and saturated aqueous NH Cl, the mixture was extracted three times with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 3:1) to give compound 150 (1.95 g, 100%) as a colorless oil.

[0362] Compound 150: [α] D 27 +48.8 (c 0.95, CHCl3); IR (neat) 1706, 1458, 1409, 1232, 1164, 1082, 1017, 950, 724 cm -1 ; 1H NMR (400 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.90 (d, J = 6.4 Hz, 3H), 0.90 (s, 3H), 1.00-1.13 (m, 3H), 1.18-1.60 (m, 9H), 1.64-1.85 (m, 4H), 1.94 (dt, J = 2.7, 12.8 Hz, 1H), 2.24-2.38 (m, 2H), 3.98-4.00 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ -5.2, -4.8, 13.7, 17.7, 18.0, 18.5, 21.3, 23.0, 25.8, 27.2, 34.5, 35.0, 35.2, 40.7, 42.1, 53.0, 56.5, 69.4, 179.8; HRMS (ESI - ) calcd for C 22 H 41 O3Si [MH] - 381.2830, found 381.2824.

[0363] (1R,3aR,4S,7aR)-1-[(2R)-6-(Difluoromethyl)-7,7-difluoro-6-hydroxyheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (151) [ka]

[0364] To a solution of compound 150 (500.0 mg, 1.31 mmol) in CHCl (2.0 mL) was added N,N-dimethylformamide (20 μL, 21.2 mg, 0.29 mmol) and oxalyl chloride (190 μL, 281.9 mg, 2.22 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the crude residue was used in the next reaction without further purification.

[0365] Ph3P (1.75 g, 6.67 mmol) and N,N'-dimethylpropyleneurea (DMPU) (1.3 mL, 1.34 g, 10.5 mmol) were added to a solution of the crude residue in CH3CN (2 mL), and the mixture was cooled to 0 °C. TMSCF2Br (1.2 mL, 1.60 g, 7.68 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 10 min and at room temperature for 5 h. After that, HO (1 mL) and pyridine (423 μL, 414.5 mg, 5.24 mmol) were added and the mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with excess HO and extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 5:1) to give the crude product.

[0366] To the crude residue in MeOH (5 mL) and CHCl (5 mL) was added p-toluenesulfonic acid monohydrate (476.0 mg, 2.5 mmol), and the mixture was stirred in air at room temperature for 22 h. After the reaction was quenched with H0 and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give compound 151 (134.8 mg, 29%, 3 steps) as a white powder.

[0367] Compound 151: [α] D 27 +34.7 (c 1.52, CHCl3); IR (neat) 3417, 1465, 1379, 1116, 1070 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 0.91 (d, J = 6.4 Hz, 3H), 0.93 (s, 3H), 1.02-1.88 (m, 19H), 1.97-2.20 (m, 1H), 2.45 (brs, 1H), 4.07-4.08 (m, 1H), 5.67-6.00 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.5, 17.4, 18.4, 18.4, 22.5, 27.2, 30.0, 33.5, 35.1, 36.2, 40.3, 41.9, 52.6, 56.5, 69.4, 74.2 (sext, J = 20.0 Hz), 114.7 (t, J = 246.9 Hz); HRMS (ESI - ) calcd for C 19 H 31 O4F4[M+HCOO] - 399.2164, found 399.2155.

[0368] (1R,3aR,7aR)-1-{(2R)-6-(Difluoromethyl)-7,7-difluoro-6-[(trimethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (153) [ka]

[0369] 4-Methylmorpholine N-oxide (33.6 mg, 0.29 mmol) was added to a solution of compound 151 (55.1 mg, 0.16 mmol) in CHCl (1 mL), and the mixture was cooled to 0 °C. TPAP (29.4 mg, 0.08 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO. The mixture was directly purified by flash column chromatography on silica gel (EtO only) to give crude ketone 152, which was used in the next reaction without further purification.

[0370] TMSCl (117.9 mg, 137 μL, 1.09 mmol) was added to a solution of the crude ketone 152 and imidazole (91.6 mg, 1.35 mmol) in CHCl (2 mL) cooled to 0 °C, and the mixture was stirred at 0 °C for 1 h. After quenching the reaction with H2O, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give compound 153 (51.4 mg, 78%, 2 steps) as a colorless oil.

[0371] Compound 153: [α] D 27 +5.0 (c 3.95, CHCl3); IR (neat) 1715, 1468, 1383, 1252, 1116, 1081, 853 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.16 (s, 9H), 0.63 (s, 3H), 0.96 (d, J = 6.0 Hz, 3H), 1.04-1.10 (m, 1H), 1.24-1.64 (m, 9H), 1.68-1.76 (m, 2H), 1.85-1.93 (m, 2H), 1.98-2.03 (m, 1H), 2.09-2.12 (m, 1H), 2.18-2.29 (m, 2H), 2.44 (dd, J = 7.8, 11.4 Hz, 1H), 5.73 (t, J = 54.9Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 1.8, 12.4, 18.6, 18.7, 19.0, 24.0, 27.5, 29.9, 35.4, 36.3, 39.0, 40.9, 49.9, 56.6, 61.9, 77.2 (sext, J = HRMS (ESI + ) calcd for C 21 H 36 O2F4SiNa [M+Na]+ 447.2313, found 447.2318.

[0372] Ethyl 2-[(1R,3aS,7aR,E)-1-{(R)-6-(difluoromethyl)-7,7-difluoro-6-[(trimethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-yliden]acetate (154) [ka]

[0373] To a suspension of NaH (145.0 mg, 60% w / w liquid paraffin, 3.63 mmol) in THF (4 mL) was added (EtO)P(O)CHCOEt (926.0 mg, 827 μL, 4.12 mmol) at 0 °C, and the mixture was stirred at 0 °C for 15 min. Ketone 153 (145.1 mg, 0.34 mmol) was dissolved in THF (2 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 43 h, the reaction was quenched with H2O and saturated aqueous NH4Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 15:1) to give compound 154 (150.8 mg, 89%) as a colorless oil.

[0374] Compound 154: [α] D 27 +83.8 (c 4.38, CHCl3); IR (neat) 1712, 1642, 1464, 1383, 1255, 1185, 1112, 1081, 845 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.17 (s, 9H), 0.58 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.02 - 1.09 (m, 1H), 1.25 - 1.42 (m, 9H), 1.47 - 1.55 (m, 3H), 1.57 - 1.77 (m, 5H), 1.86 - 1.93 (m, 1H), 2.00 - 2.03 (m, 1H), 2.09 - 2.12 (m, 1H), 3.84 - 3.87 (m, 1H), 4.10 - 4.18 (m, 2H), 5.45 (brs, 1H), 5.65 - 5.83 (m, 2H); 13 13C NMR (150 MHz, CDCl3) δ 1.8, 12.1, 14.3, 18.7, 18.7, 22.1, 23.8, 27.4, 29.6, 29.9, 35.8, 36.4, 40.1, 47.1, 56.6, 56.8, 59.5, 77.3 (sext, J = 20.9 Hz), 112.0, 115.0 (t, J = 246.3 Hz), 163.2, 166.9; HRMS (ESI + ) calcd for C 25 H 43 O3F4SiNa [M+H] + 495.2912, found 495.2921.

[0375] 2-[(1R,3aS,7aR,E)-1-{(R)-6-(Difluoromethyl)-7,7-difluoro-6-[(trimethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (155)

Chem.

[0376] To a solution of ethyl ester 154 (150.8 mg, 0.31 mmol) in THF (5 mL) was added DIBAL-H (1.5 mL, 1.0 mol / L hexane solution, 1.5 mmol) at −78 °C, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was diluted with MeOH at −78 °C, and then H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (CHCl2:EtOAc = 10:1) to give alcohol 155 (125.5 mg, 91%) as a colorless oil.

[0377] Compound 155: [α] D 27 +54.9 (c 1.78, CHCl3); IR (neat) 3358, 1379, 1255, 1181, 1116, 1081, 845 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.16 (s, 9H), 0.55 (s, 3H), 0.93 (d, J = 6.0 Hz, 3H), 1.02-1.08 (m, 1H), 1.23-1.41 (m, 7H), 1.45-1.53 ​​(m, 4H), 1.59-1.74 (m, 4H), 1.82-2.00 (m, 3H), 2.60-2.63 (m, 1H), 4.16-4.22 (m, 2H), 5.21 (t, J = 6.9 Hz, 1H), 5.72 (t, J = 55.2 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 1.8, 11.8, 18.7, 22.1, 23.4, 27.6, 28.6, 29.9, 35.9, 36.4, 40.3, 45.3, 55.5, 56.4, 58.6, 77.2 (sext, J = 20.9 Hz), 115.0 (t, J = 245.6 Hz), 119.3, 143.5; - ) calcd for C 24 H 41O4F4Si [M+HCOO] - 497.2716, found 497.2721.

[0378] 2-({2-[(1R,3aS,7aR,E)-1-{(R)-6-(Difluoromethyl)-7,7-difluoro-6-[(trimethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethyl}sulfonyl)benzo[d]thiazole (157) [ka]

[0379] To a solution of 2-mercaptobenzothiazole (121.1 mg, 0.72 mmol), Ph3P (147.3 mg, 0.56 mmol), and CD ring 155 (125.5 mg, 0.28 mmol) in CHCl (3 mL) was added diisopropyl azodicarboxylate (292 μL, 1.9 mol / L toluene solution, 0.55 mmol) at 0 °C, and the mixture was stirred at 0 °C for 15 min. The mixture was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude sulfide 156, which was used in the next reaction without further purification.

[0380] The crude sulfide 156 was dissolved in EtOH (10 mL) and CHCl (1 mL), and the solution was added with 30% HO aqueous solution (1 mL) and (NH)MoO 24 4H2O (321.3 mg, 0.26 mmol) was added. After stirring at room temperature for 2 hours and 30 minutes, the mixture was poured into H2O and extracted three times with CHCl2. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give compound 157 (155.3 mg, 88%, 2 steps) as a colorless oil.

[0381] Compound 157: [α]D 27 +42.4 (c 5.89, CHCl3); IR (neat) 1471, 1333, 1248, 1147, 1112, 1081, 910, 849, 736 cm -1 ; 1 1H NMR (600 MHz, CDCl3) δ 0.16 (s, 9H), 0.26 (s, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.96 - 1.04 (m, 1H), 1.17 - 1.62 (m, 13H), 1.67 - 1.72 (m, 1H), 1.79 - 1.91 (m, 3H), 2.54 - 2.57 (m, 1H), 4.20 (dd, J = 7.2, 14.4 Hz, 1H), 4.42 (dd, J = 9.0, 14.4 Hz, 1H), 5.00 - 5.03 (m, 1H), 5.73 (t, J = 55.8 Hz, 1H), 7.57 - 7.65 (m, 2H), 8.00 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 1.8, 11.5, 18.7, 18.7, 22.0, 23.2, 27.4, 29.0, 29.9, 35.8, 36.3, 39.9, 45.7, 53.9, 55.9, 56.3, 77.2 (sext, J = 20.8 Hz), 104.2, 115.0 (t, J = 245.6 Hz), 122.2, 125.3, 127.6, 127.9, 136.9, 152.0, 152.8, 165.9; HRMS (ESI + ) calcd for C 30 H<用户输入内容有误,推测为 43 NO3F4SiS2Na [M+Na] + 656.2282, found 656.2286.

[0382]

Chemistry

[0383] 说明:原文中“<用户输入内容有误,推测为 43 ”部分是因为原文编号可能存在错误,按照翻译要求保留原内容并进行说明。你可检查原文编号是否准确,以便我提供更准确的翻译。To a solution of sulfone 157 (155.3 mg, 0.25 mmol) in THF (1.5 mL) was added LiHMDS (264 μL, 1.0 mol / L THF solution, 0.26 mmol) at −78 °C. After stirring the mixture at the same temperature for 25 min, A-ring (101.2 mg, 0.19 mmol) in THF (2.0 mL) was added, and the whole mixture was stirred at the same temperature for 3 h 30 min. After quenching the reaction with saturated aqueous NH4Cl and HO, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give the protected coupling product as an inseparable mixture of isomers.

[0384] p-Toluenesulfonic acid monohydrate (782.4 mg, 4.11 mmol) was added to a solution of the above coupling compound in MeOH (10 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 19 h. After the reaction was quenched with HO and saturated aqueous NaHCO at room temperature, the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 20:1) to give MART-10-F4 and MART-11-F4 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO solvent system (4:1) to give MART-10-F4 (29.5 mg, 23%, 2 steps) and MART-11-F4 (34.2 mg, 26%, 2 steps), respectively, as white powders.

[0385] MART-10-F4: [α] D 27 +62.1 (c 2.27, MeOH); IR (neat) 3350, 1441, 1375, 1104, 1069, 910, 732 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.52 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.05-1.11 (m, 1H), 1.23-1.73 (m, 19H), 1.86-1.91 (m, 1H), 1.98-2.00 (m, 2H), 2.11-2.24 (m, 4H), 2.56-2.59 (m, 1H), 2.78-2.83 (m, 2H), 3.05 (brs, 1H), 3.21 (brs, 1H), 3.60-3.69 (m, 3H), 4.07 (brs, 1H), 5.81 (d, J = 10.2 Hz, 1H), 5.81 (t, J = 56.1 Hz, 2H), 6.34 (d, J = 10.8 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.0, 18.4, 18.7, 22.2, 23.3, 23.4, 27.6, 28.8, 29.7, 29.9, 35.3, 35.9, 36.4, 40.4, 45.1, 45.7, 48.5, 56.2, 56.4, 62.5, 68.4, 71.2, 74.2 (sext, J = 20.1 Hz), 114.7 (t, J = 247.7 Hz), 115.4, 123.7, 131.6, 142.8; HRMS (ESI + ) calcd for C 29 H 46 O4F4Na [M+Na] + 557.3224, found 557.3235.

[0386] MART-11-F4: [α] D 27 +28.1 (c 2.63, MeOH); IR (neat) 3373, 1441, 1379, 1112, 1069, 976 cm -1 ; 1H NMR (600 MHz, CD3OD) δ 0.61 (s, 3H), 1.01 (d, J = 7.2 Hz, 3H), 1.11-1.17 (m, 1H), 1.32-1.83 (m, 22H), 1.88-1.92 (m, 1H), 1.94-2.01 (m, 1H), 2.05-2.08 (m, 1H), 2.33-2.39 (m, 2H), 2.87 (dd, J = 4.2, 12.0 Hz, 1H), 3.03 (dd, J = 4.5, 12.0 Hz, 3H), 3.54 (td, J = 3.6, 9.6 Hz, 1H), 3.60-3.62 (m, 2H), 4.07-4.08 (m, 1H), 5.89 (t, J = 54.6 Hz, 2H), 5.93 (d, J = 11.4 Hz, 1H), 6.21 (d, J = 12.0 Hz, 1H); 13 C NMR (150 MHz, CD3OD) δ 12.7, 19.6, 19.8, 23.6, 24.8, 24.8, 29.0, 30.2, 30.9, 31.5, 37.6, 38.1, 38.8, 42.2, 45.1, 47.1, 50.4, 57.8, 58.2, 63.7, 69.1, 71.6, 75.3 (sext, J = 20.1 Hz), 117.1 (t, J = 245.6 Hz), 117.4, 123.3, 134.3, 142.2; + calcd for C 29 H 46 O4F4Na [M+Na] + 557.3224, found 557.3239.

[0387] "Manufacturing Example 9:26,27-Synthesis of F2 Body"

change

[0388] tert-Butyldimethyl({(1R,3aR,4S,7aR)-7a-methyl-1-[(2R)-pent-4-yn-2-yl]octahydro-1H-inden-4-yl}oxy)silane (158) [ka]

[0389] To a solution of trimethylsilyldiazomethane (8.3 mL, 0.6 mol / L in hexane, 4.96 mmol) in THF (15 mL), n-BuLi (2.9 mL, 1.59 mol / L in hexane, 4.63 mmol) was added at −78° C., and the mixture was stirred at the same temperature for 15 min. Aldehyde 101 [see Ref. 1 above] (1.12 g, 3.31 mmol) in THF (15 mL) was added, and the solution was stirred at the same temperature for 30 min. After quenching the reaction with HO and AcOH at −78° C., the mixture was extracted three times with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (hexane only) to give compound 158 (110.1 mg, 10%) as a colorless oil.

[0390] Compound 158: [α] D 27 +55.9 (c 5.46, CHCl3); IR (neat) 3315, 2192, 1468, 1379, 1252, 1166, 1089, 1023, 837, 775, 632 cm -1 ; 11H NMR (400 MHz, CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H), 0.92 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.12 - 1.29 (m, 4H), 1.32 - 1.40 (m, 3H), 1.53 - 1.62 (m, 2H), 1.65 - 1.68 (m, 1H), 1.76 - 1.84 (m, 2H), 1.92 - 1.95 (m, 2H), 2.02 (ddd, J = 2.4, 7.8, 17.4 Hz, 1H), 2.23 (dt, J = 3.0, 16.2 Hz, 1H), 3.99 - 4.01 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.9, 17.6, 18.0, 18.9, 23.0, 25.5, 25.8, 27.2, 34.4, 34.8, 40.5, 42.1, 53.0, 55.6, 69.1, 69.4, 83.5; HRMS (ESI - ) calcd for C 22 H 39 O3Si [M+HCOO] - 379.2674, found 379.2675.

[0391] (6R)-6-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-1-fluoro-2-(fluoromethyl)hept-3-yn-2-ol (159) [Chemical formula] <00028IO>

[0392] It should be noted that there may be an error in the "

化

[0393] Compound 159: [α] D 27 +46.5 (c 4.73, CHCl3); IR (neat) 3408, 2253, 1464, 1371, 1255, 1162, 1085, 1035, 837, 775 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ -0.01 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.91 (s, 3H), 1.03 (d, J = 6.6 Hz, 3H), 1.09-1.13 (m, 2H), 1.19-1.26 (m, 2H), 1.32-1.39 (m, 3H), 1.52-1.68 (m, 4H), 1.74-1.84 (m, 2H), 1.91-1.94 (m, 1H), 2.02 (dd, J = 8.1, 16.5 Hz, 1H), 2.28 (dd, J = 3.2, 16.8 Hz, 1H), 2.51 (brs, 1H), 3.99-4.00 (m, 1H), 4.40-4.51 (m, 4H); 13C NMR (150 MHz, CDCl3) δ -5.2, -4.8, 13.8, 17.6, 18.0, 18.9, 23.0, 25.7, 25.8, 27.1, 34.3, 34.9, 40.5, 42.1, 53.0, 55.8, 68.9 (t, J = 20.9 Hz), 69.3, 76.6 (t, J = 5.8 Hz), 84.1 (dd, J = 2.9, 179.6 Hz), 88.1; - ) calcd for C 24 H 42 O2F2SiCl [M+Cl] - 463.2616, found 463.2605.

[0394] (1R,3aR,4S,7aR)-1-[(2R)-7-Fluoro-6-(fluoromethyl)-6-hydroxyheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (160) [ka]

[0395] To a solution of compound 159 (181.7 mg, 0.42 mmol) in MeOH (10 mL) was added 10% Pd / C catalyst (17.0 mg). The mixture was stirred at room temperature under 1 atmosphere of hydrogen for 14 hours. The reaction mixture was diluted with EtOAc, filtered through a pad of Celite, and concentrated under reduced pressure to give the crude alcohol, which was used in the next reaction without further purification.

[0396] p-Toluenesulfonic acid monohydrate (482.9 mg, 2.54 mmol) was added to a solution of the crude alcohol in MeOH (10 mL). The mixture was stirred in air at room temperature for 1 h. After the reaction was quenched with H2O and saturated aqueous NaHCO3 at room temperature, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane: EtOAc = 2:1) to give compound 160 (130.6 mg, 97%, 2 steps) as a colorless oil.

[0397] Compound 160: [α] D 27 +34.5 (c 1.64, CHCl3); IR (neat) 3419, 1460, 1375, 1271, 1162, 1019, 941, 914, 736 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 0.90 (d, J = 6.6 Hz, 3H), 0.92 (s, 3H), 1.01-1.09 (m, 2H), 1.14 (dt, J = 3.6, 13.2 Hz, 1H), 1.22-1.57 (m, 13H), 1.77-1.86 (m, 3H), 1.98-2.00 (m, 1H), 2.26 (d, J = 7.2 Hz, 1H), 4.06-4.07 (m, 1H), 4.28-4.42 (m, 4H); 13 C NMR (150 MHz, CDCl3) δ 13.5, 17.4, 18.4, 18.7, 22.5, 27.1, 33.0, 33.5, 35.1, 36.1, 40.3, 41.8, 52.5, 56.5, 69.4, 72.6 (t, J = 17.3 Hz), 83.5-84.8 (m); HRMS (ESI - ) calcd for C 18 H 31 O2F2[MH] - 317.2298, found 317.2285.

[0398] (1R,3aR,7aR)-1-{(2R)-7-Fluoro-6-(fluoromethyl)-6-[(trimethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-one (162) [ka]

[0399] 4-Methylmorpholine N-oxide (39.4 mg, 0.34 mmol) was added to a solution of compound 160 (21.3 mg, 0.07 mmol) in CHCl (1 mL), and the mixture was cooled to 0 °C. TPAP (14.2 mg, 0.04 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 1 h. The reaction was diluted with excess EtO. The mixture was directly purified by flash column chromatography on silica gel (EtO only) to give crude ketone 161, which was used in the next reaction without further purification.

[0400] TESCl (70.7 mg, 79 μL, 0.47 mmol) was added to a solution of the crude ketone 161 and imidazole (50.1 mg, 0.74 mmol) in CHCl (1 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 24 h. After quenching the reaction with H2O, the mixture was extracted three times with CHCl. ​​The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 20:1) to give compound 162 (23.0 mg, 80%, 2 steps) as a colorless oil.

[0401] Compound 162: [α] D 27 +2.71 (c 1.77, CHCl3); IR (neat) 1712, 1464, 1379, 1235, 1170, 1035, 744 cm -1 ; 11H NMR (400 MHz, CDCl3) δ 0.60 (q, J = 7.8 Hz, 6H), 0.64 (s, 3H), 0.94 (t, J = 7.8 Hz, 9H), 0.95 (d, J = 6.0 Hz, 3H), 1.02 - 1.09 (m, 1H), 1.23 - 1.60 (m, 10H), 1.69 - 1.76 (m, 1H), 1.85 - 1.94 (m, 2H), 1.98 - 2.04 (m, 1H), 2.10 - 2.13 (m, 1H), 2.19 - 2.29 (m, 2H), 2.44 (dd, J = 7.8, 11.8 Hz, 1H), 4.22 - 4.35 (m, 4H); 13 13C NMR (150 MHz, CDCl3) δ 6.3, 6.9, 12.5, 18.6, 18.7, 19.0, 24.0, 27.5, 33.9, 35.4, 36.1, 39.0, 40.0, 49.9, 56.6, 62.0, 75.4 (t, J = 17.9 Hz), 83.3 - 84.7 (m), 212.0; HRMS (ESI - ) calcd for C 24 H 44 O2F2SiCl [M+Cl] - 465.2773, found 465.2789.

[0402] 2-[(1R,3aS,7aR,E)-1-{(2R)-7-Fluoro-6-(fluoromethyl)-6-[(trimethylsilyl)oxy]heptan-2-yl}-7a-methyloctahydro-4H-inden-4-ylidene]ethan-1-ol (164)

Chem.

[0403] To a suspension of NaH (179.6 mg, 60% w / w liquid paraffin, 4.49 mmol) in THF (4 mL) was added (EtO)P(O)CHCOEt (1.12 g, 1.0 mL, 4.98 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. Ketone 162 (214.3 mg, 0.50 mmol) was dissolved in THF (4 mL), and the solution was added to the mixture at the same temperature. After stirring at room temperature for 40 h, the reaction was quenched with H2O and saturated aqueous NH4Cl at room temperature. The mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 15:1) to give crude ester 163 (230.0 mg) as a colorless oil.

[0404] To a solution of crude ethyl ester 163 (230.0 mg) in THF (7 mL) was added DIBAL-H (2.5 mL, 1.0 mol / L hexane solution, 2.5 mmol) at −78 °C, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was diluted with MeOH at −78 °C, and then H2O and saturated aqueous potassium sodium tartrate solution were added at room temperature. The mixture was extracted three times with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (CHCl2:EtOAc = 4:1) and repurified by silica gel flash column chromatography (CHCl2:EtOAc = 10:1) to give alcohol 164 (102.5 mg, 45%, 2 steps) as a colorless oil.

[0405] Compound 164: [α] D 27 +63.6 (c 1.00, CHCl3); IR (neat) 3327, 1460, 1383, 1235, 1170, 1089, 1035, 744 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.55 (s, 3H), 0.60 (q, J = 8.4 Hz, 6H), 0.93 - 0.95 (m, 12H), 1.02 - 1.08 (m, 1H), 1.22 - 1.68 (m, 16H), 1.82 - 2.01 (m, 3H), 2.61 - 2.64 (m, 1H), 4.17 - 4.36 (m, 6H), 5.22 (t, J = 7.5 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.3, 6.9, 11.8, 18.7, 18.7, 22.1, 23.5, 27.6, 28.7, 34.0, 36.0, 36.3, 40.3, 45.3, 55.6, 56.5, 58.7, 75.4 (t, J = 17.9 Hz), 83.4 - 84.8 (m), 119.2, 143.7; HRMS (ESI + ) calcd for C 26 H 48 O2F2SiNa [M+Na] + 481.3284, found 481.3291.

[0406] 2 - ({2 - [(1R,3aS,7aR,E) - 1 - {(2R) - 7 - Fluoro - 6 - (fluoromethyl) - 7,7 - 6 - [(trimethylsilyl)oxy]heptan - 2 - yl} - 7a - methyloctahydro - 4H - inden - 4 - ylidene]ethyl}sulfonyl)benzo[d]thiazole (166)

Chem.

[0407] To a solution of 2-mercaptobenzothiazole (102.6 mg, 0.61 mmol), PhP (121.0 mg, 0.46 mmol), and CD ring 164 (102.5 mg, 0.22 mmol) in CHCl (8 mL) was added diisopropyl azodicarboxylate (235 μL, 1.9 mol / L in toluene, 0.45 mmol) at 0 °C, and the mixture was stirred at 0 °C for 20 min. The mixture was directly purified by flash column chromatography on silica gel (hexane:EtOAc = 10:1) to give crude sulfide 165, which was used in the next reaction without further purification.

[0408] The crude sulfide 165 was dissolved in EtOH (15 mL) and CHCl (2 mL), and the solution was added with 30% aqueous HO (3 mL) and (NH)MoO 24 4H2O (197.9 mg, 0.16 mmol) was added. After stirring at room temperature for 4 h, the mixture was poured into H2O and extracted three times with CHCl2. The organic layer was washed with saturated Na2S2O3, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give compound 166 (134.3 mg, 94%, 2 steps) as a colorless oil.

[0409] Compound 166: [α] D 27 +43.3 (c 3.47, CHCl3); IR (neat) 1471, 1325, 1235, 1150, 1031, 760, 744, 728 cm -1 ; 11H NMR (600 MHz, CDCl3) δ 0.26 (s, 3H), 0.59 (q, J = 7.8 Hz, 6H), 0.85 (d, J = 6.0 Hz, 3H), 0.91 - 1.03 (m, 10H), 1.16 - 1.56 (m, 14H), 1.78 - 1.90 (m, 3H), 2.54 - 2.56 (m, 1H), 4.18 - 4.35 (m, 5H), 4.42 (dd, J = 9.0, 14.4 Hz, 1H), 5.01 (t, J = 8.1 Hz, 1H), 7.57 - 7.64 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H); 13 13C NMR (150 MHz, CDCl3) δ 6.3, 6.9, 11.5, 18.6, 22.0, 23.1, 27.4, 29.0, 33.9, 35.8, 36.1, 37.2, 39.9, 45.7, 53.9, 55.9, 56.3, 75.4 (t, J = 17.9 Hz), 83.3 - 84.7 (m), 104.1, 122.2, 125.3, 127.5, 127.8, 136.9, 152.0, 152.8, 165.9; HRMS (ESI + ) calcd for C 33 H 51 NO3F2SiS2Na [M+Na] + 662.2940, found 662.2948.

[0410]

Chem.

[0411] To a solution of sulfone 166 (134.3 mg, 0.21 mmol) in THF (1.5 mL) was added LiHMDS (210 μL, 1.0 mol / L THF solution, 0.21 mmol) at −78 °C. After stirring the mixture at the same temperature for 20 min, A-ring (81.5 mg, 0.15 mmol) in THF (1.5 mL) was added, and the whole mixture was stirred at the same temperature for 5 h 30 min. After quenching the reaction with saturated aqueous NH4Cl and HO, the mixture was extracted three times with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc = 5:1) to give the protected coupling product as an inseparable mixture of isomers.

[0412] p-Toluenesulfonic acid monohydrate (325.3 mg, 1.71 mmol) was added to a solution of the coupling compound in MeOH (10 mL) and CHCl (5 mL). The mixture was stirred in air at room temperature for 15 h. The reaction was quenched with HO and saturated aqueous NaHCO at room temperature, and the mixture was extracted three times with CHCl. ​​The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:MeOH = 20:1) to give MART-10-F2 and MART-11-F2 as a mixture. These isomers were separated by reverse-phase HPLC (YMC-Pack ODS column) using a CHCN:HO solvent system (4:1) to give MART-10-F2 (20.5 mg, 27%, 2 steps) and MART-11-F2 (23.0 mg, 30%, 2 steps), respectively, as white powders.

[0413] MART-10-F2: [α] D 27 +31.1 (c 0.91, EtOH); IR (neat) 3361, 1371, 1212, 1019, 899, 732 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 0.53 (s, 3H), 0.93 (d, J = 7.2 Hz, 3H), 1.03-1.10 (m, 1H), 1.23-2.00 (m, 24H), 2.12-2.16 (m, 2H), 2.29 (brs, 1H), 2.43 (brs, 1H), 2.59 (dd, J = 4.5, 12.9 Hz, 1H), 2.78-2.85 (m, 2H), 3.62-3.71 (m, 3H), 4.08 (brs, 1H), 4.29-4.42 (m, 4H), 5.81 (d, J = 10.8 Hz, 1H), 6.36 (d, J = 10.8 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 12.0, 18.7, 22.2, 23.4, 23.4, 27.6, 28.9, 29.9, 33.0, 35.5, 36.0, 36.3, 40.4, 45.3, 45.8, 48.6, 56.3, 56.4, 62.7, 68.5, 71.4, 72.6 (t, J = 17.9 Hz), 84.2 (d, J = 172.4 Hz), 84.3 (d, J = 172.4 Hz), 115.3, 123.8, 131.4, 143.0; HRMS (ESI + ) calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3419.

[0414] MART-11-F2: [α] D 27 +32.8 (c 1.04, EtOH); IR (neat) 3373, 1464, 1375, 1321, 1027, 926, 709 cm -1 ; 1H NMR (400 MHz, CDCl3) δ 0.54 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 1.04-1.11 (m, 1H), 1.23-2.21 (m, 27H), 1.98-2.08 (m, 3H), 2.34-2.42 (m, 2H), 2.80 (dd, J = 4.2, 11.4 Hz, 1H), 2.33-2.42 (m, 2H), 2.79 (dd, J = 3.4, 11.9 Hz, 1H), 3.08 (dd, J = 3.4, 11.9 Hz, 1H), 3.51-3.57 (m, 1H), 3.64-3.73 (m, 2H), 4.04 (brs, 1H), 4.27-4.45 (m, 4H), 4.47-4.57 (m, 1H), 5.86 (d, J = 11.0 Hz, 1H), 6.24 (d, J = 11.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 12.0, 18.7, 22.3, 23.5, 23.7, 27.7, 29.0, 29.8, 33.0, 36.0, 36.3, 37.8, 40.4, 44.0, 45.8, 48.9, 56.3, 56.4, 62.8, 68.3, 71.1, 72.7 (t, J = 17.6 Hz), 84.1 (dd, J = 3.8, 172.6 Hz), 84.2 (dd, J = 3.8, 172.6 Hz), 115.3, 123.4, 131.3, 142.9; HRMS (ESI + calcd for C 29 H 48 O4F2Na [M+Na] + 521.3413, found 521.3420.

[0415] "Commentary Example 1: Effect of psoriasis-induced psoriasis MART10-F2" Psoriasis was induced in male Balb / c mice (6 weeks old) by daily application of 12.5 mg of 5% imiquimod cream (Veselna Cream, Mochida Pharmaceutical) to the left ear. Six hours after application of the 5% imiquimod cream, 5 μL of a vitamin D derivative ethanol solution at a concentration of 0, 10, or 50 μg / g was dripped onto the left ear. The vitamin D derivative synthesized, 24F2-MART-10 (hereinafter also referred to as MART10-F2), prepared in Preparation Example 2, was selected and compared with calcipotriol (Sigma-Aldrich), a compound already used as a therapeutic agent. The above treatment was carried out for three days, and ear thickness was measured after three days. The results are shown in Figure 1. It can be seen that the ear thickness, which had increased due to inflammation caused by imiquimod, was reduced by application of calcipotriol. MART10-F2 significantly reduced the blemishes compared to the same amount of calcipotriol applied, and MART10-F2 showed a high effect even at 1 / 5 the amount of calcipotriol. Vitamin D derivatives other than MART10-F2 also showed a certain therapeutic effect, although the strength of the effect varied.

[0416] Evaluation Example 2: Cancer cell proliferation inhibitory effect of each derivative The inhibitory effect of vitamin D derivatives on cancer cell proliferation was investigated using human breast cancer (MCF-7) cells as follows. MCF-7 cells were cultured in E-MEM (containing L-glutamine and phenol red) medium containing 1% NEAA (Non-essential Amino Acids Solution) and 10% FBS (fetal bovine serum) at 5% CO2 and 37°C. 2.0 × 10 4 The cells were suspended in medium at a concentration of 100 cells / mL and seeded in 100 μL aliquots onto a 96-well plate. After 24 hours of incubation at 37°C, the supernatant was removed and replaced with medium containing 100 nmol / L of each vitamin D derivative. This medium was prepared by adding 1 / 500 the volume of the medium containing a 50 μmol / L ethanol solution of each vitamin D derivative, resulting in a 0.5% ethanol content. After switching to the vitamin D derivative-supplemented medium, the cells were further cultured for 3 days.

[0417] Three days after the addition of the vitamin D derivative, cell numbers were measured using the MTT assay. The MTT assay was performed as follows: The medium was removed from each well, and 100 μL of fresh medium without the vitamin D derivative was added. 10 μL of MTT (3-(4,5-Dimethylthial-2-yl)-2,5-Diphenyltetrazalium Bromide: Dojindo) 5 mg / mL dissolved in PBS(-) (phosphate-buffered saline) was added to each well, and the cells were cultured at 37°C for 4 hours. After 4 hours, the medium was removed from each well, and 200 μL of DMSO was added. After thorough mixing, the absorbance at 535 nm was measured.

[0418] Figure 2 shows the cell counts after 3 days of culture in the presence of 100 nmol / L of each derivative. The vertical axis in Figure 2 represents the relative cell count, with the cell count in medium without the derivative set to 1. Each derivative had a higher inhibitory effect on cancer cell proliferation than the natural form 1α,25D3 and EB1089 (a vitamin D derivative undergoing phase II clinical trials as a pancreatic cancer treatment). Among the synthesized derivatives, 24F2-MART-10 (MART10-F2 in Figure 2) and 24F2-MART-11 (MART11-F2 in Figure 2) produced in Production Example 2, and MART-10-F6 (MART-10-F6 in Figure 2) and MART-11-F6 (MART-11-F6 in Figure 2) produced in Production Example 1 were selected.

[0419] To examine the efficacy of MART10-F2, MART10-F6, MART11-F2, and MART11-F6 at lower concentrations, we compared the cell numbers after 7 days of culture in media containing each compound at final concentrations of 1, 10, and 100 nmol / L. The results are shown in Figure 3. All four of the evaluated derivatives were found to be effective in inhibiting cancer cell proliferation at lower concentrations than the natural form, 1α,25D3. Furthermore, vitamin D derivatives other than the four evaluated derivatives were also found to have a certain degree of inhibitory effect on cancer cell proliferation, although the strength of the effect varied.

[0420] Evaluation Example 3: Evaluation of the cancer cell proliferation inhibitory effect of 24F2-MART-10 using three-dimensional cultured cells In this evaluation example, the cancer cell proliferation inhibitory effect of 24F2-MART-10, which exhibited the highest cancer cell proliferation inhibitory effect in Evaluation Example 5, was evaluated using three-dimensional cultured cells, which form a tumor model similar to that in the living body and are expected to produce results in vitro that are similar to those in vivo.

[0421] Human breast cancer (MCF-7) cells were cultured in three dimensions using the method described below to examine the effect of vitamin D derivatives on cancer cell proliferation. MCF-7 cells were cultured under the conditions described in Evaluation Example 2 at 5.0 × 10 4 The cells were suspended in medium at a concentration of 100 cells / mL and seeded in 100 μL aliquots into ultra-low attachment polymer-coated U-bottom 96-well plates (Cell Carrier Spheroid ULA Plate, Perkin Elmer). After 3 days of incubation at 37°C, the supernatant was removed and replaced with medium containing 100 nmol / L of activated vitamin D (1,25D3) or 24F2-MART-10. This medium was prepared by adding 50 μmol / L of each compound in ethanol at a volume of 1 / 500 of the medium volume, resulting in a 0.5% ethanol content. The control group received the same amount of ethanol alone. At 4, 7, and 10 days after the addition of each compound, the medium was replaced with 50 μL / well of medium containing the compound or ethanol alone at the same concentration as above, and the cultures were continued for 14 days. Bright field photography was performed using an imaging analyzer (Operetta CLS, Perkin Elmer) 0, 4, 7, 10, and 14 days after the addition of each evaluation compound, and the area values ​​of the three-dimensional cultured cells were obtained.

[0422] Figure 7 shows the time course of the area change of three-dimensional cultured cells cultured in a medium containing each evaluation compound. In this evaluation system, 24F2-MART-10 exhibited a stronger inhibitory effect on cancer cell proliferation than active vitamin D (1,25D3). In addition, 24F2-MART-10 exerted this effect at an earlier stage than active vitamin D. [Industrial Applicability]

[0423] The present invention can be used to provide a pharmaceutical composition for treating or preventing psoriasis or cancer.

Claims

1. General formula (I): 【Chemical 1】 (wherein X represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, Y is a linear or branched alkyl group having 1 to 12 carbon atoms, which is substituted with at least one halogen atom and may be substituted with a hydroxyl group. A compound represented by the formula:

2. X is a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 1 to 5 carbon atoms which may be substituted with a hydroxyl group, 2. The compound according to claim 1, wherein Y is a linear or branched alkyl group having 3 to 10 carbon atoms, which is substituted with at least one halogen atom and which may be substituted with a hydroxyl group.

3. X is a linear or branched alkyl group having 1 to 4 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 1 to 4 carbon atoms which may be substituted with a hydroxyl group, 2. The compound according to claim 1, wherein Y is a linear or branched alkyl group having 5 to 8 carbon atoms, which is substituted with at least one halogen atom and which may be substituted with a hydroxyl group.

4. X is a linear or branched alkyl group having 3 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched alkenyl group having 3 carbon atoms which may be substituted with a hydroxyl group, 2. The compound of claim 1, wherein Y is a 4-hydroxyl-4-methylpentyl group substituted with at least one halogen atom.

5. Y is, 【Chemistry 2】 (wherein Z is a hydrogen atom or a hydroxyl group, R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom or a halogen atom; R5 and R6 each independently represent a methyl group or an ethyl group optionally substituted with 1 to 3 halogen atoms. The compound according to claim 1, wherein the group is represented by:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 as an active ingredient.

7. A pharmaceutical composition for treating or preventing psoriasis, comprising the compound according to any one of claims 1 to 5 as an active ingredient.

8. A pharmaceutical composition for treating or preventing cancer, comprising the compound according to any one of claims 1 to 5 as an active ingredient.

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