PYRAN FUSED RING COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention relates to pyran-fused ring compounds, preparation methods thereof and use thereof, especially to pyran-fused ring compounds usable for preparing Halichondrin, Eribulin, or analogues thereof, preparation methods thereof and use thereof. Use of any of the compounds of formula (I) to (XIII) of the present invention in preparation of Halichondrin B, Eribulin, analogues thereof or C1-C13 moieties thereof. Provided in the present invention are intermediates usable for preparing Halichondrin B, Eribulin, or analogues thereof, especially the key product of C1-C13 moieties, preparation methods thereof and use thereof. The starting material for the synthesis pathway of the present invention is inexpensive and readily available with sustainable source and reliable quality. Since the structural characteristics of the reactants of theirself are made full use in choosing the method of constructing the chiral centers, the efficiency in the synthesis is considerably increased, the difficulty in and the risk on quality control of the product are reduced; and using a highly toxic and expensive high-valent osmium catalyst is avoided, which have the cost and environmental friendliness significantly improved.

Claims

1-10. (canceled)

11. A method for preparing Halichondrin B, Eribulin, analogues thereof or C1-C13 moieties thereof, comprising use of a compound of formula V as shown below: ##STR00050## wherein R.sup.4, R.sup.6 are the same or different and selected independently of one another from the group consisting of hydroxyl protecting groups; R.sup.1, R.sup.2 are the same or different and selected independently of one another from the group consisting of H or —B(OR.sup.7).sub.2; R.sup.7 is selected from the group consisting of an alkyl unsubstituted or optionally substituted with one or more of R.sup.a; or the two adjacent R.sup.7 groups bind to each other to form an alkylidene unsubstituted or optionally substituted with one or more of R.sup.a, two ends of said alkylidene each binding to the O atom via a chemical bond, therefor resulting in formation of a ring with the B atom; each of the R.sup.a is the same or different and selected independently of one another from the group consisting of —F, —Cl, —Br, —I, ═O, alkyl, cycloalkyl, heterocycyl, aryl, heteroaryl, alkoxy, alkenyloxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl.

12. The method according to claim 11, comprising the steps of: reacting a compound of formula (IV) to obtain the compound of formula (V): ##STR00051##

13. The method according to claim 12, wherein said compound of formula (IV) is reacted with B.sub.2(OR.sup.7).sub.4 to obtain an intermediate of formula (IV-1) which is removed the group-B(OR.sup.7).sub.2 to obtain the compound of formula (V) in which R.sup.1, R.sup.2 are hydrogen: ##STR00052##

14. The method according to claim 11, comprising the step of: reacting the compound of formula (V) in which R.sup.1, R.sup.2 are hydrogen, that is, a compound of formula (V-1) as shown below, with a hydroxyl-protecting agent, to obtain a compound of formula (VI) ##STR00053## wherein R.sup.8, R.sup.9, R.sup.10 are the same or different and selected independently of one another from the group consisting of hydroxyl protecting groups.

15. The method according to claim 14, further comprising the steps of: reacting the compound of formula (VI) under a condition for removing the R.sup.6 group, to obtain a compound of formula (VII) ##STR00054## and reacting the compound of formula (VII) in the presence of the oxidizing agent, to obtain a compound of formula (VIII) ##STR00055##

16. The method according to claim 15, further comprising the step of: reacting the compound of formula (VIII) to obtain a compound of formula (IX) ##STR00056## X is selected from the group consisting of Cl, Br, I or R.sup.14S(O).sub.2—; R.sup.14 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl unsubstituted or optionally substituted with one or more of R.sup.a.

17. The method according to claim 16, comprising the steps of: reacting the compound of formula (IX) to obtain a compound of formula (X); ##STR00057## and reacting the compound of formula (X) to obtain a compound of formula (XI) and/or tautomeric isomers thereof; ##STR00058## Y may be an alkoxy unsubstituted or optionally substituted with one or more of R.sup.a; and reacting the compound of formula (XI) to obtain a compound of formula (XII); ##STR00059## wherein X, Y are defined in the same way as in the formula (XI); and reacting the compound of formula (XII) with the hydroxyl-protecting agent, to obtain the compound of formula (XIII) ##STR00060## wherein X and Y are defined in the same way as in the formula (XI); R.sup.11, R.sup.12 and R.sup.13 are the same or different and selected independently of one another from the group consisting of hydroxyl protecting groups.

18. The method according to claim 11, comprising the step of removing the hydroxyl protecting group R.sup.4 from the compound of formula (V) in which R.sup.1 and R.sup.2 are hydrogen, that is, the compound of formula (V-1) as shown below, to synthesize a compound (V-2) subsequently ##STR00061## or the compound (V-4) being oxidized to generate an aldehyde (V-5), subsequently yielding the compound (XIII): ##STR00062##

19. A compound selected from the compounds shown as follows: the compound of formula V: ##STR00063## or the compound of formula V-1: ##STR00064## or the compound of formula IV: ##STR00065## or the compound of formula VI: ##STR00066## or the compound of formula VII: ##STR00067## or the compound of formula VIII: ##STR00068## or the compound of formula IX: ##STR00069## or the compound of formula X: ##STR00070## or the compound of formula XI: ##STR00071## or the compound of formula (XII); ##STR00072## or the compound of formula (XIII); ##STR00073## wherein R.sup.1, R.sup.2 are the same or different and selected independently of one another from the group consisting of H or —B(OR.sup.7).sub.2, R.sup.4, R.sup.6 are the same or different and selected independently of one another from the group consisting of hydroxyl protecting groups, R.sup.7 is selected from the group consisting of an alkyl unsubstituted or optionally substituted with one or more of R.sup.a; or the two adjacent R.sup.7 groups bind to each other to form an alkylidene unsubstituted or optionally substituted with one or more of R.sup.a, two ends of said alkylidene each binding to the O atom via a chemical bond, therefor resulting in formation of a ring with the B atom; R.sup.8, R.sup.9, R.sup.10 are the same or different and selected independently of one another from the group consisting of hydroxyl protecting groups, X is selected from the group consisting of Cl, Br, I or R.sup.14S(O).sub.2—, R.sup.14 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl unsubstituted or optionally substituted with one or more of R.sup.a Y may be an alkoxy unsubstituted or optionally substituted with one or more of R.sup.a, each of the R.sup.a is the same or different and selected independently of one another from the group consisting of —F, —Cl, —Br, —I, ═O, alkyl, cycloalkyl, heterocycyl, aryl, heteroaryl, alkoxy, alkenyloxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, and R.sup.11, R.sup.12, R.sup.13 are the same or different and selected independently of one another from the group consisting of acyl groups.

20. The method of preparing the compound according to claim 19, wherein the compound is the formula (IV), comprising the steps of: 1) selectively epoxidized a diene compound (III) or compound (III-4) at the positions C8, C9: ##STR00074## R.sup.5 is selected from hydroxyl protecting groups; or 2) a compound (III-3) or compound (III-5) undergoes an intra-molecular S.sub.N2 reaction ##STR00075##

21. The method of preparing the compound according to claim 19, comprising the steps of: reacting the compound of formula (IV) to obtain the compound of formula (V) in which R.sup.1, R.sup.2 are —B(OR.sup.7).sub.2: ##STR00076##

22. The method according to claim 21, further comprising the steps of: remove the group-B(OR.sup.7).sub.2 to obtain the compound of formula (V) in which R.sup.1, R.sup.2 are hydrogen: ##STR00077##

23. The method of preparing the compound according to claim 19, comprising the steps of: reacting the compound of formula (VIII) to obtain the compound of formula (IX) ##STR00078##

24. The method of preparing the compound according to claim 19, comprising the steps of: reacting the compound of formula (VI) to obtain the compound of formula (VII) ##STR00079##

25. The method of preparing the compound according to claim 19, comprising the steps of: reacting the compound of formula (VII) to obtain the compound of formula (VIII) ##STR00080##

Description

PARTICULAR EMBODIMENTS

[0139] The above and other characteristics and advantages of the present invention will be explained and illustrated below in more details by describing the Examples of the present invention. It should be understood that the Examples below are intended to illustrate exemplarily the technical solutions of the present invention, but not to limit in any way the scope of protection of the present invention defined in the claims and the equivalents thereof.

[0140] Unless otherwise specified, materials and reagents herein are all the commercially available products, or can be prepared according to the state of the art by the person of skill.

[0141] It should be understood by those skilled in the art that the starting materials, reagents, intermediates, the target compounds or reaction formulas in the Examples below are all exemplary technology solutions for the compounds of general formula hereinabove or the reaction therefor, where one or more of the particular compounds or the particular reaction formulas all can be combined with generic technology solutions of the present invention, and the technology solution arising after the combination should be construed as the technology solution documented in the specification.

[0142] Unless otherwise specified, the yield in the Examples below is calculated as product purity of more than 99.5%.

Example 1. Preparation of Compound 26

[0143] ##STR00028##

[0144] Under protection with argon gas, (E)-4-bromobut-2-en-1-ol (19 g, 0.126 mol) was dissolved in dry toluene, triphenyl phosphine (66 g, 0.25 mol) was added with stirring, heated at 60° C. to react. The reaction was completed after 3 hrs, stopped, filtered, washed with anhydrous ethyl ether, resulting in 40 g of the target compound 26, with a yield of 76%.

[0145] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78-7.65 (m, 15H), 6.03-5.98 (m, 1H), 5.66-5.61 (m, 1H), 4.49-4.44 (m, 2H), 3.99 (s, 1H), 3.94 (s, 2H).

Example 2. Preparation of Compound 28

[0146] 2.1 Preparation of Compound 2-03

##STR00029##

[0147] Under protection with argon gas, 2-01 (50 g, 0.18 mol) was dissolved in dry DCM (225 mL) at room temperature, isopropyl alcohol (57.5 mL) was added with stirring, and boron trifluoride ethylether (35 mL) was dropped slowly. The starting material disappeared 15 min after end of the addition and the reaction was stopped. The reactant was poured into an ice-cold aqueous sodium bicarbonate solution and stirred quickly for 15 min, extracted with DCM, dried and concentrated, obtaining 2-02. Dry methanol (1 L) was added into the resulting residue to dissolve, and water (125 mL) and triethyl amine (125 mL) were added with stirring. The resulting system was heated to 50° C. to react. After 3 hrs, the starting material disappeared and the reaction was stopped. The solvent was evaporated off and DCM was added to dissolve the residue. The resulting solution washed subsequently with water, dilute hydrogen chloride, and saturated sodium bicarbonate solution, dried and concentrated, followed by recrystallization with petroleum and ether-ethyl acetate, obtaining 25.8 g of 2-03, with a yield of 74% for the two steps.

[0148] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.94 (d, J=10 Hz, 1H), 5.72 (d, J=10 Hz, 1H), 5.08 (s, 1H), 4.20 (s, 1H), 3.99-3.94 (m, 1H), 3.85 (s, 2H), 3.74-3.73 (m, 1H), 1.24 (d, J=5 Hz, 3H), 1.18 (d, J=5 Hz, 3H).

[0149] 2.2 Preparation of Compound 2-04

##STR00030##

[0150] At room temperature, 2-03 (26 g, 0.138 mol) was dissolved in dry DMF (260 mL), imidazole (37.6 g, 0.55 mol) was added with stirring, TBSCl (62.2 g, 0.41 mol) was added batch wise and then the reaction system was heated to 60° C. to react. After 2 h the reaction was completed and stopped, ethyl acetate was added to dissolve. The resulting solution was sequentially washed with water and saturation sodium chloride solution, dried, and evaporated off the solvent, and separated by column chromatography, resulting in 49.5 g of the target compound 2-04, with a yield of 86%.

[0151] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.82 (d, J=12 Hz, 1H), 5.64 (dt, J=4 Hz, J=12 Hz, 1H), 5.05 (s, 1H), 4.12-4.10 (m, 1H), 4.03-3.97 (m, 1H), 3.88-3.83 (m, 2H), 3.74-3.69 (m, 1H), 1.24 (d, J=5 Hz, 3H), 1.16 (d, J=5 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.08-0.07 (m, 12H).

[0152] 2.3 Preparation of Compound 2-06

##STR00031##

[0153] At room temperature, 2-04 (2 g, 4.8 mmol) was added into isopropanol (10 mL), 10% palladium on carbon (100 mg) was added to perform hydrogenation under atmospheric pressure. After 3 hrs the reaction was completed. The reaction was stopped and filtered. The solvent was evaporated off under the reduced pressure, obtaining Compound 2-05. Methanol and dichloromethane (32 mL, 1/1, v/v) were added to dissolve, and cooled with ice-water bath. Camphorsulfonic acid (CSA) (80 mg, 0.34 mmol) was added with stirring. After being reacted at 0° C. for 1 hour, the starting material disappeared. The reaction was stopped and washed sequentially with saturated sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulphate, concentrated and separated by column chromatography, obtaining 1.28 g of the target compound 2-06, with a yield of 87%.

[0154] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 4.83 (s, 1H), 3.90-3.85 (m, 1H), 3.78-3.73 (m, 1H), 3.68-3.55 (m, 3H), 1.84-1.69 (m, 4H), 1.21 (d, J=5 Hz, 3H), 1.12 (d, J=5 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 6H).

[0155] 2.4 Preparation of Compound 28

##STR00032##

[0156] Under protection with argon gas, 2-06 (35 g, 115 mmol), DIPEA (50.9 mL), and DMSO (41.3 mL) were dissolved in dry DCM (212 mL) and cooled in an ice-water bath. Pyridine-sulphur trioxide (py SO.sub.3) (36.5 g, 0.23 mol) was added batch wise. After addition, the reaction proceeded for 1 hour and the starting material disappeared. DCM was added to dilute. The resulting mixture was subsequently washed with water, 0.1N HCl, saturated aqueous NaHCO.sub.3 solution, and aqueous NaCl solution, dried, and separated by column chromatography, resulting in 34 g of the compound 28, with a yield of 97%.

[0157] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.79 (s, 1H), 4.96 (s, 1H), 4.14 (d, J=8 Hz, 1H), 3.91-3.85 (m, 1H), 3.72 (dt, J=8 Hz, J=4 Hz, 1H), 1.85-1.69 (m, 4H), 1.18 (d, J=8 Hz, 3H), 1.11 (d, J=8 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).

Example 3. Preparation of Compound 29

[0158] ##STR00033##

[0159] Under protection with argon gas, phosphonium 26 (15.9 g, 3.8 mmol) was dissolved in dry THF (220 mL) and chilled at −78° C. t-BuOK (4.4 g, 3.9 mmol) was added batch wise and stirred for 40 min. The reaction solution became from colorless to deep red. Then the solution of the compound 28/THF (10 g/20 mL) was dropped slowly (lasting for about 1.3 h). About 1 h after completing addition, the reaction was quenched by adding the saturated aqueous NH.sub.4Cl solution. The resulting reaction mixture was extracted with ethyl acetate, subsequently washed with saturated NaHCO.sub.3, NaCl solutions, dried and concentrated. Ethyl ether/n-hexane (1:2) was added. The resulting mixture was stirred quickly and filtered. The filtrate was concentrated and separated on a column (PE:EA=10:1), resulting in 9.6 g of the compound 29, with a yield of 82%.

[0160] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.60 (t, J=10 Hz, 1H), 6.18 (t, J=10 Hz, 1H), 5.88-5.82 (m, 1H), 5.34 (t, J=10 Hz, 1H), 4.86 (s, 1H), 4.46 (t, J=10 Hz, 1H), 4.19 (d, J=10 Hz, 2H), 3.93-3.89 (m, 1H), 3.42-3.37 (m, 1H), 1.90-1.76 (m, 4H), 1.24 (d, J=5 Hz, 3H), 1.12 (d, J=5 Hz, 3H), 0.83 (s, 9H), 0.02 (s, 3H), −0.03 (s, 3H).

Example 4. Preparation of Compound 33

[0161] ##STR00034##

[0162] Under protection with argon gas, the compound 29 (11.5 g, 32 mmol) was dissolved in dry DCM (220 mL), VO(acac).sub.2 (856 mg, 3.2 mmol) was added and cooled in an ice-water bath, t-BuOOH (16.8 mL, 64.6 mmol) was dropped slowly (over 20-30 min), About 1 h after completing addition, the starting material disappeared and the reaction was quenched by adding Na2S.sub.2O.sub.3.H.sub.2O. The resulting reaction mixture was extracted with DCM, washed with saturated NaHCO.sub.3 and NaCl solutions, dried and concentrated before being dissolved in dry DMF. The resulting solution was dropped slowly into NaH/DMF (1.9 g, 48 mmol/58 mL) (at −5° C.). After completing addition, stirring proceeded for 20 min. Para-methoxybenzyl bromide (8.4 g, 42 mmol) was added and reacted at −5° C. for about 3 hrs. The reaction was quenched by adding saturated NH.sub.4Cl solution. The resulting mixture was extracted with ethyl ether, washed with saturated NaHCO.sub.3 and NaCl solutions, dried and concentrated. Then a solution of 1 M tetrabutylammonium fluoride in THF (64 mL) was added. After reacting at room temperature for 1 h, the starting material disappeared, methanol (105 mL) was added to dissolve, and t-BuOK (10.8 g, 96 mmol) was added batch wise. After reacting at room temperature for 2 hrs, the starting material disappeared and the reaction was stopped. Under the reduced pressure, a part of the solvent was evaporated off. The resulting mixture was extracted with ethyl acetate, washed with saturation NaCl solution, dried and concentrated, followed by column chromatography separation, resulting in 6.59 g of the compound 33, with a yield of 54%.

[0163] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26 (d, J=8 Hz, 2H), 6.88 (d, J=8 Hz, 2H), 5.94 (dd, J=40 Hz, J=12 Hz, 2H), 4.91 (s, 1H), 4.50 (s, 2H), 4.12-4.10 (m, 2H), 3.96-3.84 (m, 2H), 3.80 (s, 3H), 3.70 (dd, J=8 Hz, J=4 Hz, 1H), 3.59-3.55 (m, 1H), 3.25-3.21 (m, 1H), 2.52 (d, J=4 Hz, 1H), 1.84-1.72 (m, 4H), 1.20 (d, J=4 Hz, 3H), 1.14 (d, J=4 Hz, 3H).

Example 5. Preparation of Compound 33

[0164] ##STR00035##

[0165] At room temperature, the compound 29 (2 g, 5.6 mmol) was dissolved in THF (10 mL) and a solution of 1 M tetrabutylammonium fluoride in THF (8.4 mL) was added with stirring. After reacting at room temperature for 1 h, the starting material disappeared and the reaction was stopped. The solvent was evaporated off under the reduced pressure, followed by separation on a column (PE:EA=1:1), resulting in 1.17 g of the compound 34, with a yield of 86%.

[0166] Under protection with argon gas, 4 Å molecular sieve (306 mg) was added to dry DCM (8 mL) and chilled at −40° C. Subsequently, L-(+)-diethyl tartarate (255 mg, 1.2 mmol) and tetraisopropoxytitanium (282 mg, 0.99 mmol) was added with stirring. After 30 min, cumene hydroperoxide (628 mg, 3.3 mmol) was added. After 30 min, the compound 34 (200 mg, 0.82 mmol) was added and warmed up to −25° C. to react over night. The starting material disappeared and the reaction was stopped. Tributylphosphine was added to quench the reaction. After stirring for 20 min aqueous L-(+)-tartaric acid solution was added and stirred sufficiently. The resulting mixture was extracted with ethyl acetate, dried and concentrated, followed by being separated by column chromatography, resulting in 142 mg of the compound 36, with a yield of 66%.

[0167] At room temperature, the compound 36 (512 mg, 1.98 mmol) was dissolved in THF (5 mL) and cooled in an ice-water bath. NaH (87 mg, 2.1 mmol) was added. After stirring for 30 min, p-methoxybenzyl bromide (436 mg, 2.1 mmol) was added. After 1 h, the starting material disappeared. The resulting reaction was separated by column chromatography, resulting in 585 mg of the compound 33, with a yield of 78%.

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26 (d, J=8 Hz, 2H), 6.88 (d, J=8 Hz, 2H), 6.00-5.87 (m, 2H), 4.91 (s, 1H), 4.50 (s, 2H), 4.12-4.10 (m, 2H), 3.96-3.84 (m, 2H), 3.80 (s, 3H), 3.70 (dd, J=8 Hz, J=4 Hz, 1H), 3.59-3.55 (m, 1H), 3.25-3.21 (m, 1H), 2.52 (d, J=4 Hz, 1H), 1.84-1.72 (m, 4H), 1.20 (d, J=4 Hz, 3H), 1.14 (d, J=4 Hz, 3H).

Example 6. Preparation of Compound 38

[0169] ##STR00036##

[0170] Bis(pinacolato) diboron(26.9 g, 0.106 mol) and cesium carbonate (8.6 g, 26 mmol) were added in a reaction flask in which argon gas was purged 3 times. Then, the compound 33 (10 g, 26 mmol) THF solution (55 mL), and dry methanol (18 mL) were added. After completion of the addition, the reaction was heated under protection with argon gas to reflux (at about 70° C.) over night. Then the reaction was stopped and cooled to room temperature. The solvent was evaporated off and THF (170 mL) and water (120 mL) were added to dissolve the residue. Sodium peroxoborate tetra-hydrate (30 g, 0.196 mol) was added batch wise while being cooled in an ice-water bath. After completion of the addition, the reaction was warmed up spontaneously to room temperature to proceed. After about 2 hrs, the reaction was completed, filtered, extracted with DCM, dried and concentrated, resulting in a crude. The resulting crude was separated by column chromatography, resulting in 5.6 g of the compound 38, with a yield of 50%.

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25 (d, J=8 Hz, 2H), 6.86 (d, J=8 Hz, 2H), 4.92 (s, 1H), 4.85 (t, J=8 Hz, 1H), 4.49 (s, 2H), 4.12 (s, 1H), 3.97-3.95 (m, 1H), 3.89-3.82 (m, 2H), 3.78 (s, 3H), 3.64 (dd, J=8 Hz, J=4 Hz, 1H), 3.54-3.47 (m, 3H), 1.76-1.67 (m, 4H), 1.18 (d, J=10 Hz, 3H), 1.12 (d, J=10 Hz, 3H).

Example 7. Preparation of Compound 39

[0172] ##STR00037##

[0173] At room temperature, the compound 38 (12 g, 29 mmol) was dissolved in Py/Ac.sub.2O (90 mL, v/v=1:1) and DMAP (388 mg, 3.1 mmol) was added. After completion of the addition, the system was allowed to react at room temperature for 5 hrs. The starting material disappeared and the reaction was stopped. Ethyl acetate was added to dissolve the system. The resulting solution washed with 1 N HCl, saturated NaHCO.sub.3 and NaCl solutions, dried and concentrated, resulting in 14 g of the target compound 39, with a yield of 89%.

[0174] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.26 (d, J=10 Hz, 2H), 6.87 (d, J=10 Hz, 2H), 6.14 (s, 1H), 5.54 (s, 1H), 5.20-5.19 (m, 1H), 4.86 (s, 1H), 4.51 (dd, J=50 Hz, J=10 Hz, 2H), 3.87-3.80 (m, 5H), 3.67-3.65 (m, 2H), 3.57-3.50 (m, 2H), 2.22 (s, 3H), 2.04 (s, 3H), 1.96 (s, 3H), 1.77-1.61 (m, 4H), 1.20 (d, J=5 Hz, 3H), 1.10 (d, J=5 Hz, 3H).

Example 8. Preparation of Compound 40

[0175] ##STR00038##

[0176] The Compound 39 (8.66 g, 16 mmol) was dissolved in a mixed solvent of DCM and H.sub.2O (176 mL, DCM/H.sub.2O=10/1), and the reaction was cooled in an ice-water bath, and DDQ (6.03 g, 32 mmol) was added batch wise. After completion of the addition, the reaction was warmed up spontaneously to room temperature to proceed. By being monitored by TLC, the reaction was completed after about 3 hrs. The reaction flask was cooled again in the ice-water bath and the reaction was quenched by adding the saturated NaHCO.sub.3 solution and extracted with DCM two times. The organic phases were pooled and washed with saturated NaCl solution, dried and concentrated, followed by being separated by column chromatography, resulting in 6.03 g of the compound 40, with a yield of about 90%.

[0177] .sup.1H NMR (500 MHz, Chloroform-d) δ 6.13-5.89 (m, 1H), 5.56 (d, J=2.9 Hz, 1H), 5.22 (dd, J=6.5, 3.0 Hz, 1H), 4.89 (s, 1H), 4.19 (dd, J=9.9, 6.4 Hz, 1H), 3.86 (dd, J=13.1, 6.6 Hz, 3H), 3.70 (dd, J=9.9, 2.9 Hz, 1H), 3.66-3.55 (m, 1H), 2.21 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 1.88-1.79 (m, 4H), 1.20 (d, J=6.2 Hz, 3H), 1.12 (d, J=6.1 Hz, 3H).

Example 9. Preparation of Compound 33B

[0178] ##STR00039##

[0179] Under protection with argon gas, the compound 29 (3 g, 8.4 mmol) was dissolved in dry DCM (60 mL), VO(acac).sub.2 (223 mg, 0.84 mmol) was added and cooled in an ice-water bath, and t-BuOOH (4.1 mL, 16.8 mmol) was dropped slowly (over 20-30 min). About 1 h after completion of the addition, the starting material disappeared and the reaction was quenched by adding Na.sub.2S.sub.2O.sub.3.H.sub.2O. The resulting reaction mixture was extracted with DCM, washed with saturated NaHCO.sub.3 and NaCl solutions, dried and concentrated, resulting in a crude of 4.1 g. The crude was dissolved in dry THF and cooled in an ice-water bath. t-BuOK (1.13 g, 10.09 mmol) was added and the stirring proceeded for 20 min before benzyl bromide (1.59 g, 9.3 mmol) was added. After completion of the addition, the reaction was warmed up spontaneously to room temperature to proceed over night. The starting material disappeared. The reaction was quenched by adding the saturated NH.sub.4Cl solution, extracted with ethyl ether, washed with saturated NaHCO.sub.3 and NaCl solutions, dried and concentrated, resulting in a crude of 4.8 g. A solution of 1 M tetrabutylammonium fluoride in THF (17 mL) was added into the resulting crude. After 2 hrs of reaction at room temperature, the starting material disappeared. Methanol (28 mL) was added for solubilizing and t-BuOK (2.83 g, 25.2 mmol) added batch wise. After 2 hrs of reaction at room temperature, the starting material disappeared. The reaction was stopped and a part of the solvent was evaporated off under the reduced pressure. The remaining was extracted with ethyl acetate, washed with saturation NaCl solution, dried and concentrated, followed by being separated by column chromatography, resulting in 1.2 g of the compound 33B, with a yield of 40.9%.

[0180] .sup.1H NMR (400 MHz, Chloroform-7) δ 7.40-7.29 (m, 5H), 6.07-5.95 (m, 1H), 5.90 (d, J=10.5 Hz, 1H), 4.92 (s, 1H), 4.58 (s, 2H), 4.31-4.07 (m, 2H), 4.02-3.83 (m, 2H), 3.74 (dd, J=9.5, 3.0 Hz, 1H), 3.61 (ddd, J=9.6, 6.4, 0.9 Hz, 1H), 3.23 (t, J=9.3 Hz, 1H), 1.90-1.70 (m, 4H), 1.21 (d, J=6.3 Hz, 3H), 1.14 (d, J=6.1 Hz, 3H).

Example 10. Preparation of Compound 38B

[0181] ##STR00040##

[0182] Bis(pinacolato) diboron (2.74 g, 10.78 mmol) and cesium carbonate (878 mg, 2.7 mmol) were added in a reaction flask in which argon gas was purged 3 times. Then, the compound 33B (940 mg, 2.7 mmol) THF solution (6 mL), and dry methanol (1.86 mL) were added. After completion of the addition, the reaction was heated under protection with argon gas to reflux over night. Then the reaction was stopped and cooled to room temperature. The solvent was evaporated off and THF (17 mL) and water (17 mL) were added to dissolve the residue. Sodium peroxoborate tetra-hydrate (6.6 g, 43 mmol) was added batch wise while being cooled in an ice-water bath. After completion of the addition, the reaction was warmed up spontaneously to room temperature to proceed. After about 2 hrs, the reaction was completed, filtered, extracted with DCM, dried and concentrated, resulting in a crude. The resulting crude was separated by column chromatography, resulting in 544 mg of the compound 38B, with a yield of 52.7%.

[0183] .sup.1H NMR (500 MHz, Chloroform-7) δ 7.38-7.19 (m, 5H), 5.17-4.75 (m, 2H), 4.57 (m, 2H), 4.45-4.03 (m, 2H), 4.01-3.81 (m, 3H), 3.79-3.39 (m, 3H), 1.71 (m, 4H), 1.18 (d, J=6.2 Hz, 3H), 1.12 (d, J=6.1 Hz, 3H).

Example 11. Preparation of Compound 39

[0184] ##STR00041##

[0185] At room temperature, the compound 38B (300 mg, 0.78 mmol) was dissolved in Py/Ac.sub.2O (2 ml, v/v=1:1) and DMAP (10 mg, 0.08 mmol) was added. After completion of the addition, the system was allowed to react at room temperature for 5 hrs. The starting material disappeared and the reaction was stopped. Ethyl acetate was added to dissolve the system. The resulting solution washed with 1 N HCl, saturated NaHCO.sub.3 and NaCl solutions, dried and concentrated, resulting in 390 mg of the target compound 39B, with a yield of 97%.

[0186] .sup.1H NMR (400 MHz, Chloroform-7) δ 7.43-7.22 (m, 5H), 6.14 (ddd, J=10.0, 5.7, 2.9 Hz, 1H), 5.53 (t, J=3.0 Hz, 1H), 5.19 (dd, J=6.3, 3.0 Hz, 1H), 4.91-4.80 (m, 1H), 4.62 (d, J=12.3 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.14 (dd, J=10.1, 6.3 Hz, 1H), 3.85 (p, J=6.1 Hz, 1H), 3.66 (ddd, J=9.9, 5.7, 2.9 Hz, 2H), 3.58 (dd, J=11.1, 5.7 Hz, 1H), 3.49 (td, J=10.0, 4.4 Hz, 1H), 2.21 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.81-1.50 (m, 4H), 1.18 (d, J=6.2 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H).

Example 12. Preparation of Compound 40

[0187] ##STR00042##

[0188] The Compound 39B (260 mg, 0.51 mmol) was dissolved in THF (5 ml) and Pd/C (13 mg) was added, followed by a catalytic hydrogenation at normal temperature and under atmospheric pressure. By being monitored by TLC, the reaction was completed after about 8 hrs, filtered, dried and concentrated, followed by column chromatography separation, resulting in 210 mg of the compound 40, with a yield of 98%.

[0189] .sup.1H NMR (500 MHz, Chloroform-d) δ 6.13-5.89 (m, 1H), 5.56 (d, J=2.9 Hz, 1H), 5.22 (dd, J=6.5, 3.0 Hz, 1H), 4.89 (s, 1H), 4.19 (dd, J=9.9, 6.4 Hz, 1H), 3.86 (dd, J=13.1, 6.6 Hz, 3H), 3.70 (dd, J=9.9, 2.9 Hz, 1H), 3.66-3.55 (m, 1H), 2.21 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 1.88 (s, 1H), 1.79 (m, 3H), 1.20 (d, J=6.2 Hz, 3H), 1.12 (d, J=6.1 Hz, 3H).

Example 13. Preparation of Compound 42

[0190] ##STR00043##

[0191] 1) DMSO (1.26 mL, 19.8 mmol) was added into dry DCM (18 mL). The resulting mixture was placed in an acetone dry-ice bath and chilled down to −78° C. A solution of oxalyl chloride (1.13 mL, 13.4 mmol) in DCM (18 mL) was dropped. After end of the dropping, the reaction was kept at −78° C. to react for 30 min. A solution of the compound 40 (3.73 g, 8.9 mmol) as the starting material in DCM (18 mL) was dropped. After end of the dropping, the reaction was kept at −78° C. to react for 1 h. A solution of triethylamine (6.17 ml, 44.5 mmol) in DCM (18 mL) was dropped. After end of the dropping, the reaction was warmed up to room temperature to proceed for 30 min. Disappearance of the starting material speck was monitored by TLC. The reaction was quenched by adding the saturated NaHCO.sub.3 solution and subjected to liquid separation. The aqueous phase was extracted with DCM two times. The resulting organic phases were pooled, dried, filtered, concentrated and used directly in the next reaction step.

[0192] 2) CrCl.sub.2 (5.47 g, 44.5 mmol) was placed into a round-bottomed flask under argon gas protection and suspended by adding a mixed solvent of THF and dioxane (54 mL, v/v=1/3). Then the reaction flask was placed in an ice-water bath and chilled down, followed by dropping a solution of the starting material 41 and CHI.sub.3 (7.01 g, 19.8 mmol) in dioxane. The reaction solution was warmed slowly to room temperature to proceed over night (12-16 hrs). After completion of the reaction, the reaction was quenched by adding water, subjected to liquid separation, and extracted with ethyl acetate. The resulting organic phases were pooled, dried, filtered, and concentrated. 2.64 g of the compound 42 was obtained by column chromatography purification, with a yield of about 55% for the two-step reaction.

[0193] .sup.1H NMR (500 MHz, Chloroform-d) δ 6.61 (d, J=3.8 Hz, 2H), 6.28 (d, J=8.5 Hz, 1H), 5.55 (d, J=3.7 Hz, 1H), 5.17 (dd, J=6.3, 3.1 Hz, 1H), 4.88 (s, 1H), 4.03 (dd, J=9.3, 6.2 Hz, 1H), 3.94-3.79 (m, 1H), 3.68 (dd, J=10.2, 2.7 Hz, 1H), 3.49 (s, 1H), 2.22 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.79-1.72 (m, 4H), 1.20 (d, J=6.2 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H).

Example 14. Preparation of Compounds 43-45

[0194] ##STR00044##

[0195] 1) The starting material 42 (540 mg, 1 mmol) was added into a round-bottomed flask. 80% TFA aqueous solution (5 mL) was added at room temperature. The reaction system was kept at room temperature to proceed for 15 min before disappearance of the starting material speck demonstrated by TLC. The reaction flask was cooled in an ice water-bath. The reaction was quenched by adding the saturated sodium bicarbonate solution and extracted with ethyl acetate 2 times. The organic phases were pooled and washed again with the saturated sodium bicarbonate solution and the saturated sodium chloride solution, dried, filtered, and concentrate, obtaining the target Compound 43.

[0196] 2) The Compound 43 was dissolved in toluene (10 mL). Methyl (triphenylphosphoranylidene) acetate (668 mg, 2 mmol) was added at room temperature with stirring and the resulting reaction was heated to reflux for 1 h. Disappearance of the starting material speck was demonstrated by TLC, obtaining the compound 44.

[0197] 3) The reaction flask was cooled in an ice water-bath. A 40% solution of Triton B in methanol (1.36 g, 6 mmol) was added. After end of the dropping, the reaction was warmed up to room temperature to proceed. The reaction was kept at room temperature for 6 hrs before being stopped. The reaction flask was cooled in an ice water-bath. The reaction was quenched by adding 0.5 M HCl and extracted with DCM 3-4 times. The organic phases were pooled and washed with the saturated sodium bicarbonate solution and the saturated sodium chloride solution, dried, filtered, and concentrated. With column chromatography separation, 205 mg of the white solid 45 was obtained, with a yield of about 48% for the three-step reaction.

[0198] .sup.1H NMR (500 MHz, Chloroform-d) δ 6.70 (dd, J=14.5, 6.4 Hz, 1H), 6.48 (d, J=14.5 Hz, 1H), 5.23-4.98 (m, 1H), 4.28 (s, 1H), 4.03 (td, J=6.6, 3.3 Hz, 1H), 3.90 (t, J=8.7 Hz, 2H), 3.77 (dd, J=8.9, 6.2 Hz, 1H), 3.70 (s, 3H), 3.50 (m, 2H), 3.10 (dd, J=9.7, 2.8 Hz, 1H), 2.92 (s, 1H), 2.59 (dd, J=15.5, 7.6 Hz, 1H), 2.46 (dd, J=15.5, 5.1 Hz, 1H), 2.02 (p, J=4.1 Hz, 1H), 1.91-1.80 (m, 1H), 1.44 (t, J=9.6 Hz, 2H).

Example 15. Preparation of Compound 11

[0199] ##STR00045##

[0200] The starting material 45 (923 mg, 2.2 mmol) was dissolved in anhydrous DCM (22 mL). Then the reaction flask was cooled in an ice water-bath. Firstly, 2, 6-dimethylpyridine (1.52 mL, 13.2 mmol) was added and then TBSOTf (1.74 mL, 9.9 mmol) was dropped. After end of the dropping, the reaction was warmed up to room temperature to proceed. Disappearance of the starting material speck was demonstrated by TLC after 1 h and the reaction was completed. The reaction was quenched by adding 2 N KHSO.sub.4 solution, subjected to liquid separation, and extracted with DCM two times. The organic phases were pooled, dried, filtered, and concentrated. 1.52 g of the compound 11 was obtained by column chromatography purification, with a yield of about 90%.

[0201] .sup.1H NMR (400 MHz, Acetone-d.sub.6) δ 6.85 (ddd, J=14.6, 7.9, 1.3 Hz, 1H), 6.34 (dt, J=14.5, 1.2 Hz, 1H), 4.97 (dd, J=7.9, 3.8 Hz, 1H), 4.12 (q, J=2.0 Hz, 1H), 4.00 (ddd, J=7.0, 2.7, 1.4 Hz, 1H), 3.89-3.68 (m, 2H), 3.60 (d, J=1.3 Hz, 3H), 3.46 (d, J=4.6 Hz, 1H), 3.00 (dt, J=9.5, 1.7 Hz, 1H), 2.59-2.38 (m, 1H), 2.10-1.98 (m, 1H), 1.85 (dt, J=12.6, 4.0 Hz, 1H), 1.82-1.69 (m, 1H), 1.30 (dt, J=8.6, 1.5 Hz, 1H), 1.28-1.24 (m, 1H), 0.96 (d, J=1.4 Hz, 9H), 0.94 (d, J=1.3 Hz, 9H), 0.87 (d, J=1.3 Hz, 9H), 0.15 (d, J=1.5 Hz, 7H), 0.12 (d, J=1.4 Hz, 3H), 0.07 (d, J=1.3 Hz, 3H), 0.04 (d, J=1.3 Hz, 3H).

Example 16. Preparation of Compound 46

[0202] ##STR00046##

[0203] The Compound 38 (1 g, 2.4 mmol) was dissolved in THF (40 mL) at room temperature. 1 N HCl (12 mL) was added with stirring. The reaction system was heated to 55° C. to react. After 1 h the starting material disappeared. The reaction was stopped, cooled to room temperature, and subjected to liquid separation. The organic phase was dried over anhydrous sodium sulphate and the solvent was evaporated off under the reduced pressure, obtaining oily substance 38-1 for use in the next reaction step. 38-1 was dissolved in dry methanol (10 mL), methyl (triphenylphosphoranylidene) acetate (890 mg, 2.6 mmol) was added. The resulting reaction system was heated to reflux. After 6 h, the starting material disappeared and the reaction was stopped. The solvent was evaporated off under the reduced pressure, followed by adding 15 ml of toluene, and evaporated off again, resulting in 38-2 which can be used without purification in the next reaction step. 38-2 was dissolved in dry THF (50 mL). The resulting reaction system was cooled in an ice water-bath. A 40% solution of Triton B in methanol (3.29 g, 7.27 mmol) was added with stirring. The reaction proceeded at 0° C. for 20 min and then warmed up to room temperature to proceed for 3 h. The reaction was quenched by adding 2 N HCl in an ice water-bath (pH=5-6). Part of the solvent was evaporated off under the reduced pressure. The resulting residue was extracted with dichloromethane. The resulting extract was dried over anhydrous sodium sulphate, filtered and concentrated prior to separation on a silica gel column, resulting in 402 mg of the target product 46, with a yield of 38.8%.

[0204] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26 (d, J=8 Hz, 2H), 6.87 (d, J=8 Hz, 2H), 4.86-4.81 (m, 1H), 4.50 (s, 2H), 4.22 (s, 1H), 3.95-3.90 (m, 1H), 3.88-3.82 (m, 2H), 3.80 (s, 3H), 3.68 (s, 3H), 3.63 (dd, J=8 Hz, J=4 Hz, 1H), 3.53-3.47 (m, 3H), 3.05 (dd, J=8 Hz, J=4 Hz, 1H), 2.62 (dd, J=16 Hz, J=8 Hz, 1H), 2.44 (dd, J=16 Hz, J=8 Hz, 1H), 1.93-1.75 (m, 2H), 1.42-1.38 (m, 2H).

Example 17. Preparation of Compound 47

[0205] ##STR00047##

[0206] Under protection with argon gas, the Compound 46 (810 mg, 1.9 mmol) was dissolved in dry DCM (8 mL). 2,6-dimethylpyridine (1.22 g, 11.4 mmol) was added. Then TBSOTf (2.11 g, 9.5 mmol) was dropped slowly. After completion of the addition, the reaction was warmed up spontaneously to room temperature to proceed. After 1 h, the starting material disappeared and the reaction was stopped. The reaction was quenched by adding 0.5 M KHSO.sub.4 and extracted with DCM, prior to separation with silica gel column chromatography, resulting in 1.3 g of the target Compound 47, with a yield of 92%.

[0207] .sup.1H NMR (400 MHz, CDCl.sub.3) 57.27 (d, J=8 Hz, 2H), 6.86 (d, J=8 Hz, 2H), 4.56-4.54 (m, 1H), 4.43 (dd, J=32 Hz, J=8 Hz, 2H), 4.15-4.13 (m, 1H), 4.06 (s, 1H), 3.96-3.92 (m, 2H), 3.86-3.81 (m, 4H), 3.69 (s, 3H), 3.53-3.49 (m, 1H), 3.45-3.41 (m, 1H), 2.99-2.97 (m, 1H), 2.54 (dd, J=15 Hz, J=5 Hz, 1H), 2.38 (dd, J=15 Hz, J=5 Hz, 1H), 1.99-1.97 (m, 1H), 1.76-1.74 (m, 1H), 1.40-1.25 (m, 2H), 0.94-0.86 (m, 27H), 0.12-0.03 (m, 18H).

Example 18. Preparation of Compound 48

[0208] ##STR00048##

[0209] The Compound 47 (418 mg, 0.54 mmol) was dissolved in DCM/H.sub.2O (6 ml, v/v=10/1) and cooled in an ice-water bath. DDQ (308 mg, 1.35 mmol) was added with stirring. After completion of the addition, the reaction was warmed up spontaneously to room temperature. The reaction was stopped after 1 h and the saturated sodium bicarbonate solution was added, while being cooled in the ice water-bath. The resulting mixture was extracted with DCM, dried, and concentrated prior to separation on a silica gel column, resulting in 255 mg of the target Compound 48, with a yield of 72%.

[0210] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.43-4.40 (m, 1H), 4.07-4.02 (m, 2H), 3.98 (dd, J=8 Hz, J=4 Hz, 1H), 3.92 (dd, J=8 Hz, J=4 Hz, 1H), 3.86-3.81 (m, 2H), 3.67 (s, 3H), 3.64-3.58 (m, 1H), 2.97 (dd, J=8 Hz, J=4 Hz, 1H), 2.53 (dd, J=16 Hz, J=8 Hz, 1H), 2.40-2.34 (m, 2H), 2.05-2.02 (m, 1H), 1.78-1.72 (m, 1H), 1.41-1.36 (m, 2H), 0.93-0.90 (m, 27H), 0.12-0.08 (m, 18H).

Example 19. Preparation of Compound 11

[0211] ##STR00049##

[0212] DMSO (0.14 mL, 2 mmol) was added into dry DCM (2 mL). The resulting mixture was placed in an acetone dry-ice bath and chilled down to −78° C. A solution of oxalyl chloride (0.13 mL, 1.5 mmol) in DCM (2 mL) was dropped. After end of the dropping, the reaction was kept at −78° C. to react for 30 min. A solution of the starting material 48 (647 mg, 1 mmol) in DCM (2 mL) was dropped. After end of the dropping, the reaction was kept at −78° C. to react for 1 h. A solution of triethylamine (0.69 mL, 5 mmol) in DCM (2 mL) was dropped. After end of the dropping, the reaction was warmed up to room temperature to proceed for 30 min. The reaction was quenched by adding the saturated NaHCO.sub.3 solution and subjected to liquid separation. The aqueous phases were extracted with DCM two times. The resulting organic phases were pooled, dried, filtered and concentrated, resulting the compound 49 for use directly in the next reaction step.

[0213] CrCl.sub.2 (614 mg, 5 mmol) was placed into a round-bottomed flask under argon gas protection and added a mixed solvent of THF and dioxane (8 mL, v/v=1/3). Then the reaction flask was placed in an ice-water bath and chilled down, followed by dropping a solution of the starting material 49 and CHI.sub.3 (787 mg, 2 mmol) in dioxane (6 mL). The reaction solution was warmed slowly to room temperature to react over night (12-16 hrs). The reaction still had the starting material remaining. The reaction was quenched by adding water, subjected to liquid separation, and extracted with ethyl acetate. The resulting organic phases were pooled, dried, filtered, and concentrated. 231 mg of the compound 11 was obtained by column chromatography purification with PE:EA=5:1, with a yield of about 30% for the two-step reaction.

[0214] .sup.1H NMR (400 MHz, Acetone-d.sub.6) δ 6.85 (ddd, J=14.6, 7.9, 1.3 Hz, 1H), 6.34 (dt, J=14.5, 1.2 Hz, 1H), 4.97 (dd, J=1.9, 3.8 Hz, 1H), 4.12 (q, J=2.0 Hz, 1H), 4.00 (ddd, J=7.0, 2.7, 1.4 Hz, 1H), 3.89-3.68 (m, 2H), 3.60 (d, J=1.3 Hz, 3H), 3.46 (d, J=4.6 Hz, 1H), 3.00 (dt, J=9.5, 1.7 Hz, 1H), 2.59-2.38 (m, 1H), 2.10-1.98 (m, 1H), 1.85 (dt, J=12.6, 4.0 Hz, 1H), 1.82-1.69 (m, 1H), 1.30 (dt, J=8.6, 1.5 Hz, 1H), 1.28-1.24 (m, 1H), 0.96 (d, J=1.4 Hz, 9H), 0.94 (d, J=1.3 Hz, 9H), 0.87 (d, J=1.3 Hz, 9H), 0.15 (d, J=1.5 Hz, 7H), 0.12 (d, J=1.4 Hz, 3H), 0.07 (d, J=1.3 Hz, 3H), 0.04 (d, J=1.3 Hz, 3H).