Intermediate of eribulin and synthesis method and use thereof

Abstract

An intermediate compound is prepared and used for the synthesis of halichondrin B, eribulin or an analog thereof, particularly a structural fragment C27-C35 thereof. The starting materials of the synthetic route are readily available, and the optical purity of the starting materials can be ensured, so that the optical purity of the structural fragment C27-C35 in halichondrin B, eribulin or the analog thereof is ensured. Steps for constructing a chiral center of the structural fragment C27-C35 feature higher diastereoselectivity and yield, in particular preparation methods of compounds of formulae (X), (XI), (XVI) and (XV). By-products of partial reactions can be removed only by recrystallization, which results in easy purification and significant reduce in cost.

Claims

1. A compound having a structural formula of formula (XVI): ##STR00053## wherein PG.sup.1 and the PG.sup.2 are the same or different, and are each independently selected from hydroxyl protecting groups except for silyl.

2. A preparation method of the compound of formula (XVI) according to claim 1, comprising: reacting a compound of formula (XV) under a condition where PG.sup.4 and PG.sup.5 are removed to give the compound of formula (XVI): ##STR00054##

3. The preparation method of the compound of formula (XVI) according to claim 2, comprising: the crude product of the compound of formula (XVI) is purified by recrystallization so that it contains a compound of formula (XVIa) shown below in an amount of ?0.1% ##STR00055##

4. The preparation method of the compound of formula (XVI) according to claim 2, comprising: subjecting a compound of formula (XIII) and a compound of formula (XIV) to epoxide ring-opening to give the compound of formula (XV) ##STR00056##

5. The preparation method of the compound of formula (XVI) according to claim 4, comprising: hydroxyl protecting a compound of formula (XI) by reacting with a compound of formula PG.sup.5-L to give the compound of formula (XIII), ##STR00057## wherein, R.sup.7 is hydrogen or a terminal alkyne protecting group.

6. The preparation method of the compound of formula (XVI) according to claim 5, comprising: reacting a compound of formula (X) with R.sup.7C?CH in the presence of a strong base to give the compound of formula (XI) ##STR00058##

7. The preparation method of the compound of formula (XVI) according to claim 6, comprising: (1) reacting a compound of formula (IX) with ##STR00059## to give a compound of formula (IXa); (2) reacting the compound of formula (IXa) with an acid halide ##STR00060## or a halosilane R.sup.3.sub.3SiX to give a compound of formula (IXb-1) and/or a compound of formula (IXb-2); and (3) subjecting the compound of formula (IXb-1) and/or the compound of formula (IXb-2) to alcoholysis under basic conditions and further intramolecular S.sub.N2 ring closing reaction to give the compound of formula (X); ##STR00061## wherein, R.sup.1, R.sup.2 and R.sup.3 are the same or different and are each independently selected from H, alkyl and aryl; R.sup.6 is selected from alkyl; X is halogen.

8. A method for preparing a compound of formula (XIX), comprising: reacting the compound of formula (XVI) of claim 1 with ##STR00062## and ##STR00063## to obtain a compound of formula (XVII); subjecting a compound of formula (XVII) to obtain a compound of formula (XVIII) is obtained; reacting the compound of formula (XVIII) with PG.sup.6X to obtain the compound of formula (XIX), wherein PG.sup.6 is independently selected from substituted or unsubstituted aromatic acyl, PG.sup.7 is an o-dihydroxyl protecting group, and X is halogen, ##STR00064##

9. A method for preparing eribulin or a C27-C35 portion thereof, comprising: reacting the compound of formula (XVI) of claim 1 with ##STR00065## and ##STR00066## to obtain a compound of formula (XVII); subjecting the compound of formula (XVII) to hydrogenation reduction to obtain a compound of formula (XVIII); reacting the compound of formula (XVIII) with PG.sup.6X to obtain the compound of formula (XIX), wherein PG.sup.6 is independently selected from substituted or unsubstituted aromatic acyl, PG.sup.7 is an o-dihydroxyl protecting group, and X is halogen, ##STR00067## and subjecting the compound of formula (XIX) to dihydroxylation oxidation reaction in the presence of an oxidant to obtain the compound of formula (XX): ##STR00068## wherein PG.sup.1 and PG.sup.2 are the same or different, and are each independently selected from hydroxyl protecting groups except for silyl, PG.sup.6 is selected from substituted or unsubstituted aromatic acyl, and PG.sup.7 is an o-dihydroxyl protecting group.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an HPLC pattern of Compound 16.

(2) FIG. 2 is an HPLC pattern of Compound 23.

DETAILED DESCRIPTION

(3) The preparation method of the present invention will be further illustrated in detail with reference to the following specific examples. It should be understood that the following examples are merely exemplary illustration and explanation of the present invention, and should not be construed as limiting the protection scope of the present invention. All techniques implemented based on the aforementioned contents of the present invention are encompassed within the protection scope of the present invention.

(4) Unless otherwise stated, the experimental methods used in the following examples are conventional methods. Unless otherwise stated, the reagents, materials, and the like used in the following examples are commercially available.

Example 1. Synthesis of Compound 9

1.1. Synthesis of Compound 4

(5) ##STR00034##

(6) Deoxyribose 1 (100 g) was dissolved in water (400 mL), and then the mixture was cooled to about 5? C., slowly added dropwise with liquid bromine (200 g) for 3 h, heated to 30? C. and then reacted for 24 h (the disappearance of starting materials as detected by a dot plate). Post-treatment: 1) the mixture was extracted with ethyl acetate (100 mL?2) and the organic phase was at the bottom, and then ethyl acetate (50 mL) was added to extract, and the organic phase was at the top; 2) the organic phases were combined and the product contained therein was extracted with water (50 mL?2); 3) the aqueous phases were combined and the bromine was neutralized with saturated sodium thiosulfate (little amount), and then the mixture was cooled to 0? C., adjusted to pH of about 3 (the amount of solid NaOH is about 61 g), and filtered with celite; 4) the filtrate was concentrated to viscous liquid containing a small amount of solid and added with isopropanol (200 mL), and the mixture was heated to 80? C. with stirring and filtered while hot; the solid was washed with isopropanol (100 mL) and the filtrate was concentrated; the residue was dissolved in isopropanol (100 mL) and the mixture was then filtered; the solid was washed with isopropanol (40 mL), and the filtrate was concentrated; the residue was dissolved in acetone (100 mL), and the mixture was filtered; the solid was added with acetone (100 mL?2) and the mixture was heated to 80? C. for extraction; the filtrates were combined and evaporated to dryness to give a crude product of Compound 2 (about 95 g) in the form of an oil (containing a small amount of solid).

(7) The crude product of Compound 2 (44 g) was dissolved in pyridine (200 mL) and added with trityl chloride (88 g) and 4-dimethylaminopyridine (DMAP) (4.5 g), and the mixture was heated to 50? C. and reacted overnight. Post-treatment: Pyridine was evaporated off under reduced pressure, and dichloromethane (DCM, 500 mL) was added. 1 N hydrochloric acid (300+200 mL) was added for liquid separation, saturated sodium bicarbonate (200 mL) was added for washing, and the aqueous phase was extracted each time with DCM (100 mL). The organic phases were combined, dried, filtered and concentrated, and the product was directly used in the next step.

(8) The crude product of Compound 3 was dissolved in DCM (400 mL) and then added with imidazole (29 g) and DMAP (4.5 g). The mixture was cooled to 0? C. and added dropwise slowly with tert-butyldiphenylchlorosilane (TBDPSCl, 77 mL), and the resulting mixture was warmed to room temperature and reacted for 2-6 h. Post-treatment: Water (300 mL?2) was added, liquid separation was performed, and dichloromethane (100 mL) was added for extraction each time. The organic phases were combined, dried and concentrated. The residue was added with methanol (150 mL?2) and concentrated to dryness, and this procedure was performed twice. Then methanol (300 mL) and n-hexane (100 mL) were added. The mixture was concentrated to 200-300 mL under reduced pressure, and stirred and cooled to about 10? C., and white solid was precipitated out. The resulting mixture was filtered and the solid was washed with a small amount of cold methanol. The solid was removed and the residual solvent was evaporated off under reduced pressure to give Compound 4 (about 136 g). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.58-7.25 (m, 25H), 4.41 (d, J=3.5 Hz, 1H), 4.37 (d, J=6.4 Hz, 1H), 3.32 (dd, J=10.6, 3.2 Hz, 1H), 2.88 (dd, J=17.8, 6.6 Hz, 1H), 2.70 (dd, J=10.7, 3.0 Hz, 1H), 2.55 (dd, J=17.8, 1.8 Hz, 1H), 1.07 (s, 9H).

1.2. Synthesis of Compound 7

(9) ##STR00035##

(10) Compound 4 (286 g) was dissolved in dichloromethane, and then the mixture was cooled to ?20? C., added dropwise slowly with boron trichloride (233 mL of 1 M dichloromethane solution) for 1 h, and then reacted for 0.5 h. Post-treatment: absolute methanol (700 mL) was added, and the mixture was stirred for ten minutes and then added with sodium bicarbonate solution to adjust pH to alkaline. Liquid separation was performed, and the aqueous phase was extracted with dichloromethane (500 mL?2), dried, filtered, and concentrated. The residue was dissolved in absolute methanol (350 mL), and the mixture was stirred for ten minutes and filtered. The solid was washed with a small amount of methanol (more than 80% of TrOMe was removed at this step), and the filtrate was concentrated. The residue was washed twice with toluene to remove the residual methanol, thus obtaining the final product (about 190 g).

(11) The crude product 5 from the previous step was dissolved in dichloromethane (1500 mL), and camphorsulfonic acid (racemate, 16 g) was added. The mixture was cooled down in a water bath, added dropwise slowly with PMB trichloroimidate (158 g), warmed to room temperature and then reacted overnight. Post-treatment: Saturated sodium bicarbonate solution was added and liquid separation was performed. The aqueous phase was extracted with dichloromethane, and the organic phase was filtered to remove the solid camphorsulfonate, washed with saturated sodium chloride, dried, filtered, and concentrated to give a crude product of Compound 6 (about 313 g).

(12) The crude product of Compound 6 obtained in the previous step was dissolved in tetrahydrofuran (700 mL), and then the mixture was cooled down in an ice bath, added dropwise slowly with borane dimethyl sulfide (10 M, 70 mL) under argon atmosphere, warmed to room temperature, reacted for ten minutes, and then heated to 55-60? C. and reacted overnight. Post-treatment: the mixture was cooled down in an ice bath, added dropwise slowly with methanol to quench the reaction (until no bubbles were generated), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washing with saturated sodium bicarbonate, extracted with ethyl acetate, dried and concentrated. Methanol was added to the residue and then evaporated off, and this procedure was repeated twice. Column chromatography was performed to give Compound 7 (about 156 g, total yield: 68%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.72 (t, J=6.7 Hz, 4H), 7.57-7.48 (m, 2H), 7.43 (t, J=7.5 Hz, 4H), 7.22 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 4.50-4.34 (m, 2H), 3.96 (dt, J=7.8, 4.5 Hz, 2H), 3.87 (s, 3H), 3.79 (td, J=7.1, 3.5 Hz, 1H), 3.55 (td, J=8.5, 7.3, 4.1 Hz, 2H), 3.43 (dd, J=9.7, 6.7 Hz, 1H), 1.83 (ddt, J=11.3, 7.8, 3.9 Hz, 1H), 1.76 (q, J=12.7, 1H), 1.10 (s, 9H).

1.3. Synthesis of Compound 9

(13) ##STR00036##

(14) Compound 7 (103.4 g) was dissolved in acetonitrile (1 L), and then SM2 (4.7 g), potassium carbonate (37.5 g), potassium iodide (38.2 g) and benzyl bromide (37.3 mL) were added. The mixture was heated to 70-80? C. and reacted for 3-5 h (the disappearance of starting materials or the remaining of a few starting materials with no more change as detected by a dot plate). Post-treatment: The mixture was added with water, extracted with ethyl acetate for 2-3 times, dried and concentrated, and the product was directly used in the next step.

(15) The crude product of Compound 8 was dissolved in tetrahydrofuran (314 mL), and tetrabutylammonium fluoride (TBAF, 314 mL) was added, and the mixture was reacted overnight at 25? C. Post-treatment: The mixture was concentrated under reduced pressure, and the residue was dissolved in water and ethyl acetate. Liquid separation was performed and ethyl acetate was added for extraction. Drying, concentration, and column chromatography (petroleum ether:ethyl acetate=2:1-1:1) were performed to give Compound 9 (about 62 g, total yield over two steps: about 86%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.44-7.21 (m, 7H), 6.85 (s, 2H), 4.50 (s, 2H), 4.47 (s, 2H), 3.82 (m, 1H), 3.79 (s, 3H), 3.76-3.64 (m, 3H), 3.65-3.54 (m, 2H), 1.89 (m, 1H), 1.85-1.72 (m, 1H).

Example 2. Synthesis of Compound 10

(16) ##STR00037##

(17) Compound 9 (149.5 g) was dissolved in DCM (818 mL), PPTs (5.4 g) was added, and trimethyl orthoacetate (82.4 mL) was added dropwise. Then the mixture was reacted at room temperature for 1 h, and the solvent was evaporated off to give a mixture 9a of product and epimer. The Compound 9a obtained above is redissolved in DCM (818 mL), and acetyl bromide (47.9 mL) was added dropwise. Then the resulting mixture was reacted for 0.5 h at room temperature, and the solvent was evaporated off to give a mixture of compounds 9b-1 and 9b-2. The mixture of the compounds 9b-1 and 9b-2 was dissolved in absolute methanol (1500 mL), and potassium carbonate (119 g) was added, and the resulting mixture was reacted at room temperature for 8 h. Post-treatment: The resulting mixture was added with saturated ammonium chloride solution, extracted with DCM, dried, filtered, concentrated, and subjected to silica gel column chromatography to give a refined product of Compound 10 (123 g, yield: 87%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.38-7.25 (m, 7H), 6.87 (d, J=13.2 Hz, 2H), 4.60-4.38 (m, 4H), 3.79 (s, 3H), 3.73-3.65 (m, 1H), 3.62 (d, J=11.5 Hz, 2H), 3.56-3.44 (m, 1H), 3.25-3.17 (m, 1H), 3.13 (s, 1H), 2.00-1.66 (m, 2H).

Example 3. Synthesis of Compound 11

(18) ##STR00038##

(19) Under argon atmosphere, trimethylsilyl acetylene (15.5 g) was dissolved in anhydrous toluene (300 mL), and the mixture was cooled to ?50? C., added dropwise slowly with a solution of 2.5 M n-BuLi in n-hexane (64 mL), and then stirred and reacted for 30 min. A solution of Compound 10 in toluene (dissolving 26 g of Compound 10 in 100 mL of toluene) was added dropwise and then BF.sub.3Et.sub.2O (22.6 g) was added dropwise slowly while maintaining the temperature not higher than ?30? C. Then the resulting mixture was reacted for 3 h. After the reaction was completed as detected by TLC, the mixture was treated with saturated ammonium chloride (300 mL). The liquid separation was performed, and the aqueous phase was extracted twice with ethyl acetate (200 mL?2). The organic phases were combined, washed with saturated sodium chloride (300 mL?2), dried over anhydrous sodium sulfate, filtered off the drying agent, and concentrated to give a crude product (44 g), which was separated by silica gel column chromatography. The results of column chromatography were as follows: 22 g of Compound 11 was obtained (yield: 65%), and 10 g of the regioisomer shown as the following formula 11 was present.

(20) ##STR00039##
Compound 11 .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.38-7.15 (m, 7H), 6.87 (d, J=6.8 Hz, 2H), 4.56-4.45 (m, 4H), 4.00 (tt, J=6.3, 3.2 Hz, 1H), 3.80 (d, J=2.3 Hz, 3H), 3.75-3.57 (m, 4H), 2.81 (tt, J=5.0, 2.8 Hz, 1H), 2.61 (d, J=6.5 Hz, 1H), 1.95 (h, J=6.5 Hz, 1H), 1.89-1.80 (m, 1H), 0.15 (d, J=2.4 Hz, 9H). HPLC showed the content of 11 in Compound 11 was ?0.1%, and the content of other epimers in Compound 11 was ?0.1%.

Example 4. Synthesis of Compound 16

4.1. Synthesis of Compound 13

(21) ##STR00040##

(22) In an ice-water bath, Compound 11 (21 g) was dissolved in anhydrous dichloromethane (160 mL), and 2,6-dimethylpyridine (6.8 g) and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 15.6 g) were added dropwise successively. Then the mixture was warmed to room temperature and reacted for 1 h. After the reaction was completed as detected by TLC, the mixture was added with saturated aqueous ammonium chloride solution (200 mL) to quench the reaction, and then the liquid separation was performed. The aqueous phase was extracted with dichloromethane (200 mL?2), and the organic phases were combined, washed with 1 N hydrochloric acid to remove the 2,6-dimethylpyridine, then washed with saturated sodium chloride (200 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (Compound 12, 25.7 g) in the form of a brown yellow oil. The crude product of Compound 12 was dissolved in absolute methanol (200 mL), and potassium carbonate powder (13.5 g) was added. The mixture was reacted overnight at room temperature. After the reaction was completed as detected by TLC, ethyl acetate (200 mL) was added to dilute the reaction solution and the solid was filtered off through celite. The solid was washed with ethyl acetate until no product was remained, and the filtrate was concentrated to give a brown yellow viscous substance. Ethyl acetate (200 mL) was added, and the mixture was sufficiently stirred for dissolving and filtered through celite. The filter cake was washed with ethyl acetate until no product was remained, and the filtrate was concentrated to give a crude product (30 g) in the form of a brown yellow oil, which was separated by silica gel column chromatography to give Compound 13 (about 20.7 g, yield over two steps: 90%) in the form of a colorless oil. Compound 13 .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.30-7.22 (m, 3H), 7.24-7.13 (m, 4H), 6.85-6.72 (m, 2H), 4.77 (s, 1H), 4.50-4.24 (m, 4H), 4.13-3.80 (m, 1H), 3.64-3.39 (m, 3H), 2.84-2.65 (m, 1H), 2.07-1.97 (m, 1H), 1.90 (dt, J=12.7, 6.1 Hz, 1H), 1.72 (dd, J=13.8, 7.0 Hz, 1H), 0.81 (s, 9H), ?0.01 (s, 6H).

4.2. Synthesis of Compound 15

(23) ##STR00041##

(24) Under argon atmosphere, Compound 13 (10.8 g) was dissolved in anhydrous toluene (100 mL), and the mixture was cooled to ?78? C., added dropwise with a solution of 2.5 N n-butyllithium in n-hexane (11 mL), and reacted for 30 min. Compound 14 (5.64 g, a commercially available product, with an optical purity of >99%) was dissolved in toluene (50 mL), and the solution was then added to the reaction system. Then BF.sub.3Et.sub.2O (4.0 g) was added dropwise slowly. The resulting mixture was reacted for 2 h while maintaining the temperature unchanged. After the reaction was completed as detected by TLC, the mixture was added with saturated ammonium chloride (150 mL) to quench the reaction, and then the liquid separation was performed. The aqueous phase was extracted with ethyl acetate (150 mL?2), and the organic phases were combined, washed with saturated sodium chloride (150 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (17.8 g) in the form of oil, which was separated by silica gel column chromatography to give Compound 15 (about 14.5 g, yield: 96%). Compound 15 .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.42-7.24 (m, 7H), 6.90 (d, J=8.0 Hz, 2H), 4.60-4.40 (m, 4H), 4.07 (d, J=7.3 Hz, 1H), 3.90-3.74 (m, 5H), 3.75-3.59 (m, 2H), 3.53 (q, J=6.1, 5.1 Hz, 3H), 2.79 (d, J=6.8 Hz, 1H), 2.45 (d, J=6.0 Hz, 1H), 2.13-1.97 (m, 1H), 1.88-1.71 (m, 2H), 1.42-1.22 (m, 2H), 1.02-0.84 (m, 18H), 0.10 (s, 6H), 0.07 (s, 6H).

4.3. Synthesis of Compound 16

(25) ##STR00042##

(26) Under room temperature, Compound 15 (46 g) was dissolved in absolute methanol (500 mL) at room temperature and 3 N HCl/MeOH solution (13 mL) was added, and the mixture was reacted overnight at room temperature. After the reaction was completed as detected by TLC, aqueous ammonia (8 mL, 25-28%) was added, and the mixture was stirred to quench the reaction, dried over anhydrous sodium sulfate to remove water, and filtered. The residue was washed with ethyl acetate, and the filtrate was concentrated to give a light yellow oil substance (34.2 g), which was recrystallized with ethyl acetate/n-hexane to give a white crystal (26 g), a single product as detected by TLC. The white crystal was recrystallized again to give Compound 16 (25.2 g, yield: 83.3%, optical purity: >99.9%) in the form of a white crystal, and HPLC pattern is shown in FIG. 1. Compound 16 .sup.1H NMR (500 MHz, methanol-d.sub.4) ? 7.35-7.24 (m, 7H), 6.90 (dd, J=8.6, 2.9 Hz, 2H), 4.66-4.32 (m, 4H), 3.99 (dd, J=8.1, 4.3 Hz, 1H), 3.80 (s, 3H), 3.74-3.34 (m, 7H), 2.74 (s, 1H), 2.56-2.24 (m, 2H), 1.91 (td, J=7.9, 6.9, 3.1 Hz, 2H).

Example 5. Synthesis of Compound 20

5.1. Synthesis of Compound 17

(27) ##STR00043##

(28) Compound 16 (24.2 g) was dissolved in acetonitrile (70 mL), and then pentanone (25 mL), trimethyl orthoformate (9.8 mL) and scandium trifluoromethanesulfonate (270 mg) were added successively. The mixture was reacted at room temperature for 1 h. After the reaction was completed as detected by TLC, the reaction solution was added with triethylamine to quench the reaction, and evaporated off the solvent to give a crude product (29.4 g), which was separated by column chromatography to give Compound 17 (26.6 g, yield: 95%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.50-7.08 (m, 7H), 6.87 (d, J=8.2 Hz, 2H), 4.60-4.33 (m, 4H), 4.19 (t, J=6.4 Hz, 1H), 4.08 (t, J=7.1 Hz, 1H), 4.04-3.92 (m, 1H), 3.80 (s, 3H), 3.76-3.43 (m, 5H), 2.87-2.64 (m, 2H), 2.56 (dd, J=16.4, 4.7 Hz, 1H), 2.42 (dd, J=16.5, 7.6 Hz, 1H), 1.93 (dd, 0.1=14.9, 7.9 Hz, 1H), 1.79 (dq, J=9.6, 4.7 Hz, 1H), 1.63 (dq, J=22.5, 7.9, 7.4 Hz, 4H), 0.89 (q, J=7.0 Hz, 6H)

5.2. Synthesis of Compound 18

(29) ##STR00044##

(30) Compound 17 (23.8 g) was dissolved in absolute methanol (150 mL), and a Lindlar catalyst (2.4 g) was added. Hydrogenation reaction under normal pressure was carried out, and the reaction progress was monitored by TLC until the starting materials disappeared completely. The catalyst was filtered out, and the filtrate was concentrated to give a crude product of Compound 18 (23.6 g), which was directly used in the next step without further purification. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.35-7.23 (m, 7H), 6.86 (d, J=8.2 Hz, 2H), 5.61-5.55 (m, 2H), 4.51 (s, 2H), 4.44 (t, 0.1=12.3 Hz, 2H), 4.10-4.05 (m, 1H), 4.03-3.99 (m, 2H), 3.80 (s, 3H), 3.70-3.61 (m, 2H), 3.57 (t, J=8.0 Hz, 1H), 3.49-3.43 (m, 2H), 3.06 (s, 1H), 2.70 (s, 1H), 2.40 (dt, J=12.6, 5.7 Hz, 1H), 2.27 (dt, J=14.1, 5.9 Hz, 1H), 1.83-1.74 (m, 1H), 1.62 (dt, J=15.6, 7.9 Hz, 4H), 0.89 (q, J=7.7 Hz, 6H).

5.3. Synthesis of Compound 19

(31) ##STR00045##

(32) In an ice-water bath, Compound 18 (8.3 g) was dissolved in pyridine (50 mL), and benzoyl chloride (BzCl, 2.58 g) was added slowly and DMAP (200 mg) was added. The mixture was warmed to room temperature and reacted for 3 h. After the reaction was completed as detected by TLC, the reaction solution was diluted with ethyl acetate (100 mL) and added with water (100 mL) to quench the reaction. The liquid separation was performed. The aqueous phase was extracted with ethyl acetate (100 mL?2), and the organic phases were combined, washed with water (200 mL?2), then washed to neutral with 1 N diluted hydrochloric acid, washed with saturated sodium bicarbonate to remove residual HCl, finally washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a crude product (17 g), which was separated by column chromatography to give Compound 19 (about 10.1 g, yield: 99%). H NMR (400 MHz, CDCl.sub.3) ? 8.02-7.95 (m, 2H), 7.58-7.54 (m, 1H), 7.44-7.41 (m, 2H), 7.28-7.26 (m, 5H), 7.20 (d, J=9.4 Hz, 2H), 6.78 (d, J=8.0 Hz, 2H), 5.68-5.56 (m, 3H), 4.43 (d, J=2.9 Hz, 3H), 4.36 (d, J=2.8 Hz, 2H), 4.09-4.02 (m, 1H), 3.97-3.93 (m, 1H), 3.75 (s, 3H), 3.53-3.50 (m, 2H), 3.49-3.42 (m, 2H), 3.33 (dd, J=9.3, 6.3 Hz, 1H), 3.03-2.97 (m, 1H), 2.44-2.28 (m, 2H), 2.07-1.99 (m, 2H), 1.96-1.88 (m, 1H), 1.66-1.57 (m, 4H), 0.89 (dd, J=14.7, 7.2 Hz, 6H).

5.4. Synthesis of Compound 20

(33) ##STR00046##

(34) Under room temperature, Compound 19 (10 g) was dissolved in a mixed solvent of tert-butanol/water (20 mL/20 mL), and NMO (5.9 g) and a solution of osmium tetroxide in 0.05 M toluene solution (11 mL) were added successively. The mixture was heated to 45? C., stirred and reacted for 24 h. After the reaction was almost completed as detected by TLC, the mixture was added with saturated sodium sulfite (50 mL), stirred to quench the reaction, and extracted with ethyl acetate (100 mL?3). The organic phases were combined, washed with water (200 mL?2), washed with saturated sodium chloride (200 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (11 g), which was separated by silica gel column chromatography to give Compound 20 (about 9.8 g, yield: 92%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.98 (dt, J=8.4, 1.6 Hz, 2H), 7.55 (tt, J=7.0, 1.3 Hz, 1H), 7.46-7.39 (m, 2H), 7.30-7.14 (m, 7H), 6.82 (dq, J=8.7, 2.2, 1.6 Hz, 2H), 5.51 (ddd, J=8.9, 7.4, 3.1 Hz, 1H), 4.51-4.35 (m, 4H), 4.35-4.24 (m, 1H), 4.04 (dd, J=8.0, 6.0 Hz, 1H), 3.89-3.64 (m, 7H), 3.62-3.51 (m, 2H), 3.47 (td, J=8.1, 5.0 Hz, 1H), 3.30 (t, J=5.5 Hz, 2H), 2.41 (tt, J=5.4, 2.3 Hz, 1H), 2.21 (dtd, J=14.5, 7.2, 3.2 Hz, 1H), 2.13-1.91 (m, 2H), 1.74 (ddd, J=14.2, 7.6, 4.5 Hz, 1H), 1.57 (dq, J=15.1, 7.5 Hz, 4H), 0.84 (dt, J=9.8, 7.5 Hz, 6H).

5.5. Synthesis of Compound 20

(35) ##STR00047##

(36) Under room temperature, Compound 19 (90 mg) was dissolved in a mixed solvent of tert-butanol/water (1 mL/1 mL), and DABCO (17 mg), NMO (53 mg) and a solution of osmium tetroxide in 0.05 M toluene solution (0.15 mL) were added successively. The mixture was then stirred and reacted for 24 h. After the reaction was almost completed as detected by TLC, the mixture was added with saturated sodium sulfite (5 mL), stirred to quench the reaction, and extracted with ethyl acetate (10 mL?3). The organic phases were combined, washed with water (10 mL?2), washed with saturated sodium chloride (10 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (110 mg), which was separated by silica gel column chromatography to give Compound 20 (67 mg, yield: 70%).

5.6. Synthesis of Compound 20-Ac

(37) ##STR00048##

(38) Under room temperature, Compound 19-Ac (55 g) was dissolved in a mixed solvent of tert-butanol/water (425 mL/425 mL). After being cooled to 0? C., the mixture was added successively with NMO (36 g) and a solution of osmium tetroxide in 0.05 M toluene (100 mL), heated to room temperature, stirred and reacted for 24 h. After part of starting materials were left as detected by TLC, the mixture was added with saturated sodium sulfite (500 mL) and stirred to quench the reaction, and extracted with ethyl acetate (500 mL/3). The organic phases were combined, washed with water (500 mL?2), washed with saturated sodium chloride (500 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (65 g), which was separated by silica gel column chromatography and the starting material Compound 19-Ac (14.8 g) was isolated to give Compound 20-Ac (about 38.2 g, yield: 89.6%, purity: 85%) (the main isomer therein is Compound 20-Ac). .sup.1H NMR (400 MHz, Chloroform-d) ? 7.35-7.27 (m, 5H), 7.21 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.2 Hz, 2H), 5.32-5.20 (m, 1H), 4.48-4.40 (m, 4H), 4.34-4.30 (m, 1H), 4.10-4.05 (m, 1H), 3.80 (s, 31H), 3.73 (td, J=9.9, 4.7 Hz, 2H), 3.69-3.58 (m, 2H), 3.55-3.38 (m, 4H), 3.18 (s, 2H), 2.31-2.20 (m, 1H), 2.08-2.00 (m, 1H), 1.98 (s, 3H), 1.90-1.82 (m, 1H), 1.78-1.72 (m, 1H), 1.67-1.60 (m, 5H), 0.90 (t, J=7.4 Hz, 6H).

(39) ##STR00049##

Example 6. Synthesis of Compound 23

6.1. Synthesis of Compound 22

(40) ##STR00050##

(41) In an ice-water bath, Compound 20 (32 g) was dissolved in anhydrous dichloromethane (160 mL), and triethylamine (36.5 mL) and DMAP (640 mg) were added, followed by dropwise addition of MsCl (19.5 mL). Then the mixture was warmed to room temperature and reacted for 1 h. After the reaction was completed as detected by TLC, the mixture was added with saturated ammonium chloride (200 mL) to quench the reaction, and the liquid separation was performed. The aqueous phase was extracted with dichloromethane (200 mL?2), and the organic phases were combined, washed with water (250 mL?2), washed with saturated sodium chloride (250 mL?2), dried over anhydrous sodium sulfate, and concentrated to give a crude product of Compound 21 (about 39.4 g, theoretical yield: 39.8 g) in the form of a brown red oil, which was directly used in the next step without further purification. The crude product of Compound 21 (39.4 g) was dissolved in absolute methanol (300 mL), and anhydrous potassium carbonate powder (19 g) was added, and the mixture was stirred and reacted overnight. After the reaction was completed as detected by TLC, the mixture was concentrated under reduced pressure to evaporate off the solvent, added with water (300 mL) and extracted with dichloromethane (300 mL?2). The organic phases were combined, washed with saturated sodium chloride (300 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (33 g), which was separated by silica gel column chromatography to give Compound 22 (about 27 g, total yield over two steps: 90%). Compound 22 .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.38-7.17 ((m, 7H), 6.86 (d, J=8.0 Hz, 2H), 5.03 (s, 1H), 4.53-4.36 (m, 4H), 4.24 (h, J=6.5 Hz, 1H), 4.06 (t, J=6.9 Hz, 1H), 3.89 (q, 1=5.9, 5.5 Hz, 1H), 3.80 (s, 3H), 3.67 (q, J=6.6 Hz, 1H), 3.62-3.51 (m, 4H), 3.37 (t, J=8.6 Hz, 1H), 2.96 (s, 3H), 2.40 (q, J=6.6 Hz, 1H), 2.04 (dt, J=14.0, 6.8 Hz, 1H), 1.96 (dq, J=12.4, 6.3, 5.5 Hz, 3H), 1.62 (p, J=7.7 Hz, 4H), 0.89 (t, 1=7.5 Hz, 6H).

6.2. Synthesis of Compound 23

(42) ##STR00051##

(43) In an ice-water bath, Compound 22 (7.8 g) was dissolved in anhydrous tetrahydrofuran (80 mL), and a solution of 3 M methyl magnesium bromide in tetrahydrofuran (13.5 mL) was added dropwise. The mixture was warmed to room temperature and reacted overnight. After the reaction was completed as detected by TLC, the mixture was added dropwise with saturated ammonium chloride (100 mL) to quench the reaction and extracted with ethyl acetate (100 mL?3). The organic phases were combined, washed with saturated sodium chloride (200 mL?2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (8 g) in the form of a colorless oil, which was separated by silica gel column chromatography to give Compound 23 (5.8 g, yield: 86%) and Compound 23 (0.2 g). The purity of Compound 23 was >99.9%, and the HPLC pattern is shown in FIG. 2. The content of the impurity 23 shown as the following formula was 0.09%:

(44) ##STR00052##

(45) .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.35-7.28 (m, 5H), 7.22 (d, J=8.1 Hz, 2H), 6.85 (d, J=8.0 Hz, 2H), 4.49 (s, 2H), 4.43 (s, 2H), 4.32-4.27 (m, 1H), 4.08-4.04 (m, 2H), 3.86 (q, J=5.9 Hz, 1H), 3.79 (s, 3H), 3.72-3.63 (m, 2H), 3.58 (dt, J=21.2, 7.5 Hz, 2H), 3.47 (d, J=6.3 Hz, 2H), 2.13 (dd, J=7.1, 3.9 Hz, 1H), 2.10-1.97 (m, 3H), 1.93 (dt, J=19.8, 6.3 Hz, 2H), 1.63 (dq, J=14.9, 7.4 Hz, 4H), 0.89 (q, J=7.3 Hz, 6H).

(46) The examples of the present invention have been described above. However, the present invention is not limited to the above examples. Any modification, equivalent, improvement and the like made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.