PREPARATION METHOD FOR ECTEINASCIDIN COMPOUND AND INTERMEDIATE THEREOF

Abstract

The present invention provides a method for preparing an ecteinascidin compound and an intermediate thereof, and specifically provides a preparation method for a novel compound QT9, and a method of using QT9 to prepare an ecteinascidin compound. The method provided by the present invention has high reaction selectivity and high yield, the obtained compound is easy to purify, and defects in the prior art that multiple intermediates are oily substances, and the reaction selectivity is poor are solved. The method of the present invention is particularly applicable to industrial production.

Claims

1. A method for preparing compound QT9, comprising reacting compound QT10 with a hydroxyl protecting agent to obtain compound QT9: ##STR00100## wherein R.sub.1 of compound QT9 is a hydroxyl protecting group; wherein preferably, the hydroxyl protecting agent is bromomethyl methyl ether, chloromethyl methyl ether, or 2-methoxyethoxymethyl chloride, and wherein the molar ratio of the compound QT10 to the hydroxyl protecting agent is from 1:1 to 1:20, preferably the molar ratio of the compound QT10 to the hydroxyl protecting agent is from 1:1.5 to 1:2.5; wherein preferably, the compound QT10 is converted into compound QT9 under alkaline conditions using a base, and wherein the base is NaOH, KOH, NaH, LiOH, LiOCH.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3 or a mixture thereof, preferably the base is NaOH, KOH, NaH or a mixture thereof; and wherein preferably, the molar ratio of the compound QT10 to the base is from 1:1 to 1:30, preferably the molar ratio of the compound QT10 to the base is from 1:1.5 to 1:4, and wherein the reaction temperature is from −10° C. to 30° C., preferably the reaction temperature is from 0° C. to 10° C.

2. The method according to claim 1, wherein the hydroxyl protecting group R.sub.1 of compound QT9 is MOM, MEM, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

3. A method for preparing an ecteinascidin compound, comprising reacting compound QT10 with a hydroxyl protecting agent to obtain compound QT9: ##STR00101## wherein R.sub.1 of the compound QT9 is a hydroxyl protecting group; wherein preferably, the hydroxyl protecting group R.sub.1 of the compound QT9 is MOM, MEM, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl, and more preferably, the hydroxyl protecting group R.sub.1 of the compound QT9 is MOM or MEM; wherein preferably, the hydroxyl protecting agent is bromomethyl methyl ether, chloromethyl methyl ether, or 2-methoxyethoxymethyl chloride, and wherein the molar ratio of the compound QT10 to the hydroxyl protecting agent is from 1:1 to 1:20, preferably the molar ratio of the compound QT10 to the hydroxyl protecting agent is from 1:1.5 to 1:2.5; wherein preferably, the compound QT10 is converted into the compound QT9 under alkaline conditions using a base, wherein the base is NaOH, KOH, NaH, LiOH, LiOCH.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3 or a mixture thereof, preferably the base is NaOH, KOH, NaH or a mixture thereof; and wherein preferably, the molar ratio of the compound QT10 to the base is from 1:1 to 1:30, preferably the molar ratio of the compound QT10 to the base is from 1:1.5 to 1:4, and wherein the reaction temperature is from −10° C. to 30° C., preferably the reaction temperature is from 0° C. to 10° C.

4. The method according to claim 3, wherein the method further comprises selectively removing the allyl group from the compound QT9 to obtain compound QT8: ##STR00102##

5. The method according to claim 4, wherein the method further comprises oxidizing the phenolic hydroxyl group of the compound QT8 and selectively hydroxylating the resulting oxidized form of the compound QT8 to obtain compound QT7: ##STR00103##

6. The method according to claim 5, wherein the method further comprises esterifying the primary hydroxyl group of the compound QT7 with a cysteine derivative to obtain compound QT6: ##STR00104## wherein R of the cysteine derivative and the compound QT6 is an amino protecting group, preferably R of the cysteine derivative and the compound QT6 is Alloc, Cbz, Troc, or Boc.

7. The method according to claim 3, wherein the method further comprises esterifying the primary hydroxyl group of the compound QT9 with a cysteine derivative to obtain compound QT8A: ##STR00105## wherein R of the cysteine derivative and the compound QT8A is an amino protecting group, preferably R of the cysteine derivative and the compound QT8A is Alloc, Cbz, Troc, or Boc.

8. The method according to claim 7, wherein the method further comprises selectively removing the allyl group from the compound QT8A to obtain compound QT7A: ##STR00106##

9. The method according to claim 8, wherein the method further comprises oxidizing the phenolic hydroxyl group of the compound QT7A and selectively hydroxylating the resulting oxidized form of the compound QT7A to obtain compound QT6: ##STR00107##

10. The method according to claim 6, wherein the method further comprises reacting the compound QT6 with a Swern reagent and further with N-tert-butyl-N′,N′-tetramethylguanidine to obtain 1,4-bridged lactone compound QT5: ##STR00108##

11. The method according to claim 10, wherein the method further comprises selectively removing amino protecting group R from the compound QT5 to obtain compound QT4: ##STR00109##

12. The method according to claim 11, wherein the method further comprises subjecting the compound QT4 to transamination conditions to obtain compound QT3: ##STR00110##

13. The method according to claim 12, wherein the method further comprises reacting the compound QT3 with 2-[3-hydroxy-4-methoxy-phenyl]ethylamine to obtain compound QT2, selectively removing the phenol hydroxyl protecting group R1 from the compound QT2 to obtain compound ET770, and optionally converting the CN group in the compound ET770 into an OH group to obtain compound ET743: ##STR00111##

14. The method according to claim 10, wherein the method further comprises simultaneously removing the amino protecting group R and the hydroxyl protecting group R.sub.1 from the compound QT5 to obtain compound QT4A: ##STR00112##

15. The method according to claim 14, wherein the method further comprises subjecting the compound QT4A to transamination conditions to obtain compound QT3A, and optionally reacting the compound QT3A with 2-[3-hydroxy-4-methoxy-phenyl]ethylamine to obtain compound ET770, and converting the CN group in the compound ET770 into an OH group to obtain compound ET743: ##STR00113##

16-18. (canceled)

19. The method according to claim 6, wherein R.sub.1 of the compound QT7 and the compound QT6 is MEM or MOM, and wherein R of the cysteine derivative and the compound QT6 is Alloc, Cbz, or Troc.

20. The method according to claim 6, wherein R.sub.1 of the compound QT7 and the compound QT6 is MEM or MOM, and wherein R of the cysteine derivative and the compound QT6 is Boc.

21. A compound, wherein the compound has the following structure: ##STR00114##

22. The method according to claim 9, wherein the method further comprises reacting the compound QT6 with a Swern reagent and further with N-tert-butyl-N′,N′-tetramethylguanidine to obtain 1,4-bridged lactone compound QT5: ##STR00115##

23. The method according to claim 14, wherein R.sub.1 of compound QT5 is MEM or MOM, and wherein R of compound QT5 is Boc.

Description

5. EXAMPLES

Example 1: Synthesis of Compound 2

[0065] ##STR00053##

[0066] To a 1000 ml three-necked flask, 6.9 g of sodium hydroxide and 250 ml of tetrahydrofuran are added, and after the temperature is reduced to 0° C. or less, 59.8 g of compound QT10 is added, and 21.5 g of 2-methoxyethoxymethyl chloride (MEM-Cl) is dropwise added. After the dropwise addition is completed, with the temperature being maintained at 0° C. to 10° C., the reaction is stirred for 4 hours, quenched by adding a saturated ammonium chloride aqueous solution, and extracted with dichloromethane (2×500 ml); the organic layers are combined, dried over anhydrous sodium sulfate, and concentrated in vacuo; and the resulting viscous material is recrystallized from ethyl acetate and n-hexane to obtain 64.2 g of the compound as a white solid, with a yield of 91.8% and HPLC>99%.

[0067] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ6.71 (s, 1H), 06.10 (m, 1H), 5.93 (d, J=1.2 Hz, 1H), 5.87 (d, J=1.2 Hz, 1H), 5.44 (dd, J1=1.2 Hz, J2=17.2 Hz, 1H), 5.30 (dd, J1=1.2 Hz, J2=10.4 Hz, 1H), 5.27 (d, J=6 Hz, 1H), 5.18 (d, J=6 Hz, 1H), 4.26 (d, J=2.4 Hz, 1H), 4, 18-4.14 (m, 2H), 4.04 (d, J=2.4 Hz, 1H), 3.99 (t, 2H), 3.86 (m, 1H), 3.66 (s, 3H), 3.64 (m, 1H), 3.60 (t, 2H), 3.42-3.32 (m, 3H), 3.37 (s, 3H), 3.25 (dd, J1=2.8 Hz, J2=16 Hz, 1H), 3.14 (dd, J1=8.4 Hz, J2=17.4 Hz, 1H), 2.53 (d, J=18.4 Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.86-1.57 (m, 2H); MS: m/z (607.69), Found: 608.2 (M+H).sup.+.

Example 2: Synthesis of Compound 3

[0068] ##STR00054##

[0069] To a 500 ml three-necked flask, 1.15 g of sodium hydroxide and 115 ml of tetrahydrofuran are added, and after the temperature is reduced to 0° C. or less, 10.0 g of compound QT10 is added, and 2.41 g of bromomethyl methyl ether (MOM-Br) is dropwise added. After the dropwise addition is completed, with the temperature being maintained at −5° C. to 5° C., the reaction is stirred for 2 hours, quenched by adding a saturated ammonium chloride aqueous solution, and extracted with dichloromethane (2×200 ml); the organic layers are combined, dried over anhydrous sodium sulfate, and concentrated in vacuo; and the resulting foamy solid is recrystallized from ethyl acetate and n-hexane to obtain 9.8 g of the compound as a white solid, with a yield of 90.3% and HPLC>99%.

[0070] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.72 (s, 1H), 6.16-6.07 (m, 1H), 5.93 (d, J=1.6 Hz, 1H), 5.88 (d, J=1.6 Hz, 1H), 5.44 (dd, J1=1.6 Hz, J2=17.2 Hz, 1H), 5.30 (dq, J1=1.2 Hz, J2=10.4 Hz, 1H), 5.12 (s, 2H), 4.27 (d, J=2.0 Hz, 1H), 4, 12-4.11 (m, 2H), 4.05 (d, J=2.4 Hz, 1H), 3.99 (t, J=3.2 Hz, 2H), 3.71 (s, 3H), 3.68-3.63 (dt, J1=3.2 Hz, J2=10.8 Hz, 1H), 3.59 (s, 3H), 3.49-3.33 (m, 3H), 3.27 (dd, J1=2.8 Hz, J2=16.0 Hz, 1H), 3.16 (dd, J1=7.6 Hz, J2=18.0 Hz, 1H), 2.54 (d, J=18.0 Hz, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H), 1.86-1.81 (dd, J1=12 Hz, J2=15.6 Hz, 1H), 1.79-1.75 (dd, J1=2.8 Hz, J2=10.4 Hz, 1H); MS: m/z (563.64), Found: 564.5 (M+H).sup.+.

Example 3: Example 3 Synthesis of Compound 4

[0071] ##STR00055##

[0072] Under argon protection, to a 100 ml three-necked flask, 3.0 g of compound 2, 0.241 g of bis(triphenylphosphine)palladium dichloride, 1.48 g of acetic acid and 60 ml of dichloromethane are added, and 3.57 g of tri-n-butyl tin hydride is added at −15° C. to −10° C.; after the addition is completed, with the temperature being maintained at 0° C. to 5° C., the reaction is stirred for 1 hour, quenched by adding a saturated potassium fluoride aqueous solution and extracted with dichloromethane (2×40 ml); and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 2.76 g of the compound as a white foamy solid, with a yield of 98.5% and HPLC>98%.

[0073] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.68 (s, 1H), 5.89 (d, J=1.2 Hz, 1H), 5.82 (d, J=1.2 Hz, 1H), 5.44 (dd, J1=1.2 Hz, J2=17.2 Hz, 1H), 5.30 (dd, J1=1.2 Hz, J2=10.4 Hz, 1H), 5.61 (s, 1H), 5.39 (d, J=6 Hz, 1H), 5.27 (d, J=6 Hz, 1H), 4.26 (d, J=2.4 Hz, 1H), 4, 13-4.066 (m, 2H), 3.99-3.93 (m, 2H), 3.69 (s, 3H), 3.68-3.65 (m, 3H), 3.60 (t, 1H), 3.40 (s, 3H), 3.37-3.76 (m, 2H), 3.25 (dd, J=3.2, J2=14.2, 1H), 3.13 (dd, J1=8.4 Hz, J2=18.4 Hz, 1H), 2.53 (d, J=18.0 Hz, 1H), 2.34 (s, 3H), 2.20 (s, 3H), 2.08 (s, 3H), 1.83-1.77 (m, 2H);

[0074] MS: m/z (567.63), Found: 568.6 (M+H).sup.+.

Example 4: Example 4 Synthesis of Compound 5

[0075] ##STR00056##

[0076] With reference to a similar method to example 3, the compound is prepared from compound 3, with a yield of 97.3% and HPLC>96%.

[0077] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.72 (s, 1H), 6.16-6.07 (m, 1H), 5.93 (d, J=1.6 Hz, 1H), 5.88 (d, J=1.6 Hz, 1H), 5.44 (dd, J1=1.6 Hz, J2=17.2 Hz, 1H), 5.36-5.30 (m, 1H), 5.19 (t, J=6.5 Hz, 1H), 4.28 (d, J=2.4 Hz, 1H), 4.10 (d, J=2.4 Hz, 1H), 4.05-3.98 (m, 1H), 3.70 (dd, J1=5.6 Hz, J2=16.0 Hz, 7H), 3.56 (m, 1H), 3.44-3.36 (m, 2H), 3.18-3.07 (m, 2H), 2.54 (d, J=2.0 Hz, 1H), 2.38 (d, J=5.6 Hz, 3H), 2.25 (d, J=11.2 Hz, 3H), 2.10 (s, 3H), 1.84 (dd, J=15.2 Hz, 2H); MS: m/z (523.58), Found: 524.5 (M+H).sup.+.

Example 5: Example 5 Synthesis of Compound 6

[0078] ##STR00057##

[0079] Under argon protection, to a 250 ml three-necked flask, 2.7 g of compound 4 and 40 ml of dichloromethane are added, and after the temperature is reduced to −40° C. to −35° C., a solution of 1.71 g of benzeneseleninic anhydride in dichloromethane is added; with the temperature being maintained constant, the reaction is stirred for 1 hour, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×40 ml), and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 2.66 g of the compound as a light yellow solid, with a yield of 95.8% and HPLC>96%.

[0080] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.69, 6.62 (s, 1H), 5.84, 5.74 (s, 2H), 5.26, 5.08 (d, J=1.2 Hz, 1H), 5.15 (d, J=1.5 Hz, 1H), 5.61 (s, 1H), 4.23-3.30 (m, 11H), 3.90, 3.62 (s, 3H), 3.39, 3.36 (s, 3H), 3.024-2.959 (m, 1H), 2.80-2.09 (m, 2H), 2.30, 2.24 (s, 3H), 2.22, 2.19 (s, 3H), 1.80 (s, 3H); MS: m/z (583.63), Found: 584.65 (M+H).sup.+.

Example 6: Example 6 Synthesis of Compound 7

[0081] ##STR00058##

[0082] With reference to a method of example 5, compound 7 is prepared from compound 5 and obtained as a light yellow solid (8.0 g), with a yield of 97.0% and HPLC>96%.

[0083] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.72 (s, 1H), 5.86 (m, 1H), 5.93 (s, 2H), 5.12 (s, 2H), 4.10 (m, 2H), 3.92 (s, 3H), 3.88 (m, 1H), 3.80 (m, 1H), 3.62 (m, 1H), 3.52 (s, 3H), 3.34 (m, 1H), 3.04 (dd, J1=7.6, J2=18.0, 1H), 2.68 (m, 1H), 2.62 (d, J=18, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.21 (m, 1H), 2.00 (dd, J1=8.4, J2=15.2, 1H), 1.80 (s, 3H).

Example 7: Example 7 Synthesis of Compound 8

[0084] ##STR00059##

[0085] 2.5 g of compound 6 and 2.57 g of N-tert-butoxycarbonyl-(s)-fluorenylmethyl-L-cysteine are dissolved in dichloromethane, and treated with anhydrous toluene (2×20 ml), and water is azeotropically removed. Under argon protection, the mixture from which water has been removed is dissolved in 50 ml of dichloromethane, transferred to a 250 ml three-necked flask, and cooled to −10° C. or less; 0.262 g of DMAP (2.14 mmol) is added, and a solution of 1.64 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (8.57 mmol) in dichloromethane is dropwise added; after the dropwise addition is completed, the reaction is stirred at 10° C. to 15° C. for 2 hours, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×50 ml), and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 3.7 g of the compound as a light yellow solid, with a yield of 89.6%.

[0086] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.73 (t, J=6.8 Hz, 4H), 7.63 (m, 2H), 7.54 (d, J=7.6 Hz, 2H), 7.40-7.34 (m, 4H), 7.31-7.27 (m, 4H), 6.62 (s, 2H), 5.86 (s, 1H), 5.81 (s, 1H), 5.75 (s, 1H), 5.72 (s, 1H), 5.70 (s, 1H), 5.35 (d, J=6.0 Hz, 1H), 5.22 (d, J=6.0 Hz, 1H), 5.13 (d, J=6.0 Hz, 1H), 4.97 (d, J=6.0, J=8.8 Hz, 1H), 4.43 (m, 2H), 4.20-4.01 (m, 8H), 3.97-3.85 (m, 4H), 3.54 (m, 2H), 3.38 (s, 3H), 3.35 (s, 3H), 3.34-2.91 (m, 8H), 2.60-2.31 (m, 4H), 2.27 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.97 (s, 3H), 1.94-1.81 (m, 2H), 1.77 (s, 3H), 1.43 (s, 9H), 1.41 (s, 9H);

[0087] MS: m/z (965.12), Found: 966.25 (M+H).sup.+.

Example 8: Example 8 Synthesis of Compound 9

[0088] ##STR00060##

[0089] 1.5 g of compound 7 and 1.67 g of N-tert-butoxycarbonyl-(s)-fluorenylmethyl-L-cysteine are dissolved in dichloromethane, and treated with anhydrous toluene (2×15 ml), and water is azeotropically removed. Under argon protection, the mixture from which water has been removed is dissolved in 30 ml of dichloromethane, transferred to a 100 ml three-necked flask, and cooled to −10° C. or less; 0.17 g of DMAP is added and a solution of 1.07 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (5.56 mmol) in dichloromethane is dropwise added; after the dropwise addition is completed, the reaction is stirred at 10° C. to 15° C. for 2 hours, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×30 ml), and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 2.28 g of the compound as a light yellow solid, with a yield of 88.9%.

[0090] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.73-7.61 (m, 4H), 7.63 (m, 2H), 7.37-7.30 (m, 4H), 6.62 (s, 1H), 6.59 (s, 1H), 6.53 (s, 1H), 5.72 (s, 1H), 5.70 (s, 1H), 5.61 (s, 1H), 5.55 (bs, 1H), 5.34 (m, 2H), 5.08 (m, 1H), 5.01 (m, 1H), 4.67 (m, 1H), 4.50 (m, 1H), 4.38 (dd, J1=4.8, J2=12.8, 1H), 4.21 (dd, J1=6.4, J2=12.8, 1H), 4.11 (m, 1H), 4.02 (m, 3H), 3.87 (m, 1H), 3.83 (s, 3H), 3.72 (m, 1H), 3.61 (s, 3H), 3.49 (s, 3H), 3.27 (m, 1H), 3.15 (dd, J1=1.6 Hz, J2=6.0 Hz, 2H), 3.07 (d, J=6.4 Hz, 1H), 2.94 (m, 4H), 2.86 (m, 2H), 2.42 (m, 2H), 2.25 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H), 2.08 (dd, J1=2.4 Hz, J2=13.2 Hz, 1H), 1.77 (s, 3H), 1.76 (s, 3H), 1.43 (s, 9H);

[0091] MS: m/z (921.06), Found: 922.35 (M+H).sup.+.

Example 9: Example 9 Synthesis of Compound 10

[0092] ##STR00061##

[0093] Under argon protection, to a 500 ml three-necked flask, 4.1 g of dimethyl sulfoxide and 300 ml of anhydrous dichloromethane are added, and 3.5 g of trifluoromethanesulfonic anhydride is dropwise added at −70° C. to −80° C.; after the dropwise addition is completed, the reaction is stirred for 20 minutes with the temperature being maintained constant, and a solution of 10.0 g of compound 8 in dichloromethane is dropwise added, with the internal temperature being controlled to not exceed −70° C. during the dropwise addition; after the dropwise addition is completed, the temperature is raised to −45° C. to −40° C. for 1 h of reaction, and 13.40 g of diisopropylethylamine is dropwise added; after the dropwise addition is completed, the temperature is slowly returned to 0° C. and then reduced to −15° C. or less and 3.45 g of tert-butanol (46.55 mmol) is dropwise added; the mixture is stirred for 10 minutes and a solution of 17.8 g of 2-tert-butyl-1,1,3,3-tetramethylguanidine in dichloromethane is dropwise added; the temperature is slowly raised to 0° C. and then reduced to −10° C. or less, 13.22 g of acetic anhydride is slowly dropwise added; and after the dropwise addition is completed, a reaction is carried out for 15 minutes with the temperature being maintained constant, quenched by adding a saturated ammonium chloride aqueous solution and allowed for layering, and the aqueous layer is extracted with 250 ml of dichloromethane. The organic layers are combined, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, concentrated and subjected to column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to obtain an off-white foamy solid, which is recrystallized from ethyl acetate and n-hexane to obtain 6.26 g of the compound as a white powdery solid, with a yield of 74.5% and HPLC>96%.

[0094] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.78 (s, 1H), 6.09 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.33 (d, J=6.0 Hz, 1H), 5.20 (d, J=5.6 Hz, 1H), 5.03 (d, J=11.6 Hz, 1H), 4.64 (d, J=9.6 Hz, 1H), 4.51 (bs, 1H), 4.35 (d, J=4.8 Hz, 1H), 4.29-4.12 (m, 4H), 3.920 (m, 2H), 3.76 (s, 3H), 3.59-3.57 (t, J=4.8 Hz, 2H), 3.43-3.39 (m, 2H), 3.37 (s, 3H), 2.92-2.90 (m, 2H), 2.31-2.04 (m, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H), 1.45 (s, 9H);

[0095] MS: m/z (810.91), Found: 811.60 (M+H).sup.+.

Example 10: Example 10 Synthesis of Compound 11

[0096] ##STR00062##

[0097] With reference to a similar method to example 9, the compound is prepared and obtained as a white powdery solid, with a yield of 72.7% and HPLC>96%.

[0098] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.78 (s, 1H), 6.09 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.20 (d, J=5.6 Hz, 1H), 5.14 (d, J=5.6 Hz, 1H), 5.03 (d, J=11.6 Hz, 1H), 4.64 (d, J=9.6 Hz, 1H), 4.51 (s, 1H), 4.33 (d, J=4.8 Hz, 1H), 4.29-4.17 (m, 4H), 3.76 (s, 3H), 3.57 (s, 3H), 3.42 (m, 2H), 2.93 (m, 2H), 2.35 (m, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.09 (m, 1H), 2.05 (s, 3H), 1.45 (s, 9H); MS: m/z (766.86), Found: 767.50 (M+H).sup.+.

Example 11: Example 11 Synthesis of Compound QT4A

[0099] ##STR00063##

[0100] Under argon protection, to a 500 ml three-necked flask, 6.0 g of compound 10 and 300 ml of trichloromethane are added, and after the temperature is reduced to 0° C., 7.65 g of anhydrous p-toluenesulfonic acid is added; and after the addition is completed, the reaction is stirred for 44 hours with the temperature being maintained at 20° C. to 25° C. After the temperature is reduced to 10° C., the reaction is quenched by adding a saturated sodium bicarbonate aqueous solution, and the pH is adjusted to about 8; the resultant is allowed for layering; the aqueous layer is extracted with dichloromethane (2×50 ml), and the organic layers are combined, concentrated and subjected to column chromatography (n-hexane:ethyl acetate=2:1 to 1:2) followed by recrystallization from ethyl acetate and n-hexane to obtain 4.37 g of the compound as a white solid, with a yield of 94.9% and HPLC>96%.

[0101] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.52 (s, 1H), 6.07 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.73 (bs, 1H), 5.02 (d, J=11.6 Hz, 1H), 4.54 (bs, 1H), 4.25 (d, J=3.2 Hz, 2H), 4.18 (d, J=2.8 Hz, 1H), 4.14 (dd, J1=2.0 Hz, J2=11.6 Hz, 1H), 3.78 (s, 3H), 3.42-3.39 (m, 2H), 3.27 (t, J=6.8 Hz, 1H), 2.91 (m, 2H), 2.21-2.18 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H); MS: m/z (622.69), Found: 623.25 (M+H).sup.+.

Example 12: Example 12 Synthesis of Compound QT4A

[0102] ##STR00064##

[0103] With reference to a similar method to example 11, compound QT4A is prepared from compound 11, with a yield of 94.8%. .sup.1H NMR (400 MHZ, CDCl.sub.3): δ 6.52 (s, 1H), 6.07 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.73 (bs, 1H), 5.02 (d, J=11.6 Hz, 1H), 4.54 (bs, 1H), 4.25 (d, J=3.2 Hz, 2H), 4.18 (d, J=2.8 Hz, 1H), 4.14 (dd, J1=2.0 Hz, J2=11.6 Hz, 1H), 3.78 (s, 3H), 3.42-3.39 (m, 2H), 3.27 (t, J=6.8 Hz, 1H), 2.91 (m, 2H), 2.21-2.18 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H); MS: m/z (622.69), Found: 623.25 (M+H).sup.+.

Example 13: Example 13 Synthesis of Compound QT3A

[0104] ##STR00065##

[0105] According to methods known in the art, such as a method disclosed in example 20 of WO 2001087895, QT3A is prepared from QT4A, with a yield of 64.1%.

[0106] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.49 (s, 1H), 6.11 (d, J=1.2 Hz, 1H), 6.02 (d, J=1.2 Hz, 1H), 5.70 (s, 1H), 5.10 (d, J=11.6 Hz, 1H), 4.66 (bs, 1H), 4.39 (s, 1H), 4.27 (d, J=4 Hz, 1H), 4.23 (dd, J1=1.2 Hz, J2=11.2 Hz, 1H), 4.16 (d, J=2.4 Hz, 1H), 3.75 (s, 3H), 3.55 (d, J=5.2 Hz, 1H), 3.43 (d, J=8.8 Hz, 1H), 2.93-2.82 (m, 2H), 2.72 (d, J=17.6 Hz, 1H), 2.58 (dd, J=10.0 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H);

[0107] MS: m/z (621.66), Found: 622.30 (M+H).sup.+.

Example 14: Example 14 Synthesis of Compound ET770

[0108] ##STR00066##

[0109] With reference to methods known in the art, such as a method disclosed in example 21 of WO 2001087895, ET770 is prepared from QT3A, with a yield of 93% and HPLC>99%.

[0110] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.59 (s, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 6.05 (d, J=1.2 Hz, 1H), 5.98 (d, J=1.2 Hz, 1H), 5.75 (s, 1H), 5.44 (bs, 1H), 5.03 (d, J=11.6 Hz, 1H), 4.57 (bs, 1H), 4.32 (s, 1H), 4.28 (d, J=4.8 Hz, 1H), 4.18 (d, J=2.8 Hz, 1H), 4.13 (dd, J1=2.0 Hz, J2=11.6 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 3.51 (d, J=5.2 Hz, 1H), 3.42 (m, 1H), 3.12 (m, 1H), 2.95 (m, 2H), 2.79 (m, 1H), 2.60 (m, 1H), 2.49 (m, 1H), 2.36-2.11 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H); MS: m/z (770.85), Found: 771.50 (M+H).sup.+.

Example 15: Example 15 Synthesis of Compound ET743

[0111] ##STR00067##

[0112] Under argon protection, to a 250 ml three-necked flask, 2.5 g of compound ET770, 11.02 g of silver nitrate, 50 ml of acetonitrile and 37.5 ml of deionized water are added, and the mixture is stirred at 20° C. to 25° C. for 2 hours away from light and filtered over diatomaceous earth; the filtrate is added to a mixed solution of 200 ml of a saturated sodium bicarbonate aqueous solution and 100 ml of a saturated sodium chloride aqueous solution; after a large amount of white solid sufficiently precipitates out, the mixture is filtered over diatomaceous earth, and the filter cake is washed with dichloromethane; after layering, the aqueous layer is extracted with dichloromethane (3×100 ml), and the organic layers are combined, washed sequentially with a saturated sodium chloride aqueous solution, an ammonium chloride-aqueous ammonia buffer (pH 8-9) and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from dichloromethane and n-pentane to obtain 2.35 g of the compound as a white crystalline powder, with a yield of 95.1% and HPLC>99%.

[0113] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.60 (s, 1H), 6.46 (s, 1H), 6.45 (s, 1H), 6.02 (d, J=0.8 Hz, 1H), 5.94 (d, J=0.8 Hz, 1H), 5.69 (s, 1H), 5.41 (bs, 1H), 5.14 (d, J=10.8 Hz, 1H), 4.81 (s, 1H), 4.47 (bs, 1H), 4.41 (bs, 1H), 4.16 (d, J=4.0 Hz, 1H), 4.05 (dd, J1=2.0 Hz, J2=11.2 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.58 (d, J=4.8 Hz, 1H), 3.22 (m, 1H), 3.13 (m, 1H), 2.88-2.77 (m, 3H), 2.60 (m, 1H), 2.50 (m, 1H), 2.37-2.13 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 2.04 (s, 3H); MS: m/z (761.84), Found: 762.25 (M+H).sup.+.

Example 16: Example 16 Synthesis of Compound 12

[0114] ##STR00068##

[0115] 5.0 g of compound 2 and 4.93 g of N-tert-butoxycarbonyl-(s)-fluorenylmethyl-L-cysteine are dissolved in dichloromethane, and treated with anhydrous toluene (2×50 ml), and water is azeotropically removed. Under argon protection, the mixture from which water has been removed is dissolved in 100 ml of dichloromethane, transferred to a 250 ml three-necked flask, and cooled to −10° C. or less; 0.502 g of DMAP is added, and a solution of 3.15 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) in dichloromethane is dropwise added; after the dropwise addition is completed, the reaction is stirred at 10° C. to 15° C. for 2 hours, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×100 ml), and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 2:1) to obtain 7.90 g of the compound as a white foamy solid, with a yield of 97.1% and HPLC>96%.

[0116] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.73-7.70 (m, 2H), 7.61 (dd, J1=7.6 Hz, J2=15.6 Hz, 2H), 7.37 (m, 2H), 7.29-7.26 (m, 2H), 6.62 (s, 1H), 6.08-5.99 (m, 1H), 5.91 (d, J=1.2 Hz, 1H), 5.80 (d, J=1.2 Hz, 1H), 5.37 (dd, J1=1.6, J2=17.2 Hz), 5.24 (d, J=6.0 Hz, 1H), 5.14 (d, J=6.0 Hz), 5.04 (brd, J=8.8 Hz, 1H), 4.28 (m, 2H), 4.17-3.92 (m, 8H), 3.85 (m, 1H), 3.69 (s, 3H), 3.57 (m, 2H), 3.38 (s, 3H), 3.37-3.16 (m, 3H), 2.98-2.93 (m, 3H), 2.61 (m, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H), 1.75 (dd, J1=11.6, J2=15.6, 1H), 1.44 (s, 9H); [0163] MS: m/z (989.18), Found: 990.0 (M+H).sup.+.

Example 17: Example 17 Synthesis of Compound 13

[0117] ##STR00069##

[0118] With reference to a similar method to example 16, compound 13 is prepared and obtained as a white foamy solid, with a yield of 97.4% and HPLC>95%.

[0119] MS: m/z (945.13), Found: 946.50 (M+H).sup.+.

Example 18: Example 18 Synthesis of Compound 14

[0120] ##STR00070##

[0121] Under argon protection, to a 250 ml three-necked flask, 7.5 g of compound 12, 0.37 g of bis(triphenylphosphine)palladium dichloride, 2.28 g of acetic acid and 150 ml of dichloromethane are added, and 5.50 g of tri-n-butyl tin hydride is added at −15° C. to −10° C.; after the addition is completed, with the temperature being maintained at 0° C. to 5° C., the reaction is stirred for 1 hour, quenched by adding a saturated potassium fluoride aqueous solution and extracted with dichloromethane (2×100 ml); and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 7.0 g of the compound as a white foamy solid, with a yield of 97.3% and HPLC>96%. MS: m/z (949.12), Found: 950.0 (M+H).sup.+.

[0122] With reference to a similar method to example 18, compound 40 is prepared from compound 38, and compound 41 is prepared from compound 39.

[0123] With reference to a similar method to example 18, compound 33 is prepared from compound 31 and obtained as a white foamy solid, with a yield of 95.2%. MS: m/z (939.08), Found: 940.0 (M+H).sup.+.

Example 19: Example 19 Synthesis of Compound 15

[0124] ##STR00071##

[0125] With reference to a method of example 19, compound 15 is prepared and obtained as a white foamy solid, with a yield of 96.1%.

[0126] MS: m/z (905.07), Found: 906.35 (M+H).sup.+.

Example 20: Example 20 Synthesis of Compound 8

[0127] ##STR00072##

[0128] Under argon protection, to a 500 ml three-necked flask, 6.0 g of compound 14 (6.32 mmol) and 120 ml of dichloromethane are added; after the temperature is reduced to −40° C. to −35° C., a solution of 2.28 g of benzeneseleninic anhydride (6.33 mmol) in dichloromethane is added; with the temperature being raised to −20° C. to −15° C., the reaction is stirred for 1 hour, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×100 ml), and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 5.9 g of the compound as a light yellow solid, with a yield of 96.7% and HPLC>96%.

[0129] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.73 (t, J=6.8 Hz, 4H), 7.63 (m, 2H), 7.54 (d, J=7.6 Hz, 2H), 7.40-7.34 (m, 4H), 7.31-7.27 (m, 4H), 6.62 (s, 2H), 5.86 (s, 1H), 5.81 (s, 1H), 5.75 (s, 1H), 5.72 (s, 1H), 5.70 (s, 1H), 5.35 (d, J=6.0 Hz, 1H), 5.22 (d, J=6.0 Hz, 1H), 5.13 (d, J=6.0 Hz, 1H), 4.97 (d, J=6.0, J=8.8 Hz, 1H), 4.43 (m, 2H), 4.20-4.01 (m, 8H), 3.97-3.85 (m, 4H), 3.54 (m, 2H), 3.38 (s, 3H), 3.35 (s, 3H), 3.34-2.91 (m, 8H), 2.60-2.31 (m, 4H), 2.27 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.97 (s, 3H), 1.94-1.81 (m, 2H), 1.77 (s, 3H), 1.43 (s, 9H), 1.41 (s, 9H);

[0130] MS: m/z (965.12), Found: 966.25 (M+H).sup.+.

[0131] With reference to a similar method, compound 34 is prepared from compound 40; and compound 35 is prepared from compound 41.

[0132] With reference to a similar method to example 20, compound 26 is prepared from compound 32 and obtained as a light yellow solid, with a yield of 95.6%. MS: m/z (999.13), Found: 1000.05 (M+H).sup.+.

[0133] With reference to a similar method to example 20, compound 27 is prepared from compound 33 and obtained as a light yellow solid, with a yield of 96.9%. MS: m/z (955.08), Found: 956.0 (M+H).sup.+.

Example 21: Example 21 Synthesis of Compound 9

[0134] ##STR00073##

[0135] With reference to a similar method to example 20, compound 9 is prepared and obtained as a light yellow solid, with a yield of 98.3% and HPLC>98%.

[0136] MS: m/z (921.06), Found: 922.35 (M+H).sup.+.

Example 22: Example 22 Synthesis of Compound 16

[0137] ##STR00074##

[0138] 2.5 g of compound 6 (4.28 mmol) and 2.47 g of N-(allyloxycarbonyl)-S-(fluorenylmethyl)-L-cysteine (6.44 mmol) are dissolved in dichloromethane, and treated with anhydrous toluene (2×20 ml), and water is azeotropically removed. Under argon protection, the mixture from which water has been removed is dissolved in 50 ml of dichloromethane, transferred to a 250 ml three-necked flask, and cooled to −10° C. or less; 0.262 g of DMAP (2.14 mmol) is added, and a solution of 1.64 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (8.57 mmol) in dichloromethane is dropwise added; after the dropwise addition is completed, the reaction is stirred at 10° C. to 15° C. for 2 hours, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×50 ml), and the organic layers are combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 3.6 g of the compound as a light yellow solid, with a yield of 88.6%, wherein compound 16 is a mixture of two isomers.

[0139] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.74 (m, 4H), 7.63 (m, 4H), 7.38 (m, 4H), 7.29 (m, 4H), 6.61 (s, 1H), 6.54 (s, 1H), 5.89 (m, 2H), 5.72 (s, 1H), 5.70 (s, 1H), 5.69 (s, 1H), 5.62 (s, 1H), 5.55 (m, 1H), 5.32 (d, J=15.2 Hz, 1H), 5.23 (d, J=6.0 Hz, 1H), 5.22 (d, J=10.4, 1H), 5.14 (d, J=6.0 Hz, 1H), 5.13 (d, J=6.0 Hz, 1H), 5.07 (d, J=6.4 Hz, 1H), 4.67 (m, 1H), 4.56 (m, 4H), 4.51 (m, 1H), 4.38 (dd, J1=4.4, J2=12.8, 1H), 4.22 (dd, J1=6.0 Hz, J2=11.2 Hz, 1H), 4.14-3.88 (m, 12H), 3.83 (s, 3H), 3.79-3.69 (m, 4H), 3.61 (s, 3H), 3.56 (m, 4H), 3.39 (s, 3H), 3.36 (s, 3H), 3.23 (m, 2H), 3.15 (dd, J=6.0 Hz, 2H), 3.07 (d, J=6.0 Hz, 2H), 3.00-2.81 (m, 6H), 2.46-2.34 (m, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H), 2.08 (m, 1H), 1.83 (dd, J1=9.6 Hz, J2=15.2 Hz, 1H), 1.78 (s, 3H), 1.77 (s, 3H);

[0140] MS: m/z (949.07), Found: 950.0 (M+H).sup.+.

Example 23: Example 23 Synthesis of Compound 17

[0141] ##STR00075##

[0142] With reference to a similar method to example 22, compound 17 is prepared and obtained as a light yellow solid, with a yield of 87.4%.

[0143] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.75 (m, 2H), 7.62 (m, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 6.63 (s, 1H), 5.89 (m, 1H), 5.74 (s, 1H), 5.71 (s, 1H), 5.52 (d, J=8.4 Hz, 1H), 5.32 (d, J=16.8 Hz, 1H), 5.22 (d, J=10.0 Hz, 1H), 5.10 (m, 2H), 4.57 (m, 2H), 4.50 (m, 1H), 4.23 (dd, J1=6.0 Hz, J2=11.2 Hz, 1H), 4.04 (m, 1H), 4.00 (dd, J1=2.4 Hz, J2=13.2 Hz, 1H), 3.93 (m, 1H), 3.84 (s, 3H), 3.49 (s, 3H), 3.24 (m, 1H), 3.08 (m, 3H), 2.95 (m, 3H), 2.44 (d, J=18.0 Hz, 1H), 2.36 (dd, J1=5.6 Hz, J2=15.2 Hz, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.83 (dd, J1=9.6 Hz, J2=15.2 Hz, 1H), 1.78 (s, 3H); MS: m/z (905.02), Found: 906.0 (M+H).sup.+.

Example 24: Example 24 Synthesis of Compound 18

[0144] ##STR00076##

[0145] Under argon protection, to a 250 ml three-necked flask, 1.32 g of dimethyl sulfoxide (16.89 mmol) and 100 ml of anhydrous dichloromethane are added, and 1.24 g of trifluoromethanesulfonic anhydride (4.40 mmol) is dropwise added at −70° C. to −80° C.; after the dropwise addition is completed, the reaction is stirred for 20 minutes with the temperature being maintained constant, and a solution of 3.2 g of compound 16 (3.37 mmol) in dichloromethane is dropwise added, with the internal temperature being controlled to not exceed −70° C. during the dropwise addition; after the dropwise addition is completed, the temperature is raised to −45° C. to −40° C. for 50 minutes of reaction, and 4.36 g of diisopropylethylamine (33.73 mmol) is then dropwise added; after the dropwise addition is completed, the temperature is slowly raised to 0° C. and then reduced to −15° C. or less, and 1.12 g of tert-butanol (15.11 mmol) is dropwise added; the mixture is stirred for 10 minutes with the temperature being maintained constant, and a solution of 5.78 g of 2-tert-butyl-1,1,3,3-tetramethylguanidine (33.74 mmol) in dichloromethane is dropwise added; the temperature is slowly raised to 0° C. and then reduced to −10° C. or less, 4.30 g of acetic anhydride (42.54 mmol) is slowly dropwise added; and after the dropwise addition is completed, a reaction is carried out for 15 minutes with the temperature being maintained constant, quenched by adding a saturated ammonium chloride aqueous solution and allowed for layering, and the aqueous layer is extracted with 100 ml of dichloromethane. The organic layers are combined, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, concentrated and subjected to column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to obtain 2.0 g of the compound as an off-white foamy solid, with a yield of 74.6% and HPLC>96%.

[0146] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.78 (s, 1H), 6.07 (d, J=1.2 Hz, 1H), 5.98 (d, J=1.2 Hz, 1H), 5.92 (m, 1H), 5.32 (d, J=6.0 Hz, 1H), 5.31 (dd, J1=1.5 Hz, J2=16.8 Hz, 1H), 5.23 (dd, J1=1.6 Hz, J2=10.4 Hz, 1H), 5.19 (d, J=5.6 Hz, 1H), 5.01 (d, J=11.6 Hz, 1H), 4.81 (d, J=9.6 Hz, 1H), 4.53-4.51 (m, 3H), 4.35-4.27 (m, 2H), 4.24 (s, 1H), 4.18-4.13 (m, 2H), 3.943.84 (m, 2H), 3.73 (s, 3H), 3.58 (t, J=4.8 Hz, 2H), 3.43-3.37 (m, 2H), 3.36 (s, 3H), 2.92 (m, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 2.36-2.06 (m, 2H), 2.02 (s, 3H);

[0147] MS: m/z (794.97), Found: 795.55 (M+H).sup.+.

Example 25: Example 25 Synthesis of Compound 19

[0148] ##STR00077##

[0149] With reference to a similar method to example 24, compound 19 is prepared and obtained as an off-white foamy solid, with a yield of 74.3%.

[0150] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.80 (s, 1H), 6.09 (d, J=1.2 Hz, 1H), 6.00 (d, J=1.2 Hz, 1H), 5.93 (m, 1H), 5.32 (dd, J1=1.2 Hz, J2=16.8 Hz, 1H), 5.23 (d, J=10.0 Hz, 1H), 5.22 (d, J=5.6 Hz, 1H), 5.14 (d, J=5.2 Hz, 1H), 5.03 (d, J=13.2 Hz, 1H), 4.83 (d, J=9.6 Hz, 1H), 4.52 (m, 3H), 4.31 (m, 2H), 4.24 (s, 1H), 4.16 (m, 2H), 3.74 (s, 3H), 3.56 (s, 3H), 3.45 (m, 1H), 3.40 (m, 1H), 2.92 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.13 (m, 1H), 2.03 (s, 3H); MS: m/z (750.81), Found: 751.50 (M+H).sup.+.

Example 26: Example 26 Synthesis of Compound 20

[0151] ##STR00078##

[0152] Under argon protection, to a 50 ml three-necked flask, 1.0 g of compound 18 (1.89 mmol), 0.14 g of bis(triphenylphosphine)palladium dichloride (0.20 mmol), 0.68 g of acetic acid (11.32 mmol) and 15 ml of dichloromethane are added, and 1.64 g of tri-n-butyl tin hydride (5.65 mmol) is added at −15° C. to −10° C.; after the addition is completed, with the temperature being maintained at 0° C. to 5° C., the reaction is stirred for 1 hour, quenched by adding a saturated potassium fluoride aqueous solution and extracted with dichloromethane (2×20 ml); and the organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 1.28 g of the compound as a white foamy solid, with a yield of 95.4% and HPLC>95%; MS: m/z (710.79), Found: 711.55 (M+H).sup.+.

Example 27: Example 27 Synthesis of Compound 21

[0153] ##STR00079##

[0154] With reference to a similar method to example 26, compound 21 is prepared and obtained as a white solid, with a yield of 96.8% and HPLC>95%.

[0155] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.73 (s, 1H), 6.08 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.93 (m, 1H), 5.21 (d, J=3.6 Hz, 1H), 5.14 (d, J=3.6 Hz, 1H), 5.02 (d, J=12.0 Hz, 1H), 4.51 (m, 1H), 4.34 (d, J=4.8 Hz, 1H), 4.27 (s, 1H), 4.20 (d, J=3.2, 1H), 4.13 (d, J=12 Hz, 1H), 3.79 (s, 3H), 3.57 (s, 3H), 3.45 (d, J=4.8 Hz, 1H), 3.41 (m, 1H), 3.31 (m, 1H), 2.92 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 2.16 (m, 1H), 2.04 (s, 3H).

Example 28: Example 28 Synthesis of Compound 22

[0156] ##STR00080##

[0157] Under argon protection, 4.20 g of compound N-methyl-pyridine-4-carbaldehyde iodide (16.86 mmol), 40 ml of anhydrous DMF and 2 g of a molecular sieve are added to a 250 ml three-necked flask; the temperature is reduced to −5° C., and a solution of 1.2 g of compound 20 (1.69 mmol) in dichloromethane (60 ml) is dropwise added; after the dropwise addition is completed, the mixture is stirred for 5.5 hours with the temperature being maintained at 15° C. to 20° C. The temperature is reduced to −5° C., and 0.031 g of DBU (0.204 mmol) is added; and the mixture is stirred for 10 minutes, and 40 ml of a saturated oxalic acid aqueous solution is dropwise added; after the dropwise addition is completed, the mixture is stirred for 4 hours with the temperature being maintained at 15° C. to 20° C.; the temperature is reduced to 0° C., and 40 ml of a saturated potassium bicarbonate aqueous solution is added; the mixture is allowed for layering; the aqueous layer is extracted with dichloromethane (2×60 ml), and the organic layers are combined, concentrated and subjected to column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain a white solid, with a yield of 73.2% and HPLC>96%. MS: m/z (709.76), Found: 710.45 (M+H).sup.+.

Example 29: Example 29 Synthesis of Compound 23

[0158] ##STR00081##

[0159] With reference to the method of example 28, compound 23 is prepared and obtained as a white solid, with a yield of 69.6% and HPLC>96%.

[0160] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.70 (s, 1H), 6.12 (d, J=1.6 Hz, 1H), 6.03 (d, J=1.6 Hz, 1H), 5.20 (d, J=5.6 Hz, 1H), 5.13 (d, J=5.6 Hz, 1H), 5.10 (d, J=12.0 Hz, 1H), 4.68 (m, 1H), 4.40 (s, 1H), 4.38 (dd, J1=2.0 Hz, J2=5.2 Hz, 1H), 4.22 (dd, J1=2.0 Hz, J2=10.8 Hz, 1H), 4.18 (d, J=2.8 Hz, 1H), 3.75 (s, 3H), 3.58 (m, 1H), 3.57 (s, 3H), 3.44 (m, 2H), 2.90 (m, 1H), 2.82 (d, J=13.2 Hz, 1H), 2.71 (d, J=17.2 Hz, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 2.17 (m, 1H) 2.16 (s, 3H), 2.05 (s, 3H); MS: m/z (665.71), Found: 666.35 (M+H).sup.+.

Example 30: Example 30 Synthesis of Compound 24

[0161] ##STR00082##

[0162] Under argon protection, 0.6 g of compound 22 (0.845 mmol), 2.0 g of silica gel (400 mesh), 0.57 g of 3-hydroxy-4-methoxyphenethylamine (3.41 mmol) and 30 ml of anhydrous ethanol are added to a 100 ml three-necked flask; the mixture is stirred at 20° C. to 25° C. for 18 hours, concentrated under reduced pressure to remove ethanol and subjected to column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 0.67 g of compound as a white solid, with a yield of 92.5%. MS: m/z (856.98), Found: 857.65 (M+H).sup.+.

Example 31: Example 31 Synthesis of Compound 25

[0163] ##STR00083##

[0164] With reference to a similar method to example 30, compound 25 is prepared, with a yield of 91.4%.

[0165] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.86 (s, 1H), 6.52 (s, 1H), 6.51 (s, 1H), 6.12 (d, J=1.2 Hz, 1H), 6.06 (d, J=1.2 Hz, 1H), 5.26 (d, J=5.6 Hz, 1H), 5.22 (d, J=5.6 Hz, 1H), 5.06 (d, J=11.6 Hz, 1H), 4.62 (m, 1H), 4.42 (d, J=5.6 Hz, 1H), 4.36 (3, 1H), 4.25 (d, J=2.8 Hz, 1H), 4.19 (dd, J1=2.4 Hz, J2=11.2 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.63 (s, 3H), 3.55 (m, 1H), 3.48 (m, 1H), 3.42 (m, 1H), 3.12 (m, 1H), 3.00 (m, 2H), 2.85 (m, 1H), 2.76 (dd, J1=6.8 Hz, J2=13.6 Hz, 1H), 2.62 (m, 2H), 2.45 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.09 (s, 3H); [0228] MS: m/z (812.93), Found: 813.70 (M+H).sup.+.

Example 32: Example 32 Synthesis of Compound ET770

[0166] ##STR00084##

[0167] Under argon protection, to a 100 ml three-necked flask, 0.5 g of compound 24 and 25 ml of dichloromethane are added, and after the temperature is reduced to 0° C., 0.30 g of anhydrous p-toluenesulfonic acid is added; and after the addition is completed, the mixture is stirred for 12 hours with the temperature being maintained at 20° C. to 25° C. After the temperature is reduced to 10° C., the reaction is quenched by adding a saturated sodium bicarbonate aqueous solution, and the pH is adjusted to about 8; the resultant is allowed for layering; the aqueous layer is extracted with dichloromethane (2×20 ml), and the organic layers are combined, concentrated and subjected to column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 0.42 g of the compound as a white solid, with a yield of 93.4% and HPLC>99%. MS: m/z (770.85), Found: 771.50 (M+H).sup.+.

Example 33: Example 33 Synthesis of Compound ET770

[0168] ##STR00085##

[0169] With reference to the method of example 32, compound ET770 is prepared, with a yield of 92.8% and HPLC>99%.

[0170] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.59 (s, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 6.05 (d, J=1.2 Hz, 1H), 5.98 (d, J=1.2 Hz, 1H), 5.75 (s, 1H), 5.44 (bs, 1H), 5.03 (d, J=11.6 Hz, 1H), 4.57 (bs, 1H), 4.32 (s, 1H), 4.28 (d, J=4.8 Hz, 1H), 4.18 (d, J=2.8 Hz, 1H), 4.13 (dd, J1=2.0 Hz, J2=11.6 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 3.51 (d, J=5.2 Hz, 1H), 3.42 (m, 1H), 3.12 (m, 1H), 2.95 (m, 2H), 2.79 (m, 1H), 2.60 (m, 1H), 2.49 (m, 1H), 2.36-2.11 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H); MS: m/z (770.85), Found: 771.50 (M+H).sup.+.

Example 34: Example 34 Synthesis of Compound 26

[0171] ##STR00086##

[0172] With reference to a similar method to example 7, wherein the N-tert-butoxycarbonyl-(s)-fluorenylmethyl-L-cysteine in the method of example 7 is replaced by N-benzyloxycarbonyl-(s)-fluorenylmethyl-L-cysteine, compound 26 is prepared and obtained as a light yellow solid, with a yield of 93.5% and HPLC>96%.

[0173] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.73 (d, J=7.6 Hz, 2H), 7.63 (d, J=7.6 Hz, 2H), 7.40-7.29 (m, 9H), 6.59 (s, 1H), 6.52 (s, 1H), 5.68 (s, 1H), 5.66 (s, 1H), 5.58 (s, 1H), 5.56 (s, 1H), 5.23 (d, J=6.0 Hz, 1H), 5.15-5.05 (m, 4H), 4.76-4.68 (m, 1H), 4.64-4.55 (m, 1H), 4.40 (m, 1H), 4.15-3.68 (m, 8H), 3.60 (s, 3H), 3.57 (s, 3H), 3.39 (s, 3H), 3.36 (s, 3H), 3.25-2.78 (m, 7H), 2.38-2.24 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.09 (m, 1H), 2.04 (s, 3H), 1.77 (s, 3H), 1.58 (s, 3H); MS: m/z (999.13), Found: 1000.05 (M+H).sup.+.

Example 35: Example 35 Synthesis of Compound 27

[0174] ##STR00087##

[0175] With reference to a similar method to example 8, wherein the N-tert-butoxycarbonyl-(s)-fluorenylmethyl-L-cysteine in the method of example 8 is replaced by N-benzyloxycarbonyl-(s)-fluorenylmethyl-L-cysteine, compound 27 is prepared and obtained as a light yellow solid, with a yield of 90.4%.

[0176] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.73 (d, J=7.6 Hz, 2H), 7.59 (m, 2H), 7.40-7.28 (m, 9H), 6.60 (s, 1H), 5.69 (s, 1H), 5.65 (s, 1H), 5.54 (d, J=7.6 Hz, 1H), 5.11-5.08 (m, 4H), 4.52 (m, 1H), 4.21-3.90 (m, 6H), 3.83 (s, 3H), 3.49 (s, 3H), 3.21 (d, J=6.4, 1H), 3.09-2.90 (m, 6H), 2.41 (d, J=18.0 Hz, 1H), 2.34-2.31 (m, 1H), 2.25 (s, 3H), 2.19 (s, 3H) 1.88-1.83 (m, 1H), 1.77 (s, 3H); MS: m/z (955.08), Found: 956.0 (M+H).sup.+.

Example 36: Example 36 Synthesis of Compound 28

[0177] ##STR00088##

[0178] Under argon protection, to a 250 ml three-necked flask, 1.37 g of dimethyl sulfoxide and 140 ml of anhydrous dichloromethane are added, and 1.48 g of trifluoromethanesulfonic anhydride (5.25 mmol) is dropwise added at −70° C. to −80° C.; after the dropwise addition is completed, the reaction is stirred for 20 minutes with the temperature being maintained constant, and a solution of 3.5 g of compound 26 (3.50 mmol) in dichloromethane is dropwise added, with the internal temperature being controlled to not exceed −70° C. during the dropwise addition; after the dropwise addition is completed, the temperature is raised to −45° C. to −40° C. for 50 minutes of reaction, and 4.53 g of diisopropylethylamine (35.05 mmol) is then dropwise added; after the dropwise addition is completed, the temperature is slowly raised to 0° C. and then reduced to −15° C. or less, and 1.17 g of tert-butanol (15.78 mmol) is added; the mixture is stirred for 10 minutes with the temperature being maintained constant, and a solution of 6.0 g of 2-tert-butyl-1,1,3,3-tetramethylguanidine (35.03 mmol) in dichloromethane is added; the temperature is slowly raised to 0° C. and then reduced to −10° C. or less, and 4.47 g of acetic anhydride (44.22 mmol) is slowly dropwise added; and after the dropwise addition is completed, a reaction is carried out for 15 minutes with the temperature being maintained constant, quenched by adding a saturated ammonium chloride aqueous solution and allowed for layering, and the aqueous layer is extracted with 100 ml of dichloromethane. The organic layers are combined, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, concentrated and subjected to column chromatography (n-hexane:ethyl acetate=5:1 to 3:1) to obtain a white powdery solid, with a yield of 77.4% and HPLC>95%.

[0179] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.37 (m, 5H), 6.66 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1H), 5.30 (d, J=5.6 Hz, 1H), 5.17 (d, J=6.0 Hz, 1H), 5.06 (d, J=7.6 Hz, 1H), 5.00 (s, 1H), 4.83 (d, J=9.2 Hz, 1H), 4.50 (s, 1H), 4.34-4.17 (m, 7H), 3.90-3.87 (m, 2H), 3.66 (s, 3H), 3.65-3.56 (m, 2H), 3.37 (s, 3H), 2.90 (m, 2H), 2.28 (s, 3H), 2.18 (s, 3H), 2.15-2.04 (m, 2H), 2.03 (s, 3H), 1.99 (s, 3H; MS: m/z (844.93), Found: 845.75 (M+H).sup.+.

Example 37: Example 37 Synthesis of Compound 29

[0180] ##STR00089##

[0181] With reference to a similar method to example 36, compound 29 is prepared and obtained as a white powdery solid, with a yield of 72.6%.

[0182] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.37 (m, 5H), 6.67 (s, 1H), 6.08 (d, J=1.2, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.19-5.00 (m, 4H), 4.82 (d, J=9.2 Hz, 1H), 4.49 (s, 1H), 4.32-4.15 (m, 5H), 3.66 (s, 3H), 3.55 (s, 3H), 3.44 (d, J=4.8 Hz, 1H), 3.39 (d, J=6.0 Hz, 1H), 2.90 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 2.15-2.07 (m, 2H), 2.03 (s, 3H), 1.99 (s, 3H); MS: m/z (800.87), Found: 801.50 (M+H).sup.+.

Example 38: Example 38 Synthesis of Compound 20

[0183] ##STR00090##

[0184] Under argon protection, 1.5 g of compound 28 (1.78 mmol), 30 ml of methanol and 1.0 ml of formic acid are added to a 100 ml three-necked flask; the temperature is reduced to 0° C. to 5° C., and 0.4 g of 10% Pd/C is added in three portions; after the addition is completed, the mixture is stirred for 1.5 hours with the temperature being maintained constant, filtered, dissolved by adding 100 ml of dichloromethane, washed sequentially with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 1.1 g of the compound as a white foamy solid, with a yield of 87.2% and HPLC>96%. MS: m/z (710.79), Found: 711.55 (M+H).sup.+.

Example 39: Example 39 Synthesis of Compound 21

[0185] ##STR00091##

[0186] With reference to a similar method to example 38, compound 21 is prepared and obtained as a white foamy solid, with a yield of 86.1% and HPLC>95%.

[0187] MS: m/z (666.74), Found: 667.65 (M+H)+.

Example 40: Example 40 Synthesis of Compound 30

[0188] ##STR00092##

[0189] With reference to a similar method to example 16, wherein the N-tert-butoxycarbonyl-(s)-fluorenylmethyl-L-cysteine in the method of example 16 is replaced by N-benzyloxycarbonyl-(s)-fluorenylmethyl-L-cysteine, 8.2 g of compound 30 is prepared and obtained as a white foamy solid, with a yield of 97.4%. MS: m/z (1023.20), Found: 1024.0 (M+H).sup.+.

[0190] With reference to a similar method, compound 38 and compound 39 are prepared.

Example 41: Example 41 Synthesis of Compound 31

[0191] ##STR00093##

[0192] With reference to a similar method to example 16, compound 30 is prepared and obtained as a white foamy solid, with a yield of 94.4%.

[0193] MS: m/z (979.15), Found: 980.0 (M+H).sup.+.

Example 42: Example 42 Synthesis of Compound 32

[0194] ##STR00094##

[0195] With reference to a similar method to example 18, compound 32 is prepared and obtained as a white foamy solid, with a yield of 93.6%.

[0196] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.71 (d, J=7.2, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.41-7.23 (m, 9H), 6.60 (s, 1H), 5.87 (bs, 2H), 5.74 (s, 1H), 5.40 (d, J=6.4 Hz, 1H), 5.33 (d, J=6.0 Hz, 1H), 5.18 (d, J=9.2 Hz, 1H), 5.09 (d, J=12 Hz, 1H), 4.97 (d, J=12 Hz, 1H), 4.56 (dd, J1=3.2 Hz, J2=11.2 Hz, 1H), 4.19 (d, J=2.0 Hz, 1H), 4.16-3.87 (m, 9H), 3.6 (s, 3H), 3.38 (s, 3H), 3.32-3.20 (m, 3H), 2.96-2.87 (m, 3H), 2.62-2.54 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 1.97 (s, 3H), 1.82 (dd, J1=13.2 Hz, J2=15.6 Hz, 1H).

Example 43: Example 43 Synthesis of Compound 34

[0197] ##STR00095##

[0198] 2.5 g of compound 6 (4.28 mmol) and 3.3 g of N-(2,2,2)-trichloroethyloxycarbonyl-(s)-fluorenylmethyl-L-cysteine (6.95 mmol) are dissolved in dichloromethane, and treated with anhydrous toluene (2×20 ml), and water is azeotropically removed. Under argon protection, the mixture from which water has been removed is dissolved in 50 ml of dichloromethane, transferred to a 250 ml three-necked flask, and cooled to −10° C. or less; 0.262 g of DMAP (2.14 mmol) is added, and a solution of 1.64 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (8.57 mmol) in dichloromethane is dropwise added; after the dropwise addition is completed, the reaction is stirred at 10° C. to 15° C. for 2 hours, quenched by adding a saturated sodium bicarbonate aqueous solution and allowed for layering; the aqueous layer is extracted with dichloromethane (2×50 ml), and the organic layers are combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil, which is subjected to column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to obtain 3.8 g of the compound as a light yellow solid, with a yield of 85.3%. MS: m/z (1040.40), Found: 1040.25 (M+H).sup.+.

Example 44: Example 44 Synthesis of Compound 35

[0199] ##STR00096##

[0200] With reference to a similar method to example 43, compound 35 is prepared from compound 7 and obtained as a light yellow solid, with a yield of 96.7%.

[0201] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 7.76 (m, 4H), 7.65 (m, 4H), 7.39 (m, 4H), 7.29 (m, 4H), 6.62 (s, 1H), 6.55 (s, 1H), 5.79-5.63 (m, 6H), 5.09 (s, 1H), 5.02 (d, J=6.0, 1H), 4.99 (d, J=6.0 Hz, 1H), 4.80-4.63 (m, 6H), 4.60 (m, 1H), 4.50 (m, 1H), 4.38 (dd, J1=7.6, J2=12.8 Hz, 1H), 4.27 (dd, J1=7.6, J2=12.8, 1H), 4.16-3.90 (m, 10H), 3.84 (s, 3H), 3.62 (s, 3H), 3.50 (s, 3H), 3.33-2.83 (m, 14H), 2.45-2.18 (m, 2H), 2.21 (s, 6H), 2.17 (s, 6H), 1.77 (s, 6H), 1.67 (m, 2H).

Example 45: Example 45 Synthesis of Compound 37

[0202] ##STR00097##

[0203] Under argon protection, to a 100 ml three-necked flask, 0.85 g of dimethyl sulfoxide (10.86 mmol) and 60 ml of anhydrous dichloromethane are added, and 0.80 g of trifluoromethanesulfonic anhydride (2.82 mmol) is added at −70° C. to −80° C.; after the dropwise addition is completed, the reaction is stirred for 20 minutes with the temperature maintained constant, and a solution of 2.1 g of compound 9 (2.17 mmol) in dichloromethane is dropwise added, with the internal temperature being controlled to not exceed −70° C. during the dropwise addition; after the dropwise addition is completed, the temperature is raised to −45° C. to −40° C. for 50 minutes of reaction, and 2.81 g of diisopropylethylamine (21.71 mmol) is then dropwise added; after the dropwise addition is completed, the temperature is slowly raised to 0° C. and then reduced to −15° C. or less, and 0.72 g of tert-butanol (9.77 mmol) is added; the mixture is stirred for 10 minutes with the temperature being maintained constant, and a solution of 3.72 g of 2-tert-butyl 1,1,3,3-tetramethylguanidine (21.71 mmol) in dichloromethane is added; the temperature is slowly raised to 0° C. and then reduced to −10° C. or less, and 2.77 g of acetic anhydride (27.14 mmol) is slowly dropwise added; and after the dropwise addition is completed, a reaction is carried out for 15 minutes with the temperature being maintained constant, quenched by adding a saturated ammonium chloride aqueous solution, and allowed for layering, and the aqueous layer is extracted with 50 ml of dichloromethane. The organic layers are combined, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, concentrated and subjected to column chromatography (n-hexane:ethyl acetate=10:1 to 1:1) to obtain a white powdery solid, with a yield of 79.1%.

[0204] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.85 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1H), 5.20 (d, J=5.6 Hz, 1H), 5.14 (d, J=5.2 Hz), 5.03 (m, 1H), 4.82 (d, J=12.4 Hz, 1H), 4.63 (d, J=12.0 Hz, 1H), 4.52 (m, 1H), 4.35-4.17 (m, 4H), 3.76 (s, 3H), 3.56 (s, 3H), 3.45 (m, 2H), 2.91 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.12 (m, 2H), 2.03 (s, 3H).

[0205] With reference to a similar method, compound 36 is prepared, with a yield of 73.5%. MS: m/z (886.14), Found: 887.2 (M+H).sup.+.

Example 46: Example 46 Synthesis of Compound 21

[0206] ##STR00098##

[0207] Under argon protection, 1.0 g of compound 37 is dissolved in 25 ml of a 90% acetic acid aqueous solution, and 0.8 g of zinc powder is added; the mixture is stirred at 20° C. to 25° C. for 36 hours and filtered over diatomaceous earth; the filter cake is washed with dichloromethane, and the filtrate is added 100 ml of dichloromethane, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 0.69 g of the compound as a white foamy solid, with a yield of 87.2% and HPLC>95%.

[0208] .sup.1HNMR (400 MHZ, CDCl.sub.3): δ 6.73 (s, 1H), 6.08 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 5.93 (m, 1H), 5.21 (d, J=3.6 Hz, 1H), 5.14 (d, J=3.6 Hz, 1H), 5.02 (d, J=12.0 Hz, 1H), 4.51 (m, 1H), 4.34 (d, J=4.8 Hz, 1H), 4.27 (s, 1H), 4.20 (d, J=3.2, 1H), 4.13 (d, J=12 Hz, 1H), 3.79 (s, 3H), 3.57 (s, 3H), 3.45 (d, J=4.8 Hz, 1H), 3.41 (m, 1H), 3.31 (m, 1H), 2.92 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 2.16 (m, 1H), 2.04 (s, 3H).

[0209] With reference to a similar method, compound 36 is prepared, with a yield of 83.5%. MS: m/z (710.2), Found: 711.0 (M+H).sup.+.

Example 47: Example 47: Study on the Effects of Different Reaction Conditions on the Preparation of Compound QT9

[0210] ##STR00099##

in which R.sub.1 is MEM or MOM; with reference to a similar method to examples 1 and 2, compound QT9 is prepared from compound QT10, wherein the material charge amounts are shown as in the following table:

TABLE-US-00001 Protecting agent (MEMCl or Compound Type and MOMBr) and Batch QT10 amount of amount Reaction No. amount base thereof temperature Reaction situation 1 1 eq K.sub.2CO.sub.3, 20 eq 20° C. to 30° C. Yield > 50%; TLC results 30 eq show the existence of impurities 2 1 eq K.sub.2CO.sub.3, 12 eq 5° C. to 10° C. Yield > 60%; the double- 8 eq protected by-product has a content of 19.2% 3 1 eq DIPEA, 1 eq 15 eq 0° C. to 10° C. Yield > 50%; TLC results show the existence of impurities 4 1 eq NaH, 1.0 eq 2.0 eq −10° C. to 0° C. Yield > 85%; the double- protected by-product has a content of 1.3% 5 1 eq NaH, 1.5 eq 1.5 eq 5° C. to 10° C. Yield > 85%; the double- protected by-product has a content of 1.8% 6 1 eq NaH, 1.2 eq; 2.5 eq 0° C. to 5° C. Yield > 80%; the double- t-KOBu, 1.0 eq protected by-product has a content of 6.5% 7 1 eq t-KOBu, 3 eq 5 eq 5° C. to 10° C. Yield > 80%; the double- protected by-product has a content of 6.017% 8 1 eq t-KOBu, 1.0 eq 1 eq 15° C. to 25° C. Yield > 85%; the double- protected by-product has a content of 4.16% 9 1 eq t-KOBu, 5 eq 5 eq −5° C. to 5° C. Yield > 80%; the double- protected by-product has a content of 7.1% 10 1 eq t-KOBu, 5 eq 15 eq −10° C. to 0° C. Yield > 50%; TLC results show the existence of impurities 11 1 eq n-LiOBu, 10 eq 10 eq −10° C. to 15° C. Yield > 75%; the double- protected by-product has a content of 16.8% 12 1 eq KOH, 2.0 eq 2 eq 5° C. to 15° C. Yield > 85%; the double- protected by-product has a content of 1.7% 13 1 eq KOH, 15 eq 5 eq 0° C. to 10° C. Yield > 85%; the double- protected by-product has a content of 5.7% 14 1 eq LiOCH.sub.3, 2.0 eq 0° C. to 10° C. Yield > 80%; the double- 2.0 eq protected by-product has a content of 6.41% 15 1 eq NaOH, 4.0 eq 2.0 eq 0° C. to 10° C. Yield > 90%; the double- protected by-product has a content of <1% 16 1 eq NaOH, 2.5 eq 2.0 eq 5° C. to 10° C. Yield > 95%; the double- protected by-product has a content of <1% 17 1 eq NaOH, 1 eq 2.0 eq 0° C. to 5° C. Yield > 95%; the double- protected by-product has a content of <1% In the table, eq stands for molar equivalent.

[0211] As can be seen from the reaction conditions in the above table, where the base is potassium t-butoxide, lithium methoxide, potassium hydroxide, lithium t-butoxide, etc., the corresponding compound QT9 can be prepared in all these cases; in addition, where NaOH, KOH, NaH or a mixture thereof is preferably selected as the base, the molar ratio of the compound QT10 to the base is 1:1 to 10, particularly 1 to 2.5, and the molar ratio of the compound QT10 to the hydroxyl protecting agent is 1:1 to 10, particularly 1 to 2.5, a very good effect can be achieved, and the double-protected impurities can be controlled to less than 2%; moreover, a majority of the double-protected impurities may be further removed by means of recrystallization, such that the purity of the target product reaches 99% or more; furthermore, taking into account safety issues in the industrial production process, sodium hydroxide is the most preferred, and the use of sodium hydroxide results in a high conversion rate, a smaller content of side reaction impurities, and a higher safety than sodium hydride. It can also be seen from the above comparative experiment that where sodium hydroxide is used, the amount thereof may fluctuate within a larger range.