INTERMEDIATE FOR PREPARING FULVESTRANT AND PREPARATION METHOD THEREFOR

Abstract

The invention relates to a fulvestrant intermediate and a preparation method thereof. Specifically, the invention relates to a compound shown as a formula V and a preparation method thereof, and R.sup.1 is hydrogen or a hydroxyl protecting group. The invention also relates to a preparation method for the synthesis of fulvestrant from the compound as shown in the formula V. The method has the advantages of short reaction steps, mild and safe reaction conditions, high selectivity, simplicity and convenience in operation and purification, high synthesis efficiency and the like, and is suitable for large-scale production.

##STR00001##

Claims

1. A compound as shown in formula V, ##STR00049## wherein: R.sup.1 is hydrogen or hydroxyl protecting groups.

2. The compound shown in formula V according to claim 1, wherein R.sup.1 is hydrogen, benzyl, C.sub.1-6 alkyl, C.sub.1-10 alkyl acyl, aryl acyl or (C.sub.1-10 alkyl or aryl).sub.3 silyl.

3. The compound shown in formula V according to claim 1, wherein R.sup.1 is C.sub.1-10 alkyl acyl or aryl acyl.

4. The compound shown in formula V according to claim 1, wherein R.sup.1 is acetyl.

5. A preparation method of the compound shown in formula V according to claim 1, wherein it is prepared by an addition reaction of the compound shown in formula VI and the compound shown in formula VII, ##STR00050## wherein: R.sup.1 s hydrogen or hydroxyl protecting groups. M is MgCl, MgBr, MgI, Mg.sub.1/2, ZnCl, ZnBr, ZnI, Zn.sub.1/2, MnCl, Li or Na.

6. The preparation method of the compound shown in formula V according to claim 5, wherein R.sup.1 is hydrogen, benzyl, C.sub.1-6 alkyl, C.sub.1-10 alkyl acyl, aryl acyl or (C.sub.1-10 alkyl or aryl).sub.3 silyl; M is MgCl or MgBr.

7. The preparation method of the compound shown in formula V according to claim 5, wherein R.sup.1 is C.sub.1-10 alkyl acyl, aryl acryl; M is MgCl or MgBr.

8. The preparation method of the compound shown in formula V according to claim 5, wherein R.sup.1 is acetyl.

9. A compound as shown in formula VII, ##STR00051## wherein M is MgCl, MgBr, MgI, Mg.sub.1/2, ZnCl, ZnBr, ZnI, Zn.sub.1/2, MnCl, Li or Na.

10. A method for preparing a compound as shown in formula VII, wherein it is prepared by reaction with metal or exchange reaction with metal from compound as described in formula VIII, ##STR00052## wherein X is Cl, Br or I, M is MgCl, MgBr, MgI, Mg.sub.1/2, ZnCl, ZnBr, ZnI, Zn.sub.1/2, MnCl, Li or Na.

11. The compound as shown in formula VII according to claim 9, wherein the compound shown in formula VIIA, ##STR00053## wherein X is Cl, Br or I.

12. A method for preparing a compound as shown in formula VIIA, wherein it is prepared by Grignard reaction from the compound as shown in formula VIII with magnesium metal, or with Grignard reagents through Grignard exchange reaction, ##STR00054## wherein X is Cl, Br or I.

13. A compound as shown in formula III, ##STR00055## wherein R.sup.1 is hydrogen or hydroxyl protecting groups; R.sup.2 is hydroxyl protecting groups.

14. The compound shown in formula III according to claim 13, wherein R.sup.1 is benzyl, C.sub.1-6 alkyl, C.sub.1-10 alkyl acyl, aryl acyl or (C.sub.1-10 alkyl or aryl).sub.3 silyl; R.sup.2 is C.sub.1-10 alkyl acyl or aryl acyl.

15. The compound shown in formula III according to claim 13, wherein R.sup.1 is acetyl; R.sup.2 is acetyl or propionyl.

16. A preparation method for a compound as shown in formula III, wherein it is prepared by aromatization reaction and phenolic hydroxyl protection reaction of the compound shown in formula V, ##STR00056## wherein R.sup.1 is hydrogen or hydroxyl protecting groups; R.sup.1 is hydroxyl protecting groups.

17. The method for preparing the compound shown in formula III according to claim 16, wherein R.sup.1 is hydrogen, benzyl, C.sub.1-6 alkyl, C.sub.1-10 alkyl acyl, aryl acyl or (C.sub.1-10 alkyl or aryl).sub.3 silyl; R.sup.2 is C.sub.1-10 alkyl acyl or aryl acyl.

18. The method for preparing the compound shown in formula III according to claim 16, wherein R.sup.1 is C.sub.1-10 alkyl acyl or aryl acyl; R.sup.2 is C.sub.1-10 alkyl acyl or aryl acyl.

19. The method for preparing the compound shown in formula III according to claim 16, wherein R.sup.1 is acetyl; R.sup.2 is acetyl or propionyl.

20. A method for preparing fulvestrant as shown in formula I, wherein it comprises the following steps, 1) The compound shown in formula VI and the compound shown in formula VII undergo addition reaction to obtain the compound shown in formula V; 2) The compound shown in formula V undergoes aromatization reaction and phenolic hydroxyl protection reaction to obtain the compound shown in formula III; 3) The compound shown in formula III and the compound shown in formula IV undergo substitution reaction to obtain the compound as shown in formula II; 4) The compound shown in formula II undergoes oxidation reaction to obtain the compound shown in formula I; ##STR00057## wherein R.sup.1 is hydrogen or hydroxyl protecting groups; R.sup.2 is hydroxyl protecting groups; M is MgCl, MgBr, MgI, Mg.sub.1/2, ZnCl, ZnBr, ZnI, Zn.sub.1/2, MnCl, Li or Na.

21. The method of preparing the compound shown in formula I according to claim 20, wherein R.sup.1 is hydrogen, benzyl, C.sub.1-6 alkyl, C.sub.1-10 alkyl acyl, aryl acyl or (C.sub.1-10 alkyl or aryl).sub.3 silyl; R.sup.2 is C.sub.1-10 alkyl acyl or aryl acyl; M is MgCl or MgBr.

22. The method of preparing the compound shown in formula I according to claim 20, wherein R.sup.1 is C.sub.1-10 alkyl acyl or aryl acyl; R.sup.2 is C.sub.1-10 alkyl acyl or aryl acyl; M is MgCl or MgBr.

23. The method of preparing the compound shown in formula I according to claim 20, wherein R.sup.1 is acetyl; R.sup.2 is acetyl or propionyl; M is MgBr.

24. A method for preparing fulvestrant as shown in formula I, wherein it comprises the following steps, 1) The compound shown in formula VIa and the compound shown in formula VIIa undergo addition reaction to obtain the compound shown in formula Va; 2) The compound shown in formula Va undergoes aromatization reaction and phenolic hydroxyl protection reaction to obtain the compound shown in formula IIIa; 3) The compound shown in formula IIIa and the compound shown in formula IVa undergo substitution reaction to obtain the compound as shown in formula II; 4) The compound shown in formula II undergoes oxidation reaction to obtain the compound shown in formula I. ##STR00058##

25. A method for preparing fulvestrant, wherein it comprises the method for preparing the compounds shown in formula VII, VIIA, V, III according to any one of claims 5-8, 10-12 or 16-19, or a steps for preparing fulvestrant by any one of the compounds shown in formula V according to any one of claims 1-4, the compounds shown in formula VII or VIIA according to claims 9-11, or the compounds shown in formula III according to any one of claims 13-15.

26. A method for preparing fulvestrant, wherein it comprises steps for preparing fulvestrant by 1,9-dichlorononane, 1-chloro-9-bromononane or 1-chloro-9-iodononane.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0104] The following examples illustrate the present invention, so that the professional and technical personnel could understand the present invention more fully. The examples are only used to illustrate the technical solution of the present invention, and do not limit the present invention in any way.

Example 1: Preparation of Compound VIIIa

[0105] To a solution of compound IXa (50 g) in SOCl.sub.2 (50 mL) was added pyridine (10 mL) dropwisely below 20 C. The reaction mixture was kept at 20 C. for 48 h. TLC showed that the reaction was complete, the mixture was quenched with cold water, and extracted with MTBE. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound VIIIa (52.6 g, 97% yield).

[0106] .sup.1H NMR (400 MHz, Chloroform-d) 3.53 (td, J=6.7, 0.9 Hz, 2H), 3.41 (td, J=6.9, 0.8 Hz, 2H), 1.85 (p, J=7.0 Hz, 2H), 1.81-1.72 (m, 2H), 1.43 (dq, J=12.9, 6.8 Hz, 4H), 1.32 (d. J=4.5 Hz, 6H).

Example 2: Preparation of Compound VIIa

[0107] To anhydrous THE (380 mL) was added magnesium turnings (6.42 g). Compound VIIIa (46.1 g) was added slowly at 20 C. and the reaction mixture was kept at room temperature for 2 h to obtain compound VIIa.

Example 3: Preparation of Compound VIIa

[0108] To anhydrous THE (380 mL) was added compound VIIIa (46.1 g). Isopropylmagnesium bromide in THE (1.0 eq) was added dropwisely at 0 C. and the reaction mixture was stirred for 2 h to obtain compound VIIa.

Example 4: Preparation of Compound VIIb

[0109] To anhydrous THF (380 mL) was added magnesium turnings (6 g). Compound VIIIb (48 g) was added slowly at 20 C. and the reaction mixture was kept at room temperature for 2 h to obtain compound VIIb.

Example 5: Preparation of Compound VIIc

[0110] To anhydrous THF (380 mL) was added magnesium turnings (6 g). Compound VIIIc (32.7 g) was added slowly at 20 C. and the reaction mixture was kept at room temperature for 2 h to obtain compound VIIc.

Example 6: Preparation of Compound VIId

[0111] To anhydrous THF (380 mL) was added magnesium turnings (6.42 g). Compound VIIIa (46.1 g) was added slowly at 20 C. and the reaction mixture was kept at room temperature for 2 h to obtain compound VIIa. The solution of compound VIIa was cooled to 0 C., and anhydrous ZnCl.sub.2 in THF solution (1.0 eq) was added. The reaction mixture was stirred for 2 h, obtain compound VIId.

Example 7: Preparation of Compound Vile

[0112] To anhydrous THF (380 mL) was added compound VIIIa (46.1 g). Diethylzinc in THF (0.5 eq) was added dropwisely at 30 C. and the reaction mixture was stirred for 2 h to obtain compound VIIe.

Example 8: Preparation of Compound VIIf

[0113] To anhydrous THF (380 mL) was added compound VIIIa (46.1 g) tert-Butyllithium in THF (2.5 eq) was added dropwisely at 30 C. and the reaction mixture was stirred for 2 h to obtain compound VIIf.

Example 9: Preparation of Compound VIIg

[0114] To anhydrous THF (380 mL) was added magnesium turnings (6.42 g). Compound VIIIa (46.1 g) was added slowly at 20 C. and the reaction mixture was kept at room temperature for 2 h to obtain compound VIIa. The solution of compound VIIa was cooled to 0 C., and anhydrous MnCl.sub.2 in THF solution (1.0 eq) was added. The reaction mixture was stirred for 2 h, obtain compound VIIg.

Example 10: Preparation of Compound Va

[0115] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIIa (1.3 eq) in THF was added slowly at 20 C. and the reaction mixture was kept stirring at 20 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (28.0 g, 92% yield). The diastereomeric ratio of 7:70 is 9:1.

[0116] MS (ESI) m/z: 477 (M+H+).

[0117] .sup.1H NMR (400 MHz, Chloroform-d) 5.82 (s, 1H), 4.61 (t, 1H), 3.52 (t, 2H), 2.52 (dd, J=14 Hz, J=2 Hz, 1H), 2.382.42 (m, 1H), 2.212.29 (m, 3H), 2.152.21 (m, 1H), 2.03 (s, 3H), 1.962.02 (m, 1H), 1.851.88 (m, 1H), 1.681.79 (m, 5H), 1.461.60 (in, 4H), 0.951.42 (m, 18H).

Example 11: Preparation of Compound Va

[0118] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIIb (1.3 eq) in THF was added slowly at 20 C. and the reaction mixture was kept stirring at 20 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (25.2 g, 83% yield). The diastereomeric ratio of 7:7 is 8:1.

[0119] MS (ESI) m/z: 477 (M+H.sup.+).

[0120] .sup.1H NMR (400 MHz, Chloroform-d) 5.82 (s, 1H), 4.61 (t, 1H), 3.52 (t, 2H), 2.52 (dd, J=14 Hz, J=2 Hz, 1H), 2 382.42 (m, 1H), 2.212 29 (m, 3H), 2.152.21 (m, 1H), 2.03 (s, 3H), 1.962.02 (m, 1-H), 1.851.88 (m, 1H), 1.684.79 (m, 5H), 1.461.60 (m, 4H), 0.951.42 (m, 18H).

Example 12 Preparation of Compound Va

[0121] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIIc (1.3 eq) in THF was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (22.7 g, 75% yield). The diastereomeric ratio of 7:7 is 7:1.

[0122] MS (ESI) m/z: 477 (M+H.sup.+).

[0123] .sup.1H NMR (400 MHz, Chloroform-d) 5.82 (s, 1H), 4.61 (t, 1H), 3.52 (t, 2H), 2.52 (dd, 0.1=14 Hz, J=2 Hz, 1H), 2.382.42 (m, 1H), 2.212.29 (m, 3H), 2.152.21 (m, 1H), 2.03 (s, 3H), 1.962.02 (m, 1H), 1.851.88 (m, 1H), 1.681.79 (m, 5H), 1.461.60 (m, 4H), 0.951.42 (m, 18H).

Example 13: Preparation of Compound Va

[0124] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIId (1.3 eq) in THE was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (11.0 g, 38% yield).

Example 14: Preparation of Compound Va

[0125] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIIe (1.3 eq) in THF was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (10.0 g, 33% yield).

Example 15: Preparation of Compound Va

[0126] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIIf (1.3 eq) in THF was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (8.0 g, 26% yield).

Example 16: Preparation of Compound Va

[0127] To THF (120 mL) was added compound VIa (20 g) and CuCl (1.42 g). Compound VIIg (1.3 eq) in THF was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Va (18.0 g, 60% yield).

Example 17: Preparation of Compound Vb

[0128] To THF (15 mL) was added compound VIb (2 g) and CuCl (263 mg). Compound VIIa (1.5 eq) in THF was added slowly at 30 C. and the reaction mixture was kept stirring at 30 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Vb (2.24 g, 78% yield). The diastereomeric ratio of 7:7 is 9:1.

[0129] MS (ESI) m/z: 539 (M+H.sup.).

Example 18: Preparation of Compound Vc

[0130] To THF (15 mL) was added compound VIc (2 g) and CuBr (280 mg). Compound VIIa (1.5 eq) in THF was added slowly at 0 C. and the reaction mixture was kept stirring at 0 C. for 1 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Vc (2.31 g, 70% yield). The diastereomeric ratio of 7:7 is 5:1.

[0131] MS (ESI) m/z: 479 (M+H.sup.+).

Example 19: Preparation of Compound Vd

[0132] To THF (15 mL) was added compound VId (2 g) and CuI (306 mg). Compound VIIa (1.2 eq) in THF was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Vd (2.35 g, 81% yield). The diastereomeric ratio of 7:7 is 8:1.

[0133] MS (ESI) m/z: 525 (M+H.sup.+).

Example 20: Preparation of Compound Ve

[0134] To 2-methyltetrahydrofuran (15 mL) was added compound VIe (2 g) and CuOTf (244 mg). Compound VIIb (1.3 eq) in THF was added slowly at 30 C. and the reaction mixture was kept stirring at 30 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Ve (2.28 g, 80% yield). The diastereomeric ratio of 7:7 is 9:1.

[0135] MS (ESI) m/z: 549 (M+H.sup.).

Example 21: Preparation of Compound Vf

[0136] To THF (15 mL) was added compound VIf (2 g) and CuCl (122 mg). Compound VIIb (1.3 eq) in THF was added slowly at 20 C. and the reaction mixture was kept stirring at 20 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Vf (2.25 g, 77% yield). The diastereomeric ratio of 7:7 is 9:1.

[0137] MS (ESI) m/z: 519 (M+H.sup.+).

Example 22: Preparation of Compound Vg

[0138] To THF (120 mL) was added compound VIg (20 g) and CuCl (1.42 g). Compound VIIa (2.5 eq) in THF was added slowly at 10 C. and the reaction mixture was kept stirring at 10 C. for 2 h. HPLC showed that the reaction was complete, the mixture was quenched with acetic acid, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, dried, and concentrated to give compound Vg (18.6 g, 58% yield). The diastereomeric ratio of 7:7 is 8:1.

Example 23: Preparation of Compound IIIa

[0139] To acetonitrile (15 mL) was added CuBr.sub.2 (5.62 g). LiBr (1.55 g) and acetic anhydride (1.23 g). The reaction mixture was kept stirring at 20 C. for 0.5 h, and compound Va (5 g) in acetonitrile (15 mL) was added dropwisely. The reaction mixture was then kept stirring at 20 C. for 3 h. HPLC showed that the reaction was complete. The reaction mixture was quenched through dropwise addition into thiourea solution in toluene and water, and was kept stirring for 0.5 h. Then sodium bicarbonate was added and the reaction mixture was kept stirring for 10 min, filtered through celite, washed with toluene, and the combined organic layer was washed with saturated sodium chloride, dried, and concentrated to give compound IIIa (4.87 g, 90% yield).

[0140] MS (ESI) m/z: 517 (M+H.sup.+).

[0141] .sup.1H NMR (400 MHz, Chloroform-d) 7.27 (d, J=9.6 Hz, 1H), 6.87 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 4.70 (t, J=8.4 Hz, 1H), 3.53 (t, J=6.8 Hz, 2H), 2.90 (t, J=16.8 Hz, J=5.2 Hz, 1H), 2.75 (d, J=16.8 Hz, 1H), 2.292.37 (m, 1H), 2.28 (s, 3H), 2.202.26 (m, 1H), 2.06 (s, 3H), 1.841.87 (m, 1H), 1.721.79 (m, 3H), 1.591.68 (m, 3H), 1.371.55 (m, 8H), 1.180.48 (m, 18H), 0.82 (s, 1H).

Example 24: Preparation of Compound IIIb

[0142] To acetonitrile (10 mL) was added CuBr.sub.2 (3.71 g), LiBr (1.02 g) and propionic anhydride (0.77 g). The reaction mixture was kept stirring at 20 C. for 0.5 h, and compound Va (3.3 g) in acetonitrile (10 mL) was added dropwisely. The reaction mixture was then kept stirring at 20 C. for 3 h, HPLC showed that the reaction was complete. The reaction mixture was quenched through dropwise addition into thiourea solution in toluene and water, and was kept stirring for 0.5 h. Then sodium bicarbonate was added and the reaction mixture was kept stirring for 10 min. filtered through celite, washed with toluene, and the combined organic layer was washed with saturated sodium chloride, dried, and concentrated to give compound IIIb (3.24 g, 88% yield).

[0143] MS (ESI) m/z: 531 (M+H.sup.+).

[0144] .sup.1H NMR (400 MHz, Chloroform-d) 7.28 (d, J=8.8 Hz, 1H), 6.84 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 4.67 (t, J=8.4 Hz, 1H), 3.52 (t, J=6.8 Hz, 2H), 2.90 (dd, J=16.8 Hz, J=5.2 Hz, 1H), 2.75 (d, J=16.8 Hz, 1H), 2.56 (q, J=15.2 Hz, 2H), 2.192 39 (m, 3H), 2.06 (s, 3H), 1.831.87 (m, 1H), 1.721.79 (m, 3H), 1.624.67 (m, 1H), 1.391.58 (m, 8H), 1.171.27 (m, 14H), 0.82 (s, 3H).

Example 25: Preparation of Compound II

[0145] To DMF (25 mL) was added compound IIIa (4.38 g) and compound IV (4.5 g). 40% Sodium hydroxide solution (8.4 g) was added at 20 C. and the reaction mixture was kept stirring at 20 C. for 2 h HPLC showed that the reaction was complete. The reaction mixture was quenched with acetic acid, diluted with water and extracted with MTBE. The combined organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried, and concentrated to give compound II (4.51 g, 90% yield).

[0146] MS (ESI) m/z: 591 (M+H.sup.+).

[0147] .sup.1H NMR (400 MHz, Chloroform-d) 7.15 (d, J=8.4 Hz, 1H), 6.63 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.67 (s, 1H), 3.75 (t, J=7.6 Hz, 1H), 2.86 (dd, J=16.8 Hz, J=5.2 Hz, 1H), 2.71 (d, J=16.8 Hz, 1H), 2.59 (t, J=6 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.282.34 (m, 2H), 2.112.23 (m, 3H), 1.841.92 (m, 3H), 1.721.75 (m, 1H), 1.531.65 (m, 4H), 1.171.50 (m, 24 J).

Example 26: Preparation of Compound II

[0148] To DMF (20 mL) was added compound IIIb (3 g) and compound IV (3.08 g) 40% Sodium hydroxide solution (5.25 g) was added at 20 C. and the reaction mixture was kept stirring at 20 C. for 2 h HPLC showed that the reaction was complete. The reaction mixture was quenched with acetic acid, diluted with water and extracted with MTBE. The combined organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried, and concentrated to give compound II (2.77 g, 83% yield).

[0149] MS (ESI) m/z: 591 (M+H.sup.).

[0150] .sup.1H NMR (400 MHz, Chloroform-d) 7.15 (d, J=8.4 Hz, 1H), 6.63 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.67 (s, 1H), 3.75 (t, J=7.6 Hz, 1H), 2.86 (dd, J=16.8 Hz, J=5.2 Hz, 1H), 2.71 (d, J=16.8 Hz, 1H), 2.59 (t, J=6 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.282.34 (m, 2H), 2.112.23 (m, 3H), 1.841.92 (m, 3H), 1.721.75 (m, 1H), 1.531.65 (m, 4H), 1.171.50 (m, 24H).

Example 27: Preparation of Compound I

[0151] To acetic acid (2.63 g) and 17.5% H.sub.2O.sub.2 (3.12 g) was added compound II (4.31 g) in ethyl acetate (15 mL). The reaction mixture was kept stirring at 20 C. for 10 h. HPLC showed that the reaction was complete. The reaction mixture was quenched with sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried, and concentrated to give compound I (3.52 g, 80% yield, 99.7% purity).

[0152] MS (ESI) m/z: 607 (M+H.sup.+).

[0153] .sup.1H NMR (400 MHz, Chloroform-d) 7.11 (d, J=8.4 Hz, H), 6.63 (d, J=8.4 Hz, 1H), 6.55 (s, 1H), 3.74 (t, J=8.5 Hz, 1H), 2.90-2.53 (m, 6H), 2.35-2.03 (m, 7H), 1.99-1.83 (m, 1H), 1.80-1.67 (m, 3H), 1.60 (qt, J=8.5, 3.3 Hz, 2H), 1.53-1.11 (m, 191), 1.08-0.95 (m, 1H), 0.77 (s, 3H).

[0154] Since this invention has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to those of ordinary skill in the art and are intended to be included within the scope of this invention.