CN1775799A

CN1775799A - C22 steroid compounds and their synthesizing method

Info

Publication number: CN1775799A
Application number: CN 200510111267
Authority: CN
Inventors: 田伟生; 朱伟明; 许启海; 王真
Original assignee: Shanghai Institute of Organic Chemistry of CAS; Yunnan Baiyao Group Co Ltd
Current assignee: Shanghai Institute of Organic Chemistry of CAS; Yunnan Baiyao Group Co Ltd
Priority date: 2005-12-08
Filing date: 2005-12-08
Publication date: 2006-05-24
Anticipated expiration: 2025-12-08
Also published as: CN100358913C

Abstract

The invention relates to a C22 steroid compound and the method to compound. It is easy to be compounded, and is suited for manufacturing. It uses 17-alpha-hydroxyl radical-steroid lactone, which is the important intermediate for compounding steroid compound containing 17-hydroxyl radical. And it also has certain biological activity.

Description

One class C22 steroidal compounds and synthetic method thereof

Technical field

This patent relates to a class C22 steroidal compounds and a synthetic method thereof.Utilize the existing technology of contriver, the natural steroid sapogenines of degrading is the steroidal lactone, utilizes method of the present invention further to transform again, can obtain a series of C22 steroidal compounds, comprising target compound 17-Alpha-hydroxy-steroidal lactone.

Background technology

Have the alpha-hydroxy steroidal compounds of 17-and all have unique biological activity and pharmaceutical use, as marine natural product Cephalostatine (Cephalostatine) (referring to J.Chem.Soc., Chem..Commun., 1988,865; Ibid, 1988,1440), natural product OSW-1 (OSW-1) is (referring to Bioorg.﹠amp; Med.Chem.Lett, 1997,7,633) and the inclined to one side promise saponin in Yunnan white powder and the Sichuan baiyao series product (referring to pharmaceutical analysis magazine, 1997,17,153; The pharmaceutical analysis magazine, 1991,11,90; China Medicine University's journal, 1989,20,251).Although the synthetic of these compounds had bibliographical information, seek succinct more reasonably synthetic route and remain the target that synthetic chemistry man is pursued.

17-Alpha-hydroxy-steroidal lactone can be used for the steroidal compounds of the synthetic above-mentioned 17-of containing hydroxyl, and 17-Alpha-hydroxy-steroidal lactone compound itself also has biological activity (CN 200510030831.4) preferably, therefore has good application prospects.People such as Tian Weisheng are devoted for years to the reasonable utilization research in the resource compound, the particularly reasonable utilization of steroid sapogenines, the degradation of steroid sapogenin that they have developed a kind of cleaning is the method (CN00127974.2) of steroidal lactone, has developed a kind of method that the steroidal lactone is 17-hydroxyl-steroidal lactone that transforms on this basis.

Summary of the invention

The purpose of this invention is to provide a class C22 steroidal compounds.

Another object of the present invention provides the synthetic method of a class C22 steroidal compounds.

17-Alpha-hydroxy-steroidal lactone involved in the present invention has following structural formula:

Y is H ₂Perhaps O; R ¹Be H, OH, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; R ²Be H, OH, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS, OTBDPS or X; R ³Be H, OH, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS, OTBDPS or X; Perhaps R ²And R ³Become carbonyl; R ⁴Be H, OH, OMe, OEt, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS, OTBDPS or X; R ⁵Be OH, OTMS or X; R ⁶Be OH, OMs, OTs or X; Perhaps R ⁵And R ⁶Become 16, the two keys of 17-; R ⁷Be H, OH or X; Perhaps R ⁵And R ⁷Become 16, the 17-epoxy; R ⁸For H, OH,, OMe, OEt, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS, OTBDPS or X; Perhaps R ⁶And R ⁸Become oxo bridge;

When Y is O, R ⁷Be H, R ⁶And R ⁸Become oxo bridge, R ³Be H, and R ⁴During for H, R ²Can not be H, OH, OMOM, OAc, OTBS, OTBDPS or X.

Wherein, MOM is a methoxyl methyl, and Bn is a benzyl; THP is a THP trtrahydropyranyl, and Ac is an ethanoyl, and Ms is a methylsulfonyl; Ts is a p-toluenesulfonyl; Bz is a benzoyl, and Piv is a pivaloyl group, and TMS is trimethyl silicon based; TES is that triethyl is silica-based; TBS is that tertiary butyl dimethyl is silica-based, and TBDPS is that tert-butyl diphenyl is silica-based, and X is a halogen.

The synthetic method of C22 steroidal compounds of the present invention is as follows:

Each group described as defined above, Ac is an ethanoyl.Wherein, in the compound 7, work as R ²Be H and R ³During for H,

Can not for Or

1): compound 1 is dissolved in the aprotic solvent, adds reductive agent (0.5 equivalent-3 equivalent) ,-78 ℃ were reacted 0.5 hour to 24 hours to the temperature that refluxes, get compound 2; Described reductive agent can be sodium borohydride (NaBH ₄), sodium cyanoborohydride (NaBH ₃CN), POTASSIUM BOROHYDRIDE (KBH ₄), lithium borohydride (LiBH ₄), Li-Al hydrogen (LiAlH ₄) or diisobutyl aluminium hydride (DIBALH).

2): compound 2 is dissolved in the organic solvent, adds diacetyl oxide or Acetyl Chloride 98Min. (0.5 equivalent-6 equivalent) ,-78 ℃ were reacted 0.5 hour to 24 hours to reflux temperature; Add SULPHURYL CHLORIDE (1 equivalent-6 equivalent) then, heat to make in 0.5 hour to 24 hours and react completely, compound 3; Described organic solvent is non-protonic solvent, nitrogenous organic base or their mixed solvent; Described nitrogenous organic base is 1,8-diazabicylo [5,4,0] 11-7-alkene (DBU), pyridine, 4-Dimethylamino pyridine (DMAP), bipyridine, lutidine (lutidine), trimethylpyridine (collidine) or have primary amine, secondary amine or the tertiary amine of C1-18 alkyl; Described sulfonic acid acyl chlorides can be methylsulfonyl chloride, Tosyl chloride or trifluoromethanesulfchloride chloride.

3): compound 3 is dissolved in the polar solvent, and adding removes protecting group reagent (1 equivalent-6 equivalent), and-78 ℃ were reacted 0.5 hour to 24 hours to reflux temperature, get compound 4; Removing protecting group reagent can be to comprise the monovalence of sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, lime carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or oxyhydroxide, carbonate or the supercarbonate of divalent metal.

4): compound 4 is dissolved in the organic solvent, adds oxygenant (1 equivalent-9 equivalent) ,-78 ℃ were reacted 0.5 hour to 72 hours to reflux temperature, get compound 5; Wherein, recommending organic solvent can be dimethyl formamide (DMF), hexamethylphosphoramide (HMPT), the trimethyl carbinol or methylene dichloride; Oxygenant can be Manganse Dioxide, potassium manganate, potassium permanganate, chromic anhydride, Sodium chromate, chromic acid pyridinium salt, clorox, Textone or potassium chlorite.

5): compound 5 is dissolved in the non-protonic solvent, adds epoxidation reagent (1 equivalent-6 equivalent) ,-78 ℃ were reacted 0.5 hour to 6 hours to reflux temperature, get compound 6; Epoxidation reagent can be Peracetic Acid, metachloroperbenzoic acid (MCPBA), hydrogen peroxide, peroxy trifluoroacetic acid or peroxy propanone (DMDO).

6): compound 6 is dissolved in the organic solvent, adds appropriate bases (1 equivalent-9 equivalent) and hydrogen peroxide (0.5 equivalent-10 equivalent), reaction is 0.5 hour to 24 hours under 0 ℃ of-90 ℃ of temperature, gets compound 7; Recommending organic solvent can be alcoholic solvent, acetone or tetrahydrofuran (THF); Alkali can be oxyhydroxide, carbonate, supercarbonate, acetate or nitrogenous organic base.

Non-protonic solvent described in the above-mentioned reaction is CH ₂Cl ₂, CHCl ₃, CCl ₄, tetrahydrofuran (THF) (THF) or ether; Described polar solvent is acetone, acetonitrile, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, trichloromethane, methylene dichloride or water.

In order to understand content of the present invention better, be example with the compound of following structure:

The method of above-mentioned synthetic 17-Alpha-hydroxy steroidal lactone is comparatively easy, is fit to industrial production, and the guarantee of amount is provided for the widespread use (the synthetic application and active the application) of 17-Alpha-hydroxy steroidal lactone.

Embodiment

To help to understand the present invention by following embodiment, but not limit content of the present invention.EA represents ultimate analysis among the embodiment, and Calcd represents calculated value, and Fould represents measured value.

Starting compound 1a that the present invention uses and 1b are by the method synthetic (CN 00127974.2) of document.

Embodiment 1 compound 2a's is synthetic

In the 500mL exsiccant there-necked flask, add 2.17g LiAlH ₄(0.057mol), 60mL anhydrous tetrahydro furan.Other gets 17.8 steroidal lactone 1a (0.05mol), and it is dissolved in the 100mL anhydrous tetrahydro furan, is added drop-wise under the nitrogen protection in the above-mentioned solution, and stirring at room 6h, TLC follow the tracks of reaction to complete (1: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and carefully and lentamente drips 2mL water, the 2mL 2M NaOH aqueous solution and 2mL water according to the order of sequence, adds anhydrous magnesium sulfate, and placement is spent the night.Filtration under diminished pressure, and with ethyl acetate washing leaching cake 3 times, decompression and solvent recovery, solid crude product 19g.Rapid column chromatography separates (2: 1 n-C ₆H ₁₄-AcOEt wash-out), get powdery 16 β, 22-glycol 2a 17.0g (95.0% productive rate).

Compound 2a:

IR?ν _max ^KBr(cm ^-1)：3363(OH)，1099，1037.

¹H-NMR(300MHz，CDCl ₃)δ：4.40(ddd，1H，J＝4.5，7.5，7.8Hz，H-16α)，3.59(d，2H，J＝5.7Hz，H-22)，3.32(s，3H，MeO)，2.78(dd，‘t’like，1H，J＝2.7Hz，H-6α)，1.03(s，3H，H-19)，0.97(d，3H，J＝5.7Hz，H-21)，0.95(s，3H，H-18)，0.66(dd，1H，J＝4.1，7.8Hz，H-4β)，0.44(dd，1H，J＝4.8，7.8Hz，H-4α).

¹³C-NMR(75MHz，CDCl ₃)δ：33.2(t，C-1)，24.9(t，C-2)，21.6(d，C-3)，13.4(t，C-4)，35.3(s，C-5)，82.3(d，C-6)，34.8(t，C-7)，30.0(d，C-8)，47.9(d，C-9)，43.3(s，C-10)，22.4(t，C-11)，40.5(t，C-12)，43.0(s，C-13)，54.2(d，C-14)，32.5(t，C-15)，72.6(d，C-16)，62.2(d，C-17)，13.0(q，C-18)，19.2(q，C-19)，35.6(d，C-20)，16.9(q，C-21)，70.6(t，C-22)，56.5(q，MeO-).

EIMS(70eV)m/z(％)：362(M ⁺，9)，348(55)，330(29)，307(86)，290(52)，253(44)，213(41)，159(42)，145(59)，131(60)，121(49)，105(78)，91(90)，79(72)，43(100).

Anal.calcd.for?C ₂₃H ₃₈O ₃(％)：C，76.20；H，10.56.Found：C，76.13；H，10.57.

Embodiment 2 compound 2aa's is synthetic

In the 250mL exsiccant there-necked flask, put into the stirring magneton, 2.53g compound 2a (7mmol) adds the 50mL anhydrous methylene chloride, and stirring makes molten.Add 4mL anhydrous pyridine (0.049mole) and 570uL AcCl (8mmol), stir 3～5h in the nitrogen atmosphere, TLC follows the tracks of reaction to complete (2: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and adds the 50mL frozen water, tells organic layer; Water layer with the 50mL dichloromethane extraction once merges organic layer.Use saturated CuSO successively ₄The aqueous solution, water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery gets oily matter 2.9g, is foaming shape solid during the oil pump drying under reduced pressure.Rapid column chromatography separates (6: 1 n-C ₆H ₁₄-AcOEt wash-out), get the monoacylated product 2aa of oily 2.36g (83% productive rate) and diacetyl product 2ab 0.3g (9.8% productive rate).

Compound 2aa:

IR?ν _max ^KBr(cm ^-1)：3500(OH)，1727(C＝O)，1247，1091，1033，917，734.

EIMS(70eV)m/z(％)：404(M ⁺，16)，356(100)，350(63)，296(78)，253(43)，43(32).

¹H-NMR(300MHz，CDCl ₃)δ：4.35(dd，H，J＝3.0，10.8Hz，H-22b)，4.34(dd，1H，J＝3.3，7.6Hz，H-16α)，3.67(dd，H，J＝7.8，10.8Hz，H-22a)，3.31(s，3H，MeO)，2.77(dd，‘t’like，1H，J＝2.6Hz，H-6α)，2.07(s，3H，Ac-)，1.08(d，3H，J＝6.9Hz，H-21)，1.02(s，3H，H-19)，0.95(s，3H，H-18)，0.64(dd，‘t’like，1H，J＝3.9，5.1Hz，H-4β)，0.42(dd，1H，J＝4.9，7.9Hz，H-4α).

Compound 2ab:

¹H-NMR(300MHz，CDCl ₃)δ：5.10(ddd，1H，J＝4.0，7.5，7.5Hz，H-16α)，4.08(dd，1H，J＝3.1，10.6Hz，H-22b)，3.68(dd，1H，J＝7.0，10.6Hz，H-22a)，3.30(s，3H，MeO)，2.76(dd，‘t’like，1H，J＝2.6Hz，H-6α)，2.25(dq，3.6，6.6Hz，H-20)，2.04(s，3H，Ac-1)，2.03(s，3H，Ac-2)，1.05(d，3H，J＝6.6Hz，H-21)，1.02(s，3H，H-19)，0.94(s，3H，H-18)，0.64(dd，‘t’like，1H，J＝4.6Hz，H-4β)，0.43(dd，1H，J＝5.0，8.0Hz，H-4α).

¹³C-NMR(75MHz，CDCl ₃)δ：33.1(t，C-1)，24.8(t，C-2)，21.4(d，C-3)，12.9(t，C-4)，35.2(s，C-5)，82.0(d，C-6)，34.6(t，C-7)，30.1(d，C-8)，47.7(d，C-9)，43.3(s，C-10)，22.2(t，C-11)，39.8(t，C-12)，42.9(s，C-13)，54.0(d，C-14)，29.9(t，C-15)，74.8(d，C-16)，55.9(d，C-17)，12.8(q，C-18)，19.2(q，C-19)，35.1(d，C-20)，16.4(q，C-21)，68.7(t，C-22)，56.5(q，MeO-)，171.0(s)，170.6(s)，21.2(q)and?20.8(q)(two?acetyls).

Embodiment 3 compound 2ac's is synthetic

In 250mL exsiccant there-necked flask, add 2.02g compound 2aa (5mmol), 50mL anhydrous methylene chloride, stirring makes molten.Add 3mL anhydrous pyridine (37mmol) and 770uL MsCl (10mmol), stir 18h in the nitrogen atmosphere, TLC follows the tracks of reaction to complete (3: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and is poured in the 50mL frozen water, tells organic layer; Water layer again with the 50mL dichloromethane extraction once merges organic layer.Use saturated CuSO successively ₄The aqueous solution, water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery gets oily matter 4.2g.Rapid column chromatography separates (4: 1 n-C ₆H ₁₄-AcOEt wash-out), get oily sulfonylation product 2ac 1.63g (68% productive rate) and 16 alpha-chloro product 2ad 0.65g (31% productive rate).Compound 2ac:

¹H-NMR(300MHz，CDCl ₃)δ：5.17(ddd，1H，J＝4.2，7.5，7.8Hz，H-16α)，4.25(dd，H，J＝2.7，10.8Hz，H-22b)，3.90(dd，H，J＝7.3，10.8Hz，H-22a)，3.33(s，3H，MeO)，3.04(s，3H，Ms)，2.78(dd，‘t’like，1H，J＝2.7Hz，H-6α)，2.07(s，3H，Ac-)，1.07(d，3H，J＝6.9Hz，H-21)，1.03(s，3H，H-19)，0.95(s，3H，H-18)，0.66(dd，‘t’like，1H，J＝4.2Hz，H-4β)，0.45(dd，1H，J＝4.8，7.8Hz，H-4α).

Compound 2ad:

IR?ν _max ^KBr(cm ^-1)：1742(C＝O)，1243，1089，1037.

¹H-NMR(300MHz，CDCl ₃)δ：4.31(dd，1H，J＝4.2，11.2Hz，H-22b)，4.11(ddd，1H，J＝1.8，6.0，6.0Hz，H-16β)，3.96(dd，1H，J＝7.2，11.2，H-22a)，3.33(s，3H，MeO)，2.79(dd，‘t’like，1H，J＝3.0Hz，H-6α)，1.05(d，3H，J＝6.6Hz，H-21)，1.02(s，3H，H-19)，0.77(s，3H，H-18)，0.67(dd，‘t’like，1H，J＝4.5Hz，H-4β)，0.46(dd，1H，J＝5.2，8.0Hz，H-4α).

¹³C-NMR(75MHz，CDCl ₃)δ：33.2(t，C-1)，24.9(t，C-2)，21.2(d，C-3)，13.1(t，C-4)，35.2(s，C-5)，82.0(d，C-6)，34.9(t，C-7)，29.6(d，C-8)，47.7(d，C-9)，43.3(s，C-10)，22.4(t，C-11)，34.1(t，C-12)，45.1(s，C-13)，52.9(d，C-14)，38.2(t，C-15)，64.9(d，C-16)，62.5(s，C-17)，13.3(q，C-18)，19.2(q，C-19)，39.9(d，C-20)，17.4(q，C-21)，68.9(t，C-22)，56.6(q，6-MeO)，171.2(s)and?21.0(q)(22-Ac).

EIMS(70eV)m/z(％)：424(M ⁺+2，5)，422(M ⁺，15)，409(12)，407(36)，392(11)，390(36)，367(21)，367(63)，329(7)，289(11)，271(7)，159(12)，145(13)，133(16)，119(14)，105(28)，91(31)，79(27)，67(17)，55(21)，43(100).

HRMS(EI)calcd.for?C ₂₅H ₃₉O ₃Cl?422.2588，Found?422.2570.

Embodiment 4 compound 3a's is synthetic

(1) synthetic by 2ac

In 100mL exsiccant there-necked flask, add 2.5g compound 2ac (5.2mmol), 10mL anhydrous pyridine, stirring makes molten.Add 1.28g DMAP (10.4mmol), in 90-100 ℃ of stirring reaction 12h, TLC follows the tracks of (2: 1 n-C that react completely in the nitrogen atmosphere ₆H ₁₄-AcOEt launches), add 200mL CH ₂Cl ₂, wash with water once, again with saturated CuSO ₄The aqueous solution, water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery gets oily matter 1.68g.Rapid column chromatography separates (19: 1 n-C ₆H ₁₄-AcOEt wash-out), get oily 3a 1.20g (60% productive rate, 34%from 2a in three steps).

(2) synthetic by 2ad

In 100mL exsiccant there-necked flask, add 2ad 1.22g (2.89mmol), 10mL dry DMF, stirring makes molten.Add 0.61g LiBr (5.81mmol) and 0.64g Li ₂CO ₃(8.65mmol), slowly heat up in the nitrogen atmosphere, prior to 70-90 ℃ of stirring reaction 3h, again in about 110 ℃ react completely (TLC tracking, 2: 1n-C ₆H ₁₄-AcOEt launches), add 80mL CH ₂Cl ₂, water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery, the crude product rapid column chromatography separates (19: 1 n-C ₆H ₁₄-AcOEt wash-out), get oily 3a 0.83g (75.0% productive rate).

Compound 3a:

¹H-NMR(300MHz，CDCl ₃)δ：5.38(dd，‘t’like，1H，J＝1.5Hz，H-16)，4.10(dd，H，J＝5.8，10.8Hz，H-22b)，3.92(dd，H，J＝8.4，10.8Hz，H-22a)，3.33(s，3H，MeO)，2.78(dd，‘t’like，1H，J＝2.6Hz，H-6α)，2.03(s，3H，Ac-)，1.04(d，3H，J＝6.6Hz，H-21)，1.03(s，3H，H-19)，0.80(s，3H，H-18)，0.67(dd，‘t’like，1H，J＝4.4Hz，H-4β)，0.44(dd，1H，J＝5.0，8.1Hz，H-4α).

¹³C-NMR(75MHz，CDCl ₃)δ：33.1(t，C-1)，24.9(t，C-2)，21.4(d，C-3)，13.0(t，C-4)，35.3(s，C-5)，82.3(d，C-6)，35.0(t，C-7)，29.6(d，C-8)，48.6(d，C-9)，43.5(s，C-10)，22.3(t，C-11)，31.2(t，C-12)，47.3(s，C-13)，57.1(d，C-14)，29.0(t，C-15)，122.5(d，C-16)，157.0(s，C-17)，16.5(q，C-18)，19.2(q，C-19)，31.4(d，C-20)，18.7(q，C-21)，68.6(t，C-22)，56.6(q，6-MeO)，171.2(s)and?21.0(q)(22-Ac).

EIMS(70eV)m/z(％)：371(M ⁺-15，4)，327(14)，312(21)，295(48)，280(100)，254(61)，174(52)，159(42)，145(65)，131(51)，105(64)，91(63)，43(79).

Embodiment 5 compound 4a's is synthetic

In 100mL egg shape flask, add compound 3a 2.32g (6mmol), methyl alcohol 60mL, 0.68g KOH (12mmol) and water 5mL, the stirring and refluxing reaction, TLC follows the tracks of reaction (3: 1 n-C extremely fully ₆H ₁₄-AcOEt launches).Reaction finishes, and the most of methyl alcohol of pressure reducing and steaming adds entry 50mL, uses the 100mL ethyl acetate extraction.Organic layer respectively washs 2 times with water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and decompression and solvent recovery gets oily matter 2.6g.Rapid column chromatography separates (4: 1 n-C ₆H ₁₄-AcOEt wash-out), get hydrolysate 4a 2.02g (97% productive rate).

Compound 4a:

¹H-NMR(300MHz，CDCl ₃)δ：5.41(dd，‘t’like，1H，J＝1.6Hz，H-16)，3.58(dd，‘t’like，2H，J＝7.2，10.2Hz，H-22)，3.35(s，3H，MeO)，2.79(dd，‘t’like，1H，J＝2.6Hz，H-6α)，2.39(q，3H，J＝6.6Hz)，1.04(s，3H，H-19)，1.02(d，3H，J＝6.6Hz，H-21)，0.85(s，3H，H-18)，0.68(dd，‘t’like，1H，J＝4.6Hz，H-4β)，0.45(dd，1H，J＝5.0，8.0Hz，H-4α).

Embodiment 6 compound 5a's is synthetic

In 50mL exsiccant there-necked flask, add 950mg compound 4a (2.76mmol), 7mL dry DMF, stirring makes molten.Add PDC reagent: (Py.H) ⁺ ₂Cr ₂O ₇ ^2-(3.64g, 8.28mmol), stirring at room 4h, TLC follows the tracks of (5: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, contain the solid of chromium with the diatomite elimination, and use washed with dichloromethane, decompression and solvent recovery, gained oily matter separates (7: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), the mixture 475mg (50.3%total productive rate) of oily 5a 400mg (40.4% productive rate) and three kinds of aldehyde 5aa, 5ab, 5ac.

In the 100mL there-necked flask, add mixture (7.6mmol), the 40mL trimethyl carbinol, 24mL water, the 4.0g KH of 2.6g aldehyde ₂PO ₄(28.9mmol), 1.50g Resorcinol (13.6mmol) and NaClO ₂(80%purity) (2.7g, 11.4mmol), stirring at room 0.5～1h, TLC follows the tracks of (3: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished,, respectively wash 2 times through water and saturated sodium-chloride water solution with twice washing of 60mL dichloromethane extraction, anhydrous sodium sulfate drying, decompression and solvent recovery gets oily solid (180mg) and separates (7: 2n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get oily 5a 1.56g (57.3% productive rate).

Compound 5a:

¹H-NMR(300MHz，CDCl ₃)δ：5.62(dd，‘t’like，1H，J＝1.5Hz，H-16)，3.36(s，3H，MeO)，3.15(q，1H，J＝6.9Hz，H-20)，2.81(dd，‘t’like，1H，J＝2.6Hz，H-6α)，1.28(d，3H，J＝6.9Hz，H-21)，1.05(s，3H，H-19)，0.87(s，3H，H-18)，0.68(dd，‘t’like，1H，J＝4.5Hz，H-4β)，0.46(dd，1H，J＝5.2，8.2Hz，H-4α).

EIMS(70eV)m/z(％)：358(M ⁺，23)，343(88)，326(24)，311(83)，303(95)，285(39)，253(69)，159(31)，145(32)，131(40)，119(49)，105(82)，91(100)，79(65)，67(37)，55(46)，43(52).

Compound 5aa:

¹H-NMR(300MHz，CDCl ₃)δ：9.45(d，1H，J＝2.4Hz，H-22)，5.46(dd，‘t’like，1H，J＝1.5Hz，H-16)，3.35(s，3H，MeO)，3.03(q，1H，J＝6.9Hz，H-20)，2.80(dd，‘t’like，1H，J＝2.7Hz，H-6α)，1.19(d，3H，J＝6.9Hz，H-21)，1.05(s，3H，H-19)，0.84(s，3H，H-18)，0.67(dd，‘t’like，1H，J＝4.3Hz，H-4β)，0.45(dd，1H，J＝5.2，8.2Hz，H-4α).

EIMS(70eV)m/z(％)：342(M ⁺，6)，327(19)，310(7)，295(17)，287(22)，253(30)，159(20)，145(23)，131(26)，105(69)，91(100)，79(74)，67(45)，55(60)，41(76).

Compound 5ab:

IR?ν _max ^KBr(cm ^-1)：2870(CHO)，2250O，1728(C＝O)，1642(C＝C)，913，733.

¹H-NMR(300MHz，CDCl ₃)δ：10.45(s，1H，H-22)，3.36(s，3H，MeO)，2.84(dd，‘t’like，1H，J＝3.0Hz，H-6α)，1.95(s，3H，H-21)，1.16(s，3H，H-18)，1.07(s，3H，H-19)，0.70(dd，‘t’like，1H，J＝5.0Hz，H-4β)，0.50(dd，1H，J＝5.0，8.1Hz，H-4α).

EIMS(70eV)m/z(％)：342(M ⁺，4)，341(14)，329(8)，317(10)，301(12)，281(14)，253(11)，214(15)，199(15)，159(12)，145(10)，121(14)，105(24)，91(38)，84(92)，71(37)，57(56)，49(100).

Compound 5ac:

IR?ν _max ^KBr(cm ^-1)：2870(CHO)，2254，1717(C＝O)，1678(C＝C)，913，733.

¹H-NMR(300MHz，CDCl ₃)δ：10.37(s，1H，H-22)，3.36(s，3H，MeO)，2.84(dd，‘t’like，1H，J＝2.7Hz，H-6α)，2.12(s，3H，H-21)，1.28(s，3H，H-18)，1.07(s，3H，H-19)，0.71(dd，‘t’like，1H，J＝5.1Hz，H-4β)，0.50(dd，1H，J＝5.1，8.1Hz，H-4α).

EIMS(70eV)m/z(％)：342(M ⁺，24)，341(99)，324(29)，301(100)，281(15)，273(26)，214(13)，199(16)，159(20)，145(21)，123(35)，105(46)，91(66)，79(49)，55(30).

Embodiment 7 compound 6a's is synthetic

In 50mL egg shape flask, add 1.0g 5a (2.71mmol), 30mL CH ₂Cl ₂, stirring makes molten.The frozen water cooling adds 802mg m-CPBA (70%purity) (3.25mmol) down, stirs 3～4h (rising to room temperature naturally), and TLC follows the tracks of (2: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, direct column chromatography for separation (3: 1n-C ₆H ₁₄-AcOEt wash-out), get oily 6a 653mg (64.4% productive rate).

Compound 6a:

¹H-NMR(300MHz，CDCl ₃)δ：4.13(dd，1H，J＝6.9，14.2Hz，H-16β)，3.35(s，3H，MeO)，3.16(q，1H，J＝6.9Hz，H-20)，2.81(dd，‘t’like，1H，J＝2.5Hz，H-6α)，1.25(d，3H，J＝6.9Hz，H-21)，1.04(s，3H，H-19)，0.94(s，3H，H-18)，0.68(dd，‘t’like，1H，J＝4.3Hz，H-4β)，0.46(dd，1H，J＝5.0，8.0Hz，H-4α).

EIMS(70eV)m/z(％)：374(M ⁺，5)，359(11)，342(21)，324(12)，319(23)，301(10)，269(11)，145(19)，131(22)，119(24)，105(51)，91(73)，79(60)，67(47)，55(96)，41(100).

Embodiment 8 compound 7a's is synthetic

In the 50mL there-necked flask, add 628mg epoxyeicosatrienoic acid 6a (1.68mmol), 15mL dehydrated alcohol, stirring makes molten.Add 710mg LiOHH ₂O (16.8mmol) drips 30% hydrogen peroxide 5mL, and (H was added in the centre to reaction～24h under stirring also was warming up to 80 ℃ gradually ₂O ₂2mL), TLC follows the tracks of (2: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, use saturated NaHSO ₃Remove excessive hydrogen peroxide, add saturated NH ₄The Cl aqueous solution is neutralized to acidity, tells organic phase, and with 100mL ethyl acetate extraction water once.Organic phase water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery, gained oily crude product separates (4: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get oily 17 alpha-hydroxy-2 2-carboxylic acid lactone 7a 500mg (79.6% productive rate).

Compound 7a:

IR?ν _max ^KBr(cm ^-1)：3474(OH)，1755(C＝O)，1213，1096，1048，757.

¹H-NMR(300MHz，CDCl ₃)δ：4.49(dd，1H，J＝4.8，8.1，H-16α)，3.34(s，3H，MeO)，2.79(dd，‘t’like，1H，J＝2.8Hz，H-6α)，2.74(q，1H，J＝8.1Hz，H-20)，1.30(d，3H，J＝8.1Hz，H-21)，1.05(s，3H，H-19)，0.86(s，3H，H-18)，0.68(dd，‘t’like，1H，J＝4.2Hz，H-4β)，0.47(dd，1H，J＝5.5，8.5Hz，H-4α).

EIMS(70eV)m/z(％)：374(M ⁺，5)，359(11)，342(21)，324(12)，319(23)，301(10)，269(11)，159(16)，131(22)，105(51)，91(73)，79(60)，67(47)，55(96)，41(100).

HRMS(EI)：calcd.for?C ₂₃H ₃₄O ₄374.2457，Found?374.2437.

Embodiment 9 compound 2b's is synthetic

In 250mL exsiccant there-necked flask, add 420mg LiAlH ₄(11.0mmol), the 30mL anhydrous tetrahydro furan, stir.In addition 5.0g lactone 1b (8.6mmol) is dissolved in the 50mL anhydrous tetrahydro furan, is added drop-wise in the nitrogen atmosphere in the above-mentioned suspension, stirring at room 6h, TLC follow the tracks of reaction to complete (1: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and carefully and lentamente drips 1mL water, the 1mL 2M NaOH aqueous solution and 1mL water according to the order of sequence, adds anhydrous magnesium sulfate until generating white solid, and placement is spent the night.Filtration under diminished pressure, and with ethyl acetate washing leaching cake 3 times, decompression and solvent recovery, solid crude product 6g.Rapid column chromatography separates (2: 1 n-C ₆H ₁₄-AcOEt wash-out), get powdery 2b 4.8g (95% productive rate).

Compound 2b:

IR?ν _max ^KBr(cm ^-1)：3280(OH)，1590，1472，1464(phenyl)，1111，1089，865，821，701，507.

¹H-NMR(300MHz，CDCl ₃)δ：7.68(m，4H)and?7.39(m，6H)(phenyls?of?TBDPS)，5.12(d，1H，J＝5.4Hz，H-6)，4.38(m，1H，H-16α)，3.60(m，2H，H-22)，3.51(m，1H，J＝4.5，7.5，10.5Hz，H-3)，2.79(m，1H，H-20)，1.06(s，9H，tert-butyl)，0.99(s，3H，H-19)，0.96(d，3H，J＝6.6Hz，H-21)，0.90(s，3H，H-18).

EIMS(70eV)m/z(％)：585(M ⁺-1，0.2)，529(M ⁺-57，100)，511(15)，451(6)，433(3)，295(5)，253(7)，199(96)，183(7)，159(8)，135(8)，105(7)，91(5).

Embodiment 10 compound 3b's is synthetic

In 100mL exsiccant there-necked flask, add 3.0g glycol 2b (5.1mmol), 40mL anhydrous pyridine, stirring makes molten.Add Ac ₂O 0.6mL (6.7mmol), in 35～40 ℃ of stirring reaction 48h, TLC follows the tracks of reaction to complete (2: 1 n-C in the nitrogen atmosphere ₆H ₁₄-AcOEt launches).Reaction finishes, and adds MsCl 0.8mL (10.2mmol) and 60mg DMAP (0.5mmol).Heat up 80～85 ℃ gradually, continue stirring reaction 15h, solution colour is deepened.Reaction finishes, be chilled to room temperature after, add 120mL AcOEt, successively water, saturated CuSO ₄, water and saturated NaCl solution washed twice separately, through anhydrous Na ₂SO ₄After the drying, decompression and solvent recovery gets solid crude product 3.8g.Dry back rapid column chromatography separates (40: 1 n-C ₆H ₁₄-AcOEt wash-out), get powdery and eliminate product 3b 386mg (12.4% productive rate), 16 alpha-chloros-22-acetic ester 2bb 1.11g (33.8% productive rate) and 16 β-22-diacetyl product 2ba 1.46g (42.9% productive rate).

In 100mL exsiccant egg shape flask, add 16 alpha-chloro product 2bb 324mg (0.5mmol), 111mg Li in the nitrogen atmosphere ₂CO ₃H ₂O (1.5mmol), 105mg LiBr (1.0mmol), heavily steam DMF 5mL, open and stir.Be warming up to 130～140 ℃, TLC follows the tracks of reaction to complete (9: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and adds AcOEt 60mL dilute reaction solution, and respectively washs 2 times with water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and decompression and solvent recovery gets meal 0.31g.Rapid column chromatography separates (14: 1n-C ₆H ₁₄-AcOEt wash-out), get powdery 3b 290mg (95% productive rate).

Compound 3b:

IR?ν _max ^KBr(cm ^-1)：3034，1589，1475，1461(phenyl)，1236，1112，1025，801，704，613，510.

¹H-NMR(300MHz，CDCl ₃)δ：7.68(d，4H，J＝6.0Hz)and?7.38(d，6H，J＝7.2Hz)(phenyls?of?TBDPS)，5.39(br.s，1H，H-16α)，5.14(d，1H，J＝3.6Hz，H-6)，4.11(dd，1H，J＝6.0，10.5Hz，H-22a)，3.93(dd，‘t’like，1H，J＝10.5Hz，H-22b)，3.53(m，1H，H-3)，2.04(s，3H，acetyl)，1.06(s，9H，tert-butyl)，1.02(s，3H，H-19)，1.04(d，3H，J＝7.8Hz，H-21)，0.76(s，3H，H-18).

EIMS(70eV)m/z(％)：595(M ⁺-15，1)，553(M ⁺-57，39)，493(7)，311?94)，295(10)，253(4)，239(11)，199(100)，181(16)，159(8)，135(14)，109(15)，91(11).

Compound 2ba:

IR?ν _max ^KBr(cm ^-1)：3072，1590，1473(phenyl)，1246，1111，1086，1027，742，703，612，509.

¹H-NMR(300MHz，CDCl ₃)δ：7.67(m，4H)and?7.38(m，6H)(phenyls?of?TPS)，5.09(d，1H，J＝4.2Hz，H-6)，5.07(ddd，1H，J＝4.3，7.9?7.9Hz，H-16α)，4.07(dd，1H，J＝3.5，10.9Hz，H-22a)，3.65(dd，1H，J＝6.9，10.9Hz，H-22b)，3.50(m，1H，J＝4.5，7.5，10.5Hz，H-3)，2.03(s，6H，two?acetyls)，1.05(s，9H，tert-butyl)，0.98(s，3H，H-19)，1.03(d，3H，J＝6.6Hz，H-21)，0.86(s，3H，H-18).

EIMS(70eV)m/z(％)：613(M ⁺-57，56)，553(2)，535(3)，493(5)，295(15)，253(14)，199(100)，181(21)，159(10)，135(13)，121(13)，105(12)，93(10).

Compound 2bb:

¹H-NMR(300MHz，CDCl ₃)δ：7.68(m，4H)and?7.38(m，6H)(phenyls?of?TPS)，5.11(d，1H，J＝5.4Hz，H-6)，4.07(ddd，1H，J＝2.5，6.6，6.9Hz，H-16β)，4.30(dd，1H，J＝3.7，11.2Hz，H-22a)，3.94(dd，1H，J＝6.7，11.2Hz，H-22b)，3.54(m，1H，J＝4.6，10.6Hz，H-3)，2.05(s，3H，acetyls)，1.06(s，9H，tert-butyl)，0.97(s，3H，H-19)，1.03(d，3H，J＝6.9Hz，H-21)，0.69(s，3H，H-18).

EIMS(70eV)m/z(％)：592(M ⁺-36，21)，590(M ⁺-38，48)，554(13)，511(6)，494(9)，296(15)，253(14)，199(100)，181(16)，159(9)，135(9)，121(8)，105(9)，93(7).

Embodiment 11 compound 2bc's is synthetic

In 50mL exsiccant there-necked flask, add 0.59g glycol 2b (1.0mmol), 10mL anhydrous methylene chloride, stirring makes molten.Add 565 μ L anhydrous pyridines (7mmole) and 80 μ L AcCl (1.1mmol), stir 3～5h in the nitrogen atmosphere, TLC follows the tracks of reaction to complete (9: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and adds the 10mL frozen water, tells organic layer; Water layer with the 20mL dichloromethane extraction once merges organic layer.Use saturated CuSO successively ₄The aqueous solution, water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery, gained oily matter crude product separates (19: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get the monoacylated product 2bc of powdery 0.56g (88.9% productive rate).

Compound 2bc:

¹H-NMR(300MHz，CDCl ₃)δ：7.68(m，4H)and?7.38(m，6H)(phenyls?of?TPS)，5.12(d，1H，J＝4.8Hz，H-6)，5.07(dd，2H，J＝3.0，10.6Hz，H-16αand?H-22a)，3.62(dd，1H，J＝7.6，10.9Hz，H-22b)，3.52(m，1H，J＝4.5，7.5，10.5Hz，H-3)，2.08(s，3H，acetyls)，1.05(s，9H，tert-butyl)，0.99(s，3H，H-19)，1.07(d，3H，J＝6.9Hz，H-21)，0.89(s，3H，H-18).

Embodiment 12 compound 2bc's is synthetic

In 100mL egg shape flask, add monoacetate 2bc 76mg (0.12mmol), CH ₂Cl ₂5mL, stirring makes molten.Add anhydrous pyridine 0.61mL (0.78mmol), MsCl 20uL (0.26mmol) and DMAP 15mg (0.13mmol), the stirring at room reaction, TLC follows the tracks of reaction (3: 1 n-C extremely fully ₆H ₁₄-AcOEt launches).Reaction finishes, and adds entry 2mL, uses 20mL CH ₂Cl ₂Extraction.Organic layer respectively washs 2 times with water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and decompression and solvent recovery, rapid column chromatography separates (4: 1 n-C ₆H ₁₄-AcOEt wash-out), get oily sulfonylation product 2bd 61mg (71.4% productive rate).

Compound 2bd:

¹H-NMR(300MHz，CDCl ₃)δ：7.65(m，4H)and?7.35(m，6H)(phenyls?of?TPS)，5.06(d，1H，J＝4.2Hz，H-6)，5.14(ddd，1H，J＝4.2，7.8?7.8Hz，H-16α)，4.05(dd，1H，J＝3.6，10.8Hz，H-22a)，3.65(dd，1H，J＝6.9，10.8Hz，H-22b)，3.50(m，1H，J＝4.5，7.5，10.5Hz，H-3)，3.04(s，3H，Ms)，2.03(s，3H，acetyl)，1.05(s，9H，tert-butyl)，0.98(s，3H，H-19)，1.03(d，3H，J＝6.6Hz，H-21)，0.86(s，3H，H-18).

Embodiment 13 compound 4b's is synthetic

In 100mL egg shape flask, add compound 3b 320mg (0.563mmol), ethanol 20mL, 0.16g K ₂CO ₃(1.13mmol), stir.Temperature rising reflux, TLC are followed the tracks of reaction to complete (9: 1 n-C ₆H ₁₄-AcOEt launches).Reaction finishes, and pressure reducing and steaming ethanol adds saturated NH ₄Cl aqueous solution 50mL uses the 60mL ethyl acetate extraction.Organic layer respectively washs 2 times with water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and decompression and solvent recovery, the gained crude product separates (14: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get powdery 4b 266mg (90.0% productive rate).

Compound 4b:

¹H-NMR(300MHz，CDCl ₃)δ：7.68(m，4H)and?7.38(m，6H)(phenyls?of?TBDPS)，5.42(br.s，H-16α)，5.14(d，1H，J＝5.1Hz，H-6)，3.57(d，2H，J＝6.3Hz，H-22)，3.53(m，1H，H-3)，1.06(s，9H，tert-butyl)，1.02(s，3H，H-19)，1.01(d，3H，J＝6.3Hz，H-21)，0.79(s，3H，H-18).

EIMS(70eV)m/z(％)：511(M ⁺-57，62)，481(5)，433(7)，295(4)，253(8)，239(3)，199(100)，183(7)，159(6)，135(5)，105(5)，91(7).

Embodiment 14 compound 5ba's is synthetic

In 50mL exsiccant there-necked flask, add enol 4b 100mg (0.176mmol), the anhydrous CH of 10mL ₂Cl ₂, stirring makes molten.Add Dess-Martin reagent 112mg (0.264mmol), stirring at room～6h, TLC follows the tracks of (9: 1 n-C ₆H ₁₄-AcOEt launches).Along with the carrying out of reaction, it is muddy that solution becomes.After reaction is finished, add 3～5mL 2M NaOH and be stirred to muddy solution becomes clarification.The 60mL ethyl acetate extraction, the ester layer respectively washs 2 times through water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, decompression and solvent recovery, the gained crude product separates (24: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get powdery 22-aldehyde 5ba 80mg (80.3% productive rate).

Compound 5ba:

¹H-NMR(300MHz，CDCl ₃)δ：9.44(d，1H，J＝2.1Hz，H-22)，7.68(m，4H)and?7.38(m，6H)(phenyls?of?TPS)，5.46(br.s，H-16)，5.13(d，1H，J＝4.8Hz，H-6)，3.54(m，1H，H-3)，3.04(dq，1H，J＝2.1，7.2Hz，H-20β)，1.17(d，3H，J＝7.2Hz，H-21)，1.06(s，9H，ter-butylof?TPS)，1.02(s，3H，H-19)，0.78(s，3H，H-18).

Embodiment 15 compound 5b's is synthetic

(1) synthetic by 4b

In 50mL exsiccant there-necked flask, add 155mg enol 4b (0.29mmol), 2mL dry DMF, stirring makes molten.Add PDC reagent: (Py.H) ⁺ ₂Cr ₂O ₇ ^2-328mg (1.02mmol), stirring at room～2h, TLC follows the tracks of (4: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, add 10mL H ₂O, and with dichloromethane extraction (20mL * 2).Organic layer respectively washs 2 times with water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and decompression and solvent recovery, the gained crude product separates (9: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get powdery olefin(e) acid 5b 50mg (31.9% productive rate).

(2) synthetic by 5ba

In the 50mL there-necked flask, add above-mentioned 105mg 22-aldehyde 5ba (0.2mmol), the 5mL trimethyl carbinol, stirring makes molten.Add 3mL water, 118mg NaH ₂PO ₄(0.76mmol), 40mg Resorcinol (0.36mmol) and NaClO ₂(80%purity) (72mg, 0.3mmol), stirring at room 0.5～1h, TLC follows the tracks of (3: 1n-C ₆H ₁₄-AcOEt launches).After reaction is finished,, respectively wash 2 times through water and saturated sodium-chloride water solution with twice washing of 20mL dichloromethane extraction, anhydrous sodium sulfate drying, decompression and solvent recovery, the gained crude product separates (9: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get powdery olefin(e) acid 5b 91mg (84.1% productive rate).

Compound 5b:

¹H-NMR(300MHz，CDCl ₃)δ：9.44(d，1H，J＝2.1Hz，H-22)，7.67(m，4H)and?7.39(m，6H)(phenyls?of?TBDPS)，5.60(s，H-16)，5.13(d，1H，J＝5.1Hz，H-6)，3.53(m，1H，H-3)，3.12(q，1H，J＝6.9Hz，H-20β)，1.26(d，3H，J＝6.9Hz，H-21)，1.06(s，9H，t-butyl?ofTBDPS)，1.02(s，3H，H-19)，0.81(s，3H，H-18).

Embodiment 16 compound 6b and compound 6c's is synthetic

In 50mL egg shape flask, add 40mg olefin(e) acid 5b (0.07mmol), 5mL CH ₂Cl ₂, stirring makes molten.(70%purity, 0.14mmol), stirring reaction is to (TLC follows the tracks of, 2: 1 n-C fully to add 34mg m-CPBA under the room temperature ₆H ₁₄-AcOEt launches).After reaction is finished, remove organic solvent, directly column chromatography for separation is (3: 1: 1n-C ₆H ₁₄-AcOEt-AcOH wash-out), gets diepoxy-22-acid 6c 19mg (45.2% productive rate), 16,17-epoxy-22-acid 6b 3mg (7.3% productive rate) and 5,6-epoxy-22-acid 5bb 6mg (14.6% productive rate).

Compound 5bb:

¹H-NMR(300MHz，CDCl ₃)δ：7.65(m，4H)and?7.38(m，6H)(phenyls?of?TPS)，5.58(d，1H，J＝3.0Hz，H-16)，3.93(m，1H，H-3)，3.12(q，1H，J＝6.9Hz，H-20β)，2.78(dd，1H，J＝4.2，7.0Hz，H-6)，1.25(d，3H，J＝6.0Hz，H-21)，1.05(s，9H，tert-butyl?of?TPS)，0.88(s，3H，H-19)，0.74(s，3H，H-18).

Compound 6b:

¹H-NMR(300MHz，CDCl ₃)δ：7.65(m，4H)and?7.38(m，6H)(phenyls?of?TBDPS)，5.12(d，1H，J＝4.8Hz，H-6)，3.93(m，1H，H-3)，3.34(d，1H，J＝4.8Hz，H-16)，3.05(q，1H，J＝6.9Hz，H-20β)，1.21(d，3H，J＝7.2Hz，H-21)，1.03(s，9H，tert-butyl?of?TBDPS)，0.88(s，3H，H-19)，0.76(s，3H，H-18).

Compound 6c:

¹H-NMR(300MHz，CDCl ₃)δ：7.65(m，4H)and?7.36(m，6H)(phenyls?of?TBDPS)，3.92(m，1H，H-3)，3.36(d，1H，J＝4.8Hz，H-16)，3.08(q，1H，J＝6.9Hz，H-20β)，2.74(d，1H，J＝4.5Hz，H-6)，1.20(d，3H，J＝7.2Hz，H-21)，1.03(s，9H，tert-butyl?of?TBDPS)，0.88(s，3H，H-19)，0.78(s，3H，H-18).

Embodiment 17 compound 7b's is synthetic

In the 10mL there-necked flask, add 3mg epoxyeicosatrienoic acid 6b (0.005mmol), 1mL dehydrated alcohol, stirring makes molten.Add 2mg LiOHH ₂O (0.05mmol) drips 30% hydrogen peroxide 0.5mL, stirs and be warming up to gradually 80 ℃ of reaction 24h down, and TLC follows the tracks of (2: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, use saturated NaHSO ₃Remove excessive hydrogen peroxide, organic phase is told in acidifying, and with 10mL ethyl acetate extraction water once.Organic phase water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained oily crude product separates (4: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get lactone 7b 2mg (66.7% productive rate).

Compound 7b:

IR?ν _max ^KBr(cm ^-1)：3477(OH)，1758(C＝O).

¹H-NMR(300MHz，CDCl ₃)δ：7.65(m，4H)and?7.38(m，6H)(phenyls?of?TBDPS)，5.12(d，1H，J＝4.8Hz，H-6)，4.51(dd，1H，J＝4.8，8.1，H-16α)，3.93(m，1H，H-3)，2.71(q，1H，J＝7.2Hz，H-20β)，1.25(d，3H，J＝7.2Hz，H-21)，1.03(s，9H，tert-butyl?of?TBDPS)，0.98(s，3H，H-19)，0.87(s，3H，H-18).

EIMS(70eV)m/z(％)：598(M ⁺，8)，41(100).

HRMS(EI)：calcd.for?C ₃₈H ₅₀O ₄Si?598.3478，Found?598.3481.

Embodiment 18 compound 7c's is synthetic

In the 25mL there-necked flask, add 13mg epoxyeicosatrienoic acid 6c (0.021mmol), 5mL dehydrated alcohol, stirring makes molten.Add 9mg LiOHH ₂O (0.21mmol) drips 30% hydrogen peroxide 2mL, stirs and be warming up to gradually 80 ℃ of reaction 24h down, and TLC follows the tracks of (2: 1 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, use saturated NaHSO ₃Remove excessive hydrogen peroxide, organic phase is told in acidifying, and with 20mL ethyl acetate extraction water once.Organic phase water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained oily crude product separates (4: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get lactone 7c 9mg (69.2% productive rate).

Compound 7c:

IR?ν _max ^KBr(cm ^-1)：3471(OH)，1760(C＝O).

¹H-NMR(300MHz，CDCl ₃)δ：7.63(m，4H)and?7.37(m，6H)(phenyls?of?TBDPS)，4.51(dd，1H，J＝4.8，8.1，H-16α)，3.93(m，1H，H-3)，2.77(d，1H，J＝4.5Hz，H-6)，2.70(q，1H，J＝7.2Hz，H-20β)，1.21(d，3H，J＝7.2Hz，H-21)，1.02(s，9H，tert-butyl?of?TBDPS)，0.90(s，3H，H-19)，0.79(s，3H，H-18).

EIMS(70eV)m/z(％)：614(M ⁺，3)，41(100).

HRMS(EI)：calcd.for?C ₃₈H ₅₀O ₅Si?614.3428，Found?614.3424.

Embodiment 19 compound 7d's is synthetic

In the 25mL there-necked flask, add the mixed solvent (v/v 9: 1) of lactone 7a (0.1mmol), 3mL dioxane (dioxane) and the water of the protection of 38mg triatomic ring, stirring makes molten.Add PTSA 10mg, stir and be warming up to gradually 80 ℃ of reaction～4h down, TLC follows the tracks of (1: 2 n-C ₆H ₁₄-AcOEt launches).After reaction is finished, use saturated NaHCO ₃5mL neutralization, and with 10 * 3mL ethyl acetate extraction water.Organic phase water and saturated sodium-chloride water solution respectively wash 2 times, anhydrous sodium sulfate drying, and decompression and solvent recovery, gained oily crude product separates (2: 1 n-C through rapid column chromatography ₆H ₁₄-AcOEt wash-out), get powdery 17 alpha-hydroxy-2 2-carboxylic acid lactone 7d 32mg (88.9% productive rate).

Compound 7d:

¹H-NMR(300MHz，C ₅D ₅N)δ：5.36(br.d，1H，J＝3.9Hz，H-6)，4.87(dd，1H，J＝4.7，8.0，H-16α)，3.81(m，1H，H-3β)，3.05(q，1H，J＝7.5Hz，H-20β)，2.60(br.d，2H，J＝6.9Hz)，1.51(d，3H，J＝7.5Hz，H-21)，1.03(s，3H，H-19)，0.91(s，3H，H-18).

¹³C-NMR(75MHz，C ₅D ₅N)δ：180.4(s，C-22)，141.8(s，C-5)，120.7(d，C-6)，88.8(s，C-17)，86.5(d，C-16)，71.1(d，C-3)，50.9(d，C-14)，50.2(d，C-9)，46.5(s，C-13)，43.3(t，C-4)，40.7(d，C-20)，37.7(t，C-1)，36.8(s，C-10)，32.8(t，C-2)，32.4(d，C-8)，32.1(t，C-7)，32.0(t，C-12)，31.8(t，C-15)，20.4(t，C-11)，19.5(q，C-19)，14.2(q，C-18)，13.7(q，C-21).

EIMS(70eV)m/z(％)：360(M ⁺，30)，342(41)，327(29)，275(41)，199(18)，159(41)，145(68)，131(48)，119(57)，105(93)，91(100)，79(68)，55(61)，41(45).

HRMS(EI)：calcd.for?C ₂₂H ₃₂O ₄360.2301，Found?360.2303.

Embodiment 20 compound 7e's is synthetic

In 50mL exsiccant there-necked flask, add 7d 83mg (0.231mmol), the anhydrous CH of 10mL ₂Cl ₂, stirring makes molten.Add Dess-Martin reagent 147mg (0.346mmol), stirring at room to raw material disappears, and adds 3～5mL 2M NaOH and is stirred to muddy solution becomes clarification.The 60mL ethyl acetate extraction, the ester layer respectively washs 2 times through water and saturated sodium-chloride water solution, anhydrous sodium sulfate drying, decompression and solvent recovery, the gained crude product separates through rapid column chromatography, gets 17 alpha-hydroxy-2 2-carboxylic acid lactone 7e 73mg (88.4% productive rate).

Compound 7e:

¹H-NMR(300MHz，CDCl ₃)δ：5.93(s，1H，H-4)，4.37(dd，1H，J＝4.8，8.1，H-16α)，1.21(d，3H，J＝7.5Hz，H-21)，1.19(s，3H，H-19)，1.01(s，3H，H-18).

EIMS(70eV)m/z(％)：358(M ⁺，19)，340(35)，105(100).

HRMS(EI)：calcd.for?C ₂₂H ₃₀O ₄358.2144，Found?358.2141.

Embodiment 21 compound 7f's is synthetic

In 25mL exsiccant there-necked flask, add 11mg lactone 7b (0.018mmol), add the 5mL chloroform, stirring makes molten.Ice bath drips 3mg Br down ₂1mL CCl (0.019mmol) ₄Solution.TLC follows the tracks of reaction to fully, adds saturated Na ₂SO ₃Remove excessive bromine, add the 50mL chloroform, tell chloroform layer after the jolting a little, be washed to neutrality with water and saturated common salt successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, rapid column chromatography separates, and gets 5 α, 6 beta-2-dibroms-17-Alpha-hydroxy-lactone 7f 12mg (86.3% productive rate).

Compound 7f:

¹H-NMR(300MHz，CDCl ₃)δ：7.63(m，4H)and?7.36(m，6H)(phenyls?of?TBDPS)，4.50(dd，1H，J＝4.8，8.1，H-16α)，.3.90(m，1H，H-3)，3.85(br?s，1H，H-6)，1.21(d，3H，J＝7.2Hz，H-21)，1.03(s，9H，tert-butyl?of?TBDPS)，0.98(s，3H，H-19)，0.87(s，3H，H-18).

EIMS(70eV)m/z(％)：598(18)，41(100).

EA：calcd.C?60.16，H?6.64；Found?C?60.08，H?6.69.

Claims

1, a class C22 steroidal compounds is characterized in that having following structural formula:

Wherein

Or

When Y is O, R ⁷Be H, R ⁶And R ⁸Become oxo bridge, R ³Be H, and R ⁴During for H, R ²Can not be H, OH, OMOM, OAc, OTBS, OTBDPS or X;

2, a class C22 steroidal compounds as claimed in claim 1 is characterized in that having following structural formula:

The definition of each group according to claim 1, Ac is an ethanoyl.Wherein, in the compound 7, work as R ²Be H and R ³During for H,

Can not for Or

3, a class C22 steroidal compounds as claimed in claim 1 is characterized in that having following structural formula:

4, the synthetic method of a class C22 steroidal compounds as claimed in claim 1 is characterized in that using respectively method 1), 1)-2), 1)-3), 1)-4), 1)-5), 1)-6) or 1)-7) come synthetic:

1): compound 1 is dissolved in the aprotic solvent, adds reductive agent (0.5 equivalent-3 equivalent) ,-78 ℃ were reacted 0.5 hour to 24 hours to the temperature that refluxes, get compound 2; Described reductive agent can be NaBH ₄, NaBH ₃CN, KBH ₄, LiBH ₄, LiAlH ₄Perhaps diisobutyl aluminium hydride.

2): compound 2 is dissolved in the organic solvent, adds diacetyl oxide or Acetyl Chloride 98Min. (0.5 equivalent-6 equivalent) ,-78 ℃ were reacted 0.5 hour to 24 hours to reflux temperature; Add SULPHURYL CHLORIDE (1 equivalent-6 equivalent) then, heat to make in 0.5 hour to 24 hours and react completely, compound 3; Described organic solvent is non-protonic solvent, nitrogenous organic base or their mixed solvent; Described sulfonic acid acyl chlorides can be methylsulfonyl chloride, Tosyl chloride or trifluoromethanesulfchloride chloride.

4): compound 4 is dissolved in the organic solvent, adds oxygenant (1 equivalent-9 equivalent) ,-78 ℃ were reacted 0.5 hour to 72 hours to reflux temperature, get compound 5; Wherein, recommending organic solvent can be dimethyl formamide, hexamethylphosphoramide, the trimethyl carbinol or methylene dichloride; Oxygenant can be Manganse Dioxide, potassium manganate, potassium permanganate, chromic anhydride, Sodium chromate, chromic acid pyridinium salt, clorox, Textone or potassium chlorite.

5): compound 5 is dissolved in the non-protonic solvent, adds epoxidation reagent (1 equivalent-6 equivalent) ,-78 ℃ were reacted 0.5 hour to 6 hours to reflux temperature, get compound 6; Epoxidation reagent can be Peracetic Acid, metachloroperbenzoic acid, hydrogen peroxide, peroxy trifluoroacetic acid or peroxy propanone.

5, the synthetic method of a class C22 steroidal compounds as claimed in claim 3 is characterized in that described non-protonic solvent is CH ₂Cl ₂, CHCl ₃, CCl ₄, tetrahydrofuran (THF) or ether.

6, the synthetic method of a class C22 steroidal compounds as claimed in claim 3 is characterized in that described polar solvent is acetone, acetonitrile, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, CH ₂Cl ₂, CHCl ₃Or water.

7, the synthetic method of a class C22 steroidal compounds as claimed in claim 3, it is characterized in that described nitrogenous organic base is 1,8-diazabicylo [5,4,0] 11-7-alkene, pyridine, 4-Dimethylamino pyridine, bipyridine, lutidine, trimethylpyridine or have C _1-18The primary amine of alkyl, secondary amine or tertiary amine.