CN101462994B - Vitamin D derivatives - Google Patents

Abstract

The object of the present invention is to provide vitamin D derivatives that have excellent physiological activities as medicines, particularly as therapeutic agents for skin diseases such as psoriasis, and that have a reduced hypercalcemic effect. The present invention provides a vitamin D derivative of Formula (1): wherein X represents an oxygen atom or a sulfur atom; m represents a number of 1to 3; R1 and R2 each represent a hydrogen atom or an alkyl group; R4 and R5 each represent a hydrogen atom or a hydroxyl group, etc.; R3 represents -YR8, etc.; R6 represents a hydrogen atom, etc.; and R7 represents a hydrogen atom, etc.

Description

Vitamin D-derivatives

The application be that June 14 calendar year 2001, application number are 01811125.4 the applying date, invention and created name divides an application for the application of " vitamin D-derivatives ".The full content of female case is introduced this paper and is done reference.

Technical field

The present invention relates to the novel vitamin D derivatives thing, more particularly, relate to the suitable vitamin D-derivatives of doing medicine (for example, treating for skin disease agent) as the psoriasis.

Background technology

In vivo, vitamins D ₃At first be metabolised to 25-hydroxy-vitamin D at liver through the hydroxylation of 25-position ₃, it is metabolised to 1 α through the hydroxylation of 1 alpha-position or 24-position respectively at kidney again, the 25-dihydroxyvitamin D ₃Or 24R, the 25-dihydroxyvitamin D ₃In these metabolites, known 1 α, 25-dihydroxyvitamin D ₃And synthetic analogues has the physiologically active of wide region, comprises, Calcium Metabolism Regulation is active, and the growth of antitumor cell etc. or differentiation suppress active, and immunoregulatory activity.

Vitamins D ₃Relate to a problem, that is, when using for a long time continuously, might cause hypercalcemia.In order to overcome this problem, people attempt synthesise various vitamins D verivate; Someone has proposed some and has had the vitamin D-derivatives (for example, JP7-330714A and JP 10-231284A) of the hypercalcemia effect that reduces.

The purpose of this invention is to provide such vitamin D-derivatives, that is, have good physiologically active,, and have the hypercalcemia effect that reduces particularly as the medicine of the such treating for skin disease agent of psoriasis for example as medicine.

Summary of the invention

In these cases, the inventor will concentrate on to have at side chain the compound of ester structure or amide structure, and do extensive and intensive effort so that the vitamin D-derivatives with the hypercalcemia effect that reduces to be provided.As a result, the inventor has found, has realized its intended purposes through the vitamin D-derivatives of following formula (1):

Formula (1)

Wherein

X representes Sauerstoffatom or sulphur atom;

M representes 1～3 number;

R ₁And R ₂Represent Wasserstoffatoms or alkyl separately;

R ₄And R ₅Represent Wasserstoffatoms or hydroxyl separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together;

R ₃Expression-YR ₈(wherein, Y representes Sauerstoffatom or sulphur atom, R ₈The expression Wasserstoffatoms can be by the linear or branched-alkyl of fluorine atom or cycloalkyl substituted, perhaps can be by the substituted naphthenic base of fluorine atom) perhaps-NR ₉R ₁₀(wherein, R ₉And R ₁₀Represent Wasserstoffatoms separately, can perhaps can perhaps be worked as R by the linear or branched-alkyl of fluorine atom or cycloalkyl substituted by the substituted naphthenic base of fluorine atom ₄And R ₅When forming the two key between 16-and the 17-position together, R ₉And R ₁₀Can form a ring with nitrogen-atoms);

R ₆The expression Wasserstoffatoms or-OR ₁₁(wherein, R ₁₁Expression Wasserstoffatoms or protection base); And

R ₇Expression Wasserstoffatoms or protection base;

So the inventor has finally accomplished one side of the present invention.

That is to say, the invention provides the have formula vitamin D-derivatives of (1).

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1～3 number, R ₁And R ₂Represent Wasserstoffatoms or C separately ₁～C ₄Alkyl, R ₄And R ₅Represent Wasserstoffatoms or hydroxyl separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₃Expression-YR ₈(wherein, Y representes Sauerstoffatom or sulphur atom, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₁₀The substituted linear or branching C of alkyl ₁～C ₁₅Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₁₅Alkyl) perhaps-NR ₉R ₁₀(wherein, R ₉And R ₁₀Represent Wasserstoffatoms separately, can be by fluorine atom or ring C ₃～C ₁₀The substituted linear or branching C of alkyl ₁～C ₁₅Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₁₅Alkyl is perhaps worked as R ₄And R ₅When forming the two key between 16-and the 17-position together, R ₉And R ₁₀Form a 3-～10-unit ring with nitrogen-atoms), R ₆Expression Wasserstoffatoms or hydroxyl, and R ₇The expression Wasserstoffatoms.

Further preferably, in formula (1), X representes Sauerstoffatom or sulphur atom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₄And R ₅Represent Wasserstoffatoms simultaneously, perhaps R ₄Expression Wasserstoffatoms, and R ₅Expression hydroxyl, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₃Expression-YR ₈(wherein, Y representes Sauerstoffatom or sulphur atom, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₈The substituted linear or branching C of alkyl ₁～C ₁₀Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₁₂Alkyl) perhaps-NR ₉R ₁₀(wherein, R ₉And R ₁₀Represent Wasserstoffatoms separately, can be by fluorine atom or ring C ₃～C ₈The substituted linear or branching C of alkyl ₁～C ₁₀Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₁₂Alkyl is perhaps worked as R ₄And R ₅When forming the two key between 16-and the 17-position together, R ₉And R ₁₀Form a 3-～10-unit ring with nitrogen-atoms), R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₃Expression-YR ₈(wherein, Y representes Sauerstoffatom or sulphur atom, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₈The substituted linear or branching C of alkyl ₁～C ₈Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₈Alkyl) perhaps-NR ₉R ₁₀(wherein, R ₉And R ₁₀Represent Wasserstoffatoms separately, can be by fluorine atom or ring C ₃～C ₈The substituted linear or branching C of alkyl ₁～C ₈Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₈Alkyl is perhaps worked as R ₄And R ₅When forming the two key between 16-and the 17-position together, R ₉And R ₁₀Form a 3-～8-unit ring with nitrogen-atoms), R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-YR ₈(wherein, Y representes Sauerstoffatom or sulphur atom, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₆The substituted linear or branching C of alkyl ₁～C ₈Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₈Alkyl), R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₃Expression-NR ₉R ₁₀(wherein, R ₉And R ₁₀Represent Wasserstoffatoms separately, can be by fluorine atom or ring C ₃～C ₆The substituted linear or branching C of alkyl ₁～C ₈Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₈Alkyl is perhaps worked as R ₄And R ₅When forming the two key between 16-and the 17-position together, R ₉And R ₁₀Form a 3-～6-unit ring with nitrogen-atoms), R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-OR ₈(wherein, R ₈Expression branching C ₃～C ₈Alkyl), R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-SR ₈(wherein, R ₈Expression branching C ₃～C ₈Alkyl), R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom or sulphur atom, and m representes 1, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-NR ₉R ₁₀(wherein, R ₉Expression Wasserstoffatoms or linear or branching C ₁～C ₄Alkyl, R ₁₀Expression can be by the substituted linear or branching C of fluorine atom ₁～C ₈Alkyl), R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-OR ₈(wherein, R ₈Expression branching C ₆～C ₈Alkyl), R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom, and m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, condition is R ₁And R ₂In one should represent methyl, R ₃Expression-OR ₈(wherein, R ₈Expression branching C ₆～C ₈Alkyl), R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom, and m representes 1, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, condition is R ₁And R ₂In one should represent methyl, R ₃Expression-NR ₉R ₁₀(wherein, R ₉Expression Wasserstoffatoms or methyl, R ₁₀Expression can be by the substituted linear or branching C of fluorine atom ₁～C ₄Alkyl), R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

In formula (1), preferably, X representes Sauerstoffatom, and m representes 1, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, condition is R ₁And R ₂In one should represent methyl, R ₃Expression-NR ₉R ₁₀(wherein, R ₉The expression Wasserstoffatoms, R ₁₀Expression can be by the substituted propyl group of fluorine atom), R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

The preferred vitamin D-derivatives of the present invention comprises: 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9,10-open loop pregnant (s ecopregna)-5,7,10 (19), 16-tetraene; 1 α, 3 beta-dihydroxyies-20 (S)-(1-sec.-propyl-2-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene; 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-butoxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7,10 (19); The 16-tetraene, 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-hexyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene, 1 α, 3 beta-dihydroxyies-20 (S)-{ 2-(1-ethyl-1-methyl propoxycarbonyl) oxyethyl group }-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene, { (1 α, 3 beta-dihydroxyies-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl) oxygen base }-N-(2,2,3,3; 3-five fluoropropyls) ethanamide and 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19)-triolefins.

On the other hand, the invention provides a kind of pharmaceutical composition that contains said vitamin D verivate.

Aspect another, the invention provides a kind of treating for skin disease agent that is used for, it comprises the said vitamin D verivate as active ingredient.Said tetter is psoriasis preferably.

Aspect another, the invention provides said vitamin D verivate is used for the treating for skin disease agent in preparation application.Saidly be used for the treating for skin disease agent and preferably be used for the psoriasis treatment agent.

Aspect another, the invention provides the dermopathic method of a kind of application said vitamin D derivatives for treatment, for example, a kind of method, this method comprise this step of said vitamin D-derivatives to patient's administering therapeutic significant quantity of this reaction of needs.Said tetter is psoriasis preferably.

Also have, the invention provides a kind of favorable method for preparing the compound that is suitable for the midbody of making preparation said vitamin D verivate.That is, the invention provides a kind of in the presence of organoaluminum reagent and palladium catalyst in solvent, in carbon monoxide atmosphere, following formula (2) compound carbonylation prepared the method for following formula (3) compound:

Wherein

R ₁₂And R ₁₃The expression protection is basic separately,

And R ₁₄The expression leaving group,

Wherein

R ₁₂And R ₁₃Suc as formula the definition in (2), and R ₁₅The expression alkyl, aryl, alkenyl or alkynyl).

In aforesaid method, said organoaluminum reagent preferably has formula (4):

(R ₁₅) _nAlW _3-n (4)

Wherein

N representes 1～3 integer, R ₁₅The expression alkyl, aryl, alkenyl or alkynyl, and

W representes halogen atom.

Embodiment

Hereinafter will more be described the vitamin D-derivatives and the embodiment and the implementation and operation step that comprise its pharmaceutical composition of formula of the present invention (1) in detail.

The application requires the right of priority of Japanese patent application Nos.2000-179251,2000-351412 and 2000-375024, and it is for referencial use that their disclosure is all incorporated this paper into it in full.

The linear or branching C of " alkyl " ordinary representation like this paper application ₁～C ₁₅Alkyl or ring C ₃～C ₁₅Alkyl, except as otherwise noted.Like R ₁And R ₂Alkyl preferably contain 1～6 carbon atom, more preferably contain 1～4 carbon atom.Specific examples comprises: methyl, ethyl and normal-butyl, methyl are preferred.Like R ₈, R ₉And R ₁₀Linear or branched-alkyl preferably contain 1～10 carbon atom, more preferably contain 1～8 carbon atom.Most preferably, R ₈Be branching C ₆～C ₈Alkyl, and R ₉And R ₁₀Each linear naturally or branching C ₁～C ₄Alkyl.Specific examples comprises; Methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec.-butyl, isobutyl-, the tertiary butyl, n-pentyl, tert-pentyl, 1-ethyl-1-methyl-propyl, 1-sec.-propyl-2-methyl-propyl, 1; 1-diethylammonium propyl group, 1; 1-dimethylbutyl, 1,1-dimethyl-hexyl, n-hexyl, n-heptyl, n-octyl, nonyl and decyl.Preferably: methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, the tertiary butyl, tert-pentyl, 1-ethyl-1-methyl-propyl, 1-sec.-propyl 2-methyl-propyl, 1; 1-diethylammonium propyl group, 1; 1-dimethylbutyl and 1,1-dimethyl-hexyl, and more preferably: methyl, ethyl, n-propyl, the tertiary butyl, tert-pentyl, 1-ethyl-1-methyl-propyl, 1-sec.-propyl-2-methyl-propyl, 1; 1-dimethylbutyl and 1,1-dimethyl-hexyl.Most preferably, R ₈Be 1-ethyl-1-methyl-propyl or 1,1-dimethyl-hexyl, R ₉Be methyl, and R ₁₀It is n-propyl.

The instance of naphthenic base generally includes and contains 3～15 carbon atoms, preferred 3～12 carbon atoms and more preferably those of 3～8 carbon atoms.Specifically, ring C ₃～C ₆Alkyl is preferably as the substituting group on linear or the branched-alkyl.Specific examples comprises: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, cyclo-dodecyl and cyclopentadecane base.

Can be by the linear or branched-alkyl of fluorine atom or cycloalkyl substituted, perhaps can be often referred to linear a, branching or cyclic alkyl (for example, above-mentioned those) by the substituted naphthenic base of fluorine atom, its at least one Wasserstoffatoms is by fluorine atom or cycloalkyl substituted.Inhomogeneous alkyl can be replaced by the fluorine atom of different quantities, generally is 3～20 fluorine atoms, and preferably 3～15 fluorine atoms are more preferably 3～12 fluorine atoms, and most preferably are 3～8 fluorine atoms.

R for example ₇, R ₁₁, R ₁₂And R ₁₃Such protection base can be identical or different, and instance comprises: acyl group, optional substituted alkyl and substituted silyl.Specific examples comprises: methyl, methoxymethyl, methylthiomethyl, uncle's butylthio methyl, (phenyl dimetylsilyl) methoxymethyl, benzyloxymethyl, right-methoxyl group benzyloxy ylmethyl, right-benzyl chloride oxygen ylmethyl, (4-methoxyl group phenoxy) methyl, tert.-butoxy methyl, 2-methoxy ethoxy methyl, 2; 2; 2-trichlorine ethoxyl methyl, 2-(trimethyl silyl) ethoxyl methyl, thiophenyl methyl, cyclopropyl methyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 1-methoxyl group cyclohexyl, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, 4-methoxyl group tetrahydro thiapyran base S; S-dioxide, 1; 4-dioxane-2-base, tetrahydrofuran base, tetrahydro-thienyl, phenacyl-, right-bromobenzene formyl methyl, 1-ethoxyethyl group, methoxyl group sec.-propyl, 1-(2-chloroethoxy) ethyl, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl-benzyloxy ethyl, 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl, 2; 2; 2-three chloroethyls, 2-trimethyl silyl ethyl, 2; 2-two chloro-1; 1-two fluoro ethyls, allyl group, the tertiary butyl, right-chloro-phenyl-, right-p-methoxy-phenyl, 2; 4-dinitrophenyl, benzyl, right-methoxy-benzyl, 3; 4-dimethoxy-benzyl, neighbour-nitrobenzyl, right-nitrobenzyl, right-the benzyl chloride base, right-bromobenzyl, 2; 6-dichloro benzyl, right-the cyanic acid benzyl, right-phenylbenzyl, 4-(dimethylamino carbonyl) benzyl, 2-picolyl, 4-picolyl, diphenyl-methyl, right; Right '-dinitrobenzene diphenyl-methyl, 5-dibenzo suberyl, trityl, right-p-methoxy-phenyl diphenyl-methyl, two (right-p-methoxy-phenyl) phenyl methyl, three (right-p-methoxy-phenyl) methyl, 9-anthryl, 1; 3-benzo dithiolane-2-base, benzisothiazole base S; S-dioxide, trimethyl silyl, triethylsilyl, triisopropyl silyl, dimethyl-sec.-propyl silyl, diethylammonium sec.-propyl silyl, dimethyl-1; 1; 2-trimethylammonium propyl group silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silyl, three-right-xylyl silyl, triphenyl silyl, diphenyl methyl silyl, tertiary butyl p-methoxy-phenyl silyl, formyl radical, ethanoyl, chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, methoxyl group ethanoyl, propionyl group, butyryl radicals, isobutyryl, pivalyl, adamantyl, hexanaphthene carbonyl, benzoyl, 4-oil of mirbane formyl, 4-chlorobenzoyl, 4-methoxybenzoyl, naphthoyl, toluoyl, 9-fluorenes carbonyl, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 9-fluorenyl methoxy carbonyl, 2; 2; 2-trichlorine ethoxy carbonyl, 2-(trimethyl silyl) ethoxy carbonyl, 2-(methylthio group methoxyl group) ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, isobutoxy carbonyl, ethylene oxy carbonyl, allyloxy carbonyl, right-nitro-phenoxy carbonyl, 3,4-dimethoxy benzyloxycarbonyl, neighbour-nitro benzyloxycarbonyl, right-the nitro benzyloxycarbonyl, benzylthio-carbonyl, 4-oxyethyl group-1-naphthyloxy carbonyl, (methylthio group) thiocarbonyl, isobutyl-aminocarbonyl and phenylamino carbonyl.Preferably: replace silyl; For example; Trimethyl silyl, triethylsilyl, triisopropyl silyl, dimethyl-sec.-propyl silyl, diethylammonium sec.-propyl silyl, dimethyl-1; 1; 2-trimethylammonium propyl group silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silyl, three-right-xylyl silyl, triphenyl silyl, diphenyl methyl silyl and tertiary butyl p-methoxy-phenyl silyl; Perhaps acyl group; For example, formyl radical, ethanoyl, chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, methoxyl group ethanoyl, triphenyl methoxyl group ethanoyl, phenoxy ethanoyl, propionyl group, butyryl radicals, isobutyryl, 4-(methylthio group methoxyl group) butyryl radicals, pivalyl, adamantyl, hexanaphthene carbonyl, benzoyl, 4-oil of mirbane formyl, 4-chlorobenzoyl, 2-iodobenzene formyl, 4-methoxybenzoyl, right-the phenyl benzoyl, naphthoyl, toluoyl and 9-fluorenes carbonyl.More preferably, triethylsilyl, triisopropyl silyl, dimethyl-sec.-propyl silyl, diethylammonium sec.-propyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenyl silyl, diphenyl methyl silyl, ethanoyl, pivalyl, benzoyl and 4-methoxybenzoyl.

Like R ₁₄The instance of leaving group comprise: halogen atom, for example, chlorine, bromine and iodine; Sulfonyloxy, for example, trifluoro-methanesulfonyl oxy, five fluorine ethanesulfonyloxy groups, nine fluorine fourth sulfonyloxies, mesyloxy, phenylsulfonyloxy and tosyloxy; Perhaps phosphate-based; For example, solutions of dimethyl phosphoryl oxygen base, diethylammonium phosphorus acyloxy and diphenylphosphine acyloxy serve as preferred with bromine, iodine, trifluoro-methanesulfonyl oxy and nine fluorine fourth sulfonyloxies.

When the compound of preparation formula of the present invention (3), can suitably select to be used for the solvent of carbonylation, but organic solvent is preferred.Organic solvent refers to reaction substrate is the inert liquid substance, for example, and N; N-N,N-DIMETHYLACETAMIDE, N; Dinethylformamide, 1,3-dimethyl--2-imidazolone, methyl-sulphoxide, THF, 1,2-glycol dimethyl ether, 1; 4-diox, t-butyl methyl ether, ether, isopropyl ether, acetone, butanone, ETHYLE ACETATE, methylene dichloride, 1,2-ethylene dichloride, toluene, benzene and chlorobenzene.Preferably DMAC N,N, N, dinethylformamide and 1,3-dimethyl--2-imidazolone, and DMAC N,N more preferably.

When the compound of preparation formula of the present invention (3), the compound of organoaluminum reagent expression (4):

(R ₁₅) _nAlW _3-n (4)

Wherein

N representes 1,2 or 3 integer;

R ₁₅The expression alkyl, aryl, alkenyl or alkynyl, wherein, alkyl is represented the C of linear or branching ₁～C ₁₅Alkyl or ring C ₃～C ₁₅Alkyl, aryl is represented phenyl, and it can have a substituting group, and for example, alkyl, halogen or nitro, thiazolinyl represent to have the C of the linear or branching of two keys ₂～C ₁₅Substituting group, and alkynyl representes to have the C of the linear or branching of one three key ₂～C ₁₅Substituting group; And

W representes halogen atom, for example, and chlorine, bromine and iodine.

Instance comprises: trimethylaluminium; Dimethylaluminum chloride; The dimethyl-aluminum bromide; The dimethyl-aluminum iodide; Methylaluminum dichloride; The methyl aluminum dibromide; Methyl two aluminum iodides; Triethyl aluminum; Diethyl aluminum chloride; The diethylammonium aluminum bromide; The diethylammonium aluminum iodide; Ethylaluminum dichloride; Ethyl aluminum dibromide; Ethyl two aluminum iodides; Tri-n-n-propyl aluminum; Di aluminum chloride; The di aluminum bromide; The di aluminum iodide; The n-propyl al dichloride; The n-propyl aluminum dibromide; N-propyl two aluminum iodides; Three n-butylaluminum; Di-n-butyl aluminum chloride; The di-n-butyl aluminum bromide; The di-n-butyl aluminum iodide; The normal-butyl al dichloride; The normal-butyl aluminum dibromide; Normal-butyl two aluminum iodides; Triphenyl aluminum; Phenylbenzene aluminum chloride; The phenylbenzene aluminum bromide; The phenylbenzene aluminum iodide; The phenyl al dichloride; Phenyl aluminum dibromide and phenyl two aluminum iodides.Preferably trimethylaluminium, dimethylaluminum chloride, methylaluminum dichloride, triethyl aluminum, diethyl aluminum chloride, ethylaluminum dichloride, tri-n-n-propyl aluminum, di aluminum chloride, n-propyl al dichloride, three n-butylaluminum, di-n-butyl aluminum chloride, normal-butyl al dichloride, triphenyl aluminum, phenylbenzene aluminum chloride and phenyl al dichloride.More preferably dimethylaluminum chloride, diethyl aluminum chloride, di aluminum chloride, di-n-butyl aluminum chloride and phenylbenzene aluminum chloride.

Palladium catalyst is represented the palladium compound of zeroth order or divalence, and it possibly have a kind of suitable part.Instance comprises: four (triphenyl phosphine) palladium, dichloro two (triphenyl phosphine) palladium, dichloro [1; 3-two (diphenyl phosphine) propane] palladium, dichloro [1; 2-two (diphenyl phosphine) ethane] palladium, two (dibenzalacetone) palladium and three (dibenzalacetones), two palladiums, wherein four (triphenyl phosphine) palladium is preferred.

Tabulate down 1～44 show the vitamin D-derivatives of formula of the present invention (1) limiting examples.

In table 1～23, R ₃Expression OR ₈In table 24, it representes SR ₈And in table 25～44, it representes NR ₉R ₁₀

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

The vitamin D-derivatives of formula of the present invention (1) can prepare by following mode.Yet preparation is not particularly limited to these modes, but can utilize other method to synthesize.

I. wherein X is formula (1) vitamin D-derivatives synthetic of Sauerstoffatom

(wherein, X is a Sauerstoffatom to the vitamin D-derivatives of formula (1), R ₆Be hydroxyl, and R ₇Be Wasserstoffatoms) can be by following method preparation, that is, with being shown in JP 61-267550A or E.Murayama etc., chemistry is circulated a notice of (Chem.Pharm.Bull.) with pharmacy, and 34 (10), 1986,4410～4413 formula (A) compound begins:

Wherein, TBS representes t-butyldimethylsilyl.

(the formation of step 1) hydrazone

In suitable solvent, handle compound (A) and synthetic compound (B) with arylsulfonyl hydrazine or alkyl sulfonyl hydrazine.

Can be used for the arylsulfonyl hydrazine of this reaction or the instance of alkyl sulfonyl hydrazine comprises; Benzol sulfohydrazide, right-toluene sulfonyl hydrazide ,-toluene sulfonyl hydrazide, neighbour-toluene sulfonyl hydrazide, 4-ethylbenzene sulfonyl hydrazide, 2-

sulfonyl hydrazide, 4-chlorobenzene sulfonyl hydrazide, 4-isopropyl benzene sulfonyl hydrazide, 2; 4,6-tri isopropyl benzenesulfonyl hydrazine, methylsulfonyl hydrazine, 2-methyl-2-third sulfonyl hydrazide, 2-third sulfonyl hydrazide and second sulfonyl hydrazide.Preferably, benzol sulfohydrazide, right-toluene sulfonyl hydrazide and 2,4,6-tri isopropyl benzenesulfonyl hydrazine, and more preferably 2,4,6-tri isopropyl benzenesulfonyl hydrazine.

The examples of solvents that can be used for this reaction comprises: based on the solvent of hydrocarbon, ether, halogen, ester, acid amides, alcohol, sulfoxide and nitrile.Specific examples comprises: hexane, benzene, toluene, ether, THF, 1,4-diox, 1,2-glycol dimethyl ether, t-butyl methyl ether, DIPE, methylene dichloride, chloroform, 1; 2-ethylene dichloride, chlorobenzene, ETHYLE ACETATE, methyl acetate, propyl acetate, N; Dinethylformamide, DMAC N,N, 1,3-dimethyl--2-imidazolone, 1; 3-dimethyl--3; 4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, methyl alcohol, ethanol, Virahol, methyl-sulphoxide, acetonitrile and propionitrile.Preferably toluene, ether, THF, methylene dichloride and ETHYLE ACETATE, and more preferably THF and ETHYLE ACETATE.

As long as above-mentioned reaction can be carried out under the arbitrary temp that reaction is carried out, preferably under 0 ℃～100 ℃, carry out, more preferably at room temperature carry out.

(step 2) alkylation

In suitable solvent, use alkaline purification compound (B) again, then through formaldehyde (or its equivalent, for example, 1,3,5-trioxane and paraformaldehyde) or acetone treatment and synthetic compound (C).

The instance that can be used for the alkali of above-mentioned reaction comprises: n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium methide, phenyl lithium, methyl-magnesium-bromide, methylmagnesium-chloride, methyl magnesium iodide, sec.-propyl bromination magnesium, di-isopropyl magnesium, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide, 2; 2; 6; 6-tetramethyl piperidine lithium (lithium2; 2,6,6-tetramethylpiperidide), lithium amide, sodium hydride, two (trimethyl silyl) sodium amide, potassium hydride KH and two (trimethyl silyl) amination potassium.Preferably n-Butyl Lithium, s-butyl lithium, tert-butyl lithium and diisopropylaminoethyl lithium, and more preferably n-Butyl Lithium and s-butyl lithium.

In above-mentioned reaction, can with alkali reaction after add suitable metal-salt.The instance of metal-salt comprises: Cerium II Chloride, magnesium bromide, magnesium chloride, zinc chloride, titanium tetrachloride, three isopropoxy titanium chlorides, samarium trichloride and indium chloride, wherein Cerium II Chloride is preferred.

The instance that can be used for the solvent of above-mentioned reaction comprises, based on the solvent of hydrocarbon and ether.Specific examples comprises: pentane, hexane, benzene, toluene, ether, t-butyl methyl ether, THF, 1,2-glycol dimethyl ether, 1,4-diox and methyl-phenoxide.Preferably hexane, ether and THF, and more preferably hexane and THF.

This reaction also can be carried out in the presence of acid amides or amine compound.The instance of acid amides or amine compound comprises: 1, and 4-diazabicylo [2,2,2] octane, N; N, N ', N '-Tetramethyl Ethylene Diamine, 1,3-dimethyl--2-imidazolone, 1; 3-dimethyl--3,4,5; 6-tetrahydrochysene-2 (1H)-pyrimidone, N, dinethylformamide, DMAC N,N and HMPA.N,N,N, 1 preferably, 3-dimethyl--3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone and HMPA, and N,N,N more preferably.

As long as above-mentioned reaction with alkali can be carried out under the arbitrary temp that reaction is carried out, preferably under-100 ℃～50 ℃, carry out, more preferably under-80 ℃～20 ℃, carry out.

With formaldehyde (or its equivalent, for example, 1,3,5-trioxane, paraformaldehyde) as long as or the reaction of acetone can under the arbitrary temp that reaction is carried out, carry out, preferably under-100 ℃～50 ℃, carry out, more preferably under-80 ℃～20 ℃, carry out.

Work as R ₁And R ₂All be Wasserstoffatoms separately, and R ₄And R ₅When forming the two key between 16-and the 17-position together, compound (C) also can be synthetic by following method.

(step 1 ') oxirane formation

In appropriate solvent, in the presence of alkali, handle compound (A) and synthetic compound (D) with trimethylammonium sulfonium salt or trimethylammonium oxidation sulfonium salt.

Can be used for the trimethylammonium sulfonium salt of this reaction or the instance of trimethylammonium oxidation sulfonium salt comprises: iodate trimethylsulfonium, bromination trimethylsulfonium, chlorination trimethylsulfonium, trimethylsulfonium methyl sulfate, Tetrafluoroboric acid trimethylsulfonium, perchloric acid trimethylsulfonium, iodate trimethylammonium sulfoxonium, bromination trimethylammonium sulfoxonium, chlorination trimethylammonium sulfoxonium, trimethylammonium sulfoxonium methyl sulfate, Tetrafluoroboric acid trimethylammonium sulfoxonium and perchloric acid trimethylammonium sulfoxonium, wherein bromination trimethylsulfonium and iodate trimethylammonium sulfoxonium are preferred.

The instance that can be used for the alkali of above-mentioned reaction comprises: n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium methide, phenyl lithium, methyl-magnesium-bromide, methylmagnesium-chloride, methyl magnesium iodide, sec.-propyl bromination magnesium, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide, 2; 2; 6,6-tetramethyl piperidine lithium, lithium amide, sodium hydride, two (trimethyl silyl) sodium amide, potassium hydride KH, two (trimethyl silyl) amination potassium, sodium hydroxide and Pottasium Hydroxide.Preferably sodium hydride, potassium hydride KH, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, sodium hydroxide and Pottasium Hydroxide, and more preferably sodium hydride and potassium hydride KH.

The examples of solvents that can be used for this reaction comprises: based on the solvent of hydrocarbon, ether, acid amides and sulfoxide.Specific examples comprises: pentane, hexane, benzene, toluene, ether, t-butyl methyl ether, THF, 1,2-glycol dimethyl ether, 1,4-diox, methyl-phenoxide, diglyme, N; Dinethylformamide, DMAC N,N, 1,3-dimethyl--2-imidazolone, 1; 3-dimethyl--3,4,5; 6-tetrahydrochysene-2 (1H)-pyrimidone and methyl-sulphoxide, wherein methyl-sulphoxide is preferred.If necessary, can such solvent and solvent (for example, the THF) combination based on ether be used.

As long as above-mentioned reaction can be carried out under the arbitrary temp that reaction is carried out, preferably under-20 ℃～20 ℃, carry out.

The open loop of (step 2 ') epoxide

In appropriate solvent, the synthetic compound (C) with s.t. compound (D).

The instance that can be used for the acid of this reaction comprises: hydrochloric acid, sulfuric acid, acetate, phosphoric acid, aluminum methylate, aluminum ethylate, aluminium isopropoxide, three tert.-butoxy aluminium, aluminum chloride, zinc chloride, tin chloride (II), tin chloride (IV), titanium chloride (IV), tetramethyl alcohol titanium, titanium tetraethoxide and titanium tetraisopropylate.Preferably aluminum methylate, aluminum ethylate, aluminium isopropoxide and three tert.-butoxy aluminium, and aluminium isopropoxide more preferably.

The examples of solvents that can be used for this reaction comprises: based on the solvent of hydrocarbon, ether, halogen and acid amides.Specific examples comprises: pentane, hexane, benzene, 1,2-dichlorobenzene, toluene, ether, THF, 1,4-dioxane, t-butyl methyl ether, diglyme, 1; 2-glycol dimethyl ether, 1,4-dioxane, methyl-phenoxide, methylene dichloride, chloroform, tetracol phenixin, 1,2-methylene dichloride (1; 2-dichloromethane), N, dinethylformamide, DMAC N,N, 1; 3-dimethyl--2-imidazolone, 1,3-dimethyl--3,4; 5,6-tetrahydrochysene-2 (1H)-pyrimidone and methyl-sulphoxide.Benzene, 1 preferably, 2-dichlorobenzene and toluene, and more preferably 1, the 2-dichlorobenzene.

As long as above-mentioned reaction can be carried out making under the arbitrary temp that carries out of reaction, preferably 0 ℃～200 ℃, more preferably under 80 ℃～180 ℃, carry out.

Alkali capable of using replaces acid to carry out above-mentioned reaction.The instance of alkali comprises: n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium methide, phenyl lithium, methyl-magnesium-bromide, methylmagnesium-chloride, methyl magnesium iodide, sec.-propyl bromination magnesium, diethylamino lithium, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide, 2; 2; 6; 6-tetramethyl piperidine lithium, lithium amide, sodium hydride, two (trimethyl silyl) sodium amide, potassium hydride KH, two (trimethyl silyl) amination potassium, diisopropylaminoethyl diethyl aluminum, 2; 2,6,6-tetramethyl piperidine diethyl aluminum, sodium hydroxide and Pottasium Hydroxide.Preferably diethylamino lithium, di-isopropyl magnesium, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide, 2; 2,6,6-tetramethyl piperidine lithium, lithium amide, sodium hydride, two (trimethyl silyl) sodium amide, potassium hydride KH, two (trimethyl silyl) amination potassium, diisopropylaminoethyl diethyl aluminum and 2; 2; 6,6-tetramethyl piperidine diethyl aluminum, and diethylamino lithium more preferably.

The examples of solvents that can be used for this reaction comprises: based on the solvent of hydrocarbon, ether, halogen and acid amides.Specific examples comprises: pentane, hexane, benzene, 1,2-dichlorobenzene, toluene, ether, THF, 1,4-dioxane, t-butyl methyl ether, diglyme, 1; 2-glycol dimethyl ether, 1,4-dioxane, methyl-phenoxide, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, N; Dinethylformamide, DMAC N,N, 1,3-dimethyl--2-imidazolone, 1; 3-dimethyl--3,4,5; 6-tetrahydrochysene-2 (1H)-pyrimidone and methyl-sulphoxide, wherein, benzene, toluene, ether and THF are preferred.

As long as the reaction of above-mentioned and alkali can be carried out under the arbitrary temp that reaction is carried out, preferably-40 ℃～200 ℃, more preferably under 0 ℃～100 ℃, carry out.

(the introducing of step 3) side chain

In order to introduce side chain, the compound (C) of preparation and alkylating agent corresponding to side chain are reacted, under alkali so acquisition compound (E).

The alkylating agent that is suitable for is corresponding to the R in formula of the present invention (1) compound ₃That is to say that instance comprises, by corresponding to side chain R ₃The alkylating agent represented of following formula:

Z-(CH ₂) _m-COR ₃

Wherein, Z representes leaving group, for example, and halogen atom, mesyloxy, tosyloxy

Or trifluoro-methanesulfonyl oxy,

Perhaps

CH ₂＝CH-COR ₃

[JP 6-72994A, T.Mikami, T.Iwaoka, M.Kato, H.Watanabe and N.Kubodera, synthesising communication (Synth.Commun.), 27 (14), 1997,2363～2369].

Z-(CH ₂) _m-COR ₃Instance comprise: bromo-acetic acid tert-butyl, N-tert.-butyl bromide ethanamide and the N-tertiary butyl-N-monobromomethane ethanamide.

CH ₂=CH-COR ₃Instance comprise: vinylformic acid, methyl acrylate, ethyl propenoate, vinylformic acid n-propyl, isopropyl acrylate, Bing Xisuandingzhi, tert-butyl acrylate, acrylic amide, N methacrylamide, N; N-DMAA, N-ethyl acrylamide, N, N-diethylammonium acrylic amide and N tert butyl acrylamide.

The instance of alkali comprises, alkalimetal hydride, alkali metal alcoholates, metal dialkyl amides and metal alkylide.Preferably sodium hydride, potassium hydride KH, potassium tert.-butoxide, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide, lithium methide, n-Butyl Lithium and ethylmagnesium bromide, and more preferably sodium hydride and potassium hydride KH.

Above-mentioned reaction can be carried out in the presence of crown ether.The instance of crown ether comprises: 15-hat-5,18-hat-6 and dibenzo-18-hat-6.

The instance of solvent comprises: based on the solvent of hydrocarbon, ether and acid amides.Specific examples comprises: benzene, toluene, ether, THF, 1,2-glycol dimethyl ether, 1,4-diox, DMAC N,N, N; Dinethylformamide, 1,3-dimethyl--2-imidazolone and 1,3-dimethyl--3; 4,5,6-tetrahydrochysene-2 (1H)-pyrimidone.THF, 1 preferably, 2-glycol dimethyl ether, N, dinethylformamide and 1,3-dimethyl--2-imidazolone, and THF more preferably.

Said reaction is under the temperature that the classification according to substrate changes, to carry out, usually at-40 ℃ under the boiling point or the temperature in the decomposition point scope of solvent, preferably under 0 ℃～200 ℃, more preferably carry out under to about 120 ℃ in about room temperature.

The introducing of side chain is not particularly limited to aforesaid method, also can be undertaken by other method well known by persons skilled in the art.

(step 4) is gone protection

By ordinary method, remove the protection base and provide compound (F) from compound (E).

Applicablely go to protect the instance of reagent to comprise: hydrochloric acid, sulfuric acid, acetate, acidic ion exchange resin, tetrabutyl ammonium fluoride, hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine and hydrofluoric acid, wherein acidic ion exchange resin, tetrabutyl ammonium fluoride and hydrogen fluoride/pyridine are preferred.

Above-mentioned go to protect usually in solvent (preferably at THF), carry out based on ether.De-protected temperature of reaction will change according to the classification of substrate, but usually preferably under the temperature of room temperature in 65 ℃ of scopes, goes protection.

(step 5) photoresponse and thermal isomerization

By ordinary method, compound (F) is carried out photoresponse and thermal isomerization and provides compound (G).

Step 3,4 and 5 is not always undertaken by above-mentioned order.These steps can be undertaken by following order: step 3 → step 5 → step 4 or step 5 → step 3 → step 4, as long as step 4 is not prior to step 3.

In each step, if necessary, can modify side chain by currently known methods; For example, solvolysis (comprising hydrolysis)-esterification/amidation, transesterification reaction [Larock; R.C., comprehensive organic transformation (Comprehensive Organic Transformations), the 2nd edition; Wiley-VCH:New York, 1999].

In addition, following arbitrary compound all can be used as the compound of formula (C) and begins to handle from step 3 or 5.

This compound is found in JP 61-267550A or E.Murayama, K.Miyamoto, N.Kubodera, T.Mori and I.Matsunaga, chemistry and pharmacy circular, 34 (10), 1986,4410～4413.

This compound is found in JP 6-86626A and N.Kubodera, H.Watanabe, K.Miyamoto and M.Matsumoto, bioorganic chemistry and medicinal chemistry communication (Bioorg.Med.Chem.Lett.), 3 (9), 1993,1869～1872.

These compounds are found in JP 10-231284A.

II. wherein X is vitamin D-derivatives synthetic of the formula (1) of sulphur atom

(wherein, X is a sulphur atom to the vitamin D-derivatives of formula (1), R ₆Be hydroxyl, and R ₇Be Wasserstoffatoms) can promptly, begin by following method preparation from compound (C) through acquisitions such as above-mentioned steps 1,2:

The introducing of (step 3 ') sulphur functional group

For example following two of compound (C) experience is reacted and is provided compound (I):

Wherein, Z representes leaving group, for example, and chlorine atom, bromine atoms, iodine atom, mesyloxy or tosyloxy.

Can compound (C) be converted into compound (M) by ordinary method (Larock, R.C., comprehensive organic transformation, the 2nd edition, Wiley-VCH:New York, 1999) with a leaving group.

Though such scheme shows compound (C) (wherein, R ₁And R ₂All be Wasserstoffatoms separately, and R ₄And R ₅Form the two keys between 16-and the 17-position together) reaction, but also can handle other situation similarly.

In appropriate solvent, handle compound (M) and synthetic compound (I) with the metal-salt of thiocarboxylic acid or dithionic acid again.

The instance of the metal-salt of thiocarboxylic acid or dithionic acid comprises: sodium thioglycolate, thioacetic acid potassium, thiobenzoic acid sodium, thiobenzoic acid potassium, methyl-carbithionic acid sodium, methyl-carbithionic acid potassium, dithiobenzoic acid sodium and dithiobenzoic acid potassium, wherein thioacetic acid potassium is preferred.

The instance of solvent comprises: based on the solvent of hydrocarbon, ether, halogen, ketone/ester/acid amides, sulfoxide and nitrile.Specific examples comprises: hexane, benzene, toluene, ether, THF, 1,4-diox, 1,2-glycol dimethyl ether, methylene dichloride, chloroform, tetracol phenixin, acetone, ETHYLE ACETATE, N; Dinethylformamide, DMAC N,N, 1,3-dimethyl--2-imidazolone, 1; 3-dimethyl--3; 4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, methyl-sulphoxide and acetonitrile.Preferably ether, THF, 1,4-diox, 1,2-glycol dimethyl ether, acetone, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, 1,3-dimethyl--2-imidazolone and methyl-sulphoxide, and more preferably THF, acetone and methyl-sulphoxide.In addition, these solvents can also make up usefulness.

As long as above-mentioned reaction can be carried out making under the arbitrary temp that carries out of reaction, usually-50 ℃～100 ℃, preferably under room temperature, carry out at 0 ℃.

Above-mentioned two reactions can be carried out continuously,, after hydroxyl is converted into leaving group, do not carry out aftertreatment and the metal-salt processing compound (M) of available thiocarboxylic acid or dithionic acid that is.

Solvolysis of (step 4 ') alkali and S-alkylation

Under alkaline condition, make compound (I) solvolysis carry out the S-alkylation simultaneously and provide compound (J).

The instance of applicable alkali comprises in alkali solvolysis and S-alkylation: Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, sodium methylate and potassium tert.-butoxide, wherein sodium hydroxide, Pottasium Hydroxide and sodium methylate are preferred.

The instance of applicable solvent comprises: water and based on the solvent of alcohol.For example, methyl alcohol, ethanol, propyl alcohol and butanols can be separately with or with following solvent combinations usefulness based on ether, for example, ether, THF, 1,2-glycol dimethyl ether, 1,4-diox or diglyme.

Described in part i step 3, applicable alkylating agent maybe be corresponding to side chain.

This reaction usually-40 ℃～100 ℃, preferably 0 ℃～50 ℃, more preferably at room temperature carry out.

(step 5 ') gone protection

By ordinary method, remove the protection base and provide compound (K) from compound (J).

Applicablely go to protect the instance of reagent to comprise: hydrochloric acid, sulfuric acid, acetate, acidic ion exchange resin, tetrabutyl ammonium fluoride, hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine and hydrofluoric acid, wherein acidic ion exchange resin and tetrabutyl ammonium fluoride are preferred.

Above-mentioned go to protect usually in solvent (preferably at THF), carry out based on ether.De-protected temperature of reaction will change according to the classification of substrate, but usually preferably under the temperature of room temperature in 65 ℃ of scopes, goes protection.

(step 6 ') photoresponse and thermal isomerization

By ordinary method, compound (K) is carried out photoresponse and thermal isomerization and provides compound (L).

Step 3 ', 4 ', 5 ' and 6 ' can be undertaken by any order, as long as step 4 ' with 5 ' not prior to step 3 '.

In addition, following any compound (they are found among the JP 10-231284A) all can be used as formula (I) compound and from step 4 ' begin reaction.

In addition, following any compound (they are found among the JP 10-231284A) all can be used as formula (I) compound and from step 4 ' begin reaction.At this moment, can save step 6 '.

In each step of above-mentioned synthetic schemes I and II, can pass through standards method purifying and the midbody and the end product that separate separately, for example, silica gel column chromatography, tlc and recrystallization.

The present invention can make the compound that advantageously prepares following formula (3), and it can be used as the midbody of preparation formula of the present invention (1) vitamin D-derivatives.

From the compound of the compound formula (3) of formula (2) time, usually with tin tetramethide and zinc methide as reaction reagent.But; Consider and to improve the former from toxicity and reactive aspect; Because its low reactivity is carried out side reaction and desired reaction simultaneously; Need improve the latter from the reactivity consideration then is because its hyperergy makes the desired reaction of having precedence over of side reaction.

By contrast, when utilizing organoaluminum reagent to prepare formula of the present invention (3) compound, this reagent causes taking place side reaction still less, and desired reaction is carried out with highly selective, so, cause the productive rate of reaction product to increase.The reagent that utilizes still is low toxicity.Therefore, compare with routine techniques, the present invention has realized more advantageously preparing the compound of formula (3).This means that the present invention is also more favourable than routine techniques because of the benefit of preparation compound when (3) when the compound of preparation formula (1), when being applied to prepare compound (1), cause the productive rate of compound (1) to increase, and the reagent toxicity of using reduces.

In formula (2), like R ₁₂And R ₁₃The instance of protection base comprise ethanoyl and t-butyldimethylsilyl.Like R ₁₄The instance of leaving group comprise: bromine atoms, iodine atom, trifluoro-methanesulfonyl oxy and nine fluorine fourth sulfonyloxies.The compound of formula (2) can be through the method preparation of describing among the hereinafter embodiment 24 for example.

Then, available carbon monoxide is to the compound carbonylation of formula (2), promptly; At organic solvent (for example, N, dinethylformamide, methyl-sulphoxide, N; N-N,N-DIMETHYLACETAMIDE, 1; 3-dimethyl--2-imidazolone, THF, toluene) in, in the presence of the organoaluminum reagent of formula (4) and palladium catalyst, carry out carbonylation, thereby advantageously provide required formula (3) compound.

The instance of organoaluminum reagent comprises: dimethylaluminum chloride, diethyl aluminum chloride, di aluminum chloride, di-n-butyl aluminum chloride and phenylbenzene aluminum chloride.

The instance of palladium catalyst comprises: four (triphenyl phosphine) palladium, dichloro two (triphenyl phosphine) palladium, dichloro [1,3-two (diphenyl phosphine) propane] palladium, dichloro [1,2-two (diphenyl phosphine) ethane] palladium, two (dibenzalacetone) palladium and three (dibenzalacetones), two palladiums.

In the present invention, if necessary, can be with these catalyzer and following ligand combination usefulness, for example, triphenyl phosphine, tributylphosphine, tricyclohexyl phosphine or tri-butyl phosphine are so that reach higher catalytic activity or higher reaction preference.

Under 0 ℃～150 ℃ temperature, in carbon monoxide atmosphere, standard atmosphere pressure carry out under the high pressure (about at the most 20atm) carbonylation reach about 10 minutes～about 12 hours.

Formula (3) compound of preparation can be used as the midbody of synthetic formula of the present invention (1) vitamin D-derivatives like this.

That is to say, can be through the method for describing among the hereinafter embodiment 25 for example, from the compound of the compound formula (1) of formula (3).

In formula (3), R ₁₂And R ₁₃All suc as formula the definition in (2), and R ₁₅Expression: alkyl, for example, methyl, ethyl, propyl group and butyl; Aryl, for example, phenyl; Thiazolinyl, for example, vinyl; Perhaps alkynyl, for example, ethynyl.

Shown in hereinafter embodiment, formula (1) vitamin D-derivatives of preparation is to have compounds suitable for use on the medicine of less hypercalcemia effect like this.

The pharmaceutical composition that comprises vitamin D-derivatives of the present invention can be made into required formulation; For example; Tablet, particle, fine particle, capsule, pulvis, injection liquid, solution, suspension-s, emulsion, preparation absorbed through skin or suppository are with combinations such as pharmaceutically acceptable carrier, vehicle, disintegrating agent, lubricant, tackiness agent, seasonings, tinting materials.

If be used for tetter, the therapeutical agent that comprises as the vitamin D-derivatives of the present invention of active ingredient is used to psoriasic reaction etc., and this therapeutical agent can be made into the formulation that is fit to external application, for example, and ointment, emulsifiable paste or lotion.

Comprising disease category, the patient's condition, physique, quality, patient's age and sex, the drug delivery route of expection or the classification of formulation etc. that can treat as required as the dosage of the therapeutical agent of the vitamin D-derivatives of the present invention of active ingredient suitably confirms.The amount that said therapeutical agent is usually used as active ingredient is: during oral administration 0.001～10,000 μ g/ days, and preferred 0.01～1,000 μ g/ days; Injection during dispenser 0.01～10,000 μ g/ days, preferred 0.1～1,000 μ g/ days; During outside dispenser then is 1～50,000 μ g/ days, and preferred 10～5,000 μ g/ days, these dosage can be disposable employed or be divided into the equal divided dose dispenser of a day twice or three times.

If be used for tetter; The therapeutical agent that comprises as the vitamin D-derivatives of the present invention of active ingredient is used to psoriasic reaction etc.; This therapeutical agent preferably through topical application (for example; External application) comes dispenser, but in some cases, also can come the general dispenser through per os or parenteral route.

Embodiment

To in following embodiment, further describe the present invention, and provide them just in order to set forth rather than to want to limit scope of the present invention.

In these embodiment, unless otherwise indicated, each NMR spectrum all is at CDCl ₃Middle mensuration, and utilize tetramethylene silane or chloroform as interior mark.Each mass spectrum (MS) all is to measure by the EI mode with under the ionization voltage of 70eV.Each uv absorption spectrum (UV) is all measured in alcohol solvent.Column chromatography and preparative thin layer chromatography are to utilize silica gel (75～150 μ m or 40～63 μ m) and silica gel respectively (thickness: 1mm, 0.5mm or 0.25mm, each is 20 * 20cm) years old.

(embodiment 1) 17-ethanoyl thiomethyl-1 α, 3 β-two (t-butyldimethylsilyloxy base) androstane-5,7, the preparation of 16-triolefin

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(2,4,6-tri isopropyl benzenesulfonyl hydrazono-) androstane-5, the preparation of 7-diene

With 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-oxo androstane-5, (1.64g, 3.08mmol) with 2,4, (1.01g 3.39mmol) is dissolved in ETHYLE ACETATE (6ml) and also at room temperature stirred 16 hours 6-tri isopropyl benzenesulfonyl hydrazine the 7-diene.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE=15: 1) resistates that generates of purifying is given prepared title compound (1.86g, 75%) through column chromatography.

¹H?NMRδ：7.15(s，2H)，6.98(brs，1H)，5.58(d，J＝5.8Hz，1H)，5.40-5.33(m，1H)，4.28-4.20(m，2H)，4.18-3.93(m，1H)，3.70-3.63(m，1H)，2.95-2.74(m，2H)，1.30-1.22(m，24H)，0.88(s，9H)，0.85(s，9H)，0.68(s，3H)，0.09(s，3H)，0.06(s，3H)，0.04(s，3H)，0.03(s，3H)。IR(KBr)：3232，2956，2860，1600，1462，1426，1384，1372，1362，1328，1254，1214，1194，1166，1154，1102，1038，1006，968，952，938，928，916，878，834，774，716，666，548cm ^-1。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(methylol) androstane-5,7,16-triolefin

With 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(2,4; 6-tri isopropyl benzenesulfonyl hydrazono-) androstane-5; The 7-diene (32.7mg, 0.0403mmol) solution in hexane (0.8ml) and Tetramethyl Ethylene Diamine (0.16ml) is cooled to-78 ℃, then; Interpolation 1.53M n-Butyl Lithium (0.106ml, 0.161mmol).Under-78 ℃, reaction mixture was stirred 2 hours, be warmed to 0 ℃ and stirred 15 minutes then.Add paraformaldehyde (10mg, 0.33mmol) after, under 0 ℃, reaction mixture was stirred 1 hour, at room temperature stirred again 1 hour.In reaction mixture, add sodium chloride aqueous solution, use dichloromethane extraction then, dry on SODIUM SULPHATE ANHYDROUS 99PCT, evaporation and remove and desolvate.(hexane: ETHYLE ACETATE=6: 1) resistates of purifying generation provides title compound (13.6mg, 62%) through column chromatography.

(3) 17-ethanoyl thiomethyl-1 α, 3 β-two (t-butyldimethylsilyloxy base) androstane-5,7, the preparation of 16-triolefin

Toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(methylol) androstane-5,7; The 16-triolefin (4.00g, add in THF 7.34mmol) (70ml) solution triethylamine (4.10ml, 29.4mmol); Further drip methylsulfonyl chloride (1.70ml down at-10 ℃; 22.0mmol), then, stirred 20 minutes.After being warmed to room temperature, in reaction mixture, add thioacetic acid potassium (3.73g, methyl-sulphoxide 29.4mmol) (70ml) solution.Reaction mixture was stirred 30 minutes,, use water washing with the hexane dilution, dry on anhydrous magnesium sulfate again.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE=15: 1) resistates that generates of purifying provided colorless oil title compound (3.91g, 88%) through silica gel column chromatography.

IR (pure): 2954,2929,2897,2856,1695,1471,1462,1371,1360,1254,1099cm ^{-1 1}H?NMRδ：0.05(s，1H)，0.07(s，3H)，0.07(s，3H)，0.11(s，3H)，0.82(s，3H)，0.88(s，18H)，0.94(s，3H)，2.34(s，3H)，2.79-2.90(m，1H)，3.52-3.68(m，2H)，3.68-3.73(m，1H)，3.98-4.12(m，1H)，5.35-5.41(m，1H)，5.57-5.64(m，2H)。MS?m/z：602(M ⁺)，413(100％)。UV?λ _max?nm：234，261，271，281，294。

(embodiment 2)

With step (1) and (2) in the following step (1) and (2) alternate embodiment 1.

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base) androstane-5,7-diene-(17S)-spiral shell-2 '-preparation of oxyethane

(60% in oil, and 0.2821g 7.06mmol) is added in the methyl-sulphoxide (13ml) and at 80 ℃ to descend to stir 1 hour with sodium hydride.The suspension-s that forms is cooled to 0 ℃, and with THF (19ml) dilution, then, (1.33g, (9ml) solution of methyl-sulphoxide 6.50mmol) also stirred 35 minutes under 0 ℃ toward wherein dripping trimethyl sulfonium iodide.Subsequently, add 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-oxo androstane-5, (1.0g, THF 1.88mmol) (7ml) solution also at room temperature stirred 14 hours the 7-diene.With reaction mixture impouring saturated aqueous ammonium chloride, use ethyl acetate extraction, water and saturated sodium-chloride water solution washing, then, dry on SODIUM SULPHATE ANHYDROUS 99PCT.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE=6: 1) the purifying resistates provided white foam shape title compound (0.93g, 91%) through column chromatography.

¹H?NMRδ：0.05(s，3H)，0.06(s，3H)，0.07(s，3H)，0.11(s，3H)，0.88(s，3H)，0.89(s，3H)，2.65(d，J＝4.9Hz，1H)，2.93(d，J＝4.9Hz，1H)，3.71(brs，1H)，3.98-4.12(m，1H)，5.35-5.43(m，1H)，5.57-5.64(m，1H).

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(methylol) androstane-5,7, the preparation of 16-triolefin

In argon atmospher, toward 1 α, 3 β-two (t-butyldimethylsilyloxy base) androstane-5; 7-diene-(17S)-spiral shell-2 '-oxyethane (20g, 36.7mmol) 1, add aluminum isopropylate (22g in 2-dichlorobenzene (130ml) solution; 108mmol), stirred 1.5 hours down at 130 ℃.In reaction mixture, add Rochelle's salt solution, it with ethyl acetate extraction (twice), then, is used water washing, dry on SODIUM SULPHATE ANHYDROUS 99PCT.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE=6: 1) resistates that generates of purifying provided title compound (10g, 50%) white solid through column chromatography.

IR (pure): 3392,2954,2929,2856,1462,1254,1097,1082cm ^{-1 1}H?NMRδ：0.05(s，3H)，0.07(s，6H)，0.11(s，3H)，0.88(s，3H)，0.89(s，3H)，3.71(brs，1H)，4.00(brs，1H)，4.22(s，2H)，5.40(brs，1H)，5.57-5.66(m，2H)。MS?m/z：544(M ⁺)，355(100％)。UV?λ _max?nm：270，281，293。

(embodiment 3) 17-ethanoyl thiomethyl-1 α, 3 β-two (t-butyldimethylsilyloxy base) androstane-5,7, the preparation of 16-triolefin

Step among the embodiment 1 (1) and (2) are then carried out following steps afterwards and are replaced step (3).

Under 0 ℃, toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(methylol) androstane-5; 7; The 16-triolefin (100mg, 0.183mmol), triphenyl phosphine (96.0mg, 0.366mmol) and imidazoles (49.8mg; 0.732mmol) methylene dichloride (2ml) solution in add the N-bromo-succinimide (65.1mg 0.366mmol) and at room temperature stir.After 1 hour, in reaction mixture, add hexane, then, water and saturated sodium-chloride water solution washing.After drying on the anhydrous magnesium sulfate, decompression provides except that desolvating down and contains 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(brooethyl) androstane-5,7, the mixture of 16-triolefin (150mg).This mixture is dissolved in acetone (1.5ml), then, add thioacetic acid potassium (31.4mg, 0.275mmol) and stirred 30 minutes.Use the hexane diluted reaction mixture, filter.The filtrating that vapourisation under reduced pressure produces and remove and desolvate provides colorless oil title compound (70.2mg, 64%) through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=20: 1, launch once) purifying resistates.

(embodiment 4)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(N, N-dimethylamino carbonyl oxyethyl group) is pregnant-5,7, the preparation of 16-triolefin

In nitrogen gas stream, toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls pregnant-5; 7, and the 16-triolefin (400mg, (60% in oil to add sodium hydride in THF 0.72mmol) (7.2ml) solution; 46mg 1.15mmol) also at room temperature stirred 30 minutes.Add N, the N-DMAA (308mg, 3.11mmol) after; Further under uniform temp, reaction mixture was stirred 3 hours; With mixture impouring saturated aqueous ammonium chloride, with ethyl acetate extraction (3 times), with saturated sodium-chloride water solution and water washing.Dry organic layer on anhydrous magnesium sulfate.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE=2: 1) resistates that generates of purifying provided colorless oil title compound (459mg, 96.9%) through column chromatography.

IR (pure): 2954,2929,2895,2856,1655,1462,1389,1371,1254,1149,1097cm ^{-1 1}H?NMR?δ：0.05(s，3H)，0.06(s，6H)，0.11(s，3H)，0.88(s，21H)，0.94(s，3H)，1.30(d，J＝6.6Hz，3H)，2.60(t，J＝6.9Hz，2H)，2.78-2.90(m，1H)，2.94(s，3H)，3.02(s，3H)，3.57-3.80(m，3H)，3.90-4.11(m，2H)，5.35-5.43(m，1H)，5.57-5.64(m，2H)。MS?m/z：540(M ⁺-HO(CH ₂) ₂CONMe ₂)，73(100％)。UVλ _maxnm：271，282，294。

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(N, N-dimethylamino carbonyl oxyethyl group) is pregnant-5,7, the preparation of 16-triolefin

In nitrogen gas stream; Toward 1 α; 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(N, N-dimethylamino carbonyl oxyethyl group) pregnant-5,7; (100mg adds the tetrahydrofuran solution (1.5ml) of 1M tetra-n-butyl Neutral ammonium fluoride and descends stirring 1 hour at 50 ℃ the 16-triolefin in THF 0.15mmol) (6.0ml) solution.Behind the cool to room temperature, use the ETHYLE ACETATE diluted reaction mixture, subsequently,, then, dry on anhydrous magnesium sulfate successively with 0.5N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.After vapourisation under reduced pressure and remove desolvates, through preparative thin layer chromatography (1.0mm * 2 block plate, chloroform: the resistates that generates of purifying and provide colourless foam shape title compound (45mg, 70.3%) methyl alcohol=10: 1).

IR (pure): 3359,2970,2935,2918,2873,2837,1624,1417,1361,1257,1196,1151,1097,1053cm ^{-1 1}H?NMR?δ：0.87(s，3H)，0.97(s，3H)，1.29(d，J＝6.3Hz，3H)，2.59(t，J＝6.9Hz，2H)，2.73-2.85(m，1H)，2.93(s，3H)，3.02(s，3H)，3.53-3.66(m，1H)，3.69-3.81(m，2H)，3.92-4.13(m，2H)，5.40-5.48(m，1H)，5.60(brs，1H)，5.70-5.76(m，1H)。MS?m/z：312(M ⁺-HO(CH ₂) ₂CONMe ₂)，72(100％)。UVλ _maxnm：271，282，293。

(3) 1 α, 3 beta-dihydroxyies-20 (S)-(N, N-dimethylamino carbonyl oxyethyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

With 1 α, 3 beta-dihydroxyies-20 (S)-(N, N-dimethylamino carbonyl oxyethyl group) is pregnant-5,7, and (60mg 0.14mmol) is dissolved in ethanol (200ml) to the 16-triolefin.When bubbling feeds argon under 0 ℃ of stirring, utilize the 400W high voltage mercury lamp that is equipped with the Vycor filter, then, heated 2 hours down refluxing the solution irradiation that generates 5 minutes.Behind the cool to room temperature, vapourisation under reduced pressure reaction mixture and remove and to desolvate, through preparative thin layer chromatography (0.5mm * 3 block plate, methylene dichloride: ethanol=20: 1, launch three times; 0.5mm * 2 blocks of plates, hexane: ETHYLE ACETATE: ethanol=3: 7: 0.5, launch three times; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=2: 8: 0.5, launch three times) resistates that generates of purifying and provide colorless oil title compound (5.333mg, 8.9%).

IR (pure): 3400,2930,2848,1633,1628,1103,1055cm ^{-1 1}HNMR?δ：0.77(s，3H)，1.29(d，J＝6.6Hz，3H)，2.59(t，J＝6.9Hz，2H)，2.74-2.86(m，1H)，2.93(s，3H)，3.02(s，3H)3.52-3.65(m，1H)，3.68-3.80(m，1H)，3.94(q，J＝6.6Hz，1H)，4.17-4.29(m，1H)，4.39-4.48(m，1H)，5.01(brs，1H)，5.33(brs，1H)，5.57(brs，1H)，?6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：429(M ⁺)，118(100％)。UVλ _maxnm：264。

(embodiment 5)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(N, N-dimethylamino carbonyl oxyethyl group) is pregnant-5,7, the preparation of 16-triolefin

Press and identical method shown in the embodiment 4 (1), use N, N-DMAA (175mg; 1.77mmol) and sodium hydride (60% in oil, 36mg, THF 0.91mmol) (5.7ml) solution-treated 1 α; 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-hydroxyls are pregnant-5,7,16-triolefin (316mg; 0.57mmol) (handled 1.5 hours down at 0 ℃, at room temperature handled again 1.5 hours), then; Carry out aftertreatment and utilize column chromatography (hexane: purifying and provide colorless oil title compound (352mg, 93.9%) ETHYLE ACETATE=2: 1).

IR (pure): 3280,2954,2929,2885,2856,1628,1464,1402,1373, l255,1097cm ^{-1 1}H?NMR?δ：0.05(s，3H)，0.07(s，6H)，0.11(s，3H)，0.83(s，3H)，0.88(s，18H)，0.94(s，3H)，1.32(d，J＝6.3Hz，3H)，2.63(t，J＝6.9Hz，2H)，2.79-2.90(m，1H)，2.94(s，3H)，3.01(s，3H)，3.66-3.79(m，3H)，3.96-4.09(m，2H)，5.34-5.42(m，1H)，5.56-5.66(m，2H)。MS?m/z：540(M ⁺-HO(CH ₂) ₂CONMe ₂)，73(100％)。UVλ _maxnm：271，282，294。

(2) 1 α, 3 beta-dihydroxyies-20 (R)-(N, N-dimethylamino carbonyl oxyethyl group) is pregnant-5,7, the preparation of 16-triolefin

Press and identical method shown in the embodiment 4 (2), in THF (6.0ml) solution, handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(N with the tetrahydrofuran solution (1.5ml) of 1M tetra-n-butyl Neutral ammonium fluoride; N-dimethylamino carbonyl oxyethyl group) pregnant-5,7,16-triolefin (100mg; 0.15mmol) (at room temperature handled 30 minutes; Handled 1.5 hours down at 50 ℃ again), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Chloroform: purifying and provide colourless foam shape title compound (52mg, 83.0%) methyl alcohol=10: 1).

IR (pure): 3390,2962,2933,2875,1624,1456,1398,1373,1267,1157,1097,1057cm ^{-1 1}H?NMR?δ：0.84(s，3H)，0.98(s，3H)，?1.32(d，J＝6.6Hz，3H)，2.60(t，J＝7.3Hz，2H)，2.73-2.85(m，1H)，2.94(s，3H)，3.01(s，3H)，3.72(t，J＝7.3Hz，2H)，3.78(brs，1H)，3.97-4.13(m，2H)，5.42-5.49(m，1H)，5.65(brs，1H)，5.72-5.78(m，1H)。MS?m/z：312(M ⁺-HO(CH ₂) ₂CONMe ₂)，72(100％)。UVλ _maxnm：271，281，293。

(3) 1 α, 3 beta-dihydroxyies-20 (R)-(N, N-dimethylamino carbonyl oxyethyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (200ml), handle 1 α, 3 beta-dihydroxyies-20 (R)-(N; N-dimethylamino carbonyl oxyethyl group) pregnant-5,7,16-triolefin (50mg; 0.12mmol) (with photoirradiation 4 minutes 45 seconds, in the heating down 2 hours that refluxes), follow; Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch three times; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=2: 8: 0.5, launch three times) purifying and provide colorless oil title compound (3.427mg, 6.9%).

IR (pure): 3400,2929,1633,1055cm ^{-1 1}H?NMR?δ：0.73(s，3H)，1.31(d，J＝6.6Hz，3H)，2.59(t，J＝7.3Hz，2H)，2.75-2.85(m，1H)，2.94(s，3H)，3.02(s，3H)，3.72(t，J＝7.3Hz，2H)，3.99(q，J＝6.6Hz，1H)，4.18-4.30(m，1H)，4.39-4.49(m，1H)，5.01(brs，1H)，5.33(brs，1H)，5.60(brs，1H)，6.10(d，J＝11.6Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：429(M ⁺)，72(100％)。UVλ _maxnm：265。

(embodiment 6)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(N, N-dimethylamino carbonyl ethoxyl methyl) androstane-5,7, the preparation of 16-triolefin

Press and identical method shown in the embodiment 4 (1), use N, N-DMAA (540mg; 5.44mmol) and sodium hydride (60% in oil, and 105mg 2.62mmol) handles 1 α in THF (17.5ml); 3 β-two (t-butyldimethylsilyloxy base)-17-methylol androstane-5,7,16-triolefin (951mg; 1.75mmol) (handling 14 hours down at 5 ℃); Then, carry out aftertreatment and utilize column chromatography (hexane: purifying and provide yellow oily title compound (1.05g, 92.7%) ETHYLE ACETATE=2: 1).

IR (pure): 2954,2929,2895,2856,1653,1462,1398,1371,1254,1097,1074cm ^{-1 1}H?NMR?δ：0.05(s，3H)，0.06(m，6H)，0.11(s，3H)，0.82(s，3H)，0.877(s，9H)，0.881(s，9H)，0.94(s，3H)，2.62(t，J＝6.6Hz，2H)，2.80-2.90(m，1H)，2.94(s，3H)，3.02(s，3H)，3.70(brs，1H)，3.76(t，J＝6.6Hz，2H)，3.96-4.12(m，4H)，5.34-5.42(m，1H)，5.55-5.67(m，2H)。MS?m/z：644(M ⁺-1)，73(100％)。UVλ _maxnm：271，281，293。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(N, N-dimethylamino carbonyl ethoxyl methyl)-9,10-open loop androstane-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (350ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(N; N-dimethylamino carbonyl ethoxyl methyl) androstane-5,7,16-triolefin (300mg; 0.47mmol) (with photoirradiation 13 minutes 30 seconds, reflux heated 2 hours down), then; Decompression is evaporated down and is removed and desolvate, thereby provides the yellow oil (300mg) that contains required product.

(3) 1 α, 3 beta-dihydroxyies-17-(N, N-dimethylamino carbonyl ethoxyl methyl)-9,10-open loop androstane-5,7,10 (19), the preparation of 16-tetraene

The oil (300mg) of embodiment 6 (2) is dissolved in THF (30ml) and methyl alcohol (30ml), and then, toward wherein adding AMBERLYST 15 (11.1g), in nitrogen gas stream, at room temperature stirred 4 hours the dark place.Leach insoluble product through CELITE, use methanol wash.In filtrating, add sodium hydrogencarbonate and stirred then filtration 5 minutes.Concentrated filtrate under reduced pressure; Through preparative thin layer chromatography (1.0mm * 3 block plate, methylene dichloride: ethanol=20: 1, then; 0.5mm * 3 blocks of plates; Hexane: ETHYLE ACETATE: ethanol=2: 8: 0.5, launch three times) resistates that generates of purifying and provide colorless oil title compound (10.282mg, 5.5%).

IR (pure): 3400,2929,2875,2850,1633,1500,1402,1159,1059cm ^{-1 1}H?NMRδ：0.72(s，3H)，2.62(t，J＝6.6Hz，2H)，2.54-2.66(m，1H)，2.75-2.86(m，1H)，2.94(s，3H)，3.02(s，3H)，3.68-3.78(m，2H)，3.96-4.09(m，2H)，4.18-4.29(m，1H)，4.39-4.48(m，1H)，5.00(brs，1H)，5.33(brs，1H)，5.60(brs，1H)，6.09(d，J＝11.6Hz，1H)，6.36(d，J＝11.2Hz，1H)。MS?m/z：298(M ⁺-HO(CH ₂) ₂CONMe ₂)，72(100％)。UVλ _maxnm：264。

(embodiment 7) 1 α, 3 beta-dihydroxyies-20 (S)-(N, N-dimethylamino carbonyl oxyethyl group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 4 (3), in ethanol (200ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(N; N-dimethylamino carbonyl oxyethyl group) pregnant-5; 7-diene (220mg, 0.33mmol) (with photoirradiation 12 minutes, reflux heated 2 hours down); Then, decompression is evaporated down and is removed and desolvate.Press and identical method shown in the embodiment 6 (3); In THF (20ml) and methyl alcohol (20ml), handle the resistates (210mg) (at room temperature handling 5 hours) that generates with AMBERLYST 15 (7.4g); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 7 block plate, methylene dichloride: ethanol=20: 1, launch three times; 0.5mm * 2 blocks of plates, hexane: ETHYLE ACETATE: ethanol=2: 8: 0.5, launch three times; Then, 0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, launch twice) thereby purifying provides colorless oil title compound (7.202mg, two steps 5.1%).

IR (pure): 3400,2927,2873,1633,1628,1446,1417,1149,1095,1059cm ^{-1 1}H?NMR?δ：0.51(s，3H)，1.16(d，J＝5.9Hz，3H)，2.75-2.88(m，1H)，2.93(s，3H)，3.02(s，3H)，3.20-3.33(m，1H)，3.51-3.63(m，1H)，3.80-3.92(m，1H)，4.17-4.27(m，1H)，4.38-4.47(m，1H)，4.99(brs，1H)，5.32(brs，1H)，6.02(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)。MS?m/z：296(M ⁺-HO(CH ₂) ₂CONMe ₂-H ₂O)，72(100％)。UVλ _maxnm：264。

(embodiment 8)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl methoxyl group) is pregnant-5,7, the preparation of 16-triolefin

Under 72 ℃ outside temperature with 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls pregnant-5,7; The 16-triolefin (55.5mg, 0.0993mmol), sodium hydride (95%, 15mg; 0.594mmol) and 15-hat-5 (15mg, 0.0681mmol) solution stirring in THF (1ml) is 1 hour, then; At room temperature (0.05ml 0.336mmol), further stirred 5 hours 15 minutes under 72 ℃ outside temperature toward wherein adding bromo-acetic acid tert-butyl.After the ETHYLE ACETATE diluted reaction mixture, at the ice-cooled water that drips down.After the saturated sodium-chloride water solution washing, dry organic layer on anhydrous magnesium sulfate.After vapourisation under reduced pressure removes and desolvates, provide colorless oil title compound (55.1mg, 82%) through the resistates of preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=10: 1, expansion are once) purifying generation.

IR (pure): 2928,2856,1748,1088,832cm ^{-1 1}H?NMR?δ：0.05(s，3H)，0.06(s，6H)，0.10(s，3H)，0.86(s，3H)，0.88(s，18H)，0.94(s，3H)，1.36(d，J＝6.3Hz，3H)，1.46(s，9H)，2.79-2.91(m，1H)，3.69(brs，1H)，3.82(d，J＝16.5Hz，1H)，3.94(d，J＝16.5Hz，1H)，3.98-4.15(m，2H)，4.09(q，J＝6.3Hz，1H)，5.35-5.43(m，1H)，5.57-5.66(m，2H)。UVλ _maxnm：271，282，294。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (200ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl methoxyl group) pregnant-5; 7; 16-triolefin (52.2mg, 0.0775mmol) (with photoirradiation 4 minutes 20 seconds, reflux heated 2 hours down); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=20: 1, launch twice) thus purifying provides the mixture (16.6mg) that contains title compound.

(3) 20 (S)-(tert-butoxycarbonyl methoxyl group)-1 α, 3 beta-dihydroxyies-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

The mixture (16.6mg) of embodiment 8 (2) is dissolved in THF (2.5ml), then, toward wherein add hydrogen fluoride/pyridine (70%, 1ml) and at room temperature stirred 30 minutes.Use the ETHYLE ACETATE diluted reaction mixture, water (twice), saturated sodium bicarbonate aqueous solution (three times) and saturated sodium-chloride water solution (once) washing are dry on anhydrous magnesium sulfate successively, and vapourisation under reduced pressure removes and desolvates then.Through preparative thin layer chromatography (0.25mm * 1 block plate, methylene dichloride: ethanol=20: 1, launch three times; 0.25mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch five times; Then, 0.25mm * 1 block plate, methylene dichloride: ETHYLE ACETATE=3: 1, launch three times) resistates that generates of purifying and provide colorless oil title compound (1.77mg, two steps 5%).

IR (pure): 3400,2976,2932,1746,1122cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.36(d，J＝6.4Hz，3H)，1.47(s，9H)，2.37-2.47(m，1H)，2.55-2.66(m，1H)，2.76-2.89(m，1H)，3.81(d，J＝16.3Hz，1H)，3.94(d，J＝16.3Hz，1H)，4.07(q，J＝6.4Hz，1H)，4.19-4.31(m，1H)，4.41-4.50(m，1H)，5.01(s，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CO ₂C(CH ₃) ₃)，57(100％)。UVλ _maxnm：263。

(embodiment 9)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(tert-butoxycarbonyl methoxyl group) is pregnant-5,7, the preparation of 16-triolefin

Press and identical method shown in the embodiment 8 (1), (60% in oil, 77mg with sodium hydride; 1.925mmol), (67mg is 0.304mmol) with bromo-acetic acid tert-butyl (0.25ml, 1.679mmol) processing 1 α for THF (6ml), 15-hat-5; 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-hydroxyls are pregnant-5,7,16-triolefin (158mg; 0.283mmol) (under 85 ℃ outside temperature, handling 11 hours 40 minutes), then, carry out aftertreatment.ETHYLE ACETATE=10: 1) and the resistates that generates of preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=20: 1, launch twice) purifying and provide colorless oil title compound (142.6mg, 75%) through column chromatography (hexane:.

IR (pure): 2932,2856,1748,1100,834cm ^{-1 1}H?NMRδ：0.05(s，3H)，0.07(s，6H)，0.11(s，3H)，0.85(s，3H)，0.88(s，18H)，0.94(s，3H)，1.37(d，J＝6.6Hz，3H)，1.47(s，9H)，2.78-2.91(m，1H)，3.70(brs，1H)，3.86(d，J＝16.4Hz，1H)，3.96(d，J＝16.4Hz，1H)，3.98-4.13(m，1H)，4.15(q，J＝6.6Hz，1H)，5.35-5.46(m，1H)，5.61(d，J＝5.4Hz，1H)，5.66(brs，1H)。UVλ _maxnm：271，282，294。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(tert-butoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (200ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(tert-butoxycarbonyl methoxyl group) pregnant-5; 7, (108.3mg is 0.161mmol) (with photoirradiation 6.5 minutes for the 16-triolefin; Heating is 1.5 hours under refluxing), then, utilize preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE=20: 1, launch twice) purifying and provide the mixture (25.6mg) that contains title compound.

(3) 20 (R)-(tert-butoxycarbonyl methoxyl group)-1 α, 3 beta-dihydroxyies-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in 4 (2); Tetrahydrofuran solution (0.35ml with 1M tetra-n-butyl Neutral ammonium fluoride; 0.35mmol) mixture (25.6mg) of processing embodiment 9 (2) (under 47.5 ℃ outside temperature, handling 4 hours) in THF (2.5ml), carry out aftertreatment then.Through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=15: 1, launch four times; 0.25mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times; Then, 0.25mm * 1 block plate, methylene dichloride: ETHYLE ACETATE=3: 1, launch three times) resistates that generates of purifying and provide colorless oil title compound (3.169mg, 2 steps 4%).

IR (pure): 3400,2932,1744,1162,1124,1056,732cm ^{-1 1}HNMRδ：0.76(s，3H)，1.37(d，J＝6.4Hz，3H)，1.47(s，9H)，2.41-2.54(m，1H)，2.54-2.69(m，1H)，2.76-2.91(m，1H)，3.85(d，J＝16.3Hz，1H)，3.95(d，J＝16.3Hz，1H)，4.12(q，J＝6.6Hz，1H)，4.17-4.31(m，1H)，4.39-4.52(m，1H)，5.01(s，1H)，5.34(s，1H)，5.64(brs，1H)，6.10(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：312(M ⁺-HOCH ₂C(O)OC(CH ₃) ₃)，57(100％)。UVλ _maxnm：263。

(embodiment 10)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(tert-butoxycarbonyl methoxymethyl) androstane-5,7, the preparation of 16-triolefin

Under 88 ℃ outside temperature, with 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-methylol androstane-5; 7, and the 16-triolefin (1.0g, 1.84mmol), (60% in oil for sodium hydride; 220mg; 5.50mmol), 15-hat-5 (400mg, 1.82mmol) and bromo-acetic acid tert-butyl (0.55ml, 3.69mmol) solution stirring in THF (20ml) is 1 hour 15 minutes.Filter with the ETHYLE ACETATE diluted reaction mixture and through CELITE.In filtrating, drip water down ice-cooled, then, wash with saturated sodium-chloride water solution.Dry organic layer on anhydrous magnesium sulfate.After vapourisation under reduced pressure removed and desolvates, (hexane: ETHYLE ACETATE=20: 1) resistates of purifying generation provided colorless oil title compound (946.6mg, 78%) through column chromatography.

IR (pure): 2952,2928,2892,2856,1748,1460,1370,1252,1098,968,834,774cm ^{-1 1}H?NMR?δ：0.05(s，3H)，0.06(s，6H)，0.11(s，3H)，0.84(s，3H)，0.88(s，18H)，0.94(s，3H)，1.48(s，9H)，2.79-2.92(m，1H)，3.70(brs，1H)，3.95(s，2H)，4.13(s，2H)，3.97-4.20(m，1H)，5.35-5.43(m，1H)，5.60(d，J＝5.4Hz，1H)，5.69(s，1H)。MS?m/z：526(M ⁺-HOCH ₂CO ₂C(CH ₃) ₃，57(100％)。UVλ _maxnm：271，281，294。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(tert-butoxycarbonyl methoxymethyl)-9,10-open loop androstane-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (200ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-(tert-butoxycarbonyl methoxymethyl) androstane-5; 7, (168mg is 0.255mmol) (with photoirradiation 10 minutes for the 16-triolefin; Heating is 1.5 hours under refluxing), then, utilize preparative thin layer chromatography (0.5mm * 3 block plate; Hexane: ETHYLE ACETATE=15: 1, launch twice) purifying and provide the mixture (35.8mg) that contains title compound.

(3) 1 α, 3 beta-dihydroxyies-17-(tert-butoxycarbonyl methoxymethyl)-9,10-open loop androstane-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (2); Tetrahydrofuran solution (0.35ml with 1M tetra-n-butyl Neutral ammonium fluoride; 0.35mmol) mixture (35.8mg) of processing embodiment 10 (1) (under 45 ℃ outside temperature, handling 2 hours) in THF (1ml), carry out aftertreatment then.Through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=15: 1, launch once; 0.25mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times; 0.25mm * 1 block of plate, methylene dichloride: ethanol=20: 1, launch twice and methylene dichloride: ethanol=15: 1, launch twice; Then, 0.25mm * 1 block plate, methylene dichloride: ETHYLE ACETATE=3: 1, launch twice) resistates that generates of purifying and provide colorless oil title compound (0.649mg, two steps 0.6%).

IR (pure): 3352,2928,1744,1452,1368,1226,1162,1130,1056cm ^{-1 1}H?NMRδ：0.74(s，3H)，1.48(s，9H)，2.53-2.67(m，1H)，2.75-2.89(m，1H)，3.95(s，2H)，4.12(brs，2H)，4.17-4.30(m，1H)，4.39-4.50(m，1H)，5.01(s，1H)，5.33(s，1H)，5.65(s，1H)，6.09(d，J＝11.5Hz，1H)，6.37(d，J＝11.5Hz，1H)。MS?m/z：430(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 11)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3); In ethanol (270ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-5,7; 16-triolefin (1.0g; 1.79mmol) (with photoirradiation 1 hour, in the heating down 2 hours that refluxes), utilize column chromatography (hexane: methylene dichloride: ETHYLE ACETATE=9: 1: 0.5) separate and provide the level branch (250mg) that contains the required product of colourless foam shape.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(tert-butoxycarbonyl oxyethyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

With the same terms shown in the embodiment 4 (1) under, (60% in oil, 4.5mg with sodium hydride; 0.11mmol), (55mg 0.43mmol) handles 1 α that contains from embodiment 11 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9 for THF (0.7ml) and tert-butyl acrylate; 10-open loop pregnant-5,7,10 (19); The level of 16-tetraene is divided (40mg); Then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: methylene dichloride: ethanol=9: 1: 0.5) separate and provide the level that colorless oil contains required product and divide (42mg).Press and identical method shown in the embodiment 4 (2); In THF (2.4ml), further handle above-mentioned level with the tetrahydrofuran solution (0.6ml) of 1M tertiary butyl Neutral ammonium fluoride and divide (42mg) (reaching 1.5 hours); Then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice; 0.5mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch four times; Then, 0.5mm * 1 block plate, methylene dichloride: ETHYLE ACETATE=1: 3, launch four times) resistates that generates of purifying and provide colorless oil title compound (3.276mg, 3 steps 1.22%).

IR (pure): 3383,2976,2931,2869,2850,1732,1448,1367,1255,1159,1105,1054cm ^{-1 1}H?NMR?δ：0.78(s，3H)，1.28(d，J＝6.6Hz，3H)，1.45(s，9H)，2.46(t，J＝6.6Hz，2H)，2.56-2.65(m，1H)，2.76-2.87(m，1H)，3.45-3.57(m，1H)，3.60-3.72(m，1H)，3.92(q，J＝6.6Hz，1H)，4.18-4.31(m，1H)，4.39-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.57(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：458(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 12) 1 α, 3 beta-dihydroxyies-20 (R)-(N, N-dimethylamino carbonyl oxyethyl group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 4 (3), in ethanol (200ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-hydroxyls pregnant-5; 7-diene (100mg; 0.18mmol) (with photoirradiation 5 minutes 45 seconds, in the heating down 2 hours that refluxes), follow; Utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=5: 1) separate and provide the level that yellow oily contains required product and divide (18mg).Then, press and identical method shown in the embodiment 4 (1), use N; The N-DMAA (9.8mg, 0.099mmol) and sodium hydride (60% in oil, 2mg; 0.047mmol) the above-mentioned level of THF (0.32ml) solution-treated divide (handled 2 hours down at 0 ℃, at room temperature handled again 24 hours), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, ETHYLE ACETATE) to separate and provide the level that colorless oil contains required product and divide (11mg).Press and identical method shown in the embodiment 6 (3); In THF (2ml) and methyl alcohol (2ml), further handle these levels with AMBERLYST 15 (1.3g) and divide (11mg) (at room temperature handling 5 hours); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.25mm * 1 block plate, methylene dichloride: ethanol=10: 1, launch three times; Then, 0.25mm * 1 block plate, toluene: ETHYLE ACETATE=1: 9, launch five times) purifying and provide colorless oil title compound (1.261mg, 1.62%).

IR (pure): 3429,2925,2871,1628,1103,1057cm ^{-1 1}H?NMRδ：0.55(s，3H)，1.09(t，J＝5.9Hz，3H)，2.78-2.89(m，1H)，2.93(s，3H)，3.02(s，3H)，3.25-3.37(m，1H)，3.54-3.66(m，1H)，3.79-3.90(m，1H)，4.16-4.29(m，1H)，4.38-4.48(m，1H)，5.00(brs，1H)，5.32(brs，1H)，?5.99(d，J＝11.2Hz，1H)，6.38(d，J＝11.2Hz，1H)。MS?m/z：431(M ⁺)，118(100％)。UVλ _maxnm：264。

(embodiment 13) 1 α, 3 beta-dihydroxyies-20 (S)-(the N-tertiary butyl-N-amino-carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 8 (1), (60% in oil, 86mg with sodium hydride; 2.14mmol), THF (4.8ml), 15-hat-5 (80mg, 0.36mmol) (446mg 2.14mmol) handles and contains 1 α from embodiment 11 (1) for ethanamide with the N-tertiary butyl-N-monobromomethane; 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9,10-open loop pregnant-5,7; 10 (19), the level of 16-tetraene is divided (100mg), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 4 block plate, hexane: ETHYLE ACETATE=10: 1, launch four times) to separate and provide the level that colorless oil contains required product and divide (63mg).Press and identical method shown in the embodiment 4 (2); In THF (6.0ml), further handle above-mentioned level with the tetrahydrofuran solution (1.38ml) of 1M tetra-n-butyl Neutral ammonium fluoride and divide (63mg) (reaching 2 hours); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch four times; Then, 0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch five times) purifying and provide colorless oil title compound (10.683mg, 3 steps 2.35%).

IR (pure): 3390,2974,2931,2850,1651,1633,1446,1392,1365,1211,1140,1053cm ^{-1 1}H?NMR?δ：0.76(s，3H)，1.35(d，J＝6.6Hz，3H)，1.40(s，9H)，2.54-2.67(m，1H)，2.87(s，3H)，3.89(d，J＝13.9Hz，1H)，3.99-4.14(m，2H)，4.18-4.31(m，1H)，4.40-4.52(m，1H)，5.01(brs，1H)，5.33(brs，1H)，5.60(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CON(Me)t-Bu)，57(100％)。UVλ _maxnm：264。

(embodiment 14) 1 α, 3 beta-dihydroxyies-20 (S)-(N-tertiary butyl aminocarboxyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 8 (1), with sodium hydride (60% in oil, 43mg, 1.07mmol), THF (1.9ml), N; Dinethylformamide (80mg, 1.9mmol) (208mg 1.07mmol) handles and to contain 1 α from embodiment 11 (1) with N-tert-butylbromo ethanamide; 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9,10-open loop pregnant-5,7; 10 (19), the level of 16-tetraene is divided (100mg), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 4 block plate, hexane: ETHYLE ACETATE=10: 1, launch three times) to separate and provide the level that yellow oiliness contains required product and divide (35mg).Press and identical method shown in the embodiment 4 (2); In THF (3.3ml), further handle above-mentioned level with the tetrahydrofuran solution (0.78ml) of 1M tetra-n-butyl Neutral ammonium fluoride and divide (35mg) (handling 2 hours); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch three times; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch five times) purifying and provide colorless oil title compound (5.267mg, 3 steps 1.20%).

IR (pure): 3400,3323,2968,2931,2850,1666,1531,1456,1365,1227,1109,1055cm ^{-1 1}H?NMRδ：0.79(s，3H)，1.36(d，J＝6.6Hz，3H)，1.37(s，9H)，2.19-2.47(m，3H)，2.55-2.65(m，1H)，2.77-2.88(m，1H)，3.69(d，J＝15.2Hz，1H)，3.81(d，J＝15.2Hz，1H)，3.98(q，J＝6.3Hz，1H)，4.17-4.33(m，1H)，4.40-4.53(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.60(brs，1H)，6.11(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)，6.44(brs，1H)，MSm/z：312(M ⁺-HOCH ₂CONHt-Bu)，57(100％)。UVλ _maxnm：263。

(embodiment 15) 1 α, 3 beta-dihydroxyies-20 (S)-(isopropoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 8 (1), (60% in oil, 43mg with sodium hydride; 1.07mmol), THF (4.8ml), 15-hat-5 (80mg, 0.36mmol) with isopropyl acetate bromide (388mg, 2.14mmol) processing contains 1 α from embodiment 11 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9,10-open loop pregnant-5,7; 10 (19), the level of 16-tetraene is divided (100mg), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 4 block plate, hexane: ETHYLE ACETATE=10: 1) separate and provide the level that colourless oiliness contains required product and divide (20mg).Press and identical method shown in the embodiment 4 (2); In THF (2.0ml), further handle above-mentioned level with the tetrahydrofuran solution (0.46ml) of 1M tetra-n-butyl Neutral ammonium fluoride and divide (20mg) (handling 2 hours); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice; 0.5mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch four times; Then, 0.5mm * 1 block plate, methylene dichloride: ETHYLE ACETATE=1: 3, launch four times) purifying and provide colorless oil title compound (1.386mg, 3 steps 0.32%).

IR (pure): 3386,2978,2931,2850,1747,1444,1373,1286,1207,1126,1105,1052cm ^{-1 1}H?NMRδ：0.78(s，3H)，1.25(d，J＝6.3Hz，6H)，1.37(d，J＝6.6Hz，3H)，2.55-2.66(m，1H)，2.77-2.87(m，1H)，3.89(d，J＝16.5Hz，1H)，4.02(d，J＝16.2Hz，1H)，4.07(q，J＝6.3Hz，1H)，4.19-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.03-5.15(m，1H)，5.34(brs，1H)，5.61(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：430(M ⁺)，133(100％)。UVλ _maxnm：264。

(embodiment 16)

(1) 17-ethanoyl thiomethyl-1 α, 3 beta-dihydroxyies-9,10-open loop androstane-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (600ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-methylol androstane-5; 7; 16-triolefin (750mg, 1.38mmol) (with photoirradiation 30 minutes, reflux heated 2 hours down); Then, (hexane: ETHYLE ACETATE=10: 1) purifying and the providing level that contains title compound is divided (550mg) to utilize column chromatography.Then, press and identical method shown in the embodiment 1 (3), with methylsulfonyl chloride (0.23ml; 2.97mmol) and triethylamine (0.56ml; 4.02mmol) THF (5ml) solution and thioacetic acid potassium (0.457g, the above-mentioned level of methyl-sulphoxide 4.00mmol) (5ml) solution-treated is divided (methylsulfonylization 15 minutes, thioacetylization 30 minutes); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (1.0mm * 7 block plate, hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the level that contains title compound and divide (430mg).Press and identical method shown in the embodiment 6 (3); In THF (40ml) and methyl alcohol (40ml), further handling above-mentioned level with AMBERLYST 15 (18g) divides; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (1.0mm * 7 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, launch once) purifying and provide colorless oil title compound (30mg).

¹H?NMRδ：0.72(s，3H)，2.33(s，3H)，3.50-3.68(m，2H)，4.10(brs，1H)，4.43(brs，1H)，5.00(s，1H)，5.33(s，1H)，5.57(s，1H)，6.10(d，J＝11.2Hz，1H)，6.34(d，J＝11.2Hz，1H)。

(2) 17-(tert-butoxycarbonyl methylthiomethyl)-1 α, 3 beta-dihydroxyies-9,10-open loop androstane-5,7,10 (19), the preparation of 16-tetraene

In nitrogen atmosphere, toward 17-ethanoyl thiomethyl-1 α, 3 beta-dihydroxyies-9; 10-open loop androstane-5,7,10 (19); (10mg, (10mg 0.0513mmol) also at room temperature stirred 5 minutes the 16-tetraene to add bromo-acetic acid tert-butyl in THF 0.0267mmol) (0.5ml) solution.Add the methanol solution (0.5ml) of 1M Pottasium Hydroxide, further at room temperature stirred 14 hours.Use the ETHYLE ACETATE diluted reaction mixture, water and saturated sodium-chloride water solution washing, dry on SODIUM SULPHATE ANHYDROUS 99PCT then.After vapourisation under reduced pressure removes and to desolvate, provide colorless oil title compound (0.479mg, 4%) through preparative thin layer chromatography (0.25mm * 1 block plate, ETHYLE ACETATE: toluene=1: 1, launch twice) purifying resistates.

IR (pure): 2924,2848,1722,1564,1367,1294,1259,1124,1053cm ^{-1 1}H?NMRδ：0.76(s，3H)，1.48(s，9H)，3.08(s，2H)，3.28-3.31(m，2H)，4.22(brs，1H)，4.46(brs，1H)，5.01(s，1H)，5.34(s，1H)，5.59(s，1H)，6.10(d，J＝10.9Hz，1H)，6.37(d，J＝10.9Hz，1H)。MS?m/z：389(M ⁺-(CH ₃) ₃C)，57(100％)。UVλ _maxnm：264。

(embodiment 17)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

In nitrogen gas stream, toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9; 10-open loop pregnant-5,7,10 (19); 16-tetraene (848mg; 1.52mmol) THF (25ml) solution in add sodium hydride (60% in oil, 374mg, 9.34mmol) and at room temperature stirred 15 minutes.(335mg, 1.52mmol) (1.82g, THF 9.34mmol) (8ml) solution then, heated 4 hours 30 minutes under refluxing with bromo-acetic acid tert-butyl further to drip 15-hat-5.In reaction mixture impouring water, use ethyl acetate extraction, successively with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, then, dry on anhydrous magnesium sulfate.After vapourisation under reduced pressure removed and desolvates, (normal hexane: ETHYLE ACETATE=20: 1) resistates of purifying generation provided the mixture (1.47g) that contains the colorless oil title compound through column chromatography.

(2) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base] acetate

Will be from embodiment 17 (1), contain 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the mixture of 16-tetraene (1.47g) is dissolved in THF (30.0ml).Add the methanol solution (11ml) of 1M sodium methylate in this solution and at room temperature stirred 30 minutes.Further add 1M aqueous sodium hydroxide solution (11ml), at room temperature stirred again 30 minutes.Use the methylene dichloride diluted reaction mixture, in the impouring biphosphate saturated aqueous solution of sodium, use dichloromethane extraction, then, dry on anhydrous magnesium sulfate.After vapourisation under reduced pressure removed and desolvates, (methylene dichloride: ethanol=20: 1) resistates of purifying generation provided colorless oil title compound (651mg, 2 steps 69%) through column chromatography.

IR (pure): 3300-2500,2952,2929,2886,2856,1727,1471,1461,1369,1253,1083,1078cm ^{-1 1}H?NMRδ：0.04-0.09(m，12H)，0.78(s，3H)，0.88(s，18H)，1.40(d，J＝6.4Hz，3H)，2.78-2.88(m，1H)，3.93(d，J＝16.3Hz，1H)，4.01-4.25(m，3H)，4.34-4.43(m，1H)，4.87(d，J＝2.1Hz，1H)，5.20(d，J＝1.7Hz，1H)，5.64(brs，1H)，6.10(d，J＝11.4Hz，1H)，6.23(d，J＝11.2Hz，1H)。MS?m/z：616(M ⁺-1)，73(100％)。UVλ _maxnm：264。

(3) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

In nitrogen gas stream, toward [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9; 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (and 326mg, add in THF 0.53mmol) (5.3ml) solution 3-methyl-3-amylalcohol (87mg, 0.85mmol), N; N '-NSC 57182 (175mg, 0.85mmol) and 4-(dimethylamino) pyridine (65mg, 0.53mmol) and at room temperature stirred 17 hours.In reaction mixture impouring water, use ethyl acetate extraction.Dry organic layer on anhydrous magnesium sulfate.After vapourisation under reduced pressure removed and desolvates, (hexane: ETHYLE ACETATE=20: 1) resistates of purifying generation provided the mixture (319mg) that contains the colorless oil title compound through column chromatography.

(4) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

To contain 1 α from embodiment 17 (3); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5,7,10 (19); The mixture of 16-tetraene (319mg) is dissolved in THF (10ml), adds in tetrahydrofuran solution (4.55ml) and the nitrogen gas stream 50 ℃ under of 1M tetra-n-butyl Neutral ammonium fluoride stirring in this solution 2 hours.In reaction mixture impouring water, use ethyl acetate extraction, then, successively with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.Dry organic layer on anhydrous magnesium sulfate.After vapourisation under reduced pressure and remove desolvates; Through column chromatography (methylene dichloride: ethanol=20: 1) then through preparative thin layer chromatography (0.5mm * 3 block plate; Methylene dichloride: ethanol=20: 1; Launch three times) resistates that generates of purifying and provide colorless oil title compound (125.3mg, 2 steps 50%).

IR (pure): 3400,2973,2931,2883,2850,1745,1727,1459,1373,1218,1122,1052cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.85(t，J＝7.6Hz，6H)，1.36(d，J＝6.6Hz，3H)，2.56-2.66(m，1H)，2.77-2.87(m，1H)，3.84(d，J＝16.5Hz，1H)，3.96(d，J＝16.3Hz，1H)，4.08(q，J＝6.4Hz，1H)，4.19-4.29(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：472(M ⁺)，85(100％)。UVλ _maxnm：263。

(embodiment 18)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-dimethyl-butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 2-methyl-2-amylalcohol (0.1ml, 1.208mmol), N; N '-NSC 57182 (14mg, 0.067mmol) and 4-(dimethylamino) pyridine (5mg 0.042mmol) handles [{ 1 α in THF (1.0ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (26mg 0.042mmol) (at room temperature handled 18 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=6: 1, launch once) purifying and provide the mixture (20mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (1.0ml) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 18 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1; 1-dimethyl-butoxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (20mg) (under 45 ℃ outside temperature, handling 1 hour), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) purifying and provide colorless oil title compound (2.724mg, 2 steps 14%).

IR (pure): 2929,2852,1747,1635,1455,1369,1218,1122,1052cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.91(t，J＝7.0Hz，3H)，1.36(d，J＝6.2Hz，3H)，2.56-2.66(m，1H)，2.77-2.89(m，1H)，3.82(d，J＝16.5Hz，1H)，3.93(d，J＝16.5Hz，1H)，4.08(q，J＝6.2Hz，1H)，4.19-4.30(m，1H)，4.40-4.93(m，1H)，5.01(s，1H)，5.34(s，1H)，5.60(s，1H)，6.11(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS(ESI)m/z：495(M ⁺+Na)。UVλ _maxnm：263。

(embodiment 19)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-dimethyl-hexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 2-methyl-2-enanthol (0.1ml, 0.936mmol), N; N '-NSC 57182 (27mg, 0.131mmol) and 4-(dimethylamino) pyridine (0.01g, methylene dichloride 0.0822mmol) (1.0ml) solution-treated [{ 1 α; 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (50.7mg 0.0822mmol) (at room temperature handled 18 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=6: 1, launch twice) purifying and provide the mixture (30mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-hexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (1.0ml) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 19 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1; 1-dimethyl-hexyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (30mg) (under 50 ℃ outside temperature, handling 1 hour), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE: ethanol=5: 5: 1, launch twice) purifying and provide colorless oil title compound (7.414mg, 2 steps 18%).

IR (pure): 2929,2852,1745,1727,1625,1562,1450,1369,1122,1052cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.88(t，J＝7.0Hz，3H)，1.36(d，J＝6.5Hz，3H)，2.56-2.65(m，1H)，2.77-2.87(m，1H)，3.82(d，J＝16.5Hz，1H)，3.92(d，J＝16.5Hz，1H)，4.07(q，J＝6.5Hz，1H)，4.21-4.29(m，1H)，4.40-4.49(m，1H)，5.01(s，1H)，5.34(s，1H)，5.59(s，1H)，6.11(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：482(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：264。

(embodiment 20)

(1) The preparation of 1-ethyl-1-methyl-propyl propenoate

In the nitrogen atmosphere at room temperature, toward acrylate chloride (5.0g, 55.2mmol) with 3-methyl-3-amylalcohol (7.6ml, add in dichloromethane solution 60.8mmol) triethylamine (23ml, 166mmol).After at room temperature stirring 14 hours, use the methylene dichloride diluted reaction mixture, water and saturated sodium-chloride water solution washing.Dry organic layer on SODIUM SULPHATE ANHYDROUS 99PCT.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE=10: 1) resistates that generates of purifying provided colorless oil title compound (5.45g, 63%) through column chromatography.

¹H?NMR?δ：0.82(t，J＝7.6Hz，6H)，1.37(s，3H)，1.66-1.96(m，4H)，5.66(dd，J＝10.3，1.7Hz，1H)，6.00(dd，J＝17.3，10.3Hz，1H)，6.24(dd，J＝17.3，1.7Hz，1H)。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-{ 2-(1-ethyl-1-methyl propoxycarbonyl) oxyethyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

In the nitrogen atmosphere under 0 ℃, toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9; 10-open loop pregnant-5,7,10 (19); The 16-tetraene (50mg, 0.0894mmol) with 1-ethyl-1-methyl-propyl propenoate (0.1g, (60% in oil to add sodium hydride in THF 0.640mmol) (1.0ml) solution; 3.4mg, 0.085mmol).After stirring 18 hours under 5 ℃, use the ETHYLE ACETATE diluted reaction mixture, with saturated aqueous ammonium chloride and water washing.Dry organic layer on SODIUM SULPHATE ANHYDROUS 99PCT.After vapourisation under reduced pressure and remove desolvates, the resistates that generates through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (77.3mg) that contains title compound.

(3) 1 α, 3 beta-dihydroxyies-20 (S)-{ 2-(1-ethyl-1-methyl propoxycarbonyl) oxyethyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (1.0ml) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 20 (2), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-{ 2-(1-ethyl-1-methyl propoxycarbonyl) oxyethyl group }-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (77.3mg) (under 50 ℃ outside temperature, handling 1 hour), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 4 block plate; Hexane: ETHYLE ACETATE: ethanol=5: 5: 1, launch twice) purifying and provide colorless oil title compound (15.8mg, 2 steps 36%).

IR (pure): 2973,2931,2881,2850,1727,1461,1444,1367,1263,1195,1056cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.85(t，J＝7.6Hz，6H)，1.28(d，J＝6.5Hz，3H)，1.37(s，3H)，2.48(t，J＝6.8Hz，2H)，2.55-2.66(m，1H)，2.76-2.88(m，1H)，3.44-3.56(m，1H)，3.57-3.71(m，1H)，3.92(q，J＝6.5Hz，1H)，4.19-4.28(m，1H)，4.40-4.49(m，1H)，5.01(s，1H)，5.34(s，1H)，5.57(s，1H)，6.10(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MSm/z：486(M ⁺)，312(100％)。UVλ _maxnm：264。

(embodiment 21)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-sec.-propyl-2-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

With [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (30mg; 0.049mmol), 2,4-dimethyl--3-amylalcohol (17mg, 0.15mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (19mg; 0.099mmol), 4-(dimethylamino) pyridine (18mg, 0.15mmol) and methylene dichloride (1ml) mix and at room temperature stir a night, then; Utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=5: 1, launch once) to separate and provide and contain the required mixture of products of colourless foam shape (22mg).

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-sec.-propyl-2-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (0.62ml) with the tetrahydrofuran solution (0.31ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 21 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-sec.-propyl-2-methyl propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5; 7,10 (19), the mixture (22mg of 16-tetraene; 0.031mmol) (under 50 ℃ outside temperature, handling 2 hours); Then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1; Launch twice) purifying and provide flint glass shape title compound (9.336mg, 2 step 39%).

IR (pure): 3370,2966,2933,2877,2850,1751,1464,1203,1122,1053cm ^{-1 1}H?NMR?δ：0.78(s，3H)，0.83-0.91(m，12H)，1.38(d，J＝6.4Hz，3H)，2.56-2.65(m，1H)，2.77-2.87(m，1H)，3.98(d，J＝16.7Hz，1H)，4.08(d，J＝16.7Hz，1H)，4.04-4.16(m，1H)，4.18-4.36(br，1H)，4.40-4.50(br，1H)，4.67(t，J＝6.3Hz，1H)，5.01(brs，1H)，5.34(s，1H)，5.61(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS?m/z：312(M ⁺-HOCH ₂CO ₂CH(i-Pr) ₂)，57(100％)。UVλ _maxnm：264。

(embodiment 22)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(2,2,3,3,3-five fluoropropyls) ethanamide

With [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (34.1mg, 0.055mmol), 2,2; 3,3, and 3-five fluorine propylamine (41mg, 0.28mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (21mg; 0.11mmol), the I-hydroxybenzotriazole monohydrate (8mg, 0.052mmol) and methylene dichloride (0.55ml) mix and at room temperature stir a night, then; Utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=5: 1, launch once) to separate and provide (29mg) and contain the required mixture of products of colourless foam shape.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-(2,2,3,3,3-five fluoropropyls) ethanamide

By and identical method shown in the embodiment 17 (4), in THF (0.78ml), handle from embodiment 22 (1) with the tetrahydrofuran solution (0.39ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-N-(2; 2,3,3; 3-five fluoropropyls) (29mg 0.039mmol) (handled 1.5 hours under 50 ℃ outside temperature), then the mixture of ethanamide; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch once; Then, 0.5mm * 2 block plate, methylene dichloride: acetonitrile=1: 1, launch once) purifying and provide colourless foam shape title compound (9.603mg, 2 steps 33%).

IR (pure): 3419,3357,2927,2852,1684,1533,1437,1346,1198,1155,1115,1053,1028cm ^{-1 1}H?NMRδ：0.79(s，3H)，1.36(d，J＝6.6Hz，3H)，2.55-2.65(m，1H)，2.77-2.87(m，1H)，3.86(d，J＝15.5Hz，1H)，4.02(d，J＝15.5Hz，1H)，3.91-4.09(m，3H)，4.19-4.30(m，1H)，4.41-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.61(brs，1H)，6.11(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)，6.85-6.97(m，1H)。MS?m/z：519(M ⁺)，91(100％)。UVλ _maxnm：264。

(embodiment 23)

(1) The preparation of 1-ethyl-1-methyl-propyl bromacetate

In nitrogen gas stream, (add N in the 10.6g, methylene dichloride 103mmol) (49ml) solution, (15.0g, 124mmol) (25.0g 124mmol) also at room temperature stirred 2 hours accelerine with bromoacetyl bromide toward 3-methyl-3-amylalcohol.In reaction mixture impouring water,,, then, dry on sodium sulfate successively with saturated aqueous potassium hydrogen sulfate and saturated sodium bicarbonate aqueous solution washing with the t-butyl methyl ether extraction.After vapourisation under reduced pressure and remove desolvates, the resistates that generates through vacuum distilling (5mmHg, 71 ℃～72 ℃) purifying and provide colorless oil title compound (20.4g, 89%).

IR (pure): 2975,2942,2883,1731,1461,1382,1290,1180,1133,1108cm ^{-1 1}H?NMR?δ：0.88(t，J＝7.5Hz，6H)，1.41(s，3H)，1.70-1.99(m，4H)，3.76(s，2H)。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group) is pregnant-5, the preparation of 7-diene

Toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls are pregnant-5,7-diene (5.00g; 8.91mmol) THF (90ml) solution in add sodium hydride (60% in oil, 2.14g, 53.5mmol), 15-is preced with-5 (1.77ml; 8.91mmol) and 1-ethyl-1-methyl-propyl bromacetate (11.9g; 53.5mmol), then, heating is 16 hours under in argon atmospher, refluxing.Behind the cool to room temperature, with in the reaction mixture impouring saturated aqueous ammonium chloride and with ethyl acetate extraction (twice).With the organic layer that the saturated sodium-chloride water solution washing merges, dry on anhydrous magnesium sulfate.After vapourisation under reduced pressure and remove desolvates, through column chromatography (hexane: t-butyl methyl ether=30: 1, then, hexane: the resistates that generates of purifying and provide the mixture (5.59g) that contains title compound toluene=2: 1).

(3) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group) is pregnant-5, the preparation of 7-diene

To contain 1 α from embodiment 23 (2); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group) pregnant-5; The tetrahydrofuran solution of the mixture of 7-diene (5.59g), 1M tetra-n-butyl Neutral ammonium fluoride (79.5ml, 79.5ml) and acetate (2ml) mix the outside temperature be incorporated in 65 ℃ and stirred 17 hours down.Behind the cool to room temperature, use the ETHYLE ACETATE diluted reaction mixture, successively with aqueous potassium hydrogen sulfate, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, then, dry on anhydrous magnesium sulfate.After vapourisation under reduced pressure and remove desolvated, (hexane: ETHYLE ACETATE: ethanol=5: 5: 0.3) resistates that generates of purifying provided title compound (2.43g, 2 steps 57%) weak yellow foam body through column chromatography.

IR (pure): 3369,2968,2939,2875,1751,1722,1460,1375,1294,1209,1132,1055,1032cm ^{-1 1}H?NMR?δ：0.62(s，3H)，0.85(t，J＝7.5Hz，6H)，0.94(s，3H)，1.20(d，J＝6.1Hz，3H)，1.40(s，3H)，2.27-2.41(m，1H)，2.48-2.59(m，1H)，2.66-2.79(m，1H)，3.39(m，1H)，3.76(brs，1H)，3.93(d，J＝16.0Hz，1H)，4.01(d，J＝16.0Hz，1H)，4.07(m，1H)，5.36-5.45(m，1H)，5.69-5.76(m，1H)。MS?m/z：474(M ⁺)，315(100％)。UVλ _maxnm：271，282，294。

(4) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 4 (3), in THF (650ml), handle 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group) pregnant-5; The 7-diene (2.42g, 5.10mmol), different is; Photoirradiation continues 2 hours 15 minutes; Then, through column chromatography (hexane: ETHYLE ACETATE: ethanol=7: 3: 0.3, then; Methylene dichloride: ETHYLE ACETATE: purifying and provide colourless foam shape title compound (773mg, 32%) ethanol=6: 1: 0.1).

IR (pure): 3377,2968,2939,2879,1749,1716,1458,1375,1296,1213,1128,1057cm ^{-1 1}H?NMR?δ：0.53(s，3H)，0.85(t，J＝7.5Hz，6H)，1.19(d，J＝6.0Hz，3H)，1.39(s，3H)，2.25-2.37(m，1H)，2.55-2.65(m，1H)，2.77-2.88(m，1H)，3.36(m，1H)，3.92(d，J＝16.0Hz，1H)，4.00(d，J＝16.0Hz，1H)，4.17-4.29(br，1H)，4.39-4.48(br，1H)，4.99(m，1H)，5.32(m，1H)，6.03(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：474(M ⁺)，134(100％)。UVλ _maxnm：264。

(embodiment 24) (1 α, 3 β)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) is pregnant-5,7,16-triolefin-20-ketone synthetic

(1) (1 α, 3 β)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) androstane-5,7,16-triolefin-17-base triflate synthetic

With (1 α, 3 β)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) androstane-5,7-diene-17-ketone (21.0g) is dissolved in THF (140ml), at room temperature toward wherein adding 2-(N, N-two (fluoroform sulphonyl) amino) pyridine (19.1g).Reaction mixture is cooled to after-78 ℃, further drips the tetrahydrofuran solution (48.3ml) of 1.0M two (trimethyl silyl) sodium amide.Continue stirring down after 30 minutes at-78 ℃, in reaction mixture, add saturated sodium bicarbonate aqueous solution, then, with hexane/ethyl acetate=5/1 extraction.The solution of dry extraction and vapourisation under reduced pressure on SODIUM SULPHATE ANHYDROUS 99PCT and remove and desolvate.Provide title compound (23.3g, productive rate 89%) with the resistates of acetonitrile (100ml) washing generation.

¹H-NMR(270MHz，CDCl ₃)δ：5.64-5.58(m，2H)，5.43-5.37(m，1H)，4.12-3.98(m，1H)，3.74-3.68(m，1H)，2.96-2.84(m，1H)，2.48-2.26(m，5H)，2.00-1.42(m，1H)，0.97(s，3H)，0.95(s，3H)，0.89(s，18H)，0.12(s，3H)，0.107(s，6H)，0.06(s，3H)。

(2) (1 α, 3 β)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) is pregnant-5,7,16-triolefin-20-ketone synthetic

With (1 α, 3 β)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) androstane-5,7,16-triolefin-17-base triflate (40.3g) is dissolved in N,N-DIMETHYLACETAMIDE (203ml), then, adds four (triphenyl phosphine) palladium (0) (703mg).Make the mixture of generation be in decompression state, place carbon monoxide atmosphere again.Repeat twice of aforesaid operations again.At room temperature add the hexane solution (74.4ml) of 0.98M dimethylaluminum chloride in this compound, then, at room temperature stirred 20 minutes.Be heated to after 58 ℃, restir 2 hours adds water in reaction mixture, then, and with hexane/ethyl acetate=1/1 extraction.The solution of dry extraction on anhydrous magnesium sulfate under reduced pressure concentrates and provides title compound (34.0g, productive rate 100%).

¹H-NMR (300MHz, benzene-d ₆) δ: 6.01 (dd, J=2.5,2.7Hz, 1H), 5.72 (d, J=5.8Hz, 1H), 5.43-5.36 (m, 1H), 4.38-4.23 (m, 1H); 3.58-3.51 (m, 1H), 3.09-2.97 (m, 1H), 2.63-2.53 (m, 2H), 2.41-2.29 (m, 1H), 2.08-1.96 (m, 3H); 1.94 (s, 3H), 1.83-1.67 (m, 2H), 1.05 (s, 9H), 1.04 (s, 3H), 0.95 (s, 9H); 0.86 (s, 3H), 0.19 (s, 3H), 0.17 (s, 3H), 0.11 (s, 3H), 0.02 (s, 3H).

(embodiment 25) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), 16-tetraene synthetic

(1) (20S)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) is pregnant-5,7 for 1 α, 3 β, 16-triolefin-20-alcohol synthetic

With synthetic among the embodiment 24 (1 α, 3 β)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) is pregnant-5,7, and 16-triolefin-20-ketone (45.0g) is dissolved in toluene (240ml), is cooled to-20 ℃ then, stirs subsequently 30 minutes.Down add borine-dimethyl sulfide complex compound (22.9ml) in the solution of formation and stirred 5 minutes at-20 ℃.Under-20 ℃, further add 1M (R)-2-methyl-C β S-boron oxynitride heterocycle pentane (oxazaborolidine) in the solution (22.9ml) and stirred 1 hour.In reaction mixture, add methyl alcohol, then, use ethyl acetate extraction.The solution of dry extraction and vapourisation under reduced pressure on SODIUM SULPHATE ANHYDROUS 99PCT and remove and desolvate.(liquid phase: hexane/ethyl acetate=9/1) resistates of purifying generation provides title compound (23.3g, productive rate 89%) through silica gel column chromatography.

¹H-NMR (300MHz, benzene-d ₆) δ: 5.71 (d, J=4.9Hz, 1H), 5.49 (brs, 2H), 4.40-4.15 (m, 2H), 3.59 (brs, 1H), 3.13-3.03 (m; 1H), 2.61 (s, 1H), 2.59 (s, 1H), 2.46-2.37 (m, 1H), 2.20-1.92 (m, 4H), 1.85-1.47 (m; 4H), 1.24 (d, J=6.6Hz, 3H), 1.06 (s, 9H), 0.99 (s, 3H), 0.95 (s, 9H); 0.91 (s, 3H), 0.20 (s, 3H), 0.18 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H).

(2) 1-ethyl-1-methyl-propyl ((((1 α, 3 β, 20S)-1,3-two (tertiary butyl (dimethyl-) silyl) oxygen base) pregnant-5,7,16-triolefin-20-yl) oxygen base) acetic ester synthetic

Will (20S)-1,3-two ((tertiary butyl (dimethyl-) silyl) oxygen base) be pregnant-5,7 for 1 α, 3 β, and 16-triolefin-20-alcohol (210mg) and 60% sodium hydride (90mg) are dissolved in THF (3.7ml).At room temperature in the solution that forms, successively add 15-hat-5-ether (83 μ l) and 1-ethyl-1-methyl-propyl bromacetate (502mg), postheating to 60 ℃.After stirring 12 hours under 60 ℃, in solution, add methyl alcohol, then, extract with t-butyl methyl ether.The solution of dry extraction and vapourisation under reduced pressure on SODIUM SULPHATE ANHYDROUS 99PCT and remove and desolvate.Through silica gel column chromatography (liquid phase: hexane/ether=10/1) then silica gel column chromatography (liquid phase: hexanes/ch=1/2) resistates that generates of purifying provides title compound (244mg, productive rate 93%).

¹H-NMR (300MHz, benzene-d ₆) δ: 5.70 (d, J=6.9Hz, 1H), 5.56 (brs, 1H), 5.49-5.41 (m, 1H), 4.38-4.25 (m, 1H), 4.21 (q, J=6.3Hz; 1H), 3.99 (d, J=16.2Hz, 1H), 3.92 (d, J=16.2Hz, 1H), 3.63-3.55 (m, 1H), 3.10-3.00 (m, 1H); 2.64-2.53 (m, 1H), 2.47-2.36 (m, 1H), 2.23-1.44 (m, 12H), 1.41 (d, J=6.3Hz, 3H), 1.31 (s; 3H), 1.04 (s, 9H), 0.98 (s, 3H), 0.94 (s, 9H), 0.89 (s, 3H), 0.76 (t; J=7.4Hz, 6H), 0.18 (s, 3H), 0.16 (s, 3H), 0.13 (s, 3H), 0.06 (s, 3H).

(3) 1-ethyl-1-methyl-propyl (((20S)-1, the 3-dihydroxyl is pregnant-5,7,16-triolefin-20-yl for 1 α, 3 β) oxygen base) acetic ester synthetic

With 1-ethyl-1-methyl-propyl ((((1 α, 3 β, 20S)-1; 3-two (tertiary butyl (dimethyl-) silyl) oxygen base) oxygen base pregnant-5,7,16-triolefin-20-yl)) acetic ester (203mg) is dissolved in the tetrahydrofuran solution (3.0ml) of 1.0M tetrabutyl ammonium fluoride; Then, add acetate (75 μ g).The solution that forms is heated to 60 ℃, stirred 12 hours, use ethyl acetate extraction then.The solution of dry extraction and vapourisation under reduced pressure on SODIUM SULPHATE ANHYDROUS 99PCT and remove and desolvate.(liquid phase: hexane/ethyl acetate=2/3) resistates of purifying generation provides title compound (132mg, productive rate 97%) through silica gel column chromatography.

¹H-NMR (300MHz, acetone-d ₆) δ: 5.66-5.59 (m, 2H), 5.45-5.39 (m, 1H), 4.14 (q, J=6.6Hz, 1H), 4.09-3.95 (m, 1H); 3.95 (d, J=16.2Hz, 1H), 3.86 (d, J=16.2Hz, 1H), 3.80-3.70 (m, 1.5H); 3.64-3.50 (m, 0.5H), 2.49-2.39 (m, 1H), 2.38-2.17 (m, 4H), 2.12-2.06 (m, 1H); 1.96-1.62 (m, 8H), 1.54-1.42 (m, 1H), 1.37 (s, 3H), 1.30 (d, J=6.6Hz; 3H), 0.95 (s, 3H), 0.90 (s, 3H), 0.85 (t, J=7.4Hz, 6H).

(4) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), 16-tetraene synthetic

(((20S)-1, the 3-dihydroxyl is pregnant-5,7,16-triolefin-20-yl for 1 α, 3 β) oxygen base) acetic ester (132mg) is dissolved in THF (500ml) with 1-ethyl-1-methyl-propyl.In argon gas stream, this solution is cooled to 18 ℃,, that is, ultraviolet light irradiation device (Japanese patent application No.10-188880, the WO 00/01477) irradiation of xenon-mercury lamp (280～320nm, USHIO INC.) is housed with 5kW with ultraviolet light irradiation 30 minutes.With the further reflux of above-mentioned solution 2 hours, reduction vaporization and remove and desolvate.(liquid phase: dichloromethane/ethyl acetate=6/4) resistates of purifying generation provides title compound (34.2mg, productive rate 26%) through silica gel column chromatography.Preparation is identical among compound spectroscopic data alone for preparing like this and the embodiment 17 (4).

(embodiment 26)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-diethylammonium propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 3-ethyl-3-amylalcohol (9mg, 0.08mmol), N, N '-NSC 57182 (17mg; 0.08mmol) and 4-(dimethylamino) pyridine (6mg, 0.05mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.5ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (31mg 0.05mmol) (at room temperature handled 17 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=10: 1, launch twice) purifying and provide the mixture (27.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-diethylammonium propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (1.7ml) with the tetrahydrofuran solution (0.57ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 26 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1; 1-diethylammonium propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5,7,10 (19); The mixture of 16-tetraene (27mg) (under 50 ℃ outside temperature, handling 2 hours) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice; 0.5mm * 2 blocks of plates, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times; Then, 0.25mm * 2 block plate, methylene dichloride: ETHYLE ACETATE=3: 1, launch twice) resistates that generates of purifying and provide colorless oil title compound (2.966mg, 2 steps 12.2%).

IR (pure): 3386,2969,2931,2881,2852,1745,1727,1457,1288,1214,1122,1052cm ^{-1 1}H?NMRδ：0.78(s，3H)，0.81(t，J＝7.3Hz，9H)，1.36(d，J＝6.3Hz，3H)，1.84(q，J＝7.3Hz，6H)，2.18-2.47(m，3H)，2.54-2.67(m，1H)，2.76-2.88(m，1H)，3.85(d，J＝16.5Hz，1H)，3.97(d，J＝16.5Hz，1H)，4.04-4.13(m，1H)，4.19-4.30(m，1H)，4.39-4.49(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.11(d，J＝11.5Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：312(M ⁺-HOCH ₂COOCEt ₃)，57(100％)。UVλ _maxnm：263。

(embodiment 27)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(suberyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with suberyl alcohol (6 μ l, 0.0518mmol), N, N '-NSC 57182 (10mg; 0.0518mmol) and 4-(dimethylamino) pyridine (4mg, 0.0324mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.0ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (20mg 0.0324mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (26.7mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(suberyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.7ml) with the tetrahydrofuran solution (0.3ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 27 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(suberyl oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (26.7mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, launch twice) purifying and provide colorless oil title compound (4.134mg, 2 steps 25%).

IR (pure): 3326,2927,2852,2358,2321,1749,1627,1558,1448,1218,1122,1053cm ^{-1 1}H?NMR?δ：0.77(s，3H)，1.36(d，J＝6.5Hz，3H)，2.55-2.65(m，1H)，2.76-2.87(m，1H)，3.85-4.17(m，3H)，4.18-4.29(m，1H)，4.41-4.49(m，1H)，4.94-5.07(m，2H)，5.34(s，1H)，5.61(brs，1H)，6.11(d，J＝11.1Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：466(M ⁺-H ₂O)，55(100％)。UVλ _maxnm：.263。

(embodiment 28)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the 4-enanthol (7 μ l, 0.0518mmol), N, N '-NSC 57182 (10mg; 0.0518mmol) and 4-(dimethylamino) pyridine (4mg, 0.0324mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.0ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (20mg 0.0324mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (21.7mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.7ml) with the tetrahydrofuran solution (0.3ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 28 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl butoxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (21.7mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE: ethanol=5: 5: 1; Launch twice) and then another takes turns preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) resistates that generates of purifying and provide colorless oil title compound (4.266mg, 2 steps 27%).

IR (pure): 3390,3325,2956,2931,2852,1749,1627,1448,1203,1122,1053cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.90(t，J＝7.0Hz，6H)，1.37(d，J＝6.2Hz，3H)，2.53-2.65(m，1H)，2.76-2.88(m，1H)，3.87-4.17(m，3H)，4.19-4.29(m，1H)，4.39-4.49(m，1H)，4.92-5.05(m，2H)，5.34(s，1H)，5.61(brs，1H)，6.11(d，J＝11.1Hz，1H)，6.38(d，J＝11.1Hz，1H)。MS?m/z：450(M ⁺-2H ₂O)，57(100％)。UVλ _maxnm：263。

(embodiment 29)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl isophthalic acid-propyl group butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 4-methyl-4-enanthol (6.3mg, 0.048mmol), N; N '-NSC 57182 (9.9mg, 0.048mmol) and 4-(dimethylamino) pyridine (3.7mg 0.03mmol) handles [{ 1 α in methylene dichloride (0.3ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (20mg 0.03mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (14.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-methyl isophthalic acid-propyl group butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.5ml) with the tetrahydrofuran solution (0.2ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 29 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl isophthalic acid-propyl group butoxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (14mg) (under 50 ℃ outside temperature, handling 2 hours) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.25mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch three times) purifying and provide colorless oil title compound (6.351mg, 2 steps 42.3%).

IR (pure): 3417,2960,2931,2873,1747,1467,1373,1213,1122,1052cm ^{-1 1}H?NMR?δ：0.77(s，3H)，0.90(t，J＝7.3Hz，6H)，1.36(d，?J＝6.6Hz，3H)，1.40(s，3H)，2.17-2.47(m，3H)，2.56-2.66(m，1H)，2.76-2.88(m，1H)，3.81(d，J＝16.5Hz，1H)，3.94(d，J＝16.5Hz，1H)，4.02-4.13(m，1H)，4.19-4.29(m，1H)，4.40-4.51(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：312(M ⁺-HOCH ₂COOC(CH ₃)(C ₃H ₇) ₂)，71(100％)。UVλ _maxnm：264。

(embodiment 30)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methylcyclohexyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 1 methyl cyclohexanol (7 μ l, 0.0518mmol), N; N '-NSC 57182 (10mg, 0.0518mmol) and 4-(dimethylamino) pyridine (4mg 0.0324mmol) handles [{ 1 α in methylene dichloride (1.0ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (20mg 0.0324mmol) (at room temperature handled 14 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=7: 1, launch once) purifying and provide the mixture (14.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-methylcyclohexyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.7ml) with the tetrahydrofuran solution (0.3ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 30 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methylcyclohexyl oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (14.0mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.Provide colorless oil title compound (4.220mg, 2 steps 27%) through the resistates of preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, expansion are once) purifying generation.

IR (pure): 3446,2931,2852,1747,1446,1211,1124,1053,962cm ^{-1 1}H?NMRδ：0.78(s，3H)，1.37(d，J＝6.8Hz，3H)，1.49(s，3H)，2.56-2.66(m，1H)，2.77-2.89(m，1H)，3.85(d，J＝16.5Hz，1H)，?3.98(d，J＝16.5Hz，1H)，4.09(q，J＝6.8Hz，1H)，4.19-4.29(m，1H)，4.41-4.49(m，1H)，5.02(s，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.6Hz，1H)，6.38(d，J＝11.6Hz，1H)。MS?m/z：466(M ⁺-H ₂O)，55(100％)。UVλ _maxnm：263。

(embodiment 31)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclo-dodecyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with cyclododecanols (9 μ l, 0.0518mmol), N; N '-NSC 57182 (10mg, 0.0518mmol) and 4-(dimethylamino) pyridine (4mg 0.0324mmol) handles [{ 1 α in methylene dichloride (1.0ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (20mg 0.0324mmol) (at room temperature handled 14 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=7: 1, launch once) purifying and provide the mixture (21.6mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(cyclo-dodecyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.7ml) with the tetrahydrofuran solution (0.3ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 31 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclo-dodecyl oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (21.6mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.Provide colorless oil title compound (4.971mg, 2 steps 28%) through the resistates of preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, expansion are once) purifying generation.

IR (pure): 3446,2931,2850,1748,1471,1446,1205,1124,1053cm ^{-1 1}H?NMRδ：0.77(s，3H)，2.56-2.66(m，1H)，2.77-2.87(m，1H)，3.90(d，J＝16.5Hz，1H)，4.02(d，J＝16.5Hz，1H)，4.09(q，J＝6.5Hz，1H)，4.19-4.29(m，1H)，4.41-4.49(m，1H)，5.01(s，1H)，5.04-5.15(m，1H)，5.34(s，1H)，5.60(brs，1H)，?6.10(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MSm/z：518(M ⁺-2H ₂O)，55(100％)。UVλ _maxnm：263。

(embodiment 32)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl cyclopentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the 1-methylcyclopentanol (4.8mg, 0.048mmol), N; N '-NSC 57182 (9.9mg, 0.048mmol) and 4-(dimethylamino) pyridine (3.7mg 0.03mmol) handles [{ 1 α in methylene dichloride (0.3ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (30mg 0.048mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=10: 1, launch twice) purifying and provide the mixture (20.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-methyl cyclopentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.5ml) with the tetrahydrofuran solution (0.29ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 32 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl cyclopentyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (20mg) (under 50 ℃ outside temperature, handling 1.5 hours) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch three times) purifying and provide colorless oil title compound (7.666mg, 2 steps 54.3%).

IR (pure): 3392,2965,2933,2873,2850,1747,1444,1375,1222,1180,1122,1052cm ^{-1 1}H?NMR?δ：0.77(s，3H)，1.36(d，J＝6.4Hz，3H)，2.19-2.51(m，3H)，2.56-2.68(m，1H)，2.77-2.89(m，1H)，3.83(d，J＝16.3Hz，1H)，3.95(d，J＝16.3Hz，1H)，4.02-4.14(m，1H)，4.21-4.31(m，1H)，4.41-4.51(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.60(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：470(M ⁺)，312(M ⁺-?HOCH ₂COOC ₆H ₁₁)，83(100％)。UVλ _maxnm：263。

(embodiment 33)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(ring octyl group oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the ring octanol (14.0mg, 0.109mmol), N; N '-NSC 57182 (24.0mg, 0.116mmol) and 4-(dimethylamino) pyridine (10.0mg 0.082mmol) handles [{ 1 α in methylene dichloride (0.3ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (21.3mg 0.035mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice) purifying and provide the mixture (16.6mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(ring octyl group oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.25ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 33 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(ring octyl group oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (16.5mg) (under 45 ℃ outside temperature, handling 30 minutes).Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=15: 1, launch twice; Then, 0.25mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch four times) purification reaction mixture and provide colorless oil title compound (3.5mg, 2 steps 20%).

IR (pure): 3392,2928,2856,1744,1468,1204,1124,1052cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.36(d，J＝6.7Hz，3H)，2.56-2.66(m，1H)，2.78-2.89(m，1H)，3.89(d，J＝16.3Hz，1H)，4.00(d，J＝16.3Hz，1H)，4.07(q，J＝6.7Hz，1H)，4.19-4.31(m，1H)，4.41-4.50(m，1H)，4.96-5.10(m，1H)，5.02(brs，1H)，5.34(brs，1H)，5.60(brs，1H)，6.10(d，J＝11.7Hz，1H)，6.37(d，J＝11.7Hz，1H)。MS?m/z：480(M ⁺-H ₂O)，69(100％)。UVλ _maxnm：263。

(embodiment 34)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-butyl pentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the ninth of the ten Heavenly Stems-5-pure (14.0mg, 0.097mmol), N; N '-NSC 57182 (24.0mg, 0.116mmol) and 4-(dimethylamino) pyridine (10.0mg 0.082mmol) handles [{ 1 α in methylene dichloride (0.3ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (22.0mg 0.036mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice) purifying and provide the mixture (17.4mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-butyl pentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.25ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 34 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-butyl pentyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (16.4mg) (under 45 ℃ outside temperature, handling 30 minutes).Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=15: 1, launch twice; 0.25mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch four times; 0.25mm * 1 block of plate, toluene: ETHYLE ACETATE=1: 1, launch twice; Then, 0.25mm * 1 block plate, methylene dichloride: ETHYLE ACETATE=3: 1, launch once) purification reaction mixture and provide colorless oil title compound (1.7mg, 2 steps 10%).

IR (pure): 3384,2932,2860,1746,1444,1370,1204,1124,1054cm ^{-1 1}H?NMR?δ：0.77(s，3H)，0.87(t，J＝6.9Hz，3H)，0.88(t，J＝6.9Hz，3H)，1.37(d，J＝6.6Hz，3H)，2.56-2.66(m，1H)，2.78-2.89(m，1H)，3.93(d，J＝16.5Hz，1H)，4.04(d，J＝16.5Hz，1H)，4.08(q，J＝6.6Hz，1H)，4.20-4.30(m，1H)，4.40-4.50(m，1H)，4.96(qu?int，J＝6.3Hz，1H)，5.01(brs，1H)，5.34(brs，1H)，5.60(brs，1H)，6.10(d，J＝11.5Hz，1H)，6.38(d，J＝11.5Hz，1H)。MS?m/z：?312(M ⁺-CH ₃CO ₂CH(CH ₂CH ₂CH ₂CH ₃) ₂)，57(100％)。UVλ _maxnm：263。

(embodiment 35)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-dimethyl-propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with tertiary amyl alcohol (7.0mg, 0.079mmol), N; N '-NSC 57182 (7.0mg, 0.034mmol) and 4-(dimethylamino) pyridine (3.0mg 0.025mmol) handles [{ 1 α in methylene dichloride (0.2ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (13.0mg 0.021mmol) (at room temperature handled 1 hour) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice) purifying and provide the mixture (9.2mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.15ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 35 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-dimethyl-propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5; 7,10 (19), the mixture of 16-tetraene (10.0mg) (under 45 ℃ outside temperature, handling 40 minutes).Provide colorless oil title compound (3.6mg, 2 steps 34%) through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=15: 1, launch once methylene dichloride: ethanol=10: 1, launch once) purification reaction mixture.

IR (pure): 3392,2972,2932,2848,1744,1444,1370,1220,1122,1054cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.87(t，J＝7.4Hz，3H)，1.36(d，J＝6.5Hz，3H)，1.43(s，6H)，2.55-2.66(m，1H)，2.76-2.87(m，1H)，3.82(d，J＝16.3Hz，1H)，3.94(d，J＝16.3Hz，1H)，4.07(q，J＝6.5Hz，1H)，4.19-4.29(m，1H)，4.39-4.49(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.60(brs，1H)，6.10(d，J＝11.8Hz，1H)，6.37(d，J＝11.8Hz，1H)。MS?m/z：312(M ⁺-CH ₃CO ₂C(CH ₃) ₂CH ₂CH ₃)，71(100％)。UVλ _maxnm：263。

(embodiment 36)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(diamantane-2-base oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the 2-adamantanol (12mg, 0.0768mmol), N; N '-NSC 57182 (16mg, 0.0768mmol) and 4-(dimethylamino) pyridine (6mg 0.048mmol) handles [{ 1 α in methylene dichloride (1.0ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (30mg 0.048mmol) (at room temperature handled 14 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=6: 1, launch once) purifying and provide the mixture (15.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(diamantane-2-base oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (1.0ml) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 36 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(diamantane-2-base oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (15.0mg) (under 45 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) purifying and provide colorless oil title compound (1.024mg, 2 steps 4%).

IR (pure): 3325,2927,2850,1626,1576,1448,1122,1045cm ^{-1 1}H?NMRδ：0.78(s，3H)，2.56-2.67(m，1H)，2.77-2.87(m，1H)，3.92-4.17(m，3H)，4.20-4.30(m，1H)，4.40-4.50(m，1H)，4.98-5.04(m，2H)，5.34(s，1H)，5.62(brs，1H)，6.11(d，J＝11.6Hz，1H)，6.38(d，J＝11.6Hz，1H)。MS?m/z：504(M ⁺-H ₂O)，135(100％)。UVλ _maxnm：263。

(embodiment 37)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-dimethyl-pentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraeneBy and identical method shown in the embodiment 17 (3), with 2-methyl-2-hexanol (0.1ml, 0.699mmol), N; N '-NSC 57182 (14mg, 0.067mmol) and 4-(dimethylamino) pyridine (5mg 0.042mmol) handles [{ 1 α in THF (1.0ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (26mg 0.042mmol) (at room temperature handled 14 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=6: 1, launch once) purifying and provide the mixture (15.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-pentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (1.0ml) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 37 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1; 1-dimethyl-pentyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19); The mixture of 16-tetraene (15.0mg) (under 45 ℃ outside temperature, handling 1 hour) then, carries out aftertreatment.Provide colorless oil title compound (1.784mg, 2 steps 9%) through preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) purification reaction mixture.

IR (pure): 3323,2927,2852,1749,1626,1558,1448,1254,1209,1122,1053cm ^{-1 1}H?NMRδ：0.78(s，3H)，0.90(t，J＝7.0Hz，3H)，1.36(d，J＝6.8Hz，3H)，2.55-2.66(m，1H)，2.77-2.88(m，1H)，3.82(d，J＝16.2Hz，1H)，3.94(d，J＝16.2Hz，1H)，3.99-4.12(m，1H)，4.20-4.29(m，1H)，4.41-4.50(m，1H)，5.01(s，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MSm/z：468(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：262。

(embodiment 38)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1,2-trimethylammonium propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (3), with 2,3-dimethyl butyrate-2-alcohol (7.5mg; 0.073mmol), N, N '-NSC 57182 (18.0mg, 0.087mmol) and 4-(dimethylamino) pyridine (6.8mg; 0.056mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 in methylene dichloride (1.0ml); 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (20.5mg; 0.033mmol) (at room temperature handling 16 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate; Hexane: ETHYLE ACETATE=15: 1, launch once) purifying and provide the mixture (6.6mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1,2-trimethylammonium propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), contain 1 α from embodiment 38 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1 with the processing of the tetrahydrofuran solution (0.1ml) of 1M tetra-n-butyl Neutral ammonium fluoride; 1; 2-trimethylammonium propoxycarbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (6.0mg) (under 45 ℃ outside temperature, handling 20 minutes).Provide colorless oil title compound (1.6mg, 2 steps 10%) through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=15: 1, expansion are once) purification reaction mixture.

IR (pure): 3384,2972,2932,2852,1744,1444,1372,1218,1124,1054cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.89(d，J＝7.2Hz，6H)，1.36(d，J＝6.7Hz，3H)，1.41(s，3H)，1.42(s，3H)，2.54-2.66(m，1H)，2.76-2.87(m，1H)，3.82(d，J＝16.5Hz，1H)，3.94(d，J＝16.5Hz，1H)，4.07(q，J＝6.7Hz，1H)，4.18-4.29(m，1H)，4.41-4.49(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.11(d，J＝11.0Hz，1H)，6.37(d，J＝11.0Hz，1H)。MS?m/z：387(M ⁺-CH(CH ₃) ₂CH(CH ₃) ₂)，85(100％)，85(100％)。UVλ _maxnm：263。

(embodiment 39)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl cyclohexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the 1-ethyl cyclohexanol (17mg, 0.133mmol), N; N '-NSC 57182 (18mg, 0.087mmol) and 4-(dimethylamino) pyridine (16mg 0.131mmol) handles [{ 1 α in methylene dichloride (0.4ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (27mg 0.044mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (25mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl cyclohexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.66ml) with the tetrahydrofuran solution (0.33ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 39 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl cyclohexyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (25mg) (under 60 ℃ outside temperature, handling 1.5 hours) carries out aftertreatment subsequently.Provide flint glass shape title compound (7.157mg, 2 steps 33%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3380,2931,2852,1745,1448,1211,1122,1053cm ^{-1 1}H?NMR?δ：0.78(s，3H)，0.82(t，J＝7.6Hz，3H)，1.37(d，J＝6.4Hz，3H)，2.57-2.62(m，1H)，2.78-2.84(m，1H)，3.86(d，J＝16.3Hz，1H)，3.99(d，J＝16.3Hz，1H)，4.09-4.20(m，1H)，4.20-4.30(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS m/z ：312(M ⁺-HOCH ₂CO ₂C ₈H ₁₅)，69(100％)。UVλ _maxnm：264。

(embodiment 40)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl ring octyl group oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 1-methyl ring octanol (13mg, 0.091mmol), N; N '-NSC 57182 (13mg, 0.063mmol) and 4-(dimethylamino) pyridine (11mg 0.090mmol) handles [{ 1 α in methylene dichloride (0.3ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (19mg 0.031mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (15mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-methyl ring octyl group oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.46ml) with the tetrahydrofuran solution (0.23ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 40 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl ring octyl group oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (15mg) (under 60 ℃ outside temperature, handling 1.5 hours) carries out aftertreatment subsequently.Provide colourless foam shape title compound (5.527mg, 2 steps 35%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3390,2927,2852,1743,1448,1373,1205,1115,1053cm ^{-1 1}H?NMR?δ：0.77(s，3H)，1.36(d，J＝6.4Hz，3H)，2.57-2.63(m，1H)，2.79-2.84(m，1H)，3.81(d，J＝16.3Hz，1H)，3.94(d，J＝16.3Hz，1H)，4.04-4.16(m，1H)，4.20-4.30(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CO ₂C ₉H ₁₇)，69(100％)。UVλ _maxnm：263。

(embodiment 41)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-{ 4-methyl isophthalic acid-(3-methylbutyl) pentyloxy carbonyl methoxyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (3), with 2,8-dimethyl--5-nonyl alcohol (0.1g; 0.580mmol), N, N '-NSC 57182 (14mg, 0.067mmol) and 4-(dimethylamino) pyridine (5mg; 0.042mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 in methylene dichloride (1.0ml); 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (26mg; 0.042mmol) (at room temperature handling 14 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE=6: 1, launch once) purifying and provide the mixture (30.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-{ 4-methyl isophthalic acid-(3-methylbutyl) pentyloxy carbonyl methoxyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (1.0ml) with the tetrahydrofuran solution (0.8ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 41 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-{ 4-methyl isophthalic acid-(3-methylbutyl) pentyloxy carbonyl methoxyl group }-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (30.0mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) purifying and provide colorless oil title compound (8.820mg, 2 steps 39%).

IR (pure): 2953,2931,2870,2852,1749,1732,1653,1558,1468,1367,1201,1122,1053cm ^{-1 1}H?NMRδ：0.78(s，3H)，0.86(t，J＝6.4Hz，12H)，1.37(d，J＝6.5Hz，3H)，2.54-2.67(m，1H)，2.76-2.90(m，1H)，3.93(d，J＝17.6Hz，1H)，4.04(d，J＝17.6Hz，1H)，4.09(q，J＝6.8Hz，1H)，4.20-4.29(m，1H)，4.41-4.49(m，1H)，4.86-4.98(m，1H)，5.01(s，1H)，5.34(s，1H)，5.61(brs，1H)，6.11(d，J＝10.8Hz，1H)，6.38(d，J＝10.8Hz，1H)。MS?m/z：524(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：264。

(embodiment 42)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1,2,2-tetramethyl-propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (3), with 1,1,2; 2-tetramethyl-propyl alcohol (0.1g, 0.861mmol), N, N '-NSC 57182 (14mg; 0.067mmol) and 4-(dimethylamino) pyridine (5mg, 0.042mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.0ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (26mg 0.042mmol) (at room temperature handled 14 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5 mm * 1 block plate, hexane: ETHYLE ACETATE=6: 1, launch once) purifying and provide the mixture (25.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1,2,2-tetramethyl-propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (1.0ml) with the tetrahydrofuran solution (0.8ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 42 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1; 1,2,2-tetramethyl-propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5,7,10 (19); The mixture of 16-tetraene (25.0mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) purifying and provide colorless oil title compound (1.558mg, 2 steps 8%).

IR (pure): 2960,2929,2850,1747,1724,1371,1120,1053cm ^{-1 1}H?NMR?δ：0.77(s，3H)，0.96(s，9H)，1.36(d，J＝6.5Hz，3H)，2.54-2.66(m，1H)，2.75-2.88(m，1H)，3.81(d，J＝16.2Hz，1H)，3.94(d，J＝16.2Hz，1H)，4.08(q，J＝5.9Hz，1H)，4.19-4.30(m，1H)，4.40-4.49(m，1H)，5.02(s，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：387(M ⁺-C ₇H ₁₅)，57(100％)。UVλ _maxnm：264。

(embodiment 43)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl cyclopentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 1-ethyl cyclopentanol (11.3mg, 0.099mmol), N; N '-NSC 57182 (13.1mg, 0.064mmol) and 4-(dimethylamino) pyridine (4.7mg 0.039mmol) handles [{ 1 α in methylene dichloride (0.5ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (22.0mg 0.036mmol) (at room temperature handled 4 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=15: 1, launch once) purifying and provide the mixture (13.5mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl cyclopentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.2ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 43 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl cyclopentyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (12.5mg) (under 45 ℃ outside temperature, handling 20 minutes).Provide colorless oil title compound (4.2mg, 2 steps 26%) through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=15: 1, launch twice) purification reaction mixture.

IR (pure): 3400,2932,2876,1742,1446,1370,1218,1120,1054cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.85(t，J＝7.4Hz，3H)，1.36(d，J＝6.6Hz，3H)，2.55-2.64(m，1H)，2.76-2.89(m，1H)，3.84(d，J＝16.3Hz，1H)，3.96(d，J＝16.3Hz，1H)，4.08(q，J＝6.6Hz，1H)，4.19-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.10(d，J＝11.1Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：484(M ⁺)，55(100％)。UVλ _maxnm：263。

(embodiment 44)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-cyclopropyl-1-methyl ethoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 2-cyclopropyl-2-propyl alcohol (29mg, 0.290mmol), N; N '-NSC 57182 (39mg, 0.189mmol) and 4-(dimethylamino) pyridine (35mg 0.286mmol) handles [{ 1 α in methylene dichloride (0.95ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (58.4mg 0.095mmol) (at room temperature handled 15 hours) acetate; Then, carry out aftertreatment and utilize column chromatography (hexane: purifying and provide the mixture (54mg) that contains title compound ETHYLE ACETATE=10: 1).

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-cyclopropyl-1-methyl ethoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (1.4ml) with the tetrahydrofuran solution (0.7ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 44 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-cyclopropyl-1-methyl ethoxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (49mg) (under 60 ℃ outside temperature, handling 2 hours) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 4 block plate, methylene dichloride: ETHYLE ACETATE: ethanol=10: 10: 1, launch once; Then, 0.5mm * 2 block plate, toluene: ETHYLE ACETATE=5: 6, launch once) resistates that generates of purifying and provide colourless foam shape title compound (3.561mg, 2 steps 9%).

IR (pure): 3388,2972,2931,2850,1745,1442,1371,1221,1119,1053cm ^{-1 1}H?NMR?δ：0.40-0.49(m，4H)，0.77(s，3H)，2.21-2.45(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.81(d，J＝16.3Hz，1H)，3.93(d，J＝16.3Hz，1H)，4.03-4.22(m，1H)，4.20-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.60(brs，1H)，6.10(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CO ₂C ₆H ₁₁)，83(100％)。UVλ _maxnm：264。

(embodiment 45)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1,2-trimethylammonium propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (3), with 2,4-dimethyl--2-amylalcohol (0.1g; 0.861mmol), N, N '-NSC 57182 (23mg, 0.112mmol) and 4-(dimethylamino) pyridine (10mg; 0.070mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 in methylene dichloride (1.0ml); 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (43.1mg; 0.070mmol) (at room temperature handling 14 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=6: 1, launch twice) purifying and provide the mixture (28.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1,2-trimethylammonium propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (1.0ml) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 45 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1; 1,2-trimethylammonium propoxycarbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (28.0mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 2 block plate; Methylene dichloride: ETHYLE ACETATE: ethanol=5: 5: 1; Launch once), take turns preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: methyl alcohol=20: 1 with another then; Launch once) resistates that generates of purifying and provide colorless oil title compound (2.195mg, 2 steps 7%).

IR (pure): 2952,2929,1747,1456,1369,1215,1124,1053cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.93(d，J＝6.5Hz，6H)，1.36(d，J＝6.8Hz，3H)，2.56-2.66(m，1H)，2.77-2.87(m，1H)，3.80(d，J＝16.2Hz，1H)，3.92(d，J＝16.2Hz，1H)，4.07(q，J＝6.2Hz，1H)，4.20-4.30(m，1H)，4.40-4.50(m，1H)，5.02(s，1H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.1Hz，1H)，6.38(d，J＝11.1Hz，1H)。MS?m/z：468(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：264.

(embodiment 46)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl suberyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with the 1-methyl cycloheptanol (11.3mg, 0.088mmol), N; N '-NSC 57182 (29.0mg, 0.141mmol) and 4-(dimethylamino) pyridine (6.9mg 0.056mmol) handles [{ 1 α in methylene dichloride (0.6ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (29.4mg 0.048mmol) (at room temperature handled 14 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice) purifying and provide the mixture (10.4mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-methyl suberyl oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.15ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 46 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-methyl suberyl oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (9.3mg) (under 48 ℃ outside temperature, handling 20 minutes).Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=15: 1, launch twice; Then, 0.25mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1; Launch twice) purification reaction mixture and provide colorless oil title compound (3.0mg, 2 step 14%).

IR (pure): 3376,2928,2852,1744,1444,1372,1220,1122,1050cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.36(d，J＝6.5Hz，3H)，2.54-2.65(m，1H)，2.75-2.87(m，1H)，3.83(d，J＝16.5Hz，1H)，3.95(d，J＝16.5Hz，1H)，4.08(q，J＝6.5Hz，1H)，4.19-4.29(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.60(brs，1H)，6.10(d，J＝12.1Hz，1H)，6.37(d，J＝12.1Hz，1H)。MS?m/z：387(M ⁺-C ₈H ₁₅)，67(100％)。UVλ _maxnm：264。

(embodiment 47)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-{ 3,3-dimethyl--1-(2, the 2-dimethyl propyl) butoxy carbonyl methoxyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (3), with 2,2,6; 6-tetramethyl-heptan-4-alcohol (26mg, 0.156mmol), N, N '-NSC 57182 (16mg; 0.078mmol) and 4-(dimethylamino) pyridine (6.0mg, 0.049mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.5ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (30mg 0.049mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (20.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-{ 3,3-dimethyl--1-(2, the 2-dimethyl propyl) butoxy carbonyl methoxyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), handle in THF (0.52ml) with the tetrahydrofuran solution (0.26ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 47 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-{ 3; 3-dimethyl--1-(2, the 2-dimethyl propyl) butoxy carbonyl methoxyl group }-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (20mg) (under 60 ℃ outside temperature, handling 2 hours) carries out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice) purifying and provide colorless oil title compound (12.122mg, 2 steps 45.6%).

IR (pure): 3390,2952,2869,2852,1747,1727,1367,1191,1126,1051cm ^{-1 1}H?NMR?δ：0.76(s，3H)，0.91(s，6H)，0.92(s，6H)，1.37(d，J＝6.4Hz，3H)，2.17-2.47(m，3H)，2.55-2.66(m，1H)，2.76-2.88(m，1H)，3.84(d，J＝16.7Hz，1H)，3.96(d，J＝16.5Hz，1H)，4.09(q，J＝6.4Hz，1H)，4.18-4.30(m，1H)，4.41-4.49(m，1H)，5.01(brs，1H)，5.16-5.27(m，1H)，5.34(brs，1H)，5.58(brs，1H)，6.10(d，J＝11.4Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：527(M ⁺-Me)，57(100％)。UVλ _maxnm：264。

(embodiment 48)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1,3,3-tetramethyl-butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (3), with 2,4; 4-trimethylammonium penta-2-alcohol (21.5mg, 0.165mmol), N, N '-NSC 57182 (34.0mg; 0.165mmol) and 4-(dimethylamino) pyridine (12.5mg, 0.102mmo1) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.5ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (63.1mg 0.102mmol) (at room temperature handled 15 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 4 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice) purifying and provide the mixture (7.7mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1,3,3-tetramethyl-butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), contain 1 α from embodiment 48 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1 with the processing of the tetrahydrofuran solution (0.1ml) of 1M tetra-n-butyl Neutral ammonium fluoride; 1,3,3-tetramethyl-butoxy carbonyl methoxyl group)-9; 10-open loop pregnant-5; 7,10 (19), the mixture of 16-tetraene (7.7mg) (under 43 ℃ outside temperature, handling 30 minutes).Provide colorless oil title compound (2.0mg, 2 steps 4%) through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=15: 1, expansion are once) purification reaction mixture.

IR (pure): 3400,2932,1744,1444,1368,1220,1112,1054cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.99(s，9H)，1.36(d，J＝6.6Hz，3H)，1.52(s，6H)，1.80(s，2H)，2.55-2.66(m，1H)，2.77-2.88(m，1H)，3.79(d，J＝16.3Hz，1H)，3.91(d，J＝16.3Hz，1H)，4.07(q，J＝6.6Hz，1H)，4.19-4.30(m，1H)，4.39-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.10(d，J＝11.1Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：482(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：263。

(embodiment 49)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(the 1-tertiary butyl-2,2-dimethyl-propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 0.1M 2,2,4, dichloromethane solution (0.5ml), N that 4-tetramethyl-penta-3-is pure, N '-NSC 57182 (10.0mg, 0.048mmol) and 4-(dimethylamino) pyridine (4.0mg, 0.033mmol) ¹(18.7mg 0.030mmol) (at room temperature handled 17 hours) acetate to handle [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base].Through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice) purification reaction mixture and provide the mixture (23.4mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(the 1-tertiary butyl-2,2-dimethyl-propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.3ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 49 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(the 1-tertiary butyl-2,2-dimethyl-propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5; 7,10 (19), the mixture of 16-tetraene (23.0mg) (under 42 ℃ outside temperature, handling 30 minutes).Provide colorless oil title compound (7.1mg, 2 steps 46%) through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=15: 1, launch twice) purification reaction mixture.

IR (pure): 3384,2932,1750,1478,1444,1370,1226,1124,1054cm ^{-1 1}H?NMR?δ：0.78(s，3H)，0.99(s，9H)，1.00(s，9H)，1.38(d，J＝6.3Hz，3H)，2.54-2.65(m，1H)，2.75-2.88(m，1H)，3.98(d，J＝16.8Hz，1H)，4.09(d，J＝16.8Hz，1H)，4.07-4.16(m，1H)，4.16-4.30(m，1H)，4.39-4.50(m，1H)，4.66(s，1H)，5.01(brs，1H)，5.34(brs，1H)，5.61(brs，1H)，6.11(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：496(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：264。

(embodiment 50)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1,1-diethylammonium-2-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (3), with 3-ethyl-2-methyl-3-amylalcohol (380mg, 2.92mmol), N; N '-NSC 57182 (602mg, 2.92mmol) and 4-(dimethylamino) pyridine (357mg 2.92mmol) handles [{ 1 α in methylene dichloride (9.7ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (600mg 0.97mmol) (at room temperature handled 15 hours) acetate; Then, carry out aftertreatment and utilize column chromatography (hexane: purifying and provide thick product (460mg) ETHYLE ACETATE=20: 1), with its 100mg further through preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (6.0mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1,1-diethylammonium-2-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), contain 1 α from embodiment 50 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1 with the processing of the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride; 1-diethylammonium-2-methyl propoxycarbonyl methoxyl group)-9; 10-open loop pregnant-5,7,10 (19); The mixture of 16-tetraene (6mg) (under 50 ℃ outside temperature, handling 1.5 hours) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice; Then, 0.25mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice) resistates that generates of purifying and provide colorless oil title compound (2.189mg, 2 steps 2.07%).

IR (pure): 3390,2969,2931,2883,2850,1745,1727,1461,1371,1288,1209,1122,1052cm ^{-1 1}H?NMRδ：0.77(s，3H)，0.83-0.98(m，12H)，1.37(d，J＝6.6Hz，3H)，2.55-2.66(m，1H)，2.76-2.88(m，1H)，3.86(d，J＝16.5Hz，1H)，3.99(d，J＝16.5Hz，1H)，4.05-4.16(m，1H)，4.19-4.31(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.59(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.0Hz，1H)。MS?m/z：387(M ⁺-C(Et) ₂(i-Pr))，57(100％)。UVλ _maxnm：264。

(embodiment 51)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(2, the 2-dimethyl propyl) ethanamide

Press and identical method shown in the embodiment 22 (1), with 2,2-dimethyl propylamine (11mg; 0.126mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (23mg, 0.120mmol) with the I-hydroxybenzotriazole monohydrate (3mg, 0.024mmol) in methylene dichloride (1.5ml) the processing [{ 1 α; 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (15mg 0.0243mmol) (at room temperature handled 13 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=2: 1, launch once) purifying and provide the mixture (14mg) that contains the colorless oil desired product.

(2) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 beta-dihydroxyies-9 } oxygen base]-N-(2, the 2-dimethyl propyl) ethanamide

By and identical method shown in the embodiment 17 (4), in THF (0.2ml), handle from embodiment 51 (1) with the tetrahydrofuran solution (0.2ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9; 10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-N-(2; The 2-dimethyl propyl) mixture of ethanamide (13mg) (under 55 ℃ outside temperature, handling 1 hour) carries out aftertreatment subsequently.Provide flint glass shape title compound (4.174mg, 2 steps 40%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying generation.

IR (pure): 3421,2931,2852,1670,1541,1367,1055cm ^{-1 1}H?NMRδ：0.80(s，3H)，0.93(s，9H)，1.36(d，J＝6.3Hz，3H)，2.20-2.45(m，3H)，2.55-2.64(m，1H)，2.78-2.90(m，1H)，3.05-3.15(m，2H)，3.79-4.08(m，3H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.35(s，1H)，5.61(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)，6.70(brs，1H)。MSm/z：312(M ⁺-HOCH ₂CONHCH ₂C(CH ₃) ₃)，57(100％)。UVλ _maxnm：264。

(embodiment 52)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(1-ethyl propyl) ethanamide

By and identical method shown in the embodiment 22 (1), with 1-ethyl propylamine (11mg, 0.126mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (23mg; 0.120mmol) and I-hydroxybenzotriazole monohydrate (3mg, 0.024mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.5ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (15mg; 0.0243mmol) (at room temperature handling 13 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=2: 1, launch once) purifying and provide the mixture (15mg) that contains the colorless oil desired product.

(2) (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-preparation of N-(1-ethyl propyl) ethanamide

Press and identical method shown in the embodiment 17 (4); In THF (0.2ml), handle from embodiment 52 (1) with the tetrahydrofuran solution (0.2ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (14mg) (under 55 ℃ outside temperature, handling 1 hour) of N-(1-ethyl propyl) ethanamide, carry out aftertreatment subsequently.Provide flint glass shape title compound (5.136mg, 2 steps 50%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying generation.

IR (pure): 3401,2964,2931,2875,2850,1662,1533,1458,1107,1057cm ^{-1 1}H?NMR?δ：0.80(s，3H)，0.90(t，J＝7.3Hz，3H)，1.35(d，J＝6.3Hz，3H)，2.18-2.47(m，3H)，2.58-2.62(m，1H)，2.79-2.84(m，1H)，3.80-4.08(m，4H)，4.24(brs，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.35(s，1H)，5.60(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37-6.38(m，2H)。MSm/z：312(M ⁺-HOCH ₂CONHCH(C ₂H ₅)CH ₂CH ₃)，58(100％)。UVλ _maxnm：264。

(embodiment 53)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-sec.-propyl-N-methylacetamide

By and identical method shown in the embodiment 22 (1), with the sec.-propyl methylamine (8.4mg, 0.115mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (22mg; 0.115mmol) and I-hydroxybenzotriazole monohydrate (3.5mg, 0.023mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.4ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (14.2mg; 0.023mmol) (at room temperature handling 13 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=2: 1, launch once) separates and provide the mixture (7mg) that contains the colorless oil desired product.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-sec.-propyl-N-methylacetamide

Press and identical method shown in the embodiment 17 (4); In THF (0.18ml), handle from embodiment 53 (1) with the tetrahydrofuran solution (0.09ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (6mg) (under 55 ℃ outside temperature, handling 2 hours) of N-sec.-propyl-N-methylacetamide, carry out aftertreatment subsequently.Provide flint glass shape title compound (2.330mg, 2 steps 27%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying generation.

IR (pure): 3408,2970,2931,2875,2850,1628,1367,1101,1054cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.09(d，J＝6.6Hz，3H)，1.13-1.38(m，6H)，2.79(d，J＝6.6Hz，3H)，3.90-4.30(m，5H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.61(brs，1H)，6.10(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CON(CH ₃)(i-Pr))，58(100％)。UVλ _maxnm：264。

(embodiment 54)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(1-propyl group butyl) ethanamide

By and identical method shown in the embodiment 22 (1), with the 4-heptyl amice (14mg, 0.12mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (23mg; 0.12mmol) and I-hydroxybenzotriazole monohydrate (3mg, 0.024mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.3ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (20.0mg; 0.03mmol) (at room temperature handling 13 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=2: 1, launch twice) separates and provide the mixture (18mg) that contains the colorless oil desired product.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-(1-propyl group butyl) ethanamide

Press and identical method shown in the embodiment 17 (4); In THF (0.5ml), handle from embodiment 54 (1) with the tetrahydrofuran solution (0.25ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (18mg) (under 50 ℃ outside temperature, handling 1.5 hours) of N-(1-propyl group butyl) ethanamide, carry out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, launch three times; 0.5mm * 1 block of plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch four times; Then, 0.5mm * 1 block plate, methylene dichloride: ethanol=20: 1, launch twice) resistates that generates of purifying and provide colorless oil title compound (7.089mg, 2 steps 48.7%).

IR (pure): 3401,2956,2931,2871,1666,1533,1440,1106,1054cm ^{-1 1}H?NMR?δ：0.80(s，3H)，0.91(t，J＝6.8Hz，6H)，2.18-2.48(m，3H)，2.54-2.67(m，1H)，2.77-2.89(m，1H)，3.80(d，J＝15.2Hz，1H)，3.92(d，J＝15.2Hz，1H)，3.95-4.07(m，2H)，4.19-4.29(m，1H)，4.41-4.50(m，1H)，5.01(brs，1H)，5.35(brs，1H)，5.59(brs，1H)，6.11(d，J＝11.2Hz，1H)，6.30(d，J＝9.4Hz，1H)，6.36(d，J＝11.2Hz，1H)。MS?m/z：485(M ⁺)，294(100％)。UVλ _maxnm：264。

(embodiment 55)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(2-ethyl-butyl) ethanamide

By and identical method shown in the embodiment 22 (1), with the 2-ethyl butyl amine (18mg, 0.178mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (13mg; 0.068mmol) and I-hydroxybenzotriazole monohydrate (5mg, 0.033mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.4ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (21.9mg; 0.035mmol) (at room temperature handling 5 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=3: 1, launch once) separates and provide the mixture (20mg) that contains the colorless oil desired product.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-(2-ethyl-butyl) ethanamide

Press and identical method shown in the embodiment 17 (4); In THF (0.42ml), handle from embodiment 55 (1) with the tetrahydrofuran solution (0.21ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (15mg) (under 60 ℃ outside temperature, handling 2 hours) of N-(2-ethyl-butyl) ethanamide, carry out aftertreatment subsequently.Provide colourless foam shape title compound (6.954mg, 2 steps 55%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3419,2962,2929,2875,1668,1540,1446,1106,1055cm ^{-1 1}H?NMR?δ：0.79(s，3H)，0.90(t，J＝7.3Hz，6H)，2.20-2.47(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.19-3.27(m，2H)，3.77-4.02(m，3H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.59(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)，6.58(brs，1H)。MS?m/z：471(M ⁺)，160(100％)。UVλ _maxnm：263。

(embodiment 56)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-hydroxyls-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 25 (4); In THF (500ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-hydroxyls pregnant-5,7; 16-triolefin (5.24g; 9.37mmol) (with photoirradiation 7 hours 45 minutes, 25 ℃ of following thermal isomerizations 10 days), reduction vaporization and remove and desolvate.(hexane: ETHYLE ACETATE=10: 1) resistates of purifying generation provides the colourless foam shape level branch (1.95g) that contains title compound through column chromatography.

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(tert-butoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (1), (60% in oil, 246mg with sodium hydride; 6.138mmol), 15-hat-5 (225mg, 1.023mmol) with bromo-acetic acid tert-butyl (1.20g, 6.14mmol) processing contains 1 α from embodiment 56 (1) in THF (10ml); 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-hydroxyls-9,10-open loop pregnant-5,7; 10 (19); The level of 16-tetraene is divided (572mg) (in the heating down 5.5 hours that refluxes), follows, and carries out aftertreatment and utilizes column chromatography (hexane: purifying and provide the colorless oil level branch (0.90g) that contains title compound ETHYLE ACETATE=15: 1).

(3) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (R)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base] acetate

Press and identical method shown in the embodiment 17 (2); Handle in THF (10.2ml) with the methanol solution (10.2ml) of 1M sodium methylate and water (0.26ml) and to contain 1 α from embodiment 56 (2), 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(tert-butoxycarbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the level of 16-tetraene is divided (0.90g) (at room temperature handled 30 minutes, at room temperature handled 10 minutes again); Carry out aftertreatment subsequently and utilize column chromatography (methylene dichloride: purifying and provide colourless foam shape title compound (482mg, 3 step 18%) methyl alcohol=15: 1).

¹H?NMR?δ：0.07(s，6H)，0.74(s，3H)，0.88(s，9H)，0.88(s，9H)，1.39(d，J＝6.6Hz，3H)，2.40-2.51(m，2H)，2.76-2.87(m，1H)，3.96-4.42(m，5H)，4.87(brs，1H)，5.19(brs，1H)，5.68(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.23(d，J＝11.2Hz，1H)，6.60-7.80(br，1H)。

(4) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(1-ethyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with the 3-amylalcohol (15mg, 0.170mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (22mg; 0.115mmol) and 4-(dimethylamino) pyridine (21mg, 0.172mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.6ml); 10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (R)-yl } the oxygen base] acetate (35.3mg) (at room temperature handling 5 hours); Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (28mg) that contains title compound.

(5) 1 α, 3 beta-dihydroxyies-20 (R)-(1-ethyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.58ml) with the tetrahydrofuran solution (0.29ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 56 (4), 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(1-ethyl propoxycarbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (20mg) (under 60 ℃ outside temperature, handling 2 hours) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch once; Then, 0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=8: 8: 1, launch once) resistates that generates of purifying and provide flint glass shape title compound (4.302mg, 2 steps 23%).

IR (pure): 3392,2968,2933,2879,2850,1749,1371,1286,1203,1126,1055cm ^{-1 1}H?NMR?δ：0.76(s，3H)，0.88(t，J＝7.1Hz，6H)，1.37(d，J＝6.6Hz，3H)，2.21-2.50(m，3H)，2.57-2.62(m，1H)，2.78-2.84(m，1H)，3.96(d，J＝16.3Hz，1H)，4.05(d，J＝16.3Hz，1H)，4.09-4.20(m，1H)，4.20-4.30(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.65(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：458(M ⁺)，133(100％)。UVλ _maxnm：264。

(embodiment 57)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(2,2, the 2-trifluoroethyl) ethanamide

Press and identical method shown in the embodiment 22 (1), with 2,2; 2-trifluoro ethamine (29mg, 0.293mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (22mg, 0.115mmol) with I-hydroxybenzotriazole monohydrate (9mg; 0.047mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 in methylene dichloride (0.58ml); 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (36mg; 0.058mmol) (at room temperature handling 10 minutes), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE=2: 1, launch once) separates and provide the mixture (38mg) that contains the colorless oil desired product.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-(2,2, the 2-trifluoroethyl) ethanamide

By and identical method shown in the embodiment 17 (4), in THF (0.94ml), handle from embodiment 57 (1) with the tetrahydrofuran solution (0.47ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9; 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base]-N-(2; 2,2-trifluoroethyl) mixture (33mg) of ethanamide (under 65 ℃ outside temperature, handling 1.5 hours) carries out aftertreatment subsequently.Provide flint glass shape title compound (17.305mg, 2 steps 73%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3415,2933,2850,1682,1533,1279,1163,1115,1055cm ^{-1 1}H?NMR?δ：0.79(s，3H)，1.36(d，J＝6.6Hz，3H)，2.21-2.41(m，3H)，2.57-2.62(m，1H)，2.79-2.83(m，1H)，3.82-4.05(m，5H)，4.20-4.29(m，1H)，4.39-4.50(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.61(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)，6.93(brs，1H)。MS?m/z：312(M ⁺-HOCH ₂CONHCH ₂CF ₃)，91(100％)。UVλ _maxnm：263。

(embodiment 58)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclobutoxy group carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with cyclobutanol (18mg, 0.250mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (31mg; 0.162mmol) and 4-(dimethylamino) pyridine (30mg, 0.246mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.8ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (50mg; 0.081mmol) (at room temperature handling 2 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (53mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(cyclobutoxy group carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.79ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 58 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclobutoxy group carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (53mg) (under 50 ℃ outside temperature, handling 2.5 hours) carries out aftertreatment subsequently.Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, launch twice; 0.5mm * 1 block of plate, methylene dichloride: ethanol=10: 1, launch twice; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch once) resistates that generates of purifying and provide flint glass shape title compound (1.718mg, 2 steps 5%).

IR (pure): 3400,2929,2850,1751,1597,1200,1124,1053cm ^{-1 1}H?NMRδ：0.78(s，3H)，1.36(d，J＝6.4Hz，3H)，2.21-2.43(m，3H)，2.57-2.62(m，1H)，2.78-2.84(m，1H)，3.87-4.19(m，3H)，4.20-4.30(br，1H)，4.40-4.49(br，1H)，5.01-5.07(m，2H)，5.34(s，1H)，5.61(brs，1H)，6.10(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS?m/z：312(M ⁺-HOCH ₂CO ₂C ₄H ₇)，55(100％)。UVλ _maxnm：264。

(embodiment 59)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with the 3-amylalcohol (23mg, 0.258mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (33mg; 0.172mmol) and 4-(dimethylamino) pyridine (32mg, 0.258mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.9ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (53mg; 0.086mmol) (at room temperature handling 2 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (51mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.7ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 59 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(1-ethyl propoxycarbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (45mg) (under 50 ℃ outside temperature, handling 2.5 hours) carries out aftertreatment subsequently.Provide flint glass shape title compound (12.126mg, 2 steps 35%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3390,2970,2931,2879,2850,1749,1458,1205,1124,1053cm ^{-1 1}H?NMR?δ：0.77(s，3H)，0.88(dt，J＝7.4，2.1Hz，6H)，1.37(d，J＝6.4Hz，3H)，2.21-2.45(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.91-4.13(m，3H)，4.20-4.30(br，1H)，4.40-4.50(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.61(brs，1H)，6.11(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS m/z：312(M ⁺-HOCH ₂CO ₂CH(C ₂H ₅) ₂)，71(100％)。UVλ _maxnm：263。

(embodiment 60)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclopentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with cyclopentanol (30.0mg, 0.348mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (40.0mg; 0.209mmol) and 4-(dimethylamino) pyridine (40.0mg, 0.327mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.8ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (65.1mg; 0.106mmol) (at room temperature handling 1 hour 30 minutes), then, utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=20: 1, launch three times) purifying and provide the mixture (50.4mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(cyclopentyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.35ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 60 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclopentyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (23.7mg) (under 47 ℃ outside temperature, handling 50 minutes).Through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=20: 1, launch three times; Then, 0.25mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times) purification reaction mixture and provide colorless oil title compound (4.1mg, 2 steps 23%).

IR (pure): 3392,2932,2872,1746,1440,1370,1208,1122,1052cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.36(d，J＝6.6Hz，3H)，2.54-2.65(m，1H)，2.76-2.86(m，1H)，3.89(d，J＝16.2Hz，1H)，4.00(d，J＝16.2Hz，1H)，4.06(q，J＝6.6Hz，1H)，4.20-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.19-5.29(m，1H)，5.34(brs，1H)，5.61(brs，1H)，6.10(d，J＝10.6Hz，1H)，6.37(d，J＝10.6Hz，1H)。MS?m/z：438(M ⁺-H ₂O)，69(100％)。UVλ _maxnm：264。

(embodiment 61)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclo propyl methoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with cyclopropyl-carbinol (11.0mg, 0.153mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (20.0mg; 0.104mmol) and 4-(dimethylamino) pyridine (20.0mg, 0.164mmo1) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.4ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (31.3mg 0.051mmol) (at room temperature handled 16 hours) acetate, then; Utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=20: 1, launch once; Hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (25.6mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(cyclo propyl methoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.4ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 61 (1); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclo propyl methoxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (24.0mg) (under 47 ℃ outside temperature, handling 50 minutes).Through preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: ethanol=20: 1, launch twice; Then, 0.25mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times) purification reaction mixture and provide colorless oil title compound (2.1mg, 2 steps 10%).

IR (pure): 3388,2928,2852,1750,1446,1370,1204,1122,1054cm ^{-1 1}H?NMRδ：0.25-0.33(m，2H)，0.52-0.61(m，2H)，0.78(s，3H)，1.38(d，J＝6.7Hz，3H)，2.54-2.65(m，1H)，2.76-2.88(m，1H)，3.96(d，J＝16.3Hz，1H)，4.08(d，J＝16.3Hz，1H)，4.08(q，J＝6.7Hz，1H)，4.18-4.28(m，1H)，4.41-4.48(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.62(brs，1H)，6.10(d，J＝10.3Hz，1H)，6.37(d，J＝10.3Hz，1H)。MS?m/z：442(M ⁺)。55(100％)。UVλ _maxnm：264。

(embodiment 62)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclohexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with hexalin (15mg, 0.150mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (19mg; 0.099mmol) and 4-(dimethylamino) pyridine (18mg, 0.148mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (2ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (31mg; 0.050mmol) (at room temperature handling 3 days), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (27mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(cyclohexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.37ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 62 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(cyclohexyloxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (26mg) (under 50 ℃ outside temperature, handling 1 hour) carries out aftertreatment then.Provide colourless foam shape title compound (5.218mg, 2 steps 24%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3390,2933,2856,1747,1448,1203,1120,1053cm ^{-1 1}H?NMR?δ：0.78(s，3H)，1.37(d，J＝6.6Hz，3H)，2.21-2.45(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.88-4.12(m，3H)，4.20-4.30(br，1H)，4.40-4.50(br，1H)，4.79-4.90(m，1H)，5.01(brs，2H)，5.34(s，1H)，5.61(brs，1H)，6.10(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS?m/z：470(M ⁺)，55(100％)。UVλ _maxnm：264。

(embodiment 63)

(1) The preparation of 1-[[{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base] ethanoyl] piperidines

By and identical method shown in the embodiment 21 (1), with piperidines (13mg, 0.150mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (19mg; 0.099mmol) and 4-(dimethylamino) pyridine (18mg, 0.148mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (2ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (31mg; 0.050mmol) (at room temperature handling 3 days), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=1: 1, launch once) purifying and provide the mixture (23mg) that contains title compound.

(2) The preparation of 1-[{ (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 } ethanoyl] piperidines

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.32ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1-[[{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 from embodiment 63 (1); 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] ethanoyl] mixture (22mg) (under 50 ℃ outside temperature, handling 2 hours) of piperidines, carry out aftertreatment then.Provide colourless foam shape title compound (7.499mg, 2 steps 34%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying generation.

IR (pure): 3384,2933,2854,1630,1446,1254,1053cm ^{-1 1}H?NMRδ：0.78(s，3H)，1.35(d，J＝6.4Hz，3H)，2.20-2.44(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.35-3.61(m，4H)，3.93-4.14(m，3H)，4.20-4.30(br，1H)，4.40-4.49(br，1H)，5.01(brs，2H)，5.34(s，1H)，5.60(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS?m/z：312(M ⁺-HOCH ₂COC ₅H ₁₀N)，144(100％)。UVλ _maxnm：264。

(embodiment 64)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(diamantane-1-base oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with the 1-adamantanol (30mg, 0.197mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (25mg; 0.130mmol) and 4-(dimethylamino) pyridine (24mg, 0.196mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.65ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] acetate (40mg; 0.065mmol) (at room temperature handling 15 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=5: 1, launch once) purifying and provide the mixture (18mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(diamantane-1-base oxygen base carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.46ml) with the tetrahydrofuran solution (0.23ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 64 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(diamantane-1-base oxygen base carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (17mg) (under 60 ℃ outside temperature, handling 2 hours) carries out aftertreatment then.Provide flint glass shape title compound (7.471mg, 2 steps, 23 %) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3380,2916,2852,1745,1456,1209,1122,1053cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.36(d，J＝6.3Hz，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.82(d，J＝16.3Hz，1H)，3.92(d，J＝16.3Hz，1H)，4.04-4.16(m，1H)，4.20-4.30(m，1H)，4.41-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.59(brs，1H)，6.10(d，J＝11.0Hz，1H)，6.37(d，J＝11.0Hz，1H)。MS?m/z：522(M ⁺)，135(100％)。UVλ _maxnm：264。

(embodiment 65)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(1-ethyl-1-methyl propoxycarbonyl) methoxyl group-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with 3-methyl-3-amylalcohol (28mg, 0.275mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (21mg; 0.110mmol) and 4-(dimethylamino) pyridine (20mg, 0.164mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (0.55ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (R)-yl } the oxygen base] acetate (34mg; 0.055mmol) (at room temperature handling 5 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=10: 1, launch once) purifying and provide the mixture (10mg) that contains title compound.

(2) 1 α, 3 beta-dihydroxyies-20 (R)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (0.1ml) with the tetrahydrofuran solution (0.2ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 65 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (R)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (9mg) (under 55 ℃ outside temperature, handling 2 hours) carries out aftertreatment subsequently.Provide flint glass shape title compound (3.102mg, 2 steps 13%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, expansion are once) purifying generation.

IR (pure): 3380,2971,2929,2850,1747,1460,1373,1213,1124,1055cm ^{-1 1}H?NMRδ：0.76(s，3H)，0.85(t，J＝7.4Hz，6H)，1.25(s，3H)，1.36(d，J＝6.6Hz，3H)，1.39(s，3H)，2.20-2.49(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.87(d，J＝16.3Hz，1H)，3.95(d，J＝16.3Hz，1H)，4.08-4.16(m，1H)，4.20-4.30(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.63(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CO ₂C(C ₂H ₅) ₂CH ₃)，85(100％)。UVλ _maxnm：265。

(embodiment 66)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-methoxyl group-N-methylacetamide

With [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (13.5mg, 0.0219mmol), N-methoxyl group-N-methylamine hydrochloride (11mg; 0.109mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (21mg; 0.110mmol), the I-hydroxybenzotriazole monohydrate (3mg, 0.024mmol), triethylamine (22mg, 0.217mmol) and methylene dichloride (0.4ml) mix and at room temperature stirred 15 hours.Reaction mixture is distributed between aqueous citric acid and methylene dichloride.The organic layer that forms with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing successively, dry on SODIUM SULPHATE ANHYDROUS 99PCT, filter the back reduction vaporization.Separate the resistates that generates and provide the mixture (13mg) that contains the colorless oil desired product through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=2: 1, expansion are once).

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-methoxyl group-N-methylacetamide

Press and identical method shown in the embodiment 17 (4); In THF (0.36ml), handle from embodiment 66 (1) with the tetrahydrofuran solution (0.18ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (12mg) (under 55 ℃ outside temperature, handling 2 hours) of N-methoxyl group-N-methylacetamide, carry out aftertreatment subsequently.Provide flint glass shape title compound (3.800mg, 2 steps 44%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying generation.

IR (pure): 3399,2933,2850,1668,1436,1052cm ^{-1 1}H?NMRδ：0.78(s，3H)，1.38(d，J＝6.6Hz，3H)，2.18-2.47(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.18(s，3H)，3.66(s，3H)，4.07-4.27(m，4H)，4.39-4.49(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.63(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MSm/z：312(M ⁺-HOCH ₂CON(OCH ₃)CH ₃)，91(100％)。UVλ _maxnm：264。

(embodiment 67)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-methoxyl group ethanamide

By and identical method shown in the embodiment 66 (1), with the N-methoxy amine hydrochlorate (9mg, 0.108mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (21mg; 0.110mmol), the I-hydroxybenzotriazole monohydrate (3mg, 0.024mmol) and triethylamine (22mg 0.217mmol) handles [{ 1 α in methylene dichloride (0.88ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (13.6mg 0.0220mmol) (at room temperature handled 15 hours) acetate; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=2: 1, launch once) to separate and provide the mixture (12mg) that contains the colorless oil desired product.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-methoxyl group ethanamide

Press and identical method shown in the embodiment 17 (4); In THF (0.34ml), handle from embodiment 67 (1) with the tetrahydrofuran solution (0.17ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (11mg) (under 55 ℃ outside temperature, handling 2 hours) of N-methoxyl group ethanamide, carry out aftertreatment subsequently.Provide flint glass shape title compound (3.189mg, 2 steps 38%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying generation.

IR (pure): 3384,2929,2850,1674,1441,1117,1053cm ^{-1 1}H?NMR?δ：0.78(s，3H)，1.34(d，J＝6.6Hz，3H)，2.18-2.46(m，3H)，2.57-2.62(m，1H)，2.79-2.83(m，1H)，3.81(s，3H)，3.81-4.07(m，3H)，4.20-4.30(m，1H)，4.41-4.48(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.59(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)，8.92(brs，1H)。MS?m/z：312(M ⁺-HOCH ₂CONHOMe)，91(100％)。UVλ _maxnm：264。

(embodiment 68)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(ethoxycarbonyl methoxy)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

In the nitrogen atmosphere at room temperature, toward [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (43.0mg; 0.07mmol) methylene dichloride (0.8ml) solution in add ethanol (5mg, 0.1mmol), chlorination 2-chloro-1,3-methylimidazole quinoline (17mg; 0.1mmol) and pyridine (17mg 0.21mmol), stirred 15 hours then.In reaction mixture impouring water, with ETHYLE ACETATE washing, use saturated sodium bicarbonate aqueous solution, sodium chloride aqueous solution and water washing successively, dry on anhydrous magnesium sulfate, then, reduction vaporization and remove and desolvate.Provide the mixture (28.0mg) that contains title compound through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=10: 1, expansion are once) purifying generation.

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(ethoxycarbonyl methoxy)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Handle in THF (2.0ml) with the tetrahydrofuran solution (0.65ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain 1 α from embodiment 68 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(ethoxycarbonyl methoxy)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (28mg) (under 50 ℃ outside temperature, handling 2 hours) carries out aftertreatment then.Through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=20: 1, launch twice; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times) resistates that generates of purifying and provide colorless oil title compound (3.167mg, 2 steps 10.9%).

IR (pure): 3347,2975,2931,2848,1751,1442,1369,1288,1203,1124,1052cm ^{-1 1}H?NMR?δ：0.78(s，3H)，1.27(t，J＝7.3Hz，3H)，1.37(d，J＝6.3Hz，3H)，2.19-2.48(m，3H)，2.55-2.66(m，1H)，2.78-2.87(m，1H)，3.93(d，J＝16.2Hz，1H)，4.05(d，J＝16.2Hz，1H)，4.03-4.12(m，1H)，4.15-4.30(m，3H)，4.39-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.62(brs，1H)，6.11(d，J＝11.5Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：416(M ⁺)，133(100％)。UVλ _maxnm：264。

(embodiment 69)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(isopropoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 68 (1), with Virahol (0.641ml, 9.350mmol), chlorination 2-chloro-1; 3-methylimidazole quinoline (263mg, 1.558mmol) and pyridine (260 μ l 3.117mmol) handle [{ 1 α in methylene dichloride (10ml); 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (641mg 1.039mmol) (at room temperature handled 2 hours) acetate; Then, carry out aftertreatment and utilize column chromatography (hexane: purifying and provide the mixture (669mg) that contains title compound ETHYLE ACETATE=10: 1).

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(isopropoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (5.0ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 69 (1), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(isopropoxy carbonyl methoxyl group)-9,10-open loop pregnant-5; 7; 10 (19), the mixture of 16-tetraene (669mg) (under 50 ℃ outside temperature, handling 3 hours) carries out aftertreatment then.(methylene dichloride: methyl alcohol=10: 1) resistates that generates of purifying provides colorless oil and contains 1 α, 3 beta-dihydroxyies-20 (S)-(isopropoxy carbonyl methoxyl group)-9,10-open loop pregnant-5 through column chromatography; 7,10 (19), 16-tetraene (246mg) and [{ 1 α; 3 β-dihydroxyl-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] mixture of acetate (137mg, 2 steps 33%).Then, contain 1 α through preparative thin layer chromatography (0.5mm * 8 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, expansion are once) purifying; 3 beta-dihydroxyies-20 (S)-(isopropoxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7,10 (19); The mixture of 16-tetraene and provide colorless oil 1 α, 3 beta-dihydroxyies-20 (S)-(isopropoxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene (169mg, 2 steps 37%).This compound have with embodiment 15 in preparation the identical IR of compound, MASS, ¹H NMR and UV spectrum.

For [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 beta-dihydroxyies-9 } oxygen base] acetate:

¹H?NMRδ：0.79(s，3H)，1.39(d，J＝6.8Hz，3H)，2.53-2.65(m，1H)，2.75-2.87(m，1H)，3.92(d，J＝16.5Hz，1H)，4.03-4.16(m，2H)，4.21-4.29(m，1H)，4.41-4.50(m，1H)，5.01(s，1H)，5.34(s，1H)，5.64(brs，1H)，6.11(d，J＝11.3Hz，1H)，6.36(d，J＝11.3Hz，1H)。MS?m/z：388(M ⁺)，91(100％)。UVλ _maxnm：264。

(embodiment 70)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base) 9 } oxygen base]-N-(2-methyl-propyl) ethanamide

By and identical method shown in the embodiment 68 (1), with 2-methyl propylamine (0.1ml, 0.970mmol), chlorination 2-chloro-1,3-methylimidazole quinoline (25mg; 0.146mmol) and pyridine (80 μ l, 0.970mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.0ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (60mg 0.097mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=5: 1, launch once) purifying and provide the mixture (10.0mg) that contains title compound.

(2) [ { the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 beta-dihydroxyies-9 } oxygen base]-preparation of N-(2-methyl-propyl) ethanamide

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (1.0ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base) 9,10-open loop pregnant-5 from embodiment 70 (1); 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (10mg) (under 40 ℃ outside temperature, handling 2 hours) of N-(2-methyl-propyl) ethanamide, carry out aftertreatment subsequently.Provide colorless oil title compound (0.859mg, 2 steps 2%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, expansion are once) purifying generation.

IR (pure): 3421,2956,2850,1668,1541,1437,1369,1107,1055cm ^{-1 1}H?NMRδ：0.79(s，3H)，0.93(d，J＝6.8Hz，6H)，1.35(d，J＝6.8Hz，3H)，2.50-2.66(m，1H)，2.74-2.88(m，1H)，3.02-3.20(m，2H)，3.64-4.06(m，3H)，4.13-4.30(m，1H)，4.34-4.49(m，1H)，5.01(s，1H)，5.35(s，1H)，5.60(brs，1H)，6.10(d，J＝10.8Hz，1H)，6.36(d，J＝10.8Hz，1H)，6.58-6.71(m，1H)。MS?m/z：425(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：263。

(embodiment 71)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base) 9 } oxygen base]-N-sec.-propyl ethanamide

By and identical method shown in the embodiment 68 (1), with Isopropylamine (0.1ml, 0.970mmol), chlorination 2-chloro-1,3-methylimidazole quinoline (25mg; 0.146mmol) and pyridine (80 μ l, 0.970mmol) processing [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 in methylene dichloride (1.0ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (60mg 0.097mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=5: 1, launch once) purifying and provide the mixture (44.0mg) that contains title compound.

(2) [ { the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 beta-dihydroxyies-9 } oxygen base]-preparation of N-sec.-propyl ethanamide

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (1.0ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 from embodiment 71 (1); 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base]-mixture (44mg) (under 40 ℃ outside temperature, handling 2 hours) of N-sec.-propyl ethanamide, carry out aftertreatment subsequently.Provide colorless oil title compound (13.17mg, 2 steps 31%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, expansion are once) purifying generation.

IR (pure): 3406,2972,2931,2850,1662,1531,1446,1367,1109,1055cm ^{-1 1}H?NMR?δ：0.79(s，3H)，1.17(d，J＝6.8Hz，6H)，1.35(d，J＝6.5Hz，3H)，2.48-2.66(m，1H)，2.74-2.87(m，1H)，3.58-4.29(m，4H)，4.38-4.50(m，1H)，5.01(s，1H)，5.34(s，1H)，5.59(brs，1H)，6.10(d，J＝11.1Hz，1H)，6.25-6.49(m，2H)。MS?m/z：429(M ⁺)，118(100％)。UVλ _maxnm：264。

(embodiment 72)

(1) The preparation of { the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen yl acetamide

In nitrogen atmosphere, will [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base] (15.0mg, THF 0.024mmol) (0.6ml) solution is cooled to 0 ℃ to acetate.(18.3mg, 0.18mmol) (15.6mg 0.14mmol) afterwards, stirs reaction mixture 30 minutes, feeds the further down stirring of ammonia 20 minutes at bubbling again with Vinyl chloroformate adding triethylamine.Reaction mixture is filtered, and vapourisation under reduced pressure and remove and desolvate then, utilizes preparative thin layer chromatography (0.5mm * 1 block plate, methylene dichloride: methyl alcohol=10: 1, launch once) to separate and provides the mixture (14.5mg) that contains the colorless oil desired product.

(2) The preparation of { the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 beta-dihydroxyies-9 } oxygen yl acetamide

Press and identical method shown in the embodiment 17 (4); In THF (0.5ml), handle from embodiment 72 (1) with the tetrahydrofuran solution (0.24ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain { 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5; 7; 10 (19), 16-tetraene-20 (S)-yl } mixture (14.5mg) (under 50 ℃ outside temperature, handling 2 hours) of oxygen yl acetamide, carry out aftertreatment subsequently.Through preparative thin layer chromatography (0.25mm * 2 block plate; Methylene dichloride: methyl alcohol=10: 1, launch three times, then; 0.5mm * 1 block of plate; Hexane: ETHYLE ACETATE: ethanol=10: 5: 2, launch twice) resistates that generates of purifying and provide colorless oil title compound (5.249mg, 2 steps 56.4%).

IR (pure): 3353,2960,2931,2873,1727,1681,1457,1288,1118,1056cm ^{-1 1}H?NMR?δ：0.79(s，3H)，1.35(d，J＝6.4Hz，3H)，2.18-2.47(m，3H)，2.55-2.66(m，1H)，2.76-2.88(m，1H)，3.78(d，J＝15.5Hz，1H)，3.96(d，J＝15.6Hz，1H)，3.96-4.06(m，1H)，4.19-4.30(m，1H)，4.40-4.49(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.52(brs，1H)，5.61(brs，1H)，6.11(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)，6.56(brs，1H)。MS?m/z：387(M ⁺)，312(100％)。UVλ _maxnm：264。

(embodiment 73)

(1) 1 α, 3 beta-dihydroxyies-20 (S)-(1-trifluoromethyl-2,2,2-trifluoro ethoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 21 (1), with 1,1,1; 3,3, and 3-hexafluoro-2-propyl alcohol (420mg, 2.5mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (19mg; 0.10mmol) and 4-(dimethylamino) pyridine (12mg, 0.10mmol) processing [{ 1 α, 3 beta-dihydroxyies-9,10-open loop pregnant-5 in methylene dichloride (0.25ml); 7,10 (19), 16-tetraene-20 (S)-yl } the oxygen base] acetate (9.6mg; 0.025mmol) (at room temperature handling 4 hours), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate; Hexane: ETHYLE ACETATE=1: 3, launch twice) purifying and provide flint glass shape title compound (2.867mg, 22%).

IR (pure): 3360,2931,2850,1803,1386,1290,1234,1203,1113cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.38(d，J＝6.6Hz，3H)，2.20-2.41(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，4.05-4.30(m，4H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.63(brs，1H)，5.75-5.84(m，1H)，6.11(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS?m/z：312(M ⁺-HOCH ₂CO ₂CH(CF ₃) ₂)，83(100％)。UVλ _maxnm：264。

(embodiment 74) 1 α, 3 beta-dihydroxyies-20 (S)-(isopropylthio carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 21 (1), with 2-propylmercaptan (36 μ l, 0.386 mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (74mg; 0.386mmol) and 4-(dimethylamino) pyridine (47mg, 0.386mmol) processing [{ 1 α, 3 beta-dihydroxyies-9 in methylene dichloride (0.5ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (15mg 0.0386mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate; Hexane: ETHYLE ACETATE: ethanol=5: 5: 1, launch once) purifying and provide colorless oil title compound (1.157mg, 7%).

IR (pure): 3356,2927,2850,1682,1442,1367,1254,1128,1051cm ^{-1 1}H?NMRδ：0.79(s，3H)，1.40(d，J＝6.5Hz，3H)，2.54-2.65(m，1H)，2.72-2.88(m，1H)，3.55-3.72(m，1H)，3.84-4.13(m，3H)，4.17-4.30(m，1H)，4.37-4.50(m，1H)，5.01(s，1H)，5.34(s，1H)，5.63(brs，1H)，6.10(d，J＝11.1Hz，1H)，6.37(d，J＝11.1Hz，1H)。MS?m/z：428(M ⁺-H ₂O)，55(100％)。UVλ _maxnm：263。

(embodiment 75) 1 α, 3 beta-dihydroxyies-20 (S)-(t-butylthio carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with 2-methyl-2-propylmercaptan (44 μ l, 0.386mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (74mg; 0.386mmol) and 4-(dimethylamino) pyridine (47mg, 0.386mmol) processing [{ 1 α, 3 beta-dihydroxyies-9 in methylene dichloride (0.5ml); 10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl } the oxygen base] (15mg 0.0386mmol) (at room temperature handled 2 hours) acetate, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, launch once) and another takes turns preparative thin layer chromatography (0.5mm * 1 block plate subsequently; Toluene: ETHYLE ACETATE=1: 1, launch once) purifying and provide colorless oil title compound (0.236mg, 1%).

IR (pure): 2927,2852,1676,1456,1363,1126,1051cm ^{-1 1}H?NMR?δ：0.78(s，3H)，1.39(d，J＝6.5Hz，3H)，2.52-2.66(m，1H)，2.74-2.88(m，1H)，3.84(d，J＝15.9Hz，1H)，3.93-4.08(m，2H)，4.19-4.29(m，1H)，4.37-4.49(m，1H)，5.01(s，1H)，5.34(s，1H)，5.62(brs，1H)，6.11(d，J＝11.6Hz，1H)，6.37(d，J＝11.6Hz，1H)。MS?m/z：442(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：263。

(embodiment 76)

(1) The preparation of the tertiary butyl [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base) are pregnant-5,7-diene-20 (S)-yl } oxygen base] acetic ester

Press and identical method shown in the embodiment 17 (1), (60% in oil, 65mg with sodium hydride; 1.625mmol), (16mg is 0.268mmol) with bromo-acetic acid tert-butyl (316mg, 1.62mmol) processing 1 α in THF (2.7ml) for 15-hat-5; 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls are pregnant-5, and (150mg 0.267mmol) (heated 17 hours down refluxing) the 7-diene; Then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 5 block plate, hexane: ETHYLE ACETATE=5: 1, launch once; Then, 0.5mm * 2 block plate, hexane: ETHYLE ACETATE=7: 1, launch twice) separate and provide colourless foam shape title compound (30mg, 17%).

¹H?NMRδ：0.05(s，3H)，0.06(s，6H)，0.11(s，3H)，0.61(s，3H)，0.89(s，18H)，1.20(d，J＝5.9Hz，3H)，1.48(s，9H)，2.73-2.85(m，1H)，3.32-3.46(m，1H)，3.64-4.13(m，4H)，5.29-5.38(br，1H)，5.55-5.61(br，1H)。

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(tert-butoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 4 (3); In THF (200ml), handle the tertiary butyl [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base base) are pregnant-5,7-diene-20 (S)-yl } oxygen base] acetic ester (110mg; 0.267mmol) (with photoirradiation 6 minutes 15 seconds; In the heating down 2 hours that refluxes), then, evaporation and except that desolvating.In the resistates that generates, add THF (5ml) and hydrogen fluoride/pyridine (70%; 2.31g); By handling (at room temperature handling 30 minutes), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate again with method identical shown in the embodiment 8 (3); Methylene dichloride: ethanol=10: 1, launch once; Then, 0.5mm * 2 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch twice) thereby separation provides colourless foam shape title compound (6.252mg, 9%).

IR (pure): 3380,2929,2875,1749,1369,1223,1128,1055cm ^{-1 1}H?NMRδ：0.54(s，3H)，1.18(d，J＝6.1Hz，3H)，1.47(s，9H)，?2.31(dd，J＝13.4，6.4Hz，1H)，2.57-2.63(m，1H)，2.80-2.86(m，1H)，3.31-3.41(m，1H)，3.90(d，J＝16.0Hz，1H)，3.98(d，J＝16.0Hz，1H)，4.21-4.30(br，1H)，4.40-4.49(br，1H)，4.99(brs，1H)，5.33(s，1H)，6.03(d，J＝11.4Hz，1H)，6.36(d，J＝11.4Hz，1H)。MS?m/z：446(M ⁺)，57(100％)。UVλ _maxnm：264。

(embodiment 77)

(1) The preparation of [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base) are pregnant-5,7-diene-20 (S)-yl } oxygen base] acetate

Toward the tertiary butyl [{ 1 α; 3 β-two (t-butyldimethylsilyloxy base base) pregnant-5; 7-diene-20 (S)-yl } the oxygen base] (9mg adds the methanol solution (0.13ml) of 1M sodium methylate, and at room temperature stirred 20 minutes acetic ester in THF 0.013mmol) (0.13ml) solution.Further add water (0.26ml), at room temperature stirred once more 30 minutes.Use the ETHYLE ACETATE diluted reaction mixture, with saturated SODIUM PHOSPHATE, MONOBASIC solution washing, dry on SODIUM SULPHATE ANHYDROUS 99PCT then.Under reduced pressure provide title compound (6mg, 73%) colorless solid except that desolvating.

¹H?NMRδ：0.05(s，3H)，0.07(s，6H)，0.11(s，3H)，0.61(s，3H)，0.88(s，9H)，0.89(s，9H)，2.26-2.42(m，2H)，2.74-2.85(m，1H)，3.40-3.55(m，1H)，3.65-3.73(br，1H)，3.91-4.21(m，3H)，5.31-5.37(br，1H)，5.54-5.61(m，1H)。

(2) The preparation of 1-ethyl propyl [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base) are pregnant-5,7-diene-20 (S)-yl } oxygen base] acetic ester

By and identical method shown in the embodiment 17 (3), with the 3-amylalcohol (39mg, 0.443mmol), N; N '-NSC 57182 (61mg, 0.296mmol) and 4-(dimethylamino) pyridine (54mg 0.443mmol) handles [{ 1 α in methylene dichloride (1.5ml); 3 β-two (t-butyldimethylsilyloxy base) are pregnant-5,7-diene-20 (S)-yl } the oxygen base] (91mg 0.147mmol) (at room temperature handled 15 hours) acetate; Then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=5: 1; Launch once) purifying and provide colorless oil title compound (37mg, 37%).

¹H?NMRδ：0.05(s，3H)，0.06(s，6H)，0.11(s，3H)，0.61(s，3H)，0.89(s，18H)，1.21(d，J＝5.9Hz，3H)，2.29-2.41(m，2H)，2.73-2.85(m，?1H)，3.35-3.48(m，1H)，3.66-3.73(br，1H)，3.94-4.16(m，3H)，4.78-4.91(m，1H)，5.30-5.37(br，1H)，5.54-5.63(m，1H)。

(3) 1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 4 (3); In THF (200ml), handle 1-ethyl propyl [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base) are pregnant-5,7-diene-20 (S)-yl } oxygen base] acetic ester (35mg; 0.051mmol) (with photoirradiation 4 minutes 45 seconds; In the heating down 2 hours that refluxes), then, evaporation and except that desolvating.In the resistates that generates, add THF (2ml) and hydrogen fluoride/pyridine (70%; 0.51g); By handling (at room temperature handling 1 hour), then, carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 2 block plate again with method identical shown in the embodiment 8 (3); Methylene dichloride: ethanol=10: 1, launch once; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch once) thereby purifying provides flint glass shape title compound (2.506mg, 11%).

IR (pure): 3390,2931,2877,1751,1458,1375,1286,1203,1055cm ^{-1 1}H?NMRδ：0.54(s，3H)，0.88(t，J＝7.4Hz，6H)，1.20(d，J＝6.1Hz，3H)，2.31(dd，J＝13.4，6.4Hz，1H)，2.57-2.63(m，1H)，2.80-2.86(m，1H)，3.35-3.43(m，1H)，4.02(d，J＝16.2Hz，1H)，4.10(d，J＝16.2Hz，1H)，4.21-4.30(br，1H)，4.40-4.49(br，1H)，4.79-4.88(m，1H)，4.99(brs，1H)，5.33(s，1H)，6.03(d，J＝11.4Hz，1H)，6.36(d，J＝11.4Hz，1H)。MS?m/z：460(M ⁺)，55(100％)。UVλ _maxnm：265。

(embodiment 78)

(1) The preparation of [{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (R)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]-N-(tertiary butyl) ethanamide

By and identical method shown in the embodiment 17 (1), with sodium hydride (60% in oil, 18mg, 0.44mmol), 15-is preced with-5 (16mg; 0.073mmol) and 2-bromo-N-(tertiary butyl) ethanamide (85mg, 0.44mmol) processing 1 α in THF (0.7ml), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9; 10-open loop pregnant-5,7,10 (19); The 16-tetraene (41mg, 0.073mmol) (heating is 6 hours under refluxing), then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate is used methylene dichloride separately, launch once) to separate and provide the mixture (33mg) that contains light yellow oily desired product.

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (R)-yl) oxygen base for 1 α, 3 beta-dihydroxyies-9 }-N-(tertiary butyl) ethanamide

By and identical method shown in the embodiment 17 (4), contain [{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 with the processing of the tetrahydrofuran solution (0.5ml) of 1M tetra-n-butyl Neutral ammonium fluoride from embodiment 78 (1); 10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (R)-yl } the oxygen base]-mixture (31mg) (under 60 ℃ outside temperature, handling 1 hour) of N-tertiary butyl ethanamide; Then, carry out aftertreatment.Provide flint glass shape title compound (10.028mg, 2 steps 33%) through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: ethanol=10: 1, expansion are once) purifying.

IR (pure): 3400,2968,2931,1662,1533,1365,1103,1057cm ^{-1 1}H?NMRδ：0.75(s，3H)，1.37(s，9H)，2.20-2.44(m，3H)，2.57-2.62(m，1H)，2.79-2.84(m，1H)，3.79(s，2H)，4.02-4.15(m，1H)，4.21-4.45(m，1H)，4.40-4.49(m，1H)，5.00(brs，1H)，5.34(s，1H)，5.64(brs，1H)，6.11(d，J＝11.4Hz，1H)，6.36(d，J＝11.4Hz，1H)，6.46(brs，1H)。MS?m/z：443(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 79)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(methoxycarbonyl propoxy-)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (1), with sodium hydride (60% in oil, 112.0mg, 2.800mmol), 15-is preced with-5 (580.0mg; 2.633mmol) and 4-bromo-1,1,1-trimethoxy butane (346.0mg; 1.523mmol) processing 1 α in THF (0.5ml), 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-hydroxyls-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene (147.4mg; 0.264mmol) (under 68 ℃ outside temperature, handling 17 hours 30 minutes), then, carry out aftertreatment.Through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=15: 1, launch once; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE=20: 1, launch once) resistates that generates of purifying and provide the mixture (43.1mg) that contains title compound.

(2) The butyro-preparation of 4-[{ the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9 } oxygen base]

By and identical method shown in the embodiment 17 (2), handle in methyl alcohol (0.2ml) and THF (0.5ml) with 2M aqueous sodium hydroxide solution (0.2ml) and to contain 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(methoxycarbonyl propoxy-)-9; 10-open loop pregnant-5; 7,10 (19), the mixture (21.8mg of 16-tetraene; 0.033mmol) (at room temperature handling 16 hours), carry out aftertreatment subsequently.The resistates that generates through preparative thin layer chromatography (0.25mm * 1 block plate, methylene dichloride: ethanol=30: 1, launch twice) purifying and provide colorless oil title compound (6.9mg, 49%).

IR (pure): 2936,1712,1462,1362,1252,1214,1166,1080cm ^{-1 1}H?NMRδ：0.06(s，6H)，0.07(s，3H)，0.76(s，3H)，0.88(s，18H)，1.30(d，J＝6.3Hz，3H)，2.16-2.28(m，2H)，2.34-2.55(m，2H)，2.75-2.87(m，1H)，3.25-3.39(m，1H)，3.44-3.56(m，1H)，3.87-3.98(m，1H)，4.14-4.25(m，1H)，4.35-4.40(m，1H)，4.88(brs，1H)，5.20(brs，1H)，5.57(brs，1H)，6.10(d，J＝11.0Hz，1H)，6.23(d，J＝11.0Hz，1H)。UVλ _maxnm：263。

(3) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl propoxy-)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 21 (1), with the trimethyl carbinol (288.0mg, 3.886mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (70.0mg; 0.365mmol) and 4-(dimethylamino) pyridine (71.0mg; 0.581mmol) processing 4-[{ 1 α, 3 β-two (t-butyldimethylsilyloxy base)-9,10-open loop pregnant-5 in methylene dichloride (0.05ml); 7; 10 (19), 16-tetraene-20 (S)-yl } the oxygen base] (7.5mg 0.012mmol) (at room temperature handled 30 minutes) butyric acid.Through preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=15: 1, launch twice; Methylene dichloride: ethanol=10: 1, launch twice) purification reaction mixture and provide colorless oil title compound (3.5mg, 43%) reclaims raw material (2.1mg, 28%) again.

IR (pure): 2952,2932,2856,1732,1462,1366,1254,1156,1088cm ^{-1 1}H?NMR?δ：0.06(s，6H)，0.07(s，6H)，0.76(s，3H)，0.87(s，?9H)，0.88(s，9H)，1.28(d，J＝6.6Hz，3H)，1.44(s，9H)，2.76-2.86(m，1H)，3.20-3.34(m，1H)，3.34-3.48(m，1H)，3.86(q，J＝6.6Hz，1H)，4.15-4.26(m，1H)，4.34-4.42(m，1H)，4.88(brs，1H)，5.18(brs，1H)，5.55(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.35(d，J＝11.2Hz，1H)。MS?m/z：700(M ⁺)，73(100％)。UVλ _maxnm：263。

(4) 1 α, 3 beta-dihydroxyies-20 (S)-(tert-butoxycarbonyl propoxy-)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 17 (4); Tetrahydrofuran solution (0.1ml) processing with 1M tetra-n-butyl Neutral ammonium fluoride contains 1 α from embodiment 79 (3); 3 β-two (t-butyldimethylsilyloxy base)-20 (S)-(tert-butoxycarbonyl propoxy-)-9,10-open loop pregnant-5,7; 10 (19), the mixture of 16-tetraene (5.8mg) (under 43 ℃ outside temperature, handling 20 minutes).Provide colorless oil title compound (1.1mg, 2 steps 10%) through preparative thin layer chromatography (0.25mm * 1 block plate, methylene dichloride: ethanol=15: 1, launch twice) purification reaction mixture.

IR (pure): 3388,2928,2852,1728,1446,1368,1252,1156,1106,1058cm ^{-1 1}H?NMRδ：0.77(s，3H)，1.28(d，J＝6.6Hz，3H)，1.44(s，9H)，2.30(t，J＝7.3Hz，2H)，2.56-2.65(m，1H)，2.78-2.88(m，1H)，3.22-3.33(m，1H)，3.35-3.48(m，1H)，4.19-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.55(brs，1H)，6.10(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：472(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 80)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-methyl androstane-5,7,17-triolefin 4-phenyl-1,2,4-triazoline-3, the preparation of 5-two ketone adducts

Toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-oxo androstane-5,7-diene 4-phenyl-1; 2,4-triazoline-3,5-two ketone adduct (70.0g; (14.50g 129mmol), adds methylate three phenyl phosphonium bromide (46.05g again to add potassium tert.-butoxide in THF 99mmol) (300ml) solution; 129mmol), then, heating is 2 hours under refluxing.Behind the cool to room temperature, reaction mixture is distributed between ETHYLE ACETATE and sodium chloride aqueous solution.Dry organic layer on anhydrous magnesium sulfate, vapourisation under reduced pressure and remove and to desolvate.Stir the resistates that generates in the acetonitrile at room temperature (250ml) and reach 30 minutes, subsequent filtration.The solid that forms with acetonitrile washing once more, dry and provide title compound (61.78g, 89%) colorless solid.

¹H?NMR?δ：0.06(s，3H)，0.08(s，3H)，0.09(s，3H)，0.13(s，3H)，0.87(s，9H)，0.89(s，9H)，2.35-2.72(m，5H)，3.23-3.30(m，1H)，3.85(brs，1H)，4.70(s，2H)，4.70-4.83(m，1H)，6.23(d，J＝7.9Hz，1H)，6.39(d，J＝7.9Hz，1H)，7.23-7.46(m，5H)。

(2) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxyl-17s-methyl androstane-5,7, the preparation of 17-triolefin

(4.87g, (70% aqueous solution 25ml), at room temperature stirred 20 minutes to add tert-butyl hydroperoxide in methylene dichloride 43.9mmol) (300ml) suspension-s toward tin anhydride.Further add 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-methyl androstane-5,7; 17-triolefin 4-phenyl-1,2,4-triazoline-3; (61.75g, methylene dichloride 87.7mmol) (300ml) solution stirred 15 hours down at 30 ℃ 5-two ketone adducts again.Successively with 2M aqueous sodium hydroxide solution and sodium chloride aqueous solution washing reaction mixture, drying on anhydrous magnesium sulfate, then, vapourisation under reduced pressure and except that desolvating.(hexane: methylene dichloride: acetone=5: 5: 1) resistates of purifying generation provides 1 α through column chromatography; 3 β-two (t-butyldimethylsilyloxy base)-16-hydroxyl-17-methyl androstane-5; 7,17-triolefin 4-phenyl-1,2; 4-triazoline-3,5-two ketone adducts (41.73g) colorless solid.In this solid, add 1,3-dimethyl--2-imidazolone (810ml) stirred 50 minutes down at 160 ℃.Behind the cool to room temperature, reaction mixture is distributed between ETHYLE ACETATE and sodium chloride aqueous solution.With saturated sodium-chloride water solution washing organic layer twice, dry on SODIUM SULPHATE ANHYDROUS 99PCT, then, vapourisation under reduced pressure and remove and desolvate.(hexane: ETHYLE ACETATE=9: 1) resistates of purifying generation provides title compound (12.30g through column chromatography; 2 steps 39%) light yellow solid and 1 α; 3 β-two (t-butyldimethylsilyloxy base)-16 Alpha-hydroxies-17-methyl androstane-5; 7, the light yellow foam of 17-triolefin (14.35g, 2 steps 45%).

As for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxyl-17s-methyl androstane-5,7, the 17-triolefin:

¹H?NMR?δ：0.05(s，3H)，0.06(s，3H)，0.07(s，3H)，0.11(s，3H)，?0.87(s，9H)，0.88(s，9H)，0.92(s，3H)，0.94(s，3H)，2.78-2.88(m，1H)，3.71(brs，1H)，4.00-4.15(m，1H)，4.60(brs，1H)，4.94(d，J＝1.7Hz，1H)，5.09(d，J＝1.3Hz，1H)，5.36-5.39(m，1H)，5.59(d，J＝5.6Hz，1H)。

As for 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 Alpha-hydroxies-17-methyl androstane-5,7, the 17-triolefin:

¹H?NMR?δ：0.06(s，3H)，0.07(s，6H)，0.11(s，3H)，0.74(s，3H)，0.88(s，9H)，0.89(s，9H)，0.92(s，3H)，2.80-2.91(m，1H)，3.68-3.75(br，1H)，3.98-4.14(m，1H)，4.67-4.76(m，1H)，4.93(brs，1H)，5.11(brs，1H)，5.33-5.39(m，1H)，5.56-5.62(m，1H)。

(3) { 1 α, 3 β-two (t-butyldimethylsilyloxy base) }-16 beta-hydroxyl-17s-methyl-9,10-open loop androstane-5,7,10 (19), the preparation of 17-tetraene

Press and identical method shown in the embodiment 4 (3), in ethanol (650ml), handle 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxyl-17s-methyl androstane-5; 7, (2.00g is 3.67mmol) (with photoirradiation 2.5 hours for the 17-triolefin; Heating is 2 hours under refluxing), then, carry out aftertreatment and utilize column chromatography (hexane: methylene dichloride=2: 3; Then; Hexane: ETHYLE ACETATE=9: 1) and preparative thin layer chromatography (0.5mm * 3 block plate, hexane: ETHYLE ACETATE=9: 1, launch three times) thus purifying provides the colourless foam shape level branch (0.40g) that contains title compound.

(4) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-17-methyl isophthalic acid 6-oxo-9,10-open loop androstane-5,7,10 (19), the preparation of 17-tetraene

To contain 1 α from embodiment 80 (3), 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxyl-17s-methyl-9,10-open loop androstane-5,7,10 (19), the level of 17-tetraene divides (400mg) to be dissolved in methylene dichloride (20ml).In this solution, add molecular sieve 4A (2g), then, carry out ultrasonic radiation and reach 1 minute.In reaction mixture, add Manganse Dioxide (2.40g), at room temperature stirred 10 minutes.After leaching insoluble product, under reduced pressure remove and desolvate, (hexane: ETHYLE ACETATE=9: 1) the purifying resistates provides the level branch (342mg) that contains title compound through column chromatography.

(5) 17 β-ethanoyl thiomethyl-1 α, 3 β-two (t-butyldimethylsilyloxy base)-16-oxo-9,10-open loop androstane-5,7,10 (19)-triolefins

To contain 1 α from embodiment 80 (4), 3 β-two (t-butyldimethylsilyloxy base)-17-methyl isophthalic acid 6-oxo-9,10-open loop androstane-5,7,10 (19), the level of 17-tetraene divides (340mg) to be dissolved in methylene dichloride (5ml).In this solution, add pyridine (0.6ml), then, use argon cleaning.Add in this solution thioacetic acid (480mg, 6.3mmol) and at room temperature stirred 10 minutes.After vapourisation under reduced pressure removed and desolvates, (hexane: ETHYLE ACETATE=10: 1) resistates of purifying generation provided the level branch (286mg) that contains title compound through column chromatography.

(6) 17 β-ethanoyl thiomethyl-1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-9,10-open loop androstane-5,7,10 (19)-triolefins

To contain 17 β-ethanoyl thiomethyl-1 α from embodiment 80 (5); 3 β-two (t-butyldimethylsilyloxy base)-16-oxo-9; 10-open loop androstane-5,7, the level of 10 (19)-triolefins divides (285mg) to be dissolved in THF (15ml); Again toward wherein adding the tetrahydrofuran solution (0.92ml) of 1M three tert.-butoxy lithium aluminium hydride, and at room temperature stirred 30 minutes.Adding hexane (50ml) and saturated aqueous ammonium chloride (0.5ml) afterwards, reaction mixture was stirred 30 minutes filtration and remove insoluble product.Concentrated filtrate under reduced pressure, (hexane: ETHYLE ACETATE=9: 1) purifying provides the level that contains title compound and divides (220mg) through column chromatography.

(7) 17 β-ethanoyl thiomethyl-1 α, 3 β, 16 β-trihydroxy--9,10-open loop androstane-5,7,10 (19)-triolefins

Press and identical method shown in the embodiment 6 (3); Handle in methyl alcohol (3ml) and THF (3ml) with AMBERLYST 15 (1.5g) and to contain 17 β-ethanoyl thiomethyl-1 α from embodiment 80 (6), 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-9,10-open loop androstane-5; 7; The level of 10 (19)-triolefins is divided (220mg) (at room temperature handling 2 hours), then, carries out aftertreatment.Provide flint glass shape title compound (5 step 13mg, 66%) through the resistates of preparative thin layer chromatography (0.5mm * 1 block plate is used ETHYLE ACETATE separately, launches once) purifying generation.

¹H?NMRδ：0.71(s，3H)，2.36(s，3H)，2.54-2.66(m，1H)，2.80-2.94(m，2H)，3.07-3.22(m，1H)，4.05-4.47(m，4H)，4.99(brs，1H)，5.32(brs，1H)，6.04(d，J＝11.5Hz，1H)，6.36(d，J＝11.5Hz，1H)。

(8) 17 β-tert-butoxycarbonyl methylthiomethyl-1 α, 3 β, 16 β-trihydroxy--9,10-open loop androstane-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 16 (2), with methanol solution (0.13ml) and bromo-acetic acid tert-butyl (76mg, 0.390mmol) processing 17 β-ethanoyl thiomethyl-1 α in THF (2ml) of 1M Pottasium Hydroxide; 3 β, 16 β-trihydroxy--9,10-open loop androstane-5; (5mg 0.013mmol) (at room temperature handled 16 hours) 7,10 (19)-triolefins; Then, carry out aftertreatment.Provide flint glass shape title compound (3.056mg, 52%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: acetonitrile=3: 2, expansion are once) purifying generation.

IR (pure): 3400,2933,2838,1716,1296,1257,1053cm ^{-1 1}H NMR δ：0.67(s，3H)，1.48(s，9H)，2.57-2.92(m，5H)，3.16(d，J＝15.5Hz，1H)，3.24(d，J＝15.5Hz，1H)，4.20-4.30(m，1H)，4.38-4.60(m，2H)，4.99(brs，1H)，5.31(s，1H)，6.05(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)。MS?m/z：464(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 81)

(1) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16-oxo-9, the 10-open loop is pregnant-5,7,10 (19), (17E)-preparation of tetraene

Press and identical method shown in the embodiment 80 (4), with molecular sieve 4A (10g) and Manganse Dioxide (12g, 138.1mmol) processing 1 α in methylene dichloride (100ml); 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-9,10-open loop pregnant-5,7; 10 (19); (17E)-(2.0g 3.578mmol) (at room temperature handled 10 minutes) tetraene, then; Carry out aftertreatment and utilize column chromatography (hexane: purifying and provide title compound (1.56g, 78%) white foam ETHYLE ACETATE=30: 1).

¹H?NMR(C ₆D ₆)δ：0.78(s，3H)，1.43(d，J＝7.6Hz，3H)，2.69-2.82(m，1H)，4.18-4.29(m，1H)，4.39-4.47(m，1H)，5.02(brs，1H)，5.28(brs，1H)，6.25(d，J＝11.6Hz，1H)，6.41(d，J＝11.6Hz，1H)，6.66(q，J＝7.6Hz，1H)。

(2) 20 (S)-ethanoyl sulfenyl-1 α, 3 β-two (t-butyldimethylsilyloxy base)-16-oxo-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

By and identical method shown in the embodiment 80 (5), with pyridine (2.27ml, 28.0mmol) and thioacetic acid (2.01ml; 28.0mmol) processing 1 α in methylene dichloride (50ml), 3 β-two (t-butyldimethylsilyloxy base)-16-oxo-9,10-open loop pregnant-5; 7,10 (19), (17E)-tetraene (1.56g; 2.80mmol) (at room temperature handling 1.5 hours); Then, carry out aftertreatment and utilize column chromatography (hexane: ETHYLE ACETATE=10: 1, twice) purifying and provide the mixture (1.20g) that contains title compound.

(3) 20 (S)-ethanoyl sulfenyl-1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

Press and identical method shown in the embodiment 80 (6); In THF (45ml), handle from embodiment 81 (2) with the tetrahydrofuran solution (3.8ml) of 1M three tert.-butoxy lithium aluminum hydrides and to contain 20 (S)-ethanoyl sulfenyl-1 α; 3 β-two (t-butyldimethylsilyloxy base)-16-oxo-9; The 10-open loop is pregnant-5,7, the mixture of 10 (19)-triolefins (1.20g) (at room temperature handling 1 hour); Then, carry out aftertreatment and utilize column chromatography (hexane: purifying and provide the mixture (1.02g) that contains title compound ETHYLE ACETATE=10: 1).

(4) 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-20 (S)-(tert-butoxycarbonyl methylthio group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

To contain 20 (S)-ethanoyl sulfenyl-1 α from embodiment 81 (3); 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-9; The 10-open loop is pregnant-5,7, and the mixture of 10 (19)-triolefins (20mg) is dissolved in THF (0.2ml); Then, past methyl alcohol (0.2ml) and the 2M aqueous sodium hydroxide solution (0.16ml) of wherein adding in argon atmospher.After at room temperature stirring 30 minutes, in reaction mixture, add bromo-acetic acid tert-butyl (0.046ml), further at room temperature stirred 1 hour.In reaction mixture, add ETHYLE ACETATE, water and saturated sodium-chloride water solution washing successively, dry on SODIUM SULPHATE ANHYDROUS 99PCT, filter and remove solids.After vapourisation under reduced pressure removes and desolvates, provide colorless oil title compound (12mg) through the resistates of preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE=6: 1, expansion are once) purifying generation.

¹H?NMR?δ：0.06(s，6H)，0.07(s，6H)，0.84(s，3H)，0.87(s，9H)，0.88(s，9H)，1.47(s，9H)，2.77-2.88(m，1H)，3.10(d，J＝14.6Hz，1H)，?3.22-3.34(m，2H)，4.13-4.25(m，1H)，4.34-4.50(m，2H)，4.87(s，1H)，5.20(s，1H)，6.01(d，J＝11.3Hz，1H)，6.22(d，J＝11.3Hz，1H)。

(5) 1 α, 3 β, 16 β-trihydroxy--20 (S)-(tert-butoxycarbonyl methylthio group)-9, the 10-open loop is pregnant-5,7, the preparation of 10 (19)-triolefins

In nitrogen atmosphere; Toward 1 α, 3 β-two (t-butyldimethylsilyloxy base)-16 beta-hydroxies-20 (S)-(tert-butoxycarbonyl methylthio group)-9,10-open loop pregnant-5; 7; (16mg, THF (0.5ml) solution of interpolation 1M tetra-n-butyl Neutral ammonium fluoride at room temperature stirred 2 days 10 (19)-triolefins in THF 0.0228mmol) (0.5ml) solution.In reaction mixture impouring water, use ethyl acetate extraction, then, successively with 0.5M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.Dry organic layer on SODIUM SULPHATE ANHYDROUS 99PCT filters and removes solids.After vapourisation under reduced pressure removes and desolvates, provide colorless oil title compound (5.821mg, 53%) through the resistates of preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=5: 5: 1, expansion are once) purifying generation.

IR (pure): 2925,2863,2358,2332,1699,1647,1296,1128,1053cm ^{-1 1}H?NMRδ：0.85(s，3H)，1.47(s，9H)，2.77-2.87(m，1H)，3.09(d，J＝14.0Hz，1H)，3.22-3.35(m，2H)，4.18-4.29(m，1H)，4.38-4.49(m，2H)，5.01(s，1H)，5.33(s，1H)，6.01(d，J＝11.3Hz，1H)，6.37(d，J＝11.3Hz，1H)。MS?m/z：478(M ⁺)，57(100％)。UVλ _maxnm：264。

(embodiment 82)

(1) { 1 α, 3 β-two (t-butyldimethylsilyloxy base) }-20 (S)-(tert-butoxycarbonyl methylthio group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

With { 1 α, 3 β-two (t-butyldimethylsilyloxy base) }-20 (S)-phenyloxycarbonyl sulfenyls-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene (20mg; 0.0220mmol), THF (0.34ml) and methyl alcohol (0.34ml) mixes, in argon atmospher toward wherein adding 2M aqueous sodium hydroxide solution (0.17ml), then; The interpolation bromo-acetic acid tert-butyl (56mg, 0.288mmol).After at room temperature stirring 30 minutes, use the ETHYLE ACETATE diluted reaction mixture, wash with sodium chloride aqueous solution again.Dry organic layer on SODIUM SULPHATE ANHYDROUS 99PCT filters, and vapourisation under reduced pressure removes and desolvates.Separate the resistates that generates and provide and contain the required mixture of products of colorless oil (10mg) through preparative thin layer chromatography (0.5mm * 2 block plate, hexane: ETHYLE ACETATE=100: 9, launch once).

(2) 1 α, 3 beta-dihydroxyies-20 (S)-(tert-butoxycarbonyl methylthio group)-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

By and identical method shown in the embodiment 17 (4), in THF (0.5ml), handle from embodiment 82 (1) with the tetrahydrofuran solution (1.0ml) of 1M tetra-n-butyl Neutral ammonium fluoride and to contain { 1 α, 3 β-two (t-butyldimethylsilyloxy base) }-20 (S)-(tert-butoxycarbonyl methylthio group)-9; 10-open loop pregnant-5; 7,10 (19), the mixture of 16-tetraene (10mg) (under 50 ℃ outside temperature, handling 1 hour); Then; Carry out aftertreatment and through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: acetonitrile=3: 2, launch once; 0.5mm * 1 block of plate, toluene: ETHYLE ACETATE=9: 11, launch twice; Then, 0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=8: 8: 1, launch once) resistates that generates of purifying and provide flint glass shape title compound (1.754mg, 2 steps 13%).

IR (pure): 3379,2929,2850,1724,1367,1292,1132,1055cm ^{-1 1}H?NMR?δ：0.81(s，3H)，1.42(d，J＝7.3Hz，3H)，1.46(s，9H)，2.22-2.43(m，3H)，2.57-2.62(m，1H)，2.79-2.83(m，1H)，3.12(s，2H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.64(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：460(M ⁺)，57(100％)。UVλ _maxnm：264。

(embodiment 83)

(1) 1 α, 3 beta-dihydroxyies-20 (S)-phenyloxycarbonyl sulfenyl-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 6 (3), in THF (5ml) and methyl alcohol (5ml), handle { 1 α, 3 β-two (t-butyldimethylsilyloxy base) }-20 (S)-phenyloxycarbonyl sulfenyls-9 with AMBERLYST 15 (2g); 10-open loop pregnant-5,7,10 (19); (55mg 0.0791mmol) (at room temperature handled 3 hours) the 16-tetraene, then; Carry out aftertreatment and utilize preparative thin layer chromatography (0.5mm * 3 block plate; Methylene dichloride: ethanol=10: 1, launch once) purifying and provide flint glass shape title compound (17mg, 46%).

¹H?NMRδ：0.86(s，3H)，1.58(d，J＝6.9Hz，3H)，2.54-2.66(m，1H)，?2.77-2.88(m，1H)，4.12(q，J＝7.3Hz，1H)，4.19-4.29(m，1H)，4.40-4.48(m，1H)，5.01(brs，1H)，5.34(s，1H)，5.74(brs，1H)，6.11(d，J＝10.9Hz，1H)，6.37(d，J＝10.9Hz，1H)，7.12-7.41(m，5H)。

(2) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) sulfenyl for 1 α, 3 beta-dihydroxyies-9 }-N-(tertiary butyl) ethanamide

Press and identical method shown in the embodiment 16 (2), with methanol solution (0.5ml) and 2-bromo-N-(tertiary butyl) ethanamide (10mg, 0.0515mmol) processing 1 α of 1M Pottasium Hydroxide; 3 beta-dihydroxyies-20 (S)-phenyloxycarbonyl sulfenyl-9,10-open loop pregnant-5,7; 10 (19), (6mg 0.0129mmol) (at room temperature handled 15 hours) the 16-tetraene; Then, carry out aftertreatment.Provide flint glass shape title compound (3.874mg, 66%) through the resistates of preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: acetonitrile=3: 2, expansion are once) purifying generation.

IR (pure): 3340,2964,2931,1653,1525,1454,1223,1057cm ^{-1 1}H?NMRδ：0.83(s，3H)，1.36(s，9H)，2.22-2.42(m，3H)，2.57-2.62(m，1H)，2.79-2.83(m，1H)，3.07(s，2H)，3.33-3.48(m，1H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.63(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)，6.72(brs，1H)。MS?m/z：459(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 84) The preparation of { (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) sulfenyl for 1 α, 3 beta-dihydroxyies-9 }-N-(tertiary butyl)-N-methyl-ethanamide

Press and identical method shown in the embodiment 16 (2), with methanol solution (0.5ml) and 2-bromo-N-(tertiary butyl)-N-methylacetamide (10mg, 0.0481mmol) processing 1 α of 1M Pottasium Hydroxide; 3 beta-dihydroxyies-20 (S)-phenyloxycarbonyl sulfenyl-9,10-open loop pregnant-5,7; 10 (19), (5mg 0.0107mmol) (at room temperature handled 15 hours) the 16-tetraene; Then, carry out aftertreatment.The resistates that generates through preparative thin layer chromatography (0.5mm * 2 block plate, methylene dichloride: acetonitrile=2: 1, launch twice) purifying and provide flint glass shape title compound (3.102mg, 61%).

IR (pure): 3380,2927,2850,1630,1367,1211,1093,1057cm ^{-1 1}H?NMRδ：0.82(s，3H)，1.41(s，9H)，1.46(d，J＝6.9Hz，3H)，?2.21-2.42(m，3H)，2.57-2.62(m，1H)，2.79-2.83(m，1H)，2.94(s，3H)，3.19-3.29(m，2H)，3.58-3.66(m，1H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.66(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：473(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 85) { (1 α, 3 beta-dihydroxyies-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene-20 (S)-yl) sulfenyl }-N-methoxyl group-N-methylacetamide and { (1 α, 3 beta-dihydroxyies-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (S)-yl) sulfenyl }-preparation of N-methylacetamide

Press and identical method shown in the embodiment 16 (2), with methanol solution (0.5ml) and 2-bromo-N-methoxyl group-N-methylacetamide (10mg, 0.0549mmol) processing 1 α of 1M Pottasium Hydroxide; 3 beta-dihydroxyies-20 (S)-phenyloxycarbonyl sulfenyl-9,10-open loop pregnant-5,7; 10 (19), (5mg 0.0107mmol) (at room temperature handled 15 hours) the 16-tetraene; Then, carry out aftertreatment.Through preparative thin layer chromatography (0.5mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 10: 1, launch once; Then, 0.5mm * 1 block plate, methylene dichloride: acetonitrile=1: 1, launch once) resistates that generates of purifying and provide flint glass shape { (1 α; 3 beta-dihydroxyies-9,10-open loop pregnant-5,7,10 (19); 16-tetraene-20 (S)-yl) sulfenyl }-N-methoxyl group-N-methylacetamide (0.847mg, 18%) and flint glass shape { (1 α, 3 beta-dihydroxyies-9,10-open loop pregnant-5; 7,10 (19), 16-tetraene-20 (S)-yl) sulfenyl }-N-methylacetamide (0.839mg, 19%).

For (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) sulfenyl for 1 α, 3 beta-dihydroxyies-9 }-N-methoxyl group-N-methylacetamide:

IR (pure): 3401,2922,2850,1647,1446,1055cm ^{-1 1}H?NMRδ：0.83(s，3H)，1.44(d，J＝6.9Hz，3H)，2.22-2.39(m，3H)，2.57-2.62(m，1H)，2.79-2.83(m，1H)，3.20(s，3H)，3.24-3.38(m，2H)，3.66-3.73(m，1H)，3.73(s，3H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.34(s，1H)，5.67(brs，1H)，6.10(d，J＝10.9Hz，1H)，6.37(d，J＝10.9Hz，1H)。MS?m/z：429(M ⁺-H ₂O)，91(100％)。UVλ _maxnm：263。

For (the 10-open loop is pregnant-5,7,10 (19), 16-tetraene-20 (S)-yl) sulfenyl for 1 α, 3 beta-dihydroxyies-9 }-the N-methylacetamide:

IR (pure): 3326,2924,2850,1653,1417,1122,1055cm ^{-1 1}H?NMRδ：0.81(s，3H)，1.41(d，J＝6.9Hz，3H)，2.20-2.36(m，3H)，2.57-2.62(m，1H)，2.79-2.86(m，1H)，2.85(d，J＝4.9Hz，3H)，3.16(s，2H)，3.42-3.49(m，1H)，4.20-4.30(br，1H)，4.39-4.49(br，1H)，5.01(brs，1H)，5.35(s，1H)，5.62(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.36(d，J＝11.2Hz，1H)。MS?m/z：399(M ⁺-H ₂O)，91(100％)。UVλ _maxnm：264。

(embodiment 86) 1 α, 3 beta-dihydroxyies-20 (S)-tert-butoxycarbonyl ethylmercapto group-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 16 (2), with methanol solution (0.04ml) and tert-butyl acrylate (120.0mg, 0.936mmol) processing 1 α of 1M Pottasium Hydroxide; 3 beta-dihydroxyies-20 (S)-phenyloxycarbonyl sulfenyl-9,10-open loop pregnant-5,7; 10 (19), (8.7mg 0.0186mmol) (at room temperature handled 30 minutes) the 16-tetraene; Then, carry out aftertreatment.Through preparative thin layer chromatography (0.25mm * 1 block plate, methylene dichloride: ethanol=15: 1, launch three times; Then, 0.25mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch three times) resistates that generates of purifying and provide flint glass shape title compound (3.6mg, 40%).

IR (pure): 3400,2928,1728,1450,1368,1252,1152,1056cm ^{-1 1}H?NMRδ：0.82(s，3H)，1.41(d，J＝6.9Hz，3H)，1.45(s，9H)，2.75-2.88(m，1H)，3.46(q，J＝6.9Hz，1H)，4.20-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.61(brs，1H)，6.10(d，J＝11.4Hz，1H)，6.37(d，J＝11.4Hz，1H)。MS?m/z：474(M ⁺)，57(100％)。UVλ _maxnm：263。

(embodiment 87) 1 α, 3 beta-dihydroxyies-20 (S)-tert-butoxycarbonyl rosickyite base-9, the 10-open loop is pregnant-5,7,10 (19), the preparation of 16-tetraene

Press and identical method shown in the embodiment 16 (2), with the aqueous solution (65 μ l) and the 4-bromo-butyric acid tert-butyl ester (155.0mg, 0.695mmol) processing 1 α of 2M sodium hydroxide; 3 beta-dihydroxyies-20 (S)-phenyloxycarbonyl sulfenyl-9,10-open loop pregnant-5,7; 10 (19), (6.2 mg 0.0133mmol) (at room temperature handled 30 minutes) the 16-tetraene; Then, carry out aftertreatment.Through preparative thin layer chromatography (0.25mm * 1 block plate, methylene dichloride: ethanol=20: 1, launch once methylene dichloride: ethanol=10: 1, launch once; 0.25mm * 1 block of plate, methylene dichloride: ETHYLE ACETATE=3: 1, launch once methylene dichloride: ETHYLE ACETATE=1: 1, launch once; Then, 0.25mm * 1 block plate, hexane: ETHYLE ACETATE: ethanol=10: 5: 1, launch twice) resistates that generates of purifying and provide colorless oil title compound (2.9mg, 45%).

IR (pure): 3384,2968,2928,2848,1728,1448,1368,1240,1160,1056cm ^{-1 1}H?NMR?δ：0.82(s，3H)，1.41(d，J＝7.0Hz，3H)，1.44(s，9H)，1.84(t，J＝7.3Hz，2H)，2.32(t，J＝7.3Hz，2H)，2.45(dt，J＝3.3，7.3Hz，2H)，2.55-2.65(m，1H)，2.75-2.86(m，1H)，3.44(q，J＝7.0Hz，1H)，4.19-4.30(m，1H)，4.40-4.50(m，1H)，5.01(brs，1H)，5.34(brs，1H)，5.58(brs，1H)，6.10(d，J＝11.2Hz，1H)，6.37(d，J＝11.2Hz，1H)。MS?m/z：470(M ⁺-H ₂O)，57(100％)。UVλ _maxnm：263。

(test implementation example 1)

Male Balb/c mouse applied dermally activated vitamin D to 8 ages in week ₃[1 α, 25 (OH) ₂D ₃, 125 μ g/ml are in ethanol] or compound 1～5 (vitamin D-derivatives for preparing in the above-described embodiments, 500 μ g/ml are in ethanol) or independent ethanol (as a comparison).With these samples with the amount of 2ml/kg at mouse dorsal part skin (about 1.5 * 2.0cm ²) on be coated with once.Then, each mouse is put on the necklace braces in order to avoid per os is taken in.Next day, the position of cleaning dispenser removes the necklace braces.Dispenser is got blood from each mouse two days later, detects the ionised calcium level through the ion specific electrode method.The group that is divided into 3 mouse/groups is detected.Table 45 shows the result of acquisition.Ionised calcium level in the table is represented with MV.

(test implementation example 2)

Will be from the keratinocyte (Clonetics) of people newborn infant's foreskin with 2 * 10 ³The cell density in individual/hole is seeded in 96 holes dull and stereotyped (COSTAR 3595).Then, in the hole, add the activated vitamin D of given concentration ₃[1 α, 25 (OH) ₂D ₃] or compound 1～5, then, at 37 ℃ of following 5%CO ₂In 95% air, with 2 * 10 ³The cell density in individual cell/200 μ l/ holes was cultivated 3 days in the KGM-2 substratum.Add in each hole [ ³H] thymidine (7.4kBq/ hole), again plate further is incubated 1 day.Phosphate buffered saline buffer [code 05913 for DulbeccoShi phosphate buffered saline (PBS) (-), Nissui, and pH 7.3～7.65] with no calcium and no magnesium washs each hole once, then, peels off cell with 0.25% trypsin treatment.Through liquid scintillation counter (1450MicroBeta, Wallac) measure cell [ ³H] the thymidine intake.Table 45 shows the result of acquisition.In the table to the growth-inhibiting of people's keratinocyte with every kind of compound and activated vitamin D ₃The relative value of comparing is represented: relative inhibition=[activated vitamin D ₃IC ₅₀(mol/l)]/[IC of every kind of compound ₅₀(mol/l)].

Table 45

Compound 1 is 20 (S)-(tert-butoxycarbonyl methoxyl group)-1 α of preparation among the embodiment 8 (3), 3 beta-dihydroxyies-9,10-open loop pregnant-5,7,10 (19); 16-tetraene, compound 2 are 1 α of preparation among the embodiment 13,3 beta-dihydroxyies-20 (S)-(the N-tertiary butyl-N-amino-carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene, compound 3 are 1 α of preparation among the embodiment 11 (2), 3 beta-dihydroxyies-20 (S)-(tert-butoxycarbonyl oxyethyl group)-9; The 10-open loop is pregnant-5,7,10 (19), the 16-tetraene; Compound 4 is 1 α of preparation among the embodiment 14,3 beta-dihydroxyies-20 (S)-(N-tertiary butyl aminocarboxyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), the 16-tetraene, and compound 5 is 1 α of preparation among the embodiment 15,3 beta-dihydroxyies-20 (S)-(isopropoxy carbonyl methoxyl group)-9; The 10-open loop is pregnant-5,7,10 (19), the 16-tetraene.

(test implementation example 3)

Same procedure shown in the repeated test embodiment 1 is to detect the blood ion calcium level in the mouse, and different is to use compound 6～12 as vitamin D-derivatives.Table 46 shows the result of acquisition.Ionised calcium level in the table is represented with MV.

(test implementation example 4)

Will be from the keratinocyte (Clonetics) of adult skin with 1 * 10 ³The cell density in individual/hole is seeded in 96 holes dull and stereotyped (COSTAR 3595).Then, in the hole, add the activated vitamin D of given concentration ₃[1 α, 25 (OH) ₂D ₃] or compound 6～12, then, at 37 ℃ of following 5%CO ₂In 95% air, with 1 * 10 ³The cell density in individual cell/200 μ l/ holes was cultivated 3 days in the KGM-2 substratum.Add in each hole [ ³H] thymidine (7.4kBq/ hole), again plate further is incubated 1 day.Remove after the substratum, handle each hole and peel off cell with 0.05% trypsinase/0.53mMEDTA.Through liquid scintillation counter (1450MicroBeta, Wallac) measure be incorporated into cell [ ³H] the thymidine amount.Table 46 shows the result of acquisition.In the table to the growth-inhibiting of keratinocyte with every kind of compound and activated vitamin D ₃The relative value of comparing is represented: relative inhibition=[activated vitamin D ₃IC ₅₀(mol/l)]/[IC of test compounds ₅₀(mol/l)].

Table 46

Compound 6 is 1 α of preparation among the embodiment 17 (4), 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, and the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene; Compound 7 is 1 α of preparation among the embodiment 21 (2), 3 beta-dihydroxyies-20 (S)-(1-sec.-propyl-2-methyl propoxycarbonyl methoxyl group)-9, and the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene; Compound 8 is 1 α of preparation among the embodiment 18 (2), 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-butoxy carbonyl methoxyl group)-9,10-open loop pregnant-5,7; 10 (19), 16-tetraene, compound 9 are 1 α of preparation among the embodiment 23 (4), 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9,10-open loop pregnant-5; 7,10 (19)-triolefins, compound 10 are 1 α of preparation among the embodiment 19 (2), 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-hexyloxy carbonyl methoxyl group)-9; The 10-open loop is pregnant-5,7,10 (19), and 16-tetraene, compound 11 are 1 α of preparation among the embodiment 20 (3); 3 beta-dihydroxyies-20 (S)-{ 2-(1-ethyl-1-methyl propoxycarbonyl) oxyethyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene; And compound 12 is preparation { (1 α, 3 beta-dihydroxyies-9,10-open loops pregnant-5,7,10 (19) among the embodiment 22 (2); 16-tetraene-20 (S)-yl) oxygen base }-N-(2,2,3,3,3-five fluoropropyls) ethanamide.

Industrial usability

Compare with conventional vitamin D-derivatives, vitamin D-derivatives of the present invention not only has excellent physiologically active, also has less hypercalcemia effect.So, thereby vitamin D-derivatives of the present invention can effectively be treated and can only be used the disease that conventional vitamin D-derivatives is avoided hypercalcemia and other problem limitedly.

Claims (20)

1. the vitamin D-derivatives of formula (1):

Formula (1)

Wherein

X representes Sauerstoffatom or sulphur atom;

M representes 1～3 number;

R ₁And R ₂Represent Wasserstoffatoms or alkyl separately;

R ₄And R ₅Represent Wasserstoffatoms or hydroxyl separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together;

R ₃Expression-YR ₈, wherein, Y representes Sauerstoffatom or sulphur atom, R ₈The expression Wasserstoffatoms can be by the linear or branched-alkyl of fluorine atom or cycloalkyl substituted, perhaps can be by the substituted naphthenic base of fluorine atom;

R ₆The expression Wasserstoffatoms or-OR ₁₁, wherein, R ₁₁Expression Wasserstoffatoms or protection base; And

R ₇Expression Wasserstoffatoms or protection base.

2. the vitamin D-derivatives of claim 1, wherein, R ₁And R ₂Represent Wasserstoffatoms or C separately ₁～C ₄Alkyl, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₁₀The substituted linear or branching C of alkyl ₁～C ₁₅Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₁₅Alkyl, R ₆Expression Wasserstoffatoms or hydroxyl, and R ₇The expression Wasserstoffatoms.

3. the vitamin D-derivatives of claim 2, wherein, m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₄And R ₅Represent Wasserstoffatoms simultaneously, R ₄Represent Wasserstoffatoms and R ₅Expression hydroxyl, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₈The substituted linear or branching C of alkyl ₁～C ₁₀Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₁₂Alkyl, and R ₆The expression hydroxyl.

4. the vitamin D-derivatives of claim 3, wherein, R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, and R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₈The substituted linear or branching C of alkyl ₁～C ₈Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₈Alkyl.

5. the vitamin D-derivatives of claim 4, wherein, R ₈The expression Wasserstoffatoms can be by fluorine atom or ring C ₃～C ₆The substituted linear or branching C of alkyl ₁～C ₈Alkyl perhaps can be by the substituted ring of fluorine atom C ₃～C ₈Alkyl.

6. the vitamin D-derivatives of claim 1, wherein, m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-OR ₈, wherein, R ₈Expression branching C ₃～C ₈Alkyl, R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

7. the vitamin D-derivatives of claim 1, wherein, m representes 1～2 number, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, R ₃Expression-SR ₈, wherein, R ₈Expression branching C ₃～C ₈Alkyl, R ₄And R ₅Represent Wasserstoffatoms separately, perhaps R ₄And R ₅Form the two keys between 16-and the 17-position together, R ₆Expression hydroxyl, and R ₇The expression Wasserstoffatoms.

8. the vitamin D-derivatives of claim 6, wherein, X representes Sauerstoffatom, and R ₈Expression branching C ₆～C ₈Alkyl.

9. the vitamin D-derivatives of claim 8, wherein, R ₁And R ₂Represent Wasserstoffatoms or methyl separately, condition is R ₁And R ₂In one should represent methyl, and R ₄And R ₅Form the two keys between 16-and the 17-position together.

10.1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene.

11.1 α, 3 beta-dihydroxyies-20 (S)-(1-sec.-propyl-2-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene.

12.1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-butoxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene.

13.1 α, 3 beta-dihydroxyies-20 (S)-(1,1-dimethyl-hexyloxy carbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene.

14.1 α, 3 beta-dihydroxyies-20 (S)-{ 2-(1-ethyl-1-methyl propoxycarbonyl) oxyethyl group }-9, the 10-open loop is pregnant-5,7,10 (19), the 16-tetraene.

15.1 α, 3 beta-dihydroxyies-20 (S)-(1-ethyl-1-methyl propoxycarbonyl methoxyl group)-9, the 10-open loop is pregnant-5,7,10 (19)-triolefins.

16. a pharmaceutical composition, it comprises each vitamin D-derivatives of claim 1～15.

17. one kind is used for the treating for skin disease agent, it comprises as each vitamin D-derivatives of the claim 1～15 of active ingredient.

18. claim 17 be used for the treating for skin disease agent, wherein, said tetter is a psoriasis.

19. each vitamin D-derivatives of claim 1～15 is used for treating the application of dermopathic medicine in preparation.

20. the application of claim 19, wherein, said tetter is a psoriasis.