HK1023991B - Vitamin d3 derivatives - Google Patents

Description

Vitamin D3Derivatives of the same

no marking

The present invention relates to a hitherto unknown class of compounds having potent activity in inducing differentiation of some cells, including cancer cells and skin cells, and inhibiting undesired proliferation thereof, and having anti-inflammatory and immunomodulatory effects. The invention is also directed to pharmaceutical formulations containing these compounds, to dosage units of such formulations, and to their use in the treatment and prevention of hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, diseases characterized by abnormal cell differentiation and/or proliferation, such as cancer, leukemia, myelofibrosis, and psoriasis, a range of disease states including diabetes, hypertension, acne, alopecia, skin aging, AIDS, neurodegenerative disorders, such as Alzheimer's disease, host-versus-graft reactions, transplant rejection, inflammatory diseases, such as rheumatoid arthritis and asthma, and in the prevention and/or treatment of steroid-induced skin atrophy and in the promotion of osteogenesis and in the treatment of osteoporosis.

The compounds of the present invention represented by the general formula I,wherein Q is C₁-C₆An alkylene diyl group; y is a single bond, carbonyl or methylene, ethylene, -CH (OH) -, -O- (C)₆H₄) - (ortho, meta, para) or-S- (C)₆H₄) - (ortho, meta, para) diyl; r₁And R₂May be the same or different and represents hydrogen or C₁-C₆A hydrocarbyl group; or R₁And R₂Together with the carbon atom bearing the group Z (indicated by an asterisk in formula I) forming C₃-C₆A carbocyclic ring; and Z is hydrogen or hydroxy; provided that when Q is ethylene, Y is methylene, R₁And R₂Represents methyl or trifluoromethyl and Z is hydroxy, or when Q is ethylene, Y is carbonyl or-CH (OH) -, R₁And R₂Represents a methyl group, and when Z is a hydroxyl group, the configuration of C-20 cannot be R.

In the context of the present invention, an alkyl group (hydrocarbylenediyl) refers to a residue obtained by removing 1(2) hydrogen atoms from a linear, branched or cyclic, saturated or unsaturated hydrocarbon.

Examples of Q are, but are not limited to, methylene, ethylene, tri-, tetra-and pentamethylene, -C-, -CH-, -CH-C-, -CH-, -CH-C ≡ C-, -CH ═ CH-CH-, -CH₂-(C₆H₄) - (ortho, meta, para), -C.ident.C-CH₂-，-CH(R)-(CH₂)₂-, -CH (R) -CH ═ CH-, and CH (R) -C ≡ C-, where R is hydroxy, C₁-C₄Alkoxy or C₁-C₄An alkyl group. Wherein Q is- (CH)₂)_nParticular preference is given to compounds of the formula I in which n is an integer from 1 to 4, or represents a straight carbon chain with one or two (in the latter case conjugated) double or triple bonds, or represents CH (R) -C.ident.C- (R is as defined above).

When considered separately, R¹And R²Examples of (C) include, but are not limited to, hydrogen, methyl, ethylVinyl, n-, iso-and cyclopropyl and trifluoromethyl.

When taken together, R¹And R²Examples of (b) include di, tri, tetra and pentamethylene.

The compounds of the invention comprise more than one stereoisomeric form (e.g. of C-20)ROrSConfiguration; when a double bond is present in the group QEOrZConfiguration). The present invention encompasses all such stereoisomers both in pure form and as mixtures thereof.

In addition, prodrugs of formula I which carry one or more groups which are present in masked form and which are convertible in vivo into hydroxyl groups are also included within the scope of the present invention.

Compounds of formula I wherein Z is hydroxy may also be prodrugs because these compounds are relatively inactive in vitro, but they may be converted to the active compounds of formula I by enzymatic hydroxylation following administration to a patient.

It has been shown that 1 alpha, 25-dihydroxyvitamin D₃(1，25-(OH)₂D₃) Influence the action and/or production of interleukins (interleukins) (Muller, K.et al, immunological communication,17,361-366(,1988)). This result indicates that the compounds have potential use in the treatment of diseases characterized by a dysregulated immune system, such as autoimmunity, AIDS, host response to transplant, transplant rejection or other diseases characterized by aberrant interleukin-1 production, inflammatory diseases like rheumatoid arthritis and asthma.

1, 25- (OH) has been found in the literature₂D₃Can promote cell differentiation and inhibit excessive cell proliferation (Abe, E, et al, Proc. Natl. Acad. Sci. USA,784990-4994(1981)), which suggests that the compounds may be used to treat diseases characterized by abnormal cell proliferation and/or cell differentiation, such as leukemia, myelofibrosis and psoriasis.

In addition, alsoIt has been proposed to use 1, 25- (OH)₂D₃Or prodrugs thereof 1 alpha-OH-D₃To treat hypertension (Lind, L, et al, Scandinavia pharmaceutical school,222423-427(1987)) and diabetes (Inomata, S. et al, Bone mineral,1,187-192(1986)). About 1, 25- (OH)₂D₃Is based on the recently observed association between genetic vitamin D tolerance and alopecia: with 1, 25- (OH)₂D₃Can promote hair growth (Editorial, Lancet, March 4, p.478 (1989)). In addition for topical application 1, 25- (OH)₂D₃The volume size of sebaceous glands in the ear of the male Syrian hamster can be reduced, which suggests that the compound can be used to treat acne (Malloy v.l. et al, the tricontinent Meeting for invasive surgery, washington, (1989)).

However, the therapeutic potential for these indications is well known as 1, 25- (OH)₂D₃Strong limitation on the strong influence of calcium metabolism; elevated blood calcium levels will rapidly cause hypertension and therefore the use of this compound and its series of potential synthetic analogues as a medicament for the treatment of diseases such as psoriasis, leukaemia or for the treatment of immunological disorders requiring sustained administration at higher doses is not entirely satisfactory.

A series of vitamin D analogues have recently been described which exhibit a certain degree of selectivity for cell differentiation induction/inhibition of cell proliferation in vitro with respect to their effect on calcium metabolism in vivo, as measured by increased serum calcium concentration and/or increased urinary calcium secretion. It is therefore not subject to strict dosage restrictions and can be administered safely. On the basis of this selectivity, calcipotriol (INN) or calcipotriene (USAN) among such compounds was first developed, and it has now been widely recognized that they can be safely and effectively used as a drug for the topical treatment of psoriasis.

Research on another analogue selected on this basis (EB1089) supports the idea that: systemic administration of vitamin D analogsCan inhibit the differentiation of breast cancer cells in vivo at a subtoxic dose (coloston k.w. et al, biochemistry,442273-2280(1992) and Mathiasen, I.S. et al, J.Biol.Biol.St.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol.Biol,46，365-371(1993))。

literature (Binderup, l., biochemical pharmacology,431885-1892(1992)) reviewed the immunosuppressive activity of vitamin D analogs. Thus, a series of 20-epi-vitamin D analogues were identified as potent inhibitors of T-lymphocyte activation in vitro (binder, l. et al, biochemistry,42,1569-1575(1991)). Two compounds MC1288 and KH1060 of this analog were administered systemically in experimental animal models and showed immunosuppressive activity in vivo. Additive or synergistic effects may be observed with low doses of cyclosporin A (cyciosporin A). KH1060, alone or in combination with cyclosporin A, has also been shown to prevent autoimmune destruction of diabetic NOD mice from migrating to the islets of plants (Bouillon R. et al, vitamin D, a pluripotent steroid hormone: structural studies, molecular endocrinology and clinical applications; Norman, A.W., Bouillon R., Thomaset, M., eds.; de Gruyter, berlin, 1994, pp.551-552). MC1288 can prolong the survival of heart and small intestine transplants in rats (Johnson, C. et al, vitamin D, a pluripotent steroid hormone: structural research, molecular endocrinology and clinical applications; Norman, A.W., Bouillon R., Thomaset, M., eds.; de Gruyter, Berlin, 1994, pp.549-550). However, in all these studies, the dose of the analogue that can produce significant immunosuppression can also induce an increase in serum calcium levels, and there is a continuing need to find new analogues with an acceptable delay in therapeutic activity coupled with the appropriate minimum toxicity.

The present invention provides a hitherto undisclosed 16-dehydro-1 alpha, 25-dihydroxyvitamin D having strong immunosuppressive and cytostatic activities₃And the like. The compounds of the formula I are characterized by the presence of a 16, 17-double bond in the five-membered D ring, their absolute position at C-20Is configured asROrS。

Vitamin D analogues in which the 16, 17-double bond is present in the D ring are not new compounds. For example, Hoffmann-La Roche Inc. in U.S. Pat. Nos. 5,087,619/1992 and 5,145,846/1992 disclose 25-hydroxy-and 1 α, 25-dihydroxy-16-en-vitamin D₃Their synthesis and use of 23-ene and 23-yne analogues as well as the corresponding 26, 26, 26, 27, 27, 27-hexafluoro derivatives. Uskokovic, M R et al describe 1, 25-dihydroxy vitamin D₃The synthesis and biological activity of 16-ene analogues (vitamin D: Gene Regulation, Structure-function analysis and clinical applications; Norman, A.W., Bouillon R., Thomaset, M., eds.; de Gruyter, Berlin, 1991, pp.139-145). Hoffmann-LaRoche A.G. in European patent application 0580968/1993 discloses 25-hydroxy-and 1 alpha, 25-dihydroxy-and 1 alpha-fluoro-25-hydroxy-16-en-23-yne-vitamin D₃And their corresponding 26, 26, 26, 27, 27, 27 hexafluoro analogs of 19-nor derivatives. Mclean, J.A. et al describe 1, 25-dihydroxy-16-en-vitamin D₃(U.S. Pat. No. 5,401,733/1995) stable and active metabolism. It should be noted, however, that these and other prior art 16-dehydro-vitamin D compounds₃The compounds are all characterized by the presence of the C-20 methyl group in the natural vitamin D configuration. Further, as the remaining side chains (other substituents on C-20), they all have natural vitamin D₃Fatty six-carbon skeleton structure of side chain. Finally, these compounds optionally contain 23, 24-double or triple bonds.

The compounds of the present invention differ from the prior art 16-dehydrovitamin D in the backbone of the C-20 side chain₃Analogs, which are not limited to aliphatic or hexacyclic rings, and any double or triple bond position may not be limited to between 23 and 24 carbon atoms. Further, the configuration at C-20 may beR(Natural vitamin D)₃Can also be ofS。

To demonstrate the effectiveness of the compounds of formula I, the information in table a is denoted by "HaCaT, rel.", "MLR, rel.", and "calc., rel."; their meanings will be explained below.

One useful assay for assessing the rate of anti-skin cell proliferation activity (e.g., anti-psoriatic effect) of a test compound is by using HaCaT (a spontaneously immortalized non-tumorigenic human skin keratinocyte cell line (Mork Hansen, c.144-48(1996)) in vitro assays for determining³Uptake of H-thymine.

One in vitro assay used to evaluate the rate of immunosuppressive activity of test compounds is the mixed lymphocyte reaction assay, "MIR", which refers to the measurement of allogeneic stimulation of mouse splenic lymphocytes: by mixing with 7.5X 10⁶5X 10/ml Co-cultured cells (from CB6F1 mice (inducer))/ml⁶Lymphocytes from spleens of BALB/C and CB6F1 mice were stimulated with/ml cells from BALB/C mice (responder). The mixed lymphocyte cultures were incubated with the test compounds for 72 hours. By introduction on DNA³H-Thymidine, cellular DNA synthesis was analyzed.

Typically, 1, 25- (OH)₂D₃Classification activity effects on calcium balance in the organism, including blood calcium and urine calcium activity, are not required in the vitamin D analogues of the invention, where selectivity for, for example, some cell proliferation inhibitory and/or immunosuppressive activity is required in the invention.

The samples were collected according to the methods described previously (Binderup, l., Bramm, e., biochemical pharmacology,37889-895(1988)), the calcium activity of the compounds was determined in rats. In Table A, column "Calc., rel." selected compounds (with 1, 25- (OH)₂D₃Related) blood calcium activity; as mentioned, generally low values of the compounds of the invention are preferred.

Table A shows that selected compounds 107 and 111 are compared to 1, 25- (OH) in the HaCaT-assay (psoriasis model)₂D₃Has greater activity, and the blood calcium activity is equal to 1, 25- (OH)₂D₃Similarly.

Other important properties of the compounds of the invention and their immunosuppressive activity can be seen from the column "MLR, rel." in table a, where selected compounds 107 and 111 have a strong effect.Table a: biological assay of Compound I and reference Compound TABLE A notesThe rest of the molecule is the same as formula I. Numerical value and 1, 25- (OH)₂D₃(ii) related; a value greater than 1 indicates a ratio of activity of the compound in the assay of 1, 25- (OH)₂D₃Is large. The formation of the iron layer 1, 25- (OH)₂D₃IC of₅₀Value and IC of the Compound₅₀The ratio of the values is calculated. IC (integrated circuit)₅₀The values refer to results of 50% compared to the control³Concentration of inhibition of H-thymidine incorporation. #1, 25 ═ 1, 25- (OH)₂D₃＝1，25-(OH)₂-vitamin D₃. no ref. control compound was determined

It has been reported that the compounds of formula I can be prepared from C-20 epimeric alcohols3And4to prepare, alcohols 3 and 4 were synthesized from the vitamin D derivative aldehyde 1(Calverley, m.j., Tetrahedron,434609-4619(1987)) was prepared via 20-ketone compound 2 (Hansen, K, et al: vitamin D: gene Regulation, structure-function analysis and clinical applications; norman, a.w., Bouillon r., thomset, m., eds.; de Gruyter, Berlin, 1991, pp.161-162), for example using the general methods in schemes 1 and 2.

More particularly, scheme 1 shows an important intermediate for the synthesis of compounds of formula I, 16-dehydrotosylate, from the above starting materials13/ 14And like aldehydes15/ 16Scheme 2 shows the further conversion of the above key intermediates to compounds of formula I.

The side chain synthesis of the structural units V to VIII or their analogues can be carried out as described in the literature/International patent applications WO87/00834, WO 89/10351. The standard procedures described in WO/91/00271, WO/91/00855, WO/91/15475, WO/93/19044 and WO/95/02577.

The following standard abbreviations are used throughout this patent specification: DMF ═ N, N-dimethylformamide; DMSO ═ dimethyl sulfoxide; et ═ ethyl; hal ═ halogen; "HF" ═ 5% hydrogen fluoride acetonitrile: water (7: 1, v/v); me ═ methyl, Ph ═ phenyl; PPTS ═ pyridinium p-toluenesulfonate; TBAF ═ tetra-n-butylammonium fluoride trihydrate; TBDMS ═ tert-butyldimethylsilyl; THF ═ tetrahydrofuran; THP ═ tetrahydro-4H-pyran-2-yl; TMS ═ trimethylsilyl; ts ═ p-toluenesulfonyl (tosyl).Route 1 Route 1 notes

a) Dehydrating with phosphorus oxychloride in pyridine; 0 ℃/1h and 20 ℃/16-18 h.

b) Protecting triene system with sulfur dioxide in dichloromethane/water; 20 ℃/45-90 minutes; the C-6 epimer was chromatographed.

c) Performing carbonyl-ene reaction with paraformaldehyde/boron trifluoride etherate in dichloromethane; 0 ℃ for 5-20 minutes.

d) Deprotecting the sulfur dioxide adduct in toluene/water with sodium bicarbonate; 90 ℃ for 1-2 h.

e) P-toluenesulfonylation with p-toluenesulfonyl chloride in pyridine; 0-5 ℃ for 16-18 h.

f) Swern oxidation with oxalyl chloride/DMSO in dichloromethane; -78 ℃/20 min.Route 2Q，Y，R¹，R²And Z is as defined above; z¹Is hydroxy or a protected alcohol, such as TMS-O, TBDMS-D or THP-O; x is O or S; n is 2, 3 or 4.Route 2 annotation

a) With side chain building block V (H-X-R) in DMF in the presence of base (sodium hydride)³See below) is alkylated; 20 ℃/0.5-22 hours。

b) In Li₂CuCl₄In THF in the presence of a catalyst derived from side chain structural unit VI (R)⁴-Hal, see below) of Grignard reagents R⁴-Mg-Hal; 0 ℃/2h, then 8-10 ℃/16-20 h.

c) In the presence of a base (lithium bis (trimethylsilyl) amide) in THF with a compound derived from side chain structural unit VII (A-R)⁵See below) of A¹-R⁵The ylide is reacted at-45 deg.C for 0.5-1.5 hours.

d) At elevated temperature in toluene with a unit derived from the side chain structure VIII (A)¹-R⁶See below) of A¹-R⁶The reaction of the ylide is carried out at 90-110 deg.C for 2-8 hours.

e) Modification of any functional group on the side chain of the compound of formula II.

f) The compounds of formulae IIa and III are isomerized to the corresponding compounds of formula IV using UV light in the presence of a triple sensitizer, such as anthracene or 9-acetyl anthracene.

g) Deprotection of a compound of formula IV by treatment with, for example, TBAF or "HF" produces the corresponding compound of formula I. V H-X-R³ R³＝-(C₆H₄)-C(R¹)(R²)-Z¹(ortho-, meta-, para-) VI R⁴-Hal R⁴＝-CH₂-(CH₂)_n-C(R¹)(R²)-Z¹

Hal ═ Cl or BrVII A-R⁵ A＝Ph₃P⁺-^-CH₂Or (EtO)₂P(O)-CH₂-

R⁵＝-CH＝CH-CO-OmeVIII A-R⁶A has the meaning given above

In A¹-R⁵And A¹-R⁶In (A)¹Represents Ph₃P⁺-^-CH^-Or (EtO)₂P(O)-CHLi-，R⁵And R⁶The definition of (A) is as above.

The compounds of the invention are intended for use in pharmaceutical compositions capable of the local or systemic treatment of the above-mentioned human and veterinary disorders.

The compounds of the present invention may be used in combination with other pharmaceutical or therapeutic methods. In the treatment of psoriasis, the compounds of the invention may be used in combination with steroids or other therapeutic methods (e.g. light or uv light therapy or PUVA therapy). The compounds of the present invention may be used in combination with other anti-cancer drugs or anti-cancer therapies (e.g., radiation therapy) in the treatment of cancer, and preferably with other immunosuppressive/immunomodulatory drugs and therapies (e.g., cyclosporin A) in the prevention of graft rejection or graft-versus-host reactions or in the treatment of autoimmune diseases.

The amount of the compound of formula I (hereinafter referred to as the active ingredient) required to produce a therapeutic effect will, of course, vary with the particular compound, the route of administration, and the condition of the mammal being treated. The compounds of the invention may be administered parenterally, intraarticularly, enterally or topically. Absorption is better when administered by the enteral route, and therefore, this is the preferred route of administration for treating systemic disorders. Topical or enteral administration is preferred in the treatment of skin disorders or eye diseases such as psoriasis.

Although the active ingredient may be administered alone in the form of the crude compound, it is preferably used in the form of its pharmaceutical preparation. Typically, the formulations contain 0.1ppm to 0.1% by weight of active ingredient.

Thus, the formulations of the invention for use in veterinary and human medicine comprise the active ingredient in admixture with a pharmaceutically acceptable carrier therefor and any other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations include dosage forms suitable for oral, ocular, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), transdermal, intraarticular, and topical, nasal, or buccal administration.

The term "dosage unit" means a unit, i.e., a single dose, which can be administered to a patient, which is conveniently controlled and packaged, containing the active ingredient by itself or in admixture with a solid or liquid pharmaceutical diluent or carrier, which is physically and chemically stable.

Generally, the formulations will be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, all of which include the step of bringing into association the active ingredient with the carrier which consists of one or more accessory ingredients. The general preparation method is as follows: the active ingredient is introduced homogeneously and intimately into liquid carriers or finely divided solid carriers or mixtures of the two, which are then, if necessary, shaped into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, tablets or lozenges, each of which contains a predetermined dose of the active ingredient; powder or granules; solutions or suspensions of aqueous or non-aqueous liquids; or an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may be administered in the form of a bolus, electuary or paste.

Formulations for rectal administration may take the form of suppositories into which the active ingredient and the carrier are incorporated or enemas.

Formulations for parenteral administration typically contain a sterile oily or aqueous preparation of the active ingredient which is isotonic with the blood of the recipient. The transdermal formulation may be administered in the form of an ointment.

Formulations suitable for intra-articular or ophthalmic administration may be presented as sterile aqueous preparations of the active ingredient which may be in microcrystalline form, e.g., as a suspension of hydrated microcrystals. Liposomal formulations or biodegradable polymer systems may also be used for the administration of the active ingredients of the invention, both intra-articularly and ocularly.

Formulations suitable for topical or ocular administration include liquid or semi-liquid formulations such as liniments, lotions, gels, dressings, oil-in-water or water-in-oil emulsions (e.g. creams), ointments or salves; or a solution or suspension (e.g. drops).

Formulations suitable for nasal or buccal administration include powders, self-propellants and sprays, such as aerosols and nebulisers.

In addition to the aforementioned ingredients, the formulations of the present invention may contain one or more additional ingredients, such as diluents, binders, preservatives and the like.

The composition further comprises other therapeutically active compounds usually used for the treatment of the above mentioned pathological conditions, such as other immunosuppressive agents for the treatment of immunological diseases, or steroids for the treatment of dermatological diseases.

The invention further relates to a method of treating a subject suffering from one of the above-mentioned diseases, which comprises administering to the subject in need thereof an effective amount of one or more compounds of formula I, either alone or in combination with one or more other therapeutically active compounds conventionally used for the treatment of the above-mentioned diseases. The compounds of the present invention and/or their combinations with other therapeutically active compounds may be administered simultaneously or separately.

In systemic treatment, the daily dose is from 0.001 to 2. mu.g/kg body weight, preferably 0.002 to 0.3. mu.g/kg body weight of the mammal, for example 0.003 to 0.3. mu.g of a compound of formula I per kg is administered, typically corresponding to a daily dose of 0.2 to 25. mu.g for an adult. In the topical treatment of skin disorders, ointments, creams or lotions are administered which contain 0.1 to 500. mu.g/g, preferably 0.1 to 100. mu.g/g, of a compound of formula I. For topical ophthalmic ointments, drops or gels, 0.1 to 500. mu.g, preferably 0.1 to 100. mu.g, of a compound of formula I are administered. Oral compositions are generally formulated as tablets, capsules or drops containing 0.05 to 50. mu.g, preferably 0.1 to 25. mu.g, of a compound of formula I per dosage unit.

The invention will be further described below.General procedures, preparation and practiceExamples of the embodiments General content

The exemplified compounds of formula I are listed in Table 5, wherein intermediates 5-16 and general formulas II, III and IV are listed in tables 1-4.

For nuclear magnetic resonance spectroscopy (300MHz), the chemical shift value (δ) was obtained relative to a deuterated chloroform solution associated with tetramethylsilane (δ ═ 0) or chloroform (δ ═ 7.25) as internal standards. For values of multiplets, whether defined (doublet (d), triplet (t), quartet (q) or undefined (m), unless a range is given (s ═ singlet, b ═ broad), the values are taken from about the midpoint.

Ether refers to diethyl ether, dried over sodium metal. THF was dried over sodium benzophenone. Petroleum ether refers to the pentane component. Unless otherwise indicated, the reaction is typically carried out under argon at room temperature. The treatment step comprises dilution with a specified solvent (otherwise organic reaction solvent), extraction with water and brine in sequence, drying over anhydrous magnesium sulfate, and concentration under reduced pressure to give a residue. Chromatography was performed on silica gel. Intermediates of formulae 5 to 16 of Table 1 (scheme 1) preparation of Compounds Serial No. general procedures 5117 a 327 b 429 a 739 b 831111413135151566218 a 528 b 6210 a 9310 b 103121241414516166 intermediates of formulae IIa to d of Table 2 (scheme 2)

Serial number preparation of Compounds of general formula I general procedure C20 configuration

X n R¹ R² Z¹IIa 201 17 7 S O - Me Me OHIIa 202 18 7 R O - Me Me OHIIa 203 19 7 S S - Me Me OHIIa 204 20 7 R S - Me Me OHIIb 205 21 8 R - 2 Me Me OTMSIIb 206 22 8 S - 2 Me Me OTMSIIb 207 23 8 R - 3 Et Et OTMSIIb 208 24 8 R - 3 Et Et OTMSIIc 209 25 9 R - - - - -IIc 210 26 9 S - - - - -IId 213 27 10 R - - - - -IId 214 28 10 SIntermediates of general formula III in Table 3 (scheme 2)

Serial preparation of the radical Compounds number general procedure C20 configuration

Q Y R¹ R² Z305 29 11 R (CH₂)₃Single bond Me OH 3063011S (CH₂)₃Single bond Me OH 3073111R (CH₂)₄Single bond Et Et OH 3083211S (CH₂)₄Single bond Et Et OH 3093312R (CH＝CH)₂ ^aSingle bond Me Me OH 3103412S (CH＝CH)₂ ^aSingle bond Me Me OH 3113512R (CH＝CH)₂ ^aSingle bond Et Et OH 3123612S (CH＝CH)₂ ^aSingle bond Et Et OH Table 3 (continuous) intermediates of general formula III (scheme 2)

Serial preparation of the radical Compounds number general procedure C20 configuration

Q Y R¹ R² Z313 37 13 R (CH＝CH)^a CH(OH)^b CH₂-CH₂ H314 38 13 S (CH＝CH)^a CH(OH)^b CH₂-CH₂ H315 39 13 R (CH＝CH)^a CH(OH)^c CH₂-CH₂ H316 40 13 S (CH＝CH)^a CH(OH)^c CH₂-CH₂ H^a E-( E， E-) configuration of the double bond^bThe C atomSConfiguration(s)^cThe C atom isRConfigurational Table 4 intermediates of general formula IV (scheme 2)

Serial No. preparation of group Compounds No. C20 configuration No. number QY R¹ R² Z401 41 S CH₂ O-C₆H₄(m) Me Me OH 40242R CH₂ O-C₆H₄(m) Me Me OH 40343S CH₂ S-C₆H₄(m) Me Me OH 40444R CH₂ S-C₆H₄(m) Me Me OH 40545R (CH₂)₃Single bond Me OH 40646S (CH₂)₃Single bond Me OH 40747R (CH₂)₄Single bond Et Et OH 40848S (CH₂)₄Single bond Et Et OH 40949R (CH＝CH)₂ ^aSingle bond Me OH 41050S (CH＝CH)₂ ^aSingle bond Me Me OH Table 4 (continuation) intermediates of the general formula IV (route 2)

Serial preparation of the base Compounds No. C20 configuration

Q Y R¹ R² Z411 51 R (CH＝CH)₂ ^aSingle bond Et Et OH 41252S (CH＝CH)₂ ^aSingle bond Et Et OH 41353R (CH＝CH)^a CH(OH)^b CH₂-CH₂ H414 54 S (CH＝CH)^a CH(OH)^b CH₂-CH₂ H415 55 R (CH＝CH)^a CH(OH)^c CH₂-CH₂ H416 56 S (CH＝CH)^a CH(OH)^c CH₂-CH₂ H^a E-( E， E-) configuration of the double bond^bThe C atomSConfiguration(s)^cThe C atom isRConfiguration table 5 example Compound 1

Number of radical Compounds example No. C20 configuration

Q Y R¹ R² Z101 1 S CH₂ O-C₆H₄(m) Me Me OH 1022R CH₂ O-C₆H₄(m) Me Me Me OH 1033S CH₂ S-C₆H₄(m) Me Me OH 1044R CH₂ S-C₆H₄(m) Me Me OH 1055R (CH₂)₃Single bond Me OH 1066S (CH₂)₃Single bond Me Me OH 1077R (CH₂)₄Single bond Et Et OH 1088S (CH₂)₄Single bond Et Et OH 1099R (CH＝CH)₂ ^aSingle bond Me Me OH 11010S (CH＝CH)₂ ^aSingle bond Me Me OH Table 5 (continuation) example Compound 1

Serial number of radical Compounds example No. C20 configuration No. number atC20 Q Y R¹ R² Z111 11 R (CH＝CH)₂ ^aSingle bond Et Et OH 11212S (CH＝CH)₂ ^aSingle bond Et Et OH 11313R (CH＝CH)^a CH(OH)^b CH₂-CH₂ H114 14 S (CH＝CH)^a CH(OH)^b CH₂-CH₂ H115 15 R (CH＝CH)^a CH(OH)^c CH₂-CH₂ H116 16 S (CH＝CH)^a CH(OH)^c CH₂-CH₂ H^a E-( E， E-) configuration of the double bond^bThe C atomSConfiguration(s)^cThe C atom isRConfiguration(s)General procedure General procedure 1： Dehydration of Compounds 4 and 3 to give the corresponding Anhydrous Compounds 5 and 6 (preparation) 1-2)

The compound4(or3) (2.81g, 5mmol) pyridine solution (40ml) was cooled to 0 ℃ and phosphorus oxychloride (4.6ml, 50mmol) was added dropwise with stirring over 5 minutes. After stirring at low temperature for 1 hour and at room temperature for another 16 hours, the reaction mixture was poured into ice-cold ethyl acetate (120ml), and water (40ml) was carefully added with stirring. With 4N hydrochloric acid (80ml)) The apparent pH of this mixture was adjusted to 2.8 and the phases were separated. After extraction of the aqueous layer with ethyl acetate (60ml), the organic layers were combined and worked up to give the crude product which was not purified (compound)5) Directly used in the next step, or recrystallized and purified with diethyl ether-methanol6) Used in the next step.General procedure 2： The compounds 5 and 6 react with sulfur dioxide to obtain corresponding sulfur dioxide addition Substances 7a/7b and 8a/8b (preparations 3 to 6)

Under vigorous stirring, to crude compound5(or pure product)6) To a solution of (5mmol) in dichloromethane (25ml) and water (10ml) was added an ice-cold solution of about 1.5M sulfur dioxide in dichloromethane (100 ml). The mixture was stirred at room temperature for 45 minutes and poured into ice water (100 ml). The apparent pH of the mixture was adjusted to 5.6 with 2N sodium hydroxide (62ml), and the organic layer was separated. The aqueous layer was extracted again (dichloromethane, 25ml) and the organic layer was treated. The residue was chromatographed (eluent: 5% -10% diethyl ether/petroleum ether) to separate 6(S) and 6(R) SO₂Adducts 7a and 7b (or 9a and 9 b). General procedure 3: make SO₂Ene reaction of adducts 7a, 7b, 8a and 8b with paraformaldehyde to give the corresponding SO₂Protected 16-dehydroalcohols 9a, 9b, 10a and 10b (preparation 7-10)

Under stirring at 0 deg.C7a( 7b， 8a， 8b) (2.42g, 4mmol) in dichloromethane (80ml) was added paraformaldehyde (0.60g, 20mmol) and boron trifluoride etherate (0.10ml, 0.4 equiv.) was added. After stirring at 0 ℃ for 15 minutes, the reaction was terminated with 1/15M phosphate buffer (pH 6.5) (60ml), and the mixture was treated. The residue was chromatographed (eluent: 10% -15% ethyl acetate in petroleum ether) from the more polar title compound (A)9aOr9b， 10a， 10b) A small amount of less polar starting material was separated. General procedure 4: make SO₂Deprotection of the adducts 9a/9b and 10a/10b to give the corresponding 16-Dehydrools 11 and 12 (preparation 11-12)

To the compound9a( 9b) (1.27g, 2mmol) in toluene (20ml) were added water (10ml) and sodium bicarbonate (0.67g, 8mmol) and the mixture was stirred at 85-90 ℃ for 1.5 h. After cooling to room temperature. Treating the reaction mixture (toluene) to obtain the compound11It is a foam.

Treating compounds similarly10a(or10b) To obtain a compound12It is an amorphous powder.General procedure 5： Tosylation of 16-dehydroalcohols 11 and 12 to the corresponding tosylates (salts) 13 and 14 (preparation 13-14)

To the stirred compound at 0 DEG C11(or12) (2mmol) of pyridine (10ml) was added p-toluenesulfonyl chloride (0.76g, 4mmol) and the mixture was stirred at 0-5 ℃ for 2h and then left in the refrigerator overnight (16 h). The reaction mixture was poured into an ice-cold mixture of ethyl acetate (40ml) and water, and the pH was adjusted to 2.6 with 4N hydrochloric acid. After separating the aqueous phase, extraction was performed with ethyl acetate, and the combined organic layers were treated. . The residue was purified by chromatography (eluent: 5% diethyl ether in petroleum ether) to give pure product13(or14)。General procedure 6： Oxidation of 16-dehydroalcohols 11 and 12 to the corresponding aldehydes 15 and 16 (Swern) Oxidation) (preparation 15-16)

A solution of oxalyl chloride (0.45ml, 5mmol) in dry dichloromethane was cooled to-78 deg.C with stirring and a solution of 2N dimethyl sulfoxide in dry dichloromethane (5.6ml, 11.2mmol) was added via syringe. Stirring at low temperature for 10 min, adding11(or12) (4mmol) of anhydrous dichloromethane solution (12ml) (syringe). Stirring was continued for 20 min and the reaction was quenched with triethylamine (2.1ml, 15 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature and stirred for about 45 minutes to give crude compound after work-up (dichloromethane)15(or16) It was used directly in the next reaction without further purification.General procedure 7： Alkylation of Compounds 13 and 14 to give Compounds of formula IIa (preparations 17-20)

To a suitable alkylating reagent HXR³To a solution of (1.5mmol) in anhydrous DMF (10ml) was added sodium hydride (2.25mmol) and the mixture was stirred for 20 min. Injecting the compound with a syringe13(or14) To this was added anhydrous THF solution (5ml) and stirring was continued for 30-40 minutes (S-alkylation), or 16-22 hours (O-alkylation). The reaction mixture (ethyl acetate) was treated by cooling to 0-5 ℃ and adding dropwise water (0.5-1.0ml) to decompose excess reagent. The residue is purified by chromatography on silica gel (eluent: 5-10% diethyl ether in petroleum ether) to give the corresponding compound IIa.General procedure 8： Compounds 13 and 14 with structural units derived from side chains II (R) ⁴ Hal) Grignard Reagent R ⁴ MgHal reaction to give compounds of the formula IIb (preparation 21-24)

To an anhydrous flask of magnesium turnings (220mg, 1.1 atomic equivalent), under argon and with stirring, a solution of the appropriate compound VI (8.25mmol) in anhydrous THF (7.5ml) was added dropwise, and the mixture was stirred under reflux for 45 minutes under heating. Grignard reagent was treated with lithium chloride (32mg) solution and anhydrous copper chloride (50mg) in anhydrous THF (5ml) at 0 ℃ with stirring, and after 15 minutes the compound was used13(or14) Was treated with a solution of anhydrous THF (5 ml). After stirring for 18 hours at 5-10 ℃, the reaction mixture (diethyl ether) was worked up. The crude product is purified by chromatography to afford the desired compound IIb.General procedure 9： Aldehydes 15 and 16 with structural units derived from side chains VII (AR) ⁵ ) Onium salt of (2) A ¹ R ⁵ Reaction to give the Compound of formula IIc (preparation 25-26)

To aldehyde at-50 ℃ with stirring15(or16) (1.0mmol) and the appropriate compound VII (1.8mmol) in dry THF (5ml) a 1M solution of lithium bis (trimethylsilyl) amide in dry THF (1.5ml) was added dropwise via syringe. Stirring was continued at low temperature for 1 hour, and then the mixture was allowed to warm to-10 deg.C (15-20 minutes). The reaction was stopped by adding a small amount of water dropwise and worked up (diethyl ether). Residue ofPurification by silica gel chromatography gave the desired compound IIc.General procedure 10： Aldehydes 15 and 16 with units derived from the side chain structure VIII (A) ¹ R ⁶ ) Onium of (2) Salt A ¹ R ⁶ Reaction to give the compound of formula IId (preparation 27-28)

To aldehydes15(or16) (1.8mmol) in dry toluene (20ml) was added the appropriate compound VIII (3.6mmol) and the mixture was stirred at 90-110 ℃ for 2-4 h. After cooling to 0 ℃, the mixture is filtered, the filtrate is concentrated and purified by chromatography to give the desired compound IId.General procedure 11： Deprotection of Compound IIb with PPTS affords the corresponding Compound III (preparation Prepare 29-32)

To a solution of the appropriate compound IIb (0.5mmol) in dry THF (3ml) and ethanol (6ml) was added PPTS (15mg), the mixture was stirred for 1 hour, treated with ethyl acetate and the crude product obtained was purified by silica gel chromatography to give the desired compound III.General procedure 12： By reaction of alkyllithium with compound IIc to give the corresponding compound III Prepare 33-36)

A pre-cooled (-15 ℃) solution of alkyllithium in diethyl ether (3-4 molar equivalents) was added dropwise via syringe to a solution of the appropriate compound IIc (0.5mmol) in anhydrous THF (6ml) at-78 ℃. After stirring at-78 ℃ for 45 minutes, a small amount of water was added dropwise to terminate the reaction, and the reaction was warmed to 20 ℃ and treated (ether). The residue was purified by silica gel chromatography to give the desired compound III.General procedure 13： Reduction of the Compound IId to give the corresponding Compound III (preparation 37-40)

To a solution of the appropriate compound IId (0.8mmol) in THF (4ml) was added 0.4MCeCl with stirring at 0 deg.C₃.7H₂O in ethanol (2ml) and sodium borohydride (76mg, 2mmol) were added. Methanol (4ml) was added over 10 minutes with stirring, the mixture was stirred for 20 minutes, treated with ethyl acetate and the resulting residue was purified by chromatography to give the desired compound III.General procedure 14： Isomerization of Compounds IIa and III to the corresponding CompoundsCompound IV (preparation) 41-56)

A solution of the appropriate compound IIa or III (0.28mmol), anthracene (0.10g, 0.56mmol) and triethylamine (0.20ml, 1.4mmol) in dichloromethane (16ml) was placed in a 25ml round bottom Pyrex flask and the flask was irradiated with UV-light from a high pressure UV lamp (model TQ760Z2(Hanau)) for 30 minutes at about 10 ℃ with stirring. The reaction mixture was concentrated under reduced pressure and the residue was treated with petroleum ether (2X 2ml) and filtered. The filtrate was concentrated and the resulting residue was purified by chromatography to give the title compound. General procedure 15: deprotection of Compound IV by treatment with "HF" to give the corresponding Compound I(examples 1 to 8 and 13 to 16)

To a solution of the appropriate compound IV (0.25mmol) in ethyl acetate (1.5ml) was added acetonitrile (6ml) with stirring, followed by a solution of 5% hydrofluoric acid in acetonitrile-water 7: 1(2.0 ml). After stirring for an additional 45-60 minutes, 1M potassium bicarbonate solution (10ml) was added and the mixture was treated with ethyl acetate. The residue is purified by chromatography (eluent: 30% pentane in ethyl acetate) to give the desired compound I.General procedure 16： Deprotection of Compound IV by treatment with tetra-n-butylammonium fluoride affords the corresponding Compounds I (examples 9 to 12)

To a solution of the appropriate compound IV (0.18mmol) in THF (4.5ml) was added TBAF trihydrate (0.29g, 0.9mmol) and the mixture was heated under reflux for 1h with stirring. A0.2M sodium bicarbonate solution (5ml) was added and the mixture was treated with ethyl acetate. The residue is purified by chromatography (eluent: 50% ethyl acetate in pentane) to yield the title compound.Preparation of

Preparation 1： Compound 5

The method comprises the following steps: general procedure 1

Starting materials: compound 4

¹H NMR δ 0.06(m，12H)，0.76(s，3H)，0.85(s，9H)，0.89(s，9H)，1.66(m，3H)，1.45-2.50(m，13H)，2.56(dd，1H)，2.86(m，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.98(m，1H)，5.19(m，1H)，5.85(d，1H)，6.44(d，1H).

Preparation 2： Compound 6

The method comprises the following steps: general procedure 1

Starting materials: compound 3

m.p.87-88℃

Elemental analysis：C₃₃H₅₈O₂Si₂Theoretical value: c73.00, H10.77

Measured value: c72.90, H10.82

¹H NMR 50.06(m，12H)，0.62(s，3H)，0.86(s，9H)，0.90(s，9H)，1.56(d，3H)，1.20-2.10(m，10H)，2.32(m，3H)，2.57(dd，1H)，2.89(m，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.99(m，1H)，5.08(m，1H)，5.86(d，1H)，6.45(d，1H).

Preparation 3： Compound 7a

The method comprises the following steps: general procedure 2

Starting materials: compound 5

m.p.117-118℃

Elemental analysis：C₃₃H₅₈O₄SSi₂Theoretical value: c65.29, H9.63, S5.28

Measured value: c65.12, H9.54, S5.22

¹H NMR δ 0.05(m，12H)，0.86(s，9H)，0.87(s，9H)，0.87(s，3H)，1.66(m，3H)，1.40-2.50(m，14H)，2.60(m，1H)，3.60(bd，1H)，3.93(m，1H)，4.19(m，1H)，4.36(m，1H)，4.64(d，1H)，4.74(d，1H)，5.17(m，1H).

Preparation 4： Compound 7b

The method comprises the following steps: general procedure 2

Starting materials: compound 5

¹H NMR δ 0.06(m，12H)，0.78(s，3H)，0.87(s，9H)， 0.88(s，9H)，1.66(m，3H)，1.45-2.45(m，14H)，2.56(m，1H)，3.63(bd，1H)，3.92(bd，1H)，4.15(m，1H)，4.38(m，1H)，4.62(d，1H)，4.84(d，1H)，5.19(m，1H).

Preparation 5： Compound 8a

The method comprises the following steps: general procedure 2

Starting materials: compound 6

m.p.117-118℃

Elemental analysis：C₃₃H₅₈O₄SSi₂Theoretical value: c65.29, H9.63, S5.28

Measured value: c65.14, H9.54, S5.08

¹H NMR δ 0.06(m，12H)，0.72(s，3H)，0.87(s，9H)，0.88(s，9H)，1.36(m，1H)，1.55(d，3H)，1.45-2.05(m，10H)，2.10-2.45(m，3H)，2.63(m，1H)，3.60(bd，1H)，3.93(m，1H)，4.18(m，H)，4.36(m，1H)，4.65(d，1H)，4.75(d，1H)，5.10(m，1H).

Preparation 6： Compound 8b

The method comprises the following steps: general procedure 2

Starting materials: compound 6

¹H NMR δ 0.06(m，12H)，0.64(s，3H)，0.86(s，9H)，0.88(s，9H)，1.55(d，3H)，1.20-1.95(m，10H)，2.08(dd，1H)，2.30(m，3H)，2.60(m，1H)，3.63(bd，1H)，3.92(bd，1H)，4.16(m，1H)，4.38(m，1H)，4.62(d，1H)，4.85(d，1H)，5.10(m，1H).

Preparation 7： Compound 9a

The method comprises the following steps: general procedure 3

Starting materials: compound 7a

m.p.115-116℃

Elemental analysis：C₃₄H₆₀O₅SSi₂Theoretical value: c64.10, H9.49, S5.03

Measured value: c63.78, H9.55, S5.00

¹H NMR δ 0.06(m，12H)，0.82(s，3H)，0.87(s，9H)，0.88(s，9H)，1.06(d，3H)，1.35-2.50(m，14H)，2.61(m，1H)，3.57(m，3H)，3.93(m，1H)，4.18(m，1H)，4.37(m，1H)，4.63(d，1H)，4.82(d，1H)，5.43(m，1H).

Preparation 8： Compound 9b

The method comprises the following steps: general procedure 3

Starting materials: compound 7b

m.p.131-132℃

Elemental analysis：C₃₄H₆₀O₅SSi₂Theoretical value: c64.10, H9.49

Measured value: c64.18, H9.46

¹H NMR δ 0.05(m，12H)，0.72(s，3H)，0.85(s，9H)，0.87(s，9H)，1.06(d，3H)，1.35-2.02(m，9H)，2.10-2.65(m，6H)，3.58(m，3H)，3.92(bd，1H)，4.15(m，1H)，4.38(m，1H)，4.62(d，1H)，4.92(d，1H)，5.45(m，1H).

Preparation 9： Compound 10a

The method comprises the following steps: general procedure 3

Starting materials: compound 8a

m.p.125-126℃

Elemental analysis：C₃₄H₆₀O₅SSi₂Theoretical value: c64.10, H9.49, S5.03

Measured value: c63.98, H9.46, S4.82

¹H NMR δ 0.06(m，12H)，0.81(s，3H)，0.87(s，9H)，0.88(s，9H)，1.11(d，3H)，1.40-2.50(m，14H)，2.60(m，1H)，3.47(dd，1H)，3.58(dd，1H)，3.60(bd，1H)，3.93(m，1H)，4.19(m，1H)，4.37(m，1H)，4.64(m，1H)，4.82(m，1H)，5.45(m，1H).

Preparation 10： Compound 10b

The method comprises the following steps: general procedure 3

Starting materials: compound 8b

m.p.129-130℃

¹H NMR δ 0.06(m，12H)，0.72(s，3H)，0.86(s，9H)，0.88(s，9H)，1.11(d，3H)，1.35-2.00(m，9H)，2.10-2.50(m，5H)，2.57(dd，1H)，3.46(dd，1H)，3.59(dd，1H)，3.64(bd，1H)，3.92(bd，1H)，4.16(m，1H)，4.38(m，1H)，4.62(d，1H)，4.93(d，1H)，5.48(m，1H).

Preparation 11： Compound 11

The method comprises the following steps: general procedure 4

Starting materials: compound 9a or 9b

Elemental analysis：C₃₄H₆₀O₃SSi₂Theoretical value: c71.27, H10.55

Measured value: c71.00, H10.59

¹H NMR δ 0.05(m，12H)，0.71(s，3H)，0.85(s，9H)，0.90(s，9H)，1.06(d，3H)，1.35-2.00(m，8H)，2.09(m，1H)，2.28(m，2H)，2.41(m.2H)，2.58(dd，1H)，2.87(m，1H)，3.55(m，2H)，4.22(m，1H)，4.54(m，1H)，4.95(m，1H)，4.99(m，1H)，5.46(m，1H)，5.92(d，1H)，6.45(d，1H).

Preparation 12： Compound 12

The method comprises the following steps: general procedure 4

Starting materials: compound 10a or 10b

¹H NMR δ 0.06(m，12H)，0.70(s，3H)，0.85(s，9H)，0.90(s，9H)，1.11(d，3H)，1.40-1.90(m，7H)，1.93(m，1H)，2.10(m，1H)，2.20-2.50(m，4H)，2.58(dd，1H)，2.86(m，1H)，3.48(m，1H)，3.57(m，1H)，4.22(m，1H)，4.54(m，1H)，4.95(m，1H)，4.99(m，1H)，5.48(m，1H)，5.92(d，1H)，6.45(d，1H).

Preparation 13： Compound 13

The method comprises the following steps: general procedure 5

Starting materials: compound 11

m.p.77-78℃

Elemental analysis：C₄₁H₆₆O₅SSi₂Theoretical value: c67.72, H9.15, S4.41

Measured value: c67.50, H9.07, S4.67

¹H NMR δ 0.06(m，12H)，0.60(s，3H)，0.86(s，9H)，0.89(s，9H)，1.04(d，3H)，1.30-1.85(m，6H)，1.91(m，1H)，2.02(m，1H)，2.10-2.38(m，3H)，2.44(s，3H)，2.40-2.62(m，2H)，2.84(m，1H)，3.84(t，1H)，4.04(dd，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.98(m，1H)，5.31(m，1H)，5.88(d，1H)，6.43(d，1H)，7.33(d，2H)，7.78(d，2H).

Preparation 14： Compound 14

The method comprises the following steps: general procedure 5

Starting materials: compound 12

m.p.89-90℃

Elemental analysis：C₄₁H₆₆O₅SSi₂Theoretical value: c67.72, H9.15

Measured value: c67.73, H9.36

¹H NMR δ 0.06(m，12H)，0.63(s，3H)，0.85(s，9H)，0.90(s，9H)，1.09(d，3H)，2.44(s，3H)，2.56(dd，1H)，0.75-2.50(m，12H)，2.83(m，1H)，3.73(t，1H)，4.03(dd，1H)，4.22(m，1H)，4.53(m，1H)，4.95(m，1H)，4.98(m，1H)，5.37(m，1H)，5.88(d，1H)，6.42(d，1H)，7.33(d，2H)，7.78(d，2H).

Preparation 15： Compound 15

The method comprises the following steps: general procedure 6

Starting materials: compound 11

¹H NMR δ 0.06(m，12H)，0.69(s，3H)，0.85(s，9H)，0.90(s，9H)，1.21(d，3H)，1.40-2.00(m，7H)，2.14(m，1H)，2.31(m，2H)，2.44(dd，1H)，2.58(m，1H)，2.87(m，1H)，3.05(m，1H)，4.22(m，1H)，4.53(m，1H)，4.95(m，1H)，4.99(m，1H)，5.52(m，1H)，5.92(d，1H)，6.44(d，1H)，9.45(d，1H).

Preparation 16： Compound 16

The method comprises the following steps: general procedure 6

Starting materials: compound 12

¹H NMR δ 0.06(m，12H)，0.70(s，3H)，0.85(s，9H)，0.89(s，9H)，1.24(d，3H)，1.00-2.00(m，7H)，2.14(m，1H)，2.29(m，2H)，2.46(m，1H)，2.57(dd，1H)，2.86(m，1H)，3.05(m，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.99(m，1H)，5.56(m，1H)，5.92(d，1H)，6.44(d，1H)，9.45(d，1H).

Preparation 17： Compound 201

The method comprises the following steps: general procedure 7

Starting materials: compound 13

Alkylating agent: 3- (1-hydroxy-1-methyl) ethylphenol

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.72(s，3H)，0.85(s，9H)，0.90(s，9H)，1.20(d，3H)，1.57(s，6H)，1.15-2.00(m，8H)，2.09(m，1H)，2.28(m，2H)，2.43(m，1H)，2.60(m，2H)，2.87(m，1H)，3.81(t，1H)，4.00(dd，1H)，4.23(m，1H)，4.53(m，1H)，4.95(m，1H)，4.99(m，1H)，5.48(m，1H)，5.93(d，1H)，6.46(d，1H)，6.76(m，1H)，7.03(m，2H)，7.24(t，1H).

Preparation 18： Compound 202

The method comprises the following steps: general procedure 7

Starting materials: compound 14

Alkylating agent: 3- (1-hydroxy-1-methyl) ethylphenol

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.72(s，3H)，0.85(s，9H)，0.90(s，9H)，1.23(d，3H)，1.57(s，6H)，1.40-2.00(m，8H)，2.09(m，1H)，2.29(m，2H)，2.42(m，1H)，2.60(m，2H)，2.87(m，1H)，3.67(t，1H)，4.01(dd，1H)，4.23(m，1H)，4.54(m，1H)，4.95(m，1H)，4.99(m，1H)，5.51(m，1H)，5.93(d，1H)，6.46(d，1H)，6.78(m，1H)，7.04(m，2H)，7.24(t，1H).

Preparation 19： Compound 203

The method comprises the following steps: general procedure 7

Starting materials: compound 13

Alkylating agent: 3- (1-hydroxy-1-methyl) ethylphenol

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.70(s，3H)，0.86(s，9H)，0.90(s，9H)，1.19(d，3H)，1.56(s，6H)，1.15-1.87(m，7H)，1.92(m，1H)，2.07(m，1H)，2.20-2.50(m，4H)，2.57(dd，1H)，2.85(d，1H)，2.86(dd，1H)，3.20(dd，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.99(m，1H)，5.44(m，1H)，5.91(d，1H)，6.45(d，1H)，7.15-7.30(m，3H)，7.46(m，1H).

Preparation 20： Compound 204

The method comprises the following steps: general procedure 7

Starting materials: compound 14

Alkylating agent: 3- (1-hydroxy-1-methyl) ethyl thiophenol

Chromatographic eluent: 10% Ether in pentane

¹H NMRδ 0.05(m，12H)，0.67(s，3H)，0.85(s，9H)，0.90(s，9H)，1.22(d，3H)，1.56(s，6H)，1.40-1.87(m，7H)，1.93(m，1H)，2.08(m，1H)，2.25(m，2H)，2.40(m，2H)，2.58(dd，1H)，2.79(dd，1H)，2.84(m，1H)，3.18(dd，1H)， 4.22(m，1H)，4.53(m，1H)，4.95(m，1H)，4.99(m，1H)，5.47(m，1H)，5.90(d，1H)，6.44(d，1H)，7.15-7.30(m，3H)，7.48(m，1H).

Preparation 21： Compound 205

The method comprises the following steps: general procedure 8

Starting materials: compound 13

Alkylating agent: 4-bromo-2-methyl-2-trimethylsiloxybutane

Chromatographic eluent: 1% Ether in pentane

¹H NMR δ 0.07(m，21H)，0.68(s，3H)，0.85(s，9H)，0.90(s，9H)，1.02(d，3H)，1.18(s，6H)，1.10-2.45(m，18H)，2.60(dd，1H)，2.85(m，1H)，4.22(m，1H)，4.53(m，1H)，4.95(m，1H)，4.99 (m，1H)，5.30(m，1H)，5.92(d，1H)，6.46(d，1H).

Preparation 22： Compound 206

The method comprises the following steps: general procedure 8

Starting materials: compound 14

Alkylating agent: 4-bromo-2-methyl-2-trimethylsiloxybutane chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.10(s，9H)，0.69(s，3H)，0.85(s，9H)，0.90(s，9H)，1.05(d，3H)，1.19(s，6H)，1.10-2.45(m，18H)，2.59(dd，1H)，2.85(m，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.99(m，1H)，5.33(m，1H)，5.92(d，1H)，6.46(d，1H).

Preparation 23： Compound 207

The method comprises the following steps: general procedure 8

Starting materials: compound 13

Alkylating agent: 6-bromo-2-ethyl-3-trimethylsiloxy hexane

Chromatographic eluent: 1% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.08(s，9H)，0.68(s，3H)，0.80(t，6H)，0.85(s，9H)，0.90(s，9H)，1.01(d，3H)，1.44(q，4H)，0.75-2.45(m，20H)，2.58(dd，1H)，2.85(m，1H)，4.22(m，1H)，4.54(m，1H)，4.95(m，1H)，4.99(m，1H)，5.30(m，1H)，5.92(d，1H)，6.46(d，1H).

Preparation 24： Compound 208

The method comprises the following steps: general procedure 8

Starting materials: compound 14

Alkylating agent: 6-bromo-3-ethyl-3-trimethylsiloxy hexane

Chromatographic eluent: 1% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.08(s，9H)，0.69(s，3H)，0.80(t，6H)，0.85(s，9H)，0.90(s，9H)，1.04(d，3H)，1.15-2.45(m，20H)，1.44(q，4H)，2.59(dd，1H)，2.86(m，1H)，4.22(m，1H)，4.54(m，1H)，4.95(m，1H)，4.99(m，1H)，5.32(m，1H)，5.92(d，1H)，6.46(d，1H).

Preparation 25： Compound 209

The method comprises the following steps: general procedure 9

Starting materials: compound 15

Chromatographic eluent: 2.5% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.65(s，3H)，0.85(s，9H)，0.89(s，9H)，1.19(d，3H)，1.15-1.87(m，6H)，1.93(m，1H)，2.06(m，1H)，2.25(m，2H)，2.38(dd，1H)，2.58(dd，1H)，2.84(m，1H)，3.00(m，1H)，3.73(s，3H)，4.22(m，1H)，4.52(m，1H)，4.95(m，1H)，4.98(m，1H)，5.41(m，1H)，5.81(d，1H，J＝15.4Hz)，5.90(d，1H)，6.03(dd，1H，J＝15.2Hz and 7.8Hz)，6.16(dd，1H)，J＝15.2Hz and 10.5Hz)，6.44(d，1H)，7.27(dd，1H，J＝15.4Hz and 10.5Hz).

Preparation 26： Compound 210

The method comprises the following steps: general procedure 9

Starting materials: compound 16

Chromatographic eluent: 2.5% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.69(s，3H)，0.85(s，9H)，0.89(s，9H)，1.20(d，3H)，1.35-1.87(m，6H)，1.93(m，1H)，2.07(m，1H)，2.25(m，2H)，2.41(dd，1H)，2.58(dd，1H)，2.84(bd，1H)，2.98(m，1H)，3.73(s，3H)，4.22(m，1H)，4.54(m，1H)，4.95(m，1H)，4.98(m，1H)，5.41(m，1H)，5.80(d，1H，J＝15.4Hz)，5.91(d，1H)，6.11(m，2H)，6.44(d，1H)，7.27(dd，1H，J＝15.4Hz and 9.9Hz).

Preparation 27： Compound 213

The method comprises the following steps: general procedure 10

Starting materials: compound 15

Chromatographic eluent: 2.5% Ether in Petroleum Ether

¹H NMR δ 0.05(m，12H)，0.67(s，3H)，0.85(s，9H)，0.90(s，9H)，0.80-0.95(m，2H)，1.07(m，2H)，1.22(d，3H)，1.45-2.35(m，11H)，2.41(dd，1H)，2.58(dd，1H)，2.85(m，1H)，3.06(m，1H)，4.22(m，1H)，4.53(m，1H)，4.95(m，1H)，4.98(m，1H)，5.44(m，1H)，5.90(d，1H)，6.20(dd，1H，J＝1.0 and 15.8Hz)，6.44(d，1H)，6.82(dd，1H，J＝7.9 and 15.8Hz).

Preparation 28： Compound 214

The method comprises the following steps: general procedure 10

Starting materials: compound 16 chromatographic eluent: 2.5% Ether in Petroleum Ether

¹H NMR δ 0.05(m，12H)，0.70(s，3H)，0.85(s，9H)，0.90(s，9H)，0.82-0.95(m，2H)，1.07(m，2H)，1.24(d，3H)，1.35-2.50(m，12H)，2.58(dd，1H)，2.84(bd，1H)，3.04(m，1H)，4.22(m，1H)，4.53(m，1H)，4.95(m，1H)，4.98(m，1H)，5.46(m，1H)，5.91(d，1H)，6.18(dd，1H，J＝1.0 and 15.8Hz)，6.44(d，1H)，6.85(dd，1H，J＝7.7 and 15.8Hz).

Preparation 29： Compound 305

The method comprises the following steps: general procedure 11

Starting materials: compound 205

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.68(s，3H)，0.85(s，9H)，0.89(s，9H)，1.02(d，3H)，1.19(s，6H)，1.10-2.45(m，19H)，2.58(dd，1H)，2.85(m，1H)，4.22(m，1H)，4.53(m 1H)，4.94(m，1H)，4.98(m，1H)，5.31(m，1H)，5.92(d，1H)，6.45(d，1H).

Preparation 30： Compound 306

The method comprises the following steps: general procedure 11

Starting materials: compound 206

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.69(s，3H)，0.85(s，9H)，0.89(s，9H)，1.05(d，3H)，1.20(s，6H)，1.10-2.45(m，19H)，2.58(dd，1H)，2.85(m，1H)，4.22(m，1H)，4.54(m，1H)，4.94(m，1H)，4.99(m，1H)，5.33(m，1H)，5.91(d，1H)，6.45(d，1H).

Preparation 31： Compound 307

The method comprises the following steps: general procedure 11

Starting materials: compound 207

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.67(s，3H)，0.84(t，6H)，0.85(s，9H)，0.90(s，9H)，1.01(d，3H)，1.44(q，4H)，0.80-2.45(m，21H)，2.58(dd，1H)，2.85(m，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.98(m，1H)，5.29(m，1H)，5.91(d，1H)，6.45(d，1H).

Preparation 32： Compound 308

The method comprises the following steps: general procedure 11

Starting materials: compound 208

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.68(s，3H)，0.85(s，6H)，0.85(t，9H)，0.90(s，9H)，1.04(d，3H)，1.45(q，4H)，1.15-2.45(m，21H)，2.59(dd，1H)，2.86(m 1H)，4.22(m，1H)，4.54(m，1H)，4.94(m，1H)，4.99(m，1H)，5.32(m，1H)，5.91(d，1H)，6.46(d，1H).

Preparation 33： Compound 309

The method comprises the following steps: general procedure 12

Starting materials: compound 209

Organometallic reagents: methyl lithium

Chromatographic eluent: 5% Ether in Petroleum Ether

Preparation 34： Compound 310

The method comprises the following steps: general procedure 12

Starting materials: compound 210

Organometallic reagents: methyl lithium

Chromatographic eluent: 2.5% Ether in Petroleum Ether

Preparation 35： Compound 311

The method comprises the following steps: general procedure 12

Starting materials: compound 209

Organometallic reagents: ethyl lithium

Chromatographic eluent: 5% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.67(s，3H)，0.85(t，6H)，0.85(s，9H)，0.89(s，9H)，1.16(d，3H)，1.10-1.87(m，1H)，1.92(m，1H)，2.04(m，1H)，2.25(m，2H)，2.38(dd，1H)，2.59(dd，1H)，2.89(m，2H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，4.98(m，1H)，5.38(m，1H)，5.54(d，1H，J＝15.3Hz)，5.59(dd，1H，J＝14.9Hz and 8.0Hz)，5.90(d，1H)，6.02(dd，1H，J＝14.9Hz and10.3Hz)，6.17 dd，1H，J＝15.3Hz and 10.3Hz)，6.45(d，1H).

Preparation 36： Compound 312

The method comprises the following steps: general procedure 12

Starting materials: compound 210

Organometallic reagents: ethyl lithium

Chromatographic eluent: 5% Ether in pentane

0.06(m，12H)，0.69(s，3H)，0.85(s，9H)，0.86(t，6H)，0.90(s，9H)，1.17(d，3H)，1.25-1.87(m，11H)，1.93(m，1H)，2.05(m，1H)，2.26(m，2H)，2.42(dd，1H)，2.59(dd，1H)，2.86(m，2H)，4.22(m，1H)，4.54(m，1H)，4.95(m，1H)，4.99(m，1H)，5.38(m，1H)，5.54(d，1H，J＝15.3Hz)，5.64(dd，1H，J＝15.0Hz and7.7Hz)，5.91(d，1H)，6.01(dd，1H，J＝15.0Hz and 10.3Hz)，6.18(dd，1H，J＝15.3Hz and 10.3Hz)，6.45(d，1H).

Preparation 37： Compound 313

The method comprises the following steps: general procedure 13

Starting materials: compound 213

Chromatographic eluent: 10% Ether in Petroleum Ether

¹H NMR δ 0.05(m，12H)，0.22(m，1H)，0.32(m，1H)，0.49(m，2H)，0.68(s，3H)，0.85(s，9H)，0.86(s，9H)，0.97(s，1H)，1.15(d，3H)，1.40-2.10(m，9H)，2.15-2.45(m，3H)，2.58(dd，1H)，2.87(m，2H)，3.42(m，1H)，4.22(m，1H)，4.53(m，1H)，4.94(m，1H)，5.00(m，1H)，5.37(m，1H)，5.54(m，2H)，5.90(d，1H)，6.44(d，1H).

Preparation 38： Compound 314

The method comprises the following steps: general procedure 13

Starting materials: compound 214

Chromatographic eluent: 10% Ether in Petroleum Ether

Preparation 39： Compound 315

The method comprises the following steps: general procedure 13

Starting materials: compound 213

Chromatographic eluent: 10% Ether in Petroleum Ether

¹H NMR δ 0.05(m，12H)，0.23(m，1H)0.32(m，1H)，0.51(m，2H)，0.68(s，3H)，0.85(s，6H)，0.90(s，9H)，0.98(m，9H)，1.15(d，3H)，1.45-2.10(m，9H)，2.17-2.45(m，3H)，2.58(dd，1H)，2.87(m 2H)，3.46(m，1H)，4.22(m，1H)，4.54(m，1H)，4.94(m，1H)，4.98(m，1H)，5.37(m，1H)，5.58(m，2H)，5.90(d，1H)，6.45(d，1H).

Preparation 40： Compound 316

The method comprises the following steps: general procedure 13

Starting materials: compound 214

Chromatographic eluent: 10% Ether in Petroleum Ether

Preparation 41： Compound 401

The method comprises the following steps: general procedure 14

Starting materials: compound 201

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.71(s，3H)，0.86(s，9H)，0.87(s，9H)，1.19(d，3H)，1.56(s，6H)，1.15-2.70(m，14H)，2.82(m，1H)，3.80(t，1H)，4.00(dd，1H)，4.19(m，1H)，4.37(m，1H)，4.87(m，1H)，5.18(m，1H)，5.45(m，1H)，6.10(d，1H)，6.23(d，1H)，6.77(m，1H)，7.03(m，2H)，7.23(t，1H).

Preparation 42： Compound 402

The method comprises the following steps: general procedure 14

Starting materials: compound 202

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.71(s，3H)，0.87(s，18H)，1.22(d，3H)，1.57(s，6H)，1.40-2.15(m，9H)，2.23(m，2H)，2.37(m，1H)，2.45(dd，1H)，2.61(m，1H)，2.82(m，1H)，3.66(t，1H)，4.01(dd，1H)，4.19(m，1H)，4.38(m，1H)，4.88(m，1H)，5.18(m，1H)，5.48(m，1H)，6.11(d，1H)，6.23(d，1H)，6.77 m，1H)，6.95-7.10(m，2H)，7.24(t，1H).

Preparation 43： Compound 403

The method comprises the following steps: general procedure 14

Starting materials: compound 203

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.69(s，3H)，0.87(s，18H)，1.18(d，3H)，1.55(s，6H)，1.15-2.50(m，14H)，2.80(m，1H)，2.86(dd，1H)，3.20(dd，1H)，4.18(m，1H)，4.38(m，1H)，4.87(m，1H)，5.19(m，1H)，5.41(m，1H)，6.09(d，1H)，6.22(d，1H)，7.15-7.30(m，3H)，7.46(m，1H).

Preparation 44： Compound 404

The method comprises the following steps: general procedure 14

Starting materials: compound 204

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.66(s，3H)，0.86(s，9H)，0.87(s，9H)，1.21(d，3H)，1.56(s，6H)，1.30-2.50(m，14H)，2.78(dd，1H)，2.80(m，1H)，3.18(dd，1H)，4.18(m，1H)，4.37(m，1H)，4.86(m，1H)，5.18(m，1H)，5.44(m，1H)，6.08(d，1H)，6.22(d，1H)，7.15-7.30(m，3H)，7.47(m，1H).

Preparation 45： Compound 405

The method comprises the following steps: general procedure 14

Starting materials: compound 305

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.67(s，3H)，0.87(s，9H)，0.88(s，9H)，1.01(d，3H)，1.18(s，6H)，0.80-2.27(m，18H)，2.35(m，1H)，2.45(dd，1H)，2.80(m，1H)，4.19(m，1H)，4.37(m，1H)，4.87(m，1H)，5.18(m，1H)，5.28(m，1H)，6.09(d，1H)，6.23(d，1H).

Preparation 46： Compound 406

The method comprises the following steps: general procedure 14

Starting materials: compound 306

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.68(s，3H)，0.87(s，9H)，0.88(s，9H)，1.04(d，3H)，1.20(s，6H)，1.10-2.40(m，19H)，2.45(d，1H)，2.80(m，1H)，4.18(m，1H)，4.38(m，1H)，4.87(m，1H)，5.18(m，1H)，5.30(m，1H)，6.10(d，1H)，6.23(d，1H).

Preparation 47： Compound 407

The method comprises the following steps: general procedure 14

Starting materials: compound 307

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.66(s，3H)，0.84(t，6H)，0.87(s，18H)，1.00(d，3H)，1.44(q，4H)，0.75-2.27(m，20H)，2.34(m，1H)，2.44(dd，1H)，2.80(m，1H)，4.19(m，1H)，4.38(m，1H)，4.87(m，1H)，5.18(m，1H)，5.27(m，1H)，6.09(d，1H)，6.22(d，1H).

Preparation 48： Compound 408

The method comprises the following steps: general procedure 14

Starting materials: compound 308

Chromatographic eluent: 10% Ether in pentane

¹H NMR δ 0.06(m，12H)，0.68(s，3H)，0.87(t，6H)，0.87(s，9H)，0.88(s，9H)，1.02(d，3H)，1.44(q，4H)，1.15-2.50(m，22H)，2.80(m，1H)，4.19(m，1H)，4.38(m，1H)，4.87(m，1H)，5.18(m，1H)，5.29(m，1H)，6.09(d，1H)，6.23(d，1H).

Preparation 49： Compound 409

The method comprises the following steps: general procedure 14

Starting materials: compound 309

Chromatographic eluent: 5% Ether in Petroleum Ether

Preparation 50： Compound 410

The method comprises the following steps: general procedure 14

Starting materials: compound 310

Chromatographic eluent: 5% Ether in pentane

Preparation 51： Compound 411

The method comprises the following steps: general procedure 14

Starting materials: compound 311

Chromatographic eluent: 5% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.66(s，3H)，0.85(t，6H)，0.85(s，9H)，0.86(s，9H)，1.15(d，3H)，1.10-1.92(m，12H)，1.99(m，1H)，2.18(m，2H)，2.33(dd，1H)，2.45(dd，1H)，2.77(dd，1H)，2.90(m，1H)，4.18(m，1H)，4.37(m，1H)，4.87(m，1H)，5.17(m，1H)，5.35(m，1H)，5.53(d，1H，J＝15.3Hz)，5.58(dd，1H，J＝14.9Hz and 8.0Hz)，5.95-6.27(m，4H).

Preparation 52： Compound 412

The method comprises the following steps: general procedure 14

Starting materials: compound 312

Chromatographic eluent: 5% Ether in pentane

¹H NMR δ 0.05(m，12H)，0.68(s，3H)，0.86(s，9H)，0.87(s，9H)，0.83-0.95(t，6H)，1.16(d，3H)，1.10-2.30(m，15H)，2.36(dd，1H)，2.44(dd，1H)，2.79(m，1H)，2.88(m，1H)，4.18(m，1H)，4.37(m，1H)，4.87(m，1H)，5.17(m，1H)，5.35(m，1H)，5.53(d，1H，J＝15.4Hz)，5.64(dd，1H，J＝7.7 and 15.0Hz)，5.92-6.25(m，4H).

Preparation 53： Compound 413

The method comprises the following steps: general procedure 14

Starting materials: compound 313

Chromatographic eluent: 10% Ether in Petroleum Ether

¹H NMR δ 0.05(m，12H)，0.23(m，1H)，0.31(m，1H)，0.50(m，2H)，0.67(s，3H)，0.86(s，9H)0.87(s，9H)，0.97(s，1H)，1.14(d，3H)，1.30-2.07(m，9H)，2.20(m，2H)，2.32(m，1H)，2.44(dd，1H)，2.79(m，1H)，2.89(m，1H)，3.42(m，1H)，4.19(m，1H)，4.37(m，1H)，4.87(m，1H)，5.17(m，1H)，5.35(m，1H)，5.54(m，2H)，6.08(d，1H)，6.22(d，1H).

Preparation 54： Compound 414

The method comprises the following steps: general procedure 14

Starting materials: compound 314

Chromatographic eluent: 10% Ether in Petroleum Ether

Preparation 55： Compound 415

The method comprises the following steps: general procedure 14

Starting materials: compound 315

Chromatographic eluent: 10% Ether in Petroleum Ether

¹H NMR δ 0.05(m，12H)，0.23(m，1H)，0.31(m，1H)，0.50(m，2H)，0.67(s，3H)，0.86(s，9H)，0.87(s，9H)，1.14(d，3H)，0.90-2.05(m，10H)，2.19(m，2H)，2.33(m，1H)，2.44(dd，1H)，2.79(m，1H)，2.89(m，1H)，3.46(m，1H)，4.18(m，1H)，4.36(m，1H)，4.87(m，1H)，5.17(m，1H)，5.34(m，1H)，5.57(m，2H)，6.08(d，1H)，6.22(d，1H).

Preparation 56： Compound 416

The method comprises the following steps: general procedure 14

Starting materials: compound 316

Chromatographic eluent: 10% Ether in Petroleum Ether

Examples

Example 1： 1(S), 3(R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-) Methyl-ethyl) phenoxymethyl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (Compound 101)

The method comprises the following steps: general procedure 15

Starting materials: compound 401

Chromatographic eluent: 30% pentane in ethyl acetate

¹H NMR δ 0.73(s，3H)，1.20(d，3H)，1.57(s，6H)，1.15-1.97(m，9H)，2.04(m，2H)，2.17-2.45(m，3H)，2.60(m，2H)，2.83(dd，1H)，3.81(t，1H)，4.00(dd，1H)，4.23(m，1H)，4.43(m，1H)，5.01(m，1H)，5.33(m，1H)，5.45(m，1H)，6.12(d，1H)，6.37(d，1H)，6.77(m，1H)，7.04(m，2H)，7.24(t，1H).

Example 2： 1(S), 3(R) -dihydroxy-20 (R) - (3- (1-hydroxy-1-) Methyl-ethyl) phenoxymethyl) -9, 10-seco-pregnancySterols-5 (Z), 7(E), 10(19), 16-tetraene (Compound 102)

The method comprises the following steps: general procedure 15

Starting materials: compound 402

Chromatographic eluent: 30% pentane in ethyl acetate

¹H NMR δ 0.73(s，3H)，1.23(d，3H)，1.57(s，6H)，1.45-1.97(m，9H)，2.05(m，2H)，2.15-2.45(m，3H)，2.60(m，2H)，2.83(m，1H)，3.67(t，1H)，4.00(dd，1H)，4.23(m，1H)，4.43(m，1H)，5.02(m，1H)，5.34(m，1H)，5.49(m，1H)，6.12(d，1H)，6.37(d，1H)，6.77(m，1H)，7.04(m，2H)，7.24(t，1H).

Example 3： 1(S), 3(R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-) Methyl-ethyl) phenylthiomethyl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene (Compound 103)

The method comprises the following steps: general procedure 15

Starting materials: compound 403

Chromatographic eluent: 30% pentane in ethyl acetate

¹H NMR δ 0.71(s，3H)，1.19(d，3H)，1.56(s，6H)，1.15-2.50(m，15H)，2.58(dd，1H)，2.81(dd 1H)，2.87(dd，1H)，3.19(dd，1H)，4.23(m，1H)，4.43(m，1H)，5.00(m，1H)，5.33(m，1H)，5.42(m，1H)，6.11(d，1H)，6.36(d，1H)，7.15-7.30(m，3H)，7.46(m，1H).

Example 4： 1(S), 3(R) -dihydroxy-20 (R) - (3- (1-hydroxy-1-) Rinyl-ethyl) phenylthiomethyl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (Compound 104)

The method comprises the following steps: general procedure 15

Starting materials: compound 404

Chromatographic eluent: 30% pentane in ethyl acetate

¹H NMR δ 0.68(s，3H)，1.22(d，3H)，1.57(s，6H)，1.30-2.50(m，15H)，2.60(dd，1H)，2.80(dd，1H)，2.82(m，1H)，3.18(dd，1H)，4.23(m，1H)，4.44(m，1H)，5.00(m，1H)，5.33(m，1H)，5.46(m，1H)，6.10(d，1H)，6.36(d，1H)，7.15-7.30(m，3H)，7.48(m，1H).

Example 5： 1(S), 3(R) -dihydroxy-20 (R) - (4-hydroxy-4-methyl-) Pent-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene Compound 105)

The method comprises the following steps: general procedure 15

Starting materials: compound 405

Chromatographic eluent: 40% Pentane solution in Ethyl acetate

¹H NMR δ 0.69(s，3H)，1.02(d，3H)，1.19(s，6H)，0.80-2.40(m，21H)，2.60(dd，1H)，2.82(m，1H)，4.22(m，1H)，4.44(m，1H)，5.02(m，1H)，5.29(m，1H)，5.34(m，1H)，6.11(d，1H)，6.38(d，1H).

Example 6： 1(S), 3(R) -dihydroxy-20 (S) - (4-hydroxy-4-methyl-) Pent-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene Compound 106)

The method comprises the following steps: general procedure 15

Starting materials: compound 406

Chromatographic eluent: 30% pentane in ethyl acetate

¹H NMR δ 0.70(s，3H)，1.05(d，3H)，1.21(s，6H)，1.15-2.40(m，21H)，2.60(m，1H)，2.82(m，1H)，4.24(m，1H)，4.42(m，1H)，5.01(m，1H)，5.33(m，2H)，6.10(d，1H)，6.37 (d，1H).

Example 7： 1(S), 3(R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxy-) Hept-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene Compound 107)

The method comprises the following steps: general procedure 15

Starting materials: compound 407

Chromatographic eluent: 40% Pentane solution in Ethyl acetate

¹H NMR δ 0.68(s，3H)，0.85(t，6H)，1.01(d，3H)，1.45(q，4H)，0.80-2.45(m，23H)，2.60(m，1H)，2.82(m，1H)，4.23(m，1H)，4.44(m，1H)，5.02(m，1H)，5.28(m，1H)，5.34(m，1H)，6.11(d，1H)，6.38(d，1H).

Example 8： 1(S), 3(R) -dihydroxy-20 (S) - (5-ethyl-5-hydroxy-) Hept-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene Compound 108)

The method comprises the following steps: general procedure 15

Starting materials: compound 408

Chromatographic eluent: 40% Pentane solution in Ethyl acetate

¹H NMR δ 0.70(s，3H)，0.85(t，6H)，1.03(d，3H)，1.45(q，4H)，1.00-2.40(m，23H)，2.60(dd，1H)，2.81(m，1H)，4.23(m，1H)，4.43(m，1H)，5.01(m，1H)，5.31(m，1H)，5.33(m，1H)，6.11(d，1H)，6.37(d，1H).

Example 9： 1(S), 3(R) -dihydroxy-20 (R) - (5-hydroxy-5-methyl-) Hex-1 (E), 3(E) -dien-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (Compound 109)

The method comprises the following steps: general procedure 16

Starting materials: compound 409

Example 10： 1(S), 3(R) -dihydroxy-20(S) - (5-hydroxy-5-methyl) -hex-1 (E), 3(E) -dien-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene (Compound 110)

The method comprises the following steps: general procedure 15

Starting materials: compound 410

Example 11： 1(S), 3(R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxy) -hept-1 (E), 3(E) -dien-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene (Compound 111)

The method comprises the following steps: general procedure 16

Starting materials: compound 411

¹H NMR δ 0.68(s，3H)，0.86(t，6H)，1.16(d，3H)，1.56(q，4H)，1.35-2.43(m，14H)，2.59(dd，1H)，2.80(dd，1H)，2.91(m，1H)，4.23(m，1H)，4.43(m，1H)，5.00(m，1H)，5.33(m，1H)，5.37(m，1H)，5.55(d，1H，J＝15.4Hz)，5.58(dd，1H，J＝14.9Hz and 8.0Hz)，5.95-6.25(m，3H)，6.36(d，1H).

Example 12： 1(S), 3(R) -dihydroxy-20 (S) - (5-ethyl-5-hydroxy-) Hept-1 (E), 3(E) -dien-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene (Compound 112)

The method comprises the following steps: general procedure 16

Starting materials: compound 412

¹H NMR δ 0.71(s，3H)，0.86(t，6H)，1.17(d，3H)，0.83-2.45(m，18H)，2.60(dd，1H)，2.80(m，1H)，2.89(m，1H)，4.23(m，1H)，4.44(m，1H)，5.01(m，1H)，5.33(m，1H)，5.37(m，1H)，5.55(d，1H，J＝15.3Hz)，5.64(dd，1H，J＝7.7and 15.0Hz)，6.01(dd，1H，J＝10.3 and 15.0Hz)，6.11(d，1H)，6.18(dd，1H，J＝10.3 and 15.3Hz)，6.37(d，1H).

Example 13： 1(S), 3(R) -dihydroxy-20 (R) - (3-cyclopropyl-3-hydroxy Prop-1 (E) -en-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (24(S) -isomer) (Compound 113)

The method comprises the following steps: general procedure 16

Starting materials: compound 413

¹H NMR δ 0.23(m，1H)，0.32(m，1H)，0.51(m，2H)，0.70(s，3H)，0.99(m，1H)，1.15(d，3H)，1.10-2.40(m，14H)，2.59(dd，1H)，2.80(dd，1H)，2.90(m，1H)，3.42(m，1H)，4.23(m，1H)，4.43(m，1H)，5.00(m，1H)，5.33(m，1H)，5.37(m，1H)，5.55(m，2H)，6.10(d，1H)，6.36(d，1H).

Example 14： 1(S), 3(R) -dihydroxy-20 (S) - (3-cyclopropyl-3-hydroxy Prop-1 (E) -en-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (24(S) -isomer) (compound 114)

The method comprises the following steps: general procedure 16

Starting materials: compound 414

Example 15： 1(S), 3(R) -dihydroxy-20 (R) - (3-cyclopropyl-3-hydroxy Prop-1 (E) -en-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (24(R) -isomer) (compound 115)

The method comprises the following steps: general procedure 16

Starting materials: compound 415

¹H NMR δ 0.23(m，1H)，0.32(m，1H)，0.51(m，2H)，0.70(s，3H)，0.99(m，1H)，1.15(d，3H)，1.12-2.45(m，14H)，2.60(bd，1H)，2.80(m，1H)，2.90(m，1H)，3.46(m，1H)，4.23(m，1H)，4.44(m，1H)，5.00(m，1H)，5.33(m，1H)，5.36(m，1H)，5.58(m，2H)，6.10(d，1H)，6.36(d，1H).

Example 16： 1(S), 3(R) -dihydroxy-20(S) - (3-cyclopropyl-3-hydroxy) Prop-1 (E) -en-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene (24(R) -isomer) (compound 116)

The method comprises the following steps: general procedure 16

Starting materials: compound 416

Example 17： Capsules containing compound 111

Compound 111 was dissolved in peanut oil to a final concentration of 1. mu.g of compound per ml of oil. 10 parts by weight of gelatin, 5 parts by weight of glycerin, 0.08 part by weight of potassium sorbate and 14 parts by weight of distilled water were mixed and heated to form a soft gelatin capsule. To this was filled 100. mu.l of compound 111 in oil, so that each capsule contained 0.1. mu.g of compound 111.

Example 18： Skin cream containing compound 111

0.05mg of compound 111 is dissolved in 1g of almond oil. To this solution 40g of mineral oil and 20g of self-emulsifying beeswax were added. The solution was heated to a liquid state. 40ml of hot water was added and mixed well. The resulting cream contained approximately 0.5. mu.g of Compound 111 per gram of cream.

Claims (12)

1. A compound of formula IWherein formula Q is methylene; y is O-O- (C)₆H₄) -, m-O-C₆H₄para-O-C₆H₄(ii) a Or Q and Y together form tetramethylene, pentamethylene or-CH ═ CH —; r¹And R²Each independently represents methyl or ethyl; and Z represents hydrogen or hydroxy.

2. Diastereoisomers of the compound of claim 1, in pure form or as a mixture of diastereoisomers.

3. The compound of claim 1 which is:

a)1(S), 3(R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-methylethyl) phenoxymethyl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene or the corresponding 20(R) isomer,

b)1(S), 3(R) -dihydroxy-20 (S) - (4-hydroxy-4-methyl-pent-1-yl) -9, 10-seco-pregn-5 (Z), 7(E), 10(19), 16-tetraene,

c)1(S), 3(R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxy-hept-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene or the corresponding 20(S) isomer,

d)1(S), 3(R) -dihydroxy-20 (R) - (3-cyclopropyl-3-hydroxyprop-1 (E) -en-1-yl) -9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene (24(S) -isomer) or the corresponding 24(R) isomer.

4. A process for the preparation of a compound of formula I according to claim 1, which comprises:

a) the C-20 linked side chain of the compound of formula I is prepared from the 20(S) and 20(R) isomers of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20-p-toluenesulfonyloxymethyl-9, 10-seco-pregna-5 (E), 7(E), 10(19), 16-tetraene by the following reaction,

(i) reacting with a side chain structural unit H-X-R in a solvent in the presence of a base³Carrying out a reaction in which X is O or S, R³Is meta-C₆H₄-CR¹R²Z¹And Z is hydroxy or protected hydroxy, or

(ii) In Li₂CuCl₄In the presence of a solvent with a Grignard reagent R⁴-Mg-Hal, in which R is⁴is-CH₂-(CH₂)_n-CR¹R²Z¹N is 2, 3, or 4, Z¹Is as defined above, Hal is Cl or Br, and

b) the compound from step a) above may optionally be (i) isolated from the racemate, (ii) photoisomerized with a triplet sensitizer to give the 5(Z) isomer, (iii) desilylated and (iv) deprotected; the order of these reactions may be optional.

5. The process of claim 4, wherein the base in step a) (i) is NaH.

6. The process of claim 4, wherein the solvent in step a) (ii) is THF.

7. A process for the preparation of a compound of formula I according to claim 1, which comprises:

a) the C-20 attached side chain of the compound of formula I is prepared from the 20(S) and 20(R) isomers of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20-formyl-9, 10-seco-pregna-5 (E), 7(E), 10(19), 16-tetraene by the following reaction,

(i) with a Wittig-type reagent and then reacting the resulting ester with an organometallic reagent, or

(ii) With wittig-type reagents, followed by reaction in CeCl₃And b) the compound resulting from step a) may optionally be (i) isolated from the racemate, (ii) photoisomerized with a triplet sensitizer to give the 5(Z) isomer, (iii) desilylation, and (iv) deprotection; the order of these reactions may be optional.

8. The process of claim 7, wherein the reducing agent in step a) (ii) is NaBH₄。

9. Intermediates useful in the synthesis of compounds of formula I and analogs thereof:

a)1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(S) -hydroxymethyl-9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene or the corresponding 20(R) isomer,

b)1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(S) -p-toluenesulfonylmethyl-9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene or the corresponding 20(R) isomer,

c)1(S), 3(E) -bis (tert-butyldimethylsilyloxy) -20(S) -formyl-9, 10-seco-pregna-5 (Z), 7(E), 10(19), 16-tetraene or the corresponding 20(R) isomer.

10. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 3 together with pharmaceutically acceptable non-toxic carriers and/or adjuvants.

11. The pharmaceutical composition of claim 10 in the form of a dosage unit containing from 0.1ppm to 0.1% by weight of the compound of formula I.

12. The use of a compound as claimed in any of claims 1 to 3 for the preparation of medicaments for the treatment and prophylaxis of psoriasis.